ORIGINAL ARTICLE ANZJSurg.com
Breast conservation treatment for multifocal and multicentric breast cancers in women with small-volume breast tissue Mona P. Tan,* Nadya Y. Sitoh*† and Amanda S. Sim* *Breast Surgery Department, MammoCare, Singapore and †Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Key words breast cancer, breast conservation treatment, mastectomy, multifocal and multicentric breast cancer, oncoplastic breast surgery. Correspondence Dr Mona P. Tan, Breast Surgery Department, MammoCare, 38 Irrawaddy Road, #06-21, Singapore 329563. Email: [email protected] M. P. Tan FRCS (Ed), MBBS; N. Y. Sitoh; A. S. Sim BSc (Nursing) UK. This study was presented in part at the Annual Scientific Congress of the Royal Australasian College of Surgeons in May 2014. Accepted for publication 31 October 2014. doi: 10.1111/ans.12942
Abstract Background: Breast conservation treatment (BCT) is an established option in the treatment of early breast cancer, but women with small breast volume (SVB) are considered poor candidates for BCT. Multifocal and multicentric breast cancers (MFMCBC) are conventionally considered a relative contraindication to BCT. These arguments form the basis of limited eligibility for BCT for a woman with SVB and MFMCBC. This study was performed to investigate this syllogism. Methods: Consecutive patients with breast malignancies treated from 2009 to 2011 were included. Patients were deemed to have successful BCT if they had pathologically clear margins and had completed all recommended adjuvant treatment. Those who had MFMCBC based on clinical, imaging and pathological data were selected for detailed evaluation. Comparisons were made with unifocal breast cancer. Results: Data from a total of 160 patients who underwent treatment during the study period were analysed. The mean age was 48.8 years. One hundred and six patients (66.3%) were of Chinese ethnicity, 36 (22.5%) were of other Asian ethnicity and 18 were Caucasian (11.2%). Forty-one (25.6%) patients had clinical evidence of MFMCBC. Of these patients, 35 (85.4%) underwent BCT. After a mean follow-up of 45 months, none of the patients with MFMCBC developed a local recurrence. Two patients with MFMCBC, one who underwent mastectomy and one with BCT, succumbed to cancer from distant disease. Conclusion: BCT is feasible in women with MFMCBC in a predominantly Chinese community where majority are expected to have SVB. Further investigation is warranted to confirm the findings.
Introduction Breast conservation treatment (BCT) was established as an alternative to mastectomy for the treatment of breast cancer on the basis of equivalent survival outcomes,1,2 but recent data suggest BCT may be superior to mastectomy in terms of breast cancer-specific survival and local control.3–5 An absolute benefit in breast cancer-specific survival of 4% at 10 years was reported where 70% of patients underwent BCT,3 and it is estimated that for each percentage point rise mastectomy rates, seven-year survival would be reduced by 0.1%.4 Hence, in a patient population with BCT rates below 30%, survival benefit may not be evident, and treated women may suffer poorer body image and quality of life outcomes.3–7 Many contemporary series from predominantly Chinese populations report BCT rates averaging 30%.8–12 The reasons cited for these low BCT rates include cultural factors, surgeon preferences and physical © 2014 Royal Australasian College of Surgeons
attributes.9–12 Chinese women have been shown to have smaller breast volume (SVB) tissue,13 posing challenges for good cosmetic outcomes with BCT.14 The presence of ipsilateral multifocal and multicentric breast cancers (MFMCBC) compounds these challenges. The lower initial parenchymal volume serves as a barrier for the provision of adequate retained tissue to achieve a reasonable postsurgical cosmetic outcome following multiple tumour excisions. As conventional contraindications to BCT reflect the clinical situations that would compromise either local control or cosmesis,15 MFMCBC could be viewed as a contraindication for BCT in women with SVB. While the oncologic principle of achieving clear margins should not be compromised, methods can be explored to allow such women the potential benefits of BCT. This study was therefore conducted to evaluate the feasibility of performing of BCT among women who were diagnosed to have MFMCBC in a ANZ J Surg •• (2014) ••–••
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Fig. 1. (a–d) This 35-year-old patient presented with a palpable lesion in the lower inner quadrant of the right breast. Imaging demonstrated two lesions, both of which were diagnosed as grade 3 infiltrative ductal carcinoma on percutaneous core biopsy. Radio-opaque marker clips were positioned within each tumour. She had good response to neoadjuvant chemotherapy. Figure 1c illustrates the standard boomerang incision used after localization of the two marker clips. Postoperative histology revealed a single focus of ductal carcinoma in situ, 1.4 cm in maximal extent. Despite the absence of histological evidence of uninvolved intervening parenchyma, she was classified as having multifocal breast cancer. The final cosmetic result for this patient with double-A cup-sized breast tissue volume is depicted in Figure 1d.
predominantly Chinese community, where more women with SVB are expected.
Methods A retrospective analysis was performed on all patients with breast malignancies who underwent operative treatment at the authors’ centre between January 2009 and December 2011. Initial evaluation consisted of clinical examination, mammography and ultrasonography. Diagnosis was made preoperatively where possible using percutaneous needle biopsies. Where there were technical limitations, surgical diagnostic procedures were performed. Eligibility for BCT was based on the surgeon’s assessment that the combined volume of tissue excised would not exceed 25% of total breast volume. Patients considered eligible were given an option of an attempt at BCT or mastectomy, with or without reconstruction. Those with large lesions were treated with neoadjuvant medical therapy following placement of radio-opaque clip(s). Preoperative breast magnetic resonance imaging (MRI) was not routinely used in this cohort of patients. Multifocal tumours were defined as the presence of more than one focus of tumour within the same segment of the breast. Multicentric tumours were defined as separate malignant foci in different segments of the breast. Based on the ‘sick lobe theory’,16 this classification facilitates surgical planning. Multiple tumours were defined based on preoperative workup. Pathological confirmation of tumour foci was made when clinical and imaging findings were suspicious of multiple malignancies. However, intervening normal tissue was not always demonstrable for MFMCBC patients who underwent neoadjuvant chemotherapy and had pathological complete response for at least one of the lesions (Fig. 1a–d). Incidental findings of multifocal lesions following histological examination of wide excision or mastectomy specimens were not classified as MFMCBC. Where indicated, localizations of non-palpable foci were performed, and patients underwent sentinel node biopsy using blue dye based on the dominant lesion. An axillary clearance up to level III was
performed if there was lymph node positivity. For purposes of staging and analysis, calculations were made based only on the larger, dominant lesion. All patients underwent en bloc wide excisions of MFMCBC through a single incision, usually a boomerang incision or its modifications.17 This approach was most suitable for patients with at least one lesion in close proximity to the nipple-areolar complex (NAC) (Fig. 1a,b). In cases where the tumours were remote from the nipple, another appropriate incision design was used. For example, tumours in the upper outer quadrant of the breast were approached with a modification of the boomerang incision18 (Fig. 2a–f). This allows for adequate exposure for multisegment wide excision, remodelling and axillary surgery through a single incision and avoids significant deviation of the nipple without the need for de-epithelization to reposition the NAC.19 Tumour excision for multicentric lesions was performed with a multisegment resection pattern, consisting of elliptically shaped limbs around each focus, with the long axis oriented radially and connected centrally (Fig. 2). This allowed an en bloc resection through a single incision in conformity to guideline recommendations.20 After tumour extirpation, the partial mastectomy defect was repaired using only local tissue rearrangement techniques. Full thickness parenchymal flaps were mobilized off the pectoralis fascia, the tissue pillars advanced and apposed with sutures. This approach does not preclude BCT for malignancies on opposite quadrants of the breast. Volume replacement techniques with autologous flaps or implants were not used. Intraoperative frozen section analysis (IFSA) was used for margins status for each patient undergoing BCT. Further margins were taken where necessary until proven negative intraoperatively. Successful BCT of MFMCBC was defined as operative attainment of clear margins (no ink on tumour)2 on paraffin sections and an acceptable cosmetic outcome. The incision was planned such that at least one of the tumour foci was located beneath the scar to facilitate radiotherapy. Tumour beds more than 2 cm from the scar were © 2014 Royal Australasian College of Surgeons
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Fig. 2. (a–f) A modification of the boomerang incision is used when at least one of the lesions is close to the nipple–areolar complex (localized) and the other (palpable) is distant, in the upper outer quadrant of the breast. A multi-segment resection is performed and parenchymal pillars mobilized to repair the defect to obtain a cosmetic result shown in Figure 2e,f.
marked by a liga clip. Whole breast external beam radiation was delivered in divided doses with electron boosts according to the preference of the radiation oncologist. If a reasonable cosmesis was thought to be unattainable, or if patients elected against BCT, a mastectomy was performed. Anticipating the possibility that BCT was feasible for MFMCBC, the null hypothesis was that there would be no difference between conservation rates for MFMCBC and unifocal lesions. Comparisons with unifocal cancers were made where appropriate, and analyses were performed using Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL, USA) version 11 advanced statistical software module.
Results Forty-one of 160 (25.6%) patients assessed had clinical evidence of more than one focus of malignancy on preoperative evaluation. Twenty-six (16.3%) had multifocal and 15 (9.4%) had multicentric disease, proportions similar to another larger series.21 A summary of the clinicopathological characteristics of the study cohort is given in Table 1. Of the 119 patients with unifocal lesions, 102 (85.7%) underwent BCT. Twenty-two of 26 patients (84.6%) with multifocal lesions and 13 of 15 (86.7%) with multicentric cancers underwent BCT. Four of 26 (15.4%) patients with multifocal cancers underwent mastectomy, of whom two elected for the procedure against recommendations for a trial of BCT. Two of 15 (13.3%) patients with multicentric cancers underwent mastectomy as recommended. There was no significant difference between the BCT rate for unifocal lesions and MFMCBC with successful BCT (P = 0.83). Of note, 66.3% of the patients were Chinese, and expected to have SVB, while 22.5% were of other Asian origins and 11.2% were Caucasian. Twenty-four of 29 (82.8%) Chinese women with MFMCBC underwent BCT. Among those with MFMCBC, there was no significant difference in BCT rates based on ethnicity (P = 0.30). Of the 21 Chinese women with multifocal disease, 17 (81%) had BCT. Seven of eight (87.5%) Chinese women with multicentric disease © 2014 Royal Australasian College of Surgeons
underwent BCT. Of note, there was a significantly higher proportion of women with multicentric lesions who underwent neoadjuvant chemotherapy for a trial of BCT. Four patients required reoperation, one for a false-negative IFSA of the sentinel lymph node (SLN), who underwent completion axillary dissection prior to a change in axillary staging practices,22 and three for multicentric disease only detected on postoperative review. Of the patients with MFMCBC who underwent a re-operation, the mean pathological dimension of the dominant tumour was 36.3 mm (standard deviation (SD) 18.0 mm). This is in comparison with 18.3 mm (SD 13 mm), which is the mean of the largest tumour size for those who did not need another surgical procedure. All patients who underwent re-operations are currently well with no signs of local recurrence or distant disease. All patients had their margins subject to IFSA and negative margin status was confirmed on paraffin sections. At a median follow-up of 45 months, none of the patients with MFMCBC developed local recurrence. However, two have succumbed to metastatic disease, the first of whom underwent mastectomy and died 53 months after surgery while the second had BCT and died 14 months after surgery.
Discussion Although multiple ipsilateral tumour foci may occur in up to 63% of mastectomy specimens,23 equivalent survival outcomes were observed in prospective trials comparing BCT and mastectomy for clinically unifocal lesions, suggesting that the majority of these foci are not, or do not become, biologically relevant or clinically significant with appropriate treatment. Recent data on axillary treatment have also demonstrated a similar phenomenon where less surgery does not necessarily lead to inferior local control or survival outcomes.22 The concept of BCT for MFMCBC would thus be concordant with current treatment policies for unifocal tumours and axillary staging. In line with this philosophy, a recent expert consensus considered MFMCBC as a relative contraindication, rather than an
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Table 1 Summary of demographic, clinicopathological and outcome data for study population Clinicopathological characteristic
Age in years Median (range) Mean (SD) Ethnicity Chinese Malay/Indonesian Indian Other Asian Caucasian Mode of presentation Symptomatic tumours Screen detected lesions Tumour size in mm (range) Median (range) Mean (SD) T1 T2 T3 T4 Pathological stage 0 I II III IV Histological type DCIS Invasive ductal Invasive lobular Other invasive Grade DCIS 1 2 3 Unknown Neoadjuvant medical therapy Yes No Surgical procedure BCT Mastectomy by need Mastectomy by choice Re-operations Axillary dissection Missed multicentric Recurrence Local recurrence Distant disease/death Median follow-up (months) (range)
Unifocal (n = 119)
49 (30–78) 49.7 (9.8)
MFMCBC (n = 41)
P value
%
MF (26)
%
MC (15)
%
— —
46.5 (31–67) 47.62 (10.8)
— —
44 (28–52) 43.7 (6.3)
— —
77 7 9 9 17
64.7 5.9 7.6 7.6 14.3
21 0 2 3 0
80.8 0.0 7.7 11.5 —
8 2 2 2 1
53.3 13.3 13.3 13.3 6.7
86 33
72.3 27.7
20 6
76.9 23.1
10 5
66.7 33.3
18.0 (2–97) 22.2 (16.3) 76 35 6 2
— — 63.9 29.4 5.0 1.7
18.5 (3–72) 20.7 (16.2) 15 8 2 1
— — 57.7 30.8 7.7 3.8
20.0 (5–28) 17.7 (8.2) 9 6 0 0
— — 60.0 40.0 — —
— 0.04 0.30 — — — — — 0.77 — — — 0.60 0.86 — — — 0.05 — — — — — 0.28 — — — — 0.02 — — — — —
15 54 36 13 1
12.6 45.4 30.3 10.9 0.8
5 9 7 5 0
19.2 34.6 26.9 19.2 0.0
0 4 11 0 0
0.0 26.7 73.3 0.0 0.0
15 93 3 8
12.6 78.2 2.5 6.7
5 20 1 0
19.2 76.9 3.8 0.0
0 11 3 1
0.0 73.3 20.0 6.7
15 22 45 34 3
12.6 18.5 37.8 28.6 2.5
5 3 4 14 0
19.2 11.5 15.4 53.9 0.0
0 3 9 2 1
0.0 20.0 60.0 13.3 6.7
12 107
10.1 89.9
5 21
19.2 80.8
9 6
60.0 40.0
102 11 6
85.7 9.2 5.0 0.0 — —
22 2 2
84.6 7.7 7.7
13 0 2
86.7 0.0 13.3
1 0
6.7 —
0 3
— 20.0
0.006 — 0.83 — — — 0.01 — —
1.7 1.7
0 2
— —
— —
0.52 0.45
— — 2 2 —
—
— 0 45 (18–64)
BCT, breast conservation treatment; DCIS, ductal carcinoma in situ; MFMCBC, multifocal and multicentric breast cancer; SD, standard deviation.
absolute contraindication to BCT.2 This status paves the way for developing means to increase both eligibility and utilization of BCT in MFMCBC. Quality of life issues have become increasingly important with improved survivorship.24 Mastectomy results in negative body stigma, which reconstruction may not completely overcome.6,7 BCT offers an advantage with superior body image outcomes.6,7 Despite these benefits, BCT rates for early breast cancer in predominantly Chinese communities are unfortunately well below 70%,8–12 the level that may be viewed as the optimum threshold for ideal survival outcomes based on recent data.3,4 These low BCT rates, thought to be
contributed by socio-cultural attitudes, surgeon preferences and physical attributes,12 are now an issue of concern because of the potential for suboptimal cancer-specific survival on a population basis. Some of these factors may be surmounted by certain technical manoeuvres to allow improved eligibility for BCT in MFMCBC for women with SVB. However, there is a paucity in the literature on specific techniques for these circumstances. The use of double lumpectomies and oncoplastic techniques has been described for MFMCBC.25,26 The former approach may violate guidelines,20 while the latter are reported to have higher complication rates than techniques with direct parenchymal closure.14,27 The surgical approach © 2014 Royal Australasian College of Surgeons
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used in this study differs in essentials from double lumpectomy and conventional oncoplastic techniques. All patients who underwent BCT had en bloc multiple tumour excisions through a single incision, followed by local tissue arrangement procedures. In order to achieve this outcome, specific incision designs were selected. MFMCBC not involving the skin, with at least one lesion in close proximity to the nipple–areolar complex, were approached using a boomerang incision or its modifications17 (Figs 1,2). Other incisions, like a radial incision with an eccentric ellipse,18 or conventional skin-crease incisions, were applied for lesions further away from the nipple. Modifications of skin incision design from conventional recommendations may be necessary to achieve complete tumour excision as patient’s individual circumstances demand. Paradoxically, violating one set of guidelines advising skin-crease incisions28 is needed for compliance with another set of guidelines demanding excision of all lesions through a single incision.20 Innovative surgical manoeuvres may be necessary to effect a concept change in BCT utilization for MFMCBC. In contradistinction to prior definitions where multifocality and multicentricity were quadrant-based,15 definitions were segmentbased in this study. Multifocal lesions were defined as those occurring in what is expected to be the same segment, and multicentric lesions were defined as malignancies occurring in what may be expected to be a different segment, regardless of position within the quadrant. This was to allow surgical and spatial planning. An extended single segmental removal was applied for multifocal lesions,17 and a multisegment resection pattern was used for multicentric lesions (Fig. 2a–f). Multisegment resection allowed tissue from the intervening segment(s) to be incorporated into the tissue repair, which if sacrificed may have necessitated either a mastectomy or volume replacement with implants or autologous flaps in SVB. Tumour extirpation in this fashion, whether through an extended segment or multisegment resection, created a unique pattern of residual uninvolved parenchyma, which when mobilized and advanced allowed the corresponding pillars to dovetail and ‘lock’ when apposed with sutures. This approach allowed BCT to be achieved for women with SVB and MFMCBC without vitiating the final cosmetic outcome. Compared with unifocal lesions, multifocality and multicentricity have been shown to be associated with a higher risk of positive margin status requiring re-excision.29 In this study, through the use of routine IFSA, there were no patients who required a re-excision on the basis of positive margins, whether unifocal or multiple cancers. The routine use of IFSA is controversial. Opponents to its implementation have argued for an individualized approach to margin status to reduce re-excisions and the associated costs.30 On the other hand, advocates for its regular use cite fourfold higher 30-day re-operation rates in a national database when compared with an institution applying routine IFSA.31 The current study was conducted in a private healthcare facility where frozen section costs are between $457 and 985 for a single surgical procedure, compared with the expected hospital costs of between $2675 and 3645 for a repeat breast surgical procedure. Based on the data from the study by Boughey et al.31 and the cost differential at our centre, the authors perform routine IFSA in an effort to reduce both re-excision rates and costs. © 2014 Royal Australasian College of Surgeons
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In spite of IFSA, there were four patients who required a re-operation in this entire cohort. Although margin status was not the indication for re-operation in any of these cases, all four patients had MFMCBC. Three had undetected multicentric disease prior to their primary procedure. It may be argued that the use of breast MRI might have reduced the need for re-excision. However, recent data found that its routine use increases the odds of having a mastectomy without significant reduction in re-excision rates or mortality.32 Routine preoperative MRI would thus be in conflict with the objective of optimizing BCT rates for MFMCBC, and was avoided in this cohort. If MRI is not routinely done, there might be occasions when ipsilateral synchronous tumours are missed. These are rare occurrences and it is the authors’ opinion that the low possibility does not warrant a policy of routine preoperative MRI. Nevertheless, further investigations may be needed to select appropriate candidates for MRI. As two of these four patients had ductal carcinoma in situ components with microcalcification in excess of 40 mm associated, this could form an indication for preoperative MRI. The majority of patients (66.3%) in the present study cohort were of Chinese ethnicity, and most of these who had MFMCBC underwent successful BCT. This suggests that despite having SVB, BCT rates for MFMCBC in women of Chinese ethnicity is similar to those of other ethnic origin. Of the entire cohort with MFMCBC, 85.4% underwent successful BCT, without any significant difference between multifocal (84.6%) and multicentric tumours (86.7%). All these rates, individually and collectively, are higher than the 70% threshold for potentially superior survival outcomes with BCT.3 Hence, the data suggest that the physical attributes of Chinese or Asian women do not serve as an impediment to successful BCT in MFMCBC. Applying surgical techniques described herein could improve utilization of BCT in women with SVB who have MFMCBC. In a surgical era where there is a trend towards performing less invasive procedures for equivalent treatment outcomes, as in percutaneous breast biopsies and SLN biopsies, it is timely to consider therapeutic operations of a less extensive nature for the breast. While MFMCBC conventionally is an indication for mastectomy, there is contemporary evidence from retrospective studies that BCT offers acceptable local control and survival outcomes.21,25,26 Data from this study add to the growing body of evidence that BCT is feasible in the majority of patients with MFMCBC regardless of breast tissue volume, and can be achieved without compromising cosmesis or local control through attention to appropriate patient selection and surgical technique. As the small cohort size and retrospective nature of data collection serve as a limitation for the study, further investigation is warranted to confirm the findings.
Acknowledgement The authors wish to thank Dr Sitoh Yih Yiow for his invaluable help with the paper.
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18. Tan MP. Alternatives for optimising outcomes in oncoplastic breast surgery. Ann. Surg. Oncol. 2012; 19: 2327–33. 19. Clough KB, Kaufman GJ, Nos C, Buccimazza I, Sarfati IM. Improving breast cancer surgery: a classification and quadrant per quadrant atlas for oncoplastic surgery. Ann. Surg. Oncol. 2010; 17: 1375–91. 20. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. [Cited 21 Nov 2014.] Available from URL: http://www.nccn.org/professionals/physician_gls/pdf/ breast.pdf 21. Lynch SP, Lei XD, Hsu LM et al. Breast cancer multifocality and multicentricity and locoregional recurrence. Oncologist 2013; 18: 1167– 73. 22. Giuliano AE, Hunt KK, Ballman KV et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011; 305: 569– 75. 23. Holland R, Veling SHJ, Mravunac M, Mendriks JH. Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer 1985; 56: 979–90. 24. Stout NL, Binkley JM, Schmitz KH et al. A prospective surveillance model for rehabilitation for women with breast cancer. Cancer 2012; 118 (8 Suppl.): 2191–200. 25. Kapoor NS, Chung A, Huynh K, Giuliano AE. Preliminary results: double lumpectomies for multicentric breast carcinoma. Am. Surg. 2012; 78: 1345–8. 26. Gentilini O, Botteri E, Rutmensz N et al. Conservative surgery in patients with multifocal/multicentric breast cancer. Breast Cancer Res. Treat. 2009; 113: 577–83. 27. Indelicato D, Grobmyer SR, Newlin H et al. Association between operative closure type and acute infection, local recurrence, and disease surveillance in patients undergoing breast conserving therapy for earlystage breast cancer. Surgery 2007; 141: 645–53. 28. Morrow M, Strom EA, Bassett LW et al. Standard for breast conservation therapy in the management of invasive breast carcinoma. CA Cancer J. Clin. 2002; 52: 277–300. 29. Bani MR, Lux MP, Heusinger K et al. Factors correlating with reexcision after breast-conserving therapy. Eur. J. Surg. Oncol. 2009; 35: 32–7. 30. Schnitt SJ, Morrow M. Should intraoperative frozen section evaluation of breast lumpectomy margins become routine practice? Am. J. Clin. Pathol. 2012; 138: 635–8. 31. Boughey JC, Hieken TJ, Jakub JW et al. Impact of frozen section margin analysis on reoperation rates in women undergoing lumpectomy for breast cancer: evaluation of the NSQIP data. Surgery 2014; 156: 190–7. 32. Houssami N, Turner R, Morrow M. Preoperative magnetic resonance imaging in breast cancer. Ann. Surg. 2013; 257: 249–55.
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Breast conservation treatment for multifocal and multicentric breast cancers in women with small-volume breast tissue Mona P. Tan,* Nadya Y. Sitoh*† and Amanda S. Sim* *Breast Surgery Department, MammoCare, Singapore and †Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Key words breast cancer, breast conservation treatment, mastectomy, multifocal and multicentric breast cancer, oncoplastic breast surgery. Correspondence Dr Mona P. Tan, Breast Surgery Department, MammoCare, 38 Irrawaddy Road, #06-21, Singapore 329563. Email: [email protected] M. P. Tan FRCS (Ed), MBBS; N. Y. Sitoh; A. S. Sim BSc (Nursing) UK. This study was presented in part at the Annual Scientific Congress of the Royal Australasian College of Surgeons in May 2014. Accepted for publication 31 October 2014. doi: 10.1111/ans.12942
Abstract Background: Breast conservation treatment (BCT) is an established option in the treatment of early breast cancer, but women with small breast volume (SVB) are considered poor candidates for BCT. Multifocal and multicentric breast cancers (MFMCBC) are conventionally considered a relative contraindication to BCT. These arguments form the basis of limited eligibility for BCT for a woman with SVB and MFMCBC. This study was performed to investigate this syllogism. Methods: Consecutive patients with breast malignancies treated from 2009 to 2011 were included. Patients were deemed to have successful BCT if they had pathologically clear margins and had completed all recommended adjuvant treatment. Those who had MFMCBC based on clinical, imaging and pathological data were selected for detailed evaluation. Comparisons were made with unifocal breast cancer. Results: Data from a total of 160 patients who underwent treatment during the study period were analysed. The mean age was 48.8 years. One hundred and six patients (66.3%) were of Chinese ethnicity, 36 (22.5%) were of other Asian ethnicity and 18 were Caucasian (11.2%). Forty-one (25.6%) patients had clinical evidence of MFMCBC. Of these patients, 35 (85.4%) underwent BCT. After a mean follow-up of 45 months, none of the patients with MFMCBC developed a local recurrence. Two patients with MFMCBC, one who underwent mastectomy and one with BCT, succumbed to cancer from distant disease. Conclusion: BCT is feasible in women with MFMCBC in a predominantly Chinese community where majority are expected to have SVB. Further investigation is warranted to confirm the findings.
Introduction Breast conservation treatment (BCT) was established as an alternative to mastectomy for the treatment of breast cancer on the basis of equivalent survival outcomes,1,2 but recent data suggest BCT may be superior to mastectomy in terms of breast cancer-specific survival and local control.3–5 An absolute benefit in breast cancer-specific survival of 4% at 10 years was reported where 70% of patients underwent BCT,3 and it is estimated that for each percentage point rise mastectomy rates, seven-year survival would be reduced by 0.1%.4 Hence, in a patient population with BCT rates below 30%, survival benefit may not be evident, and treated women may suffer poorer body image and quality of life outcomes.3–7 Many contemporary series from predominantly Chinese populations report BCT rates averaging 30%.8–12 The reasons cited for these low BCT rates include cultural factors, surgeon preferences and physical © 2014 Royal Australasian College of Surgeons
attributes.9–12 Chinese women have been shown to have smaller breast volume (SVB) tissue,13 posing challenges for good cosmetic outcomes with BCT.14 The presence of ipsilateral multifocal and multicentric breast cancers (MFMCBC) compounds these challenges. The lower initial parenchymal volume serves as a barrier for the provision of adequate retained tissue to achieve a reasonable postsurgical cosmetic outcome following multiple tumour excisions. As conventional contraindications to BCT reflect the clinical situations that would compromise either local control or cosmesis,15 MFMCBC could be viewed as a contraindication for BCT in women with SVB. While the oncologic principle of achieving clear margins should not be compromised, methods can be explored to allow such women the potential benefits of BCT. This study was therefore conducted to evaluate the feasibility of performing of BCT among women who were diagnosed to have MFMCBC in a ANZ J Surg •• (2014) ••–••
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Fig. 1. (a–d) This 35-year-old patient presented with a palpable lesion in the lower inner quadrant of the right breast. Imaging demonstrated two lesions, both of which were diagnosed as grade 3 infiltrative ductal carcinoma on percutaneous core biopsy. Radio-opaque marker clips were positioned within each tumour. She had good response to neoadjuvant chemotherapy. Figure 1c illustrates the standard boomerang incision used after localization of the two marker clips. Postoperative histology revealed a single focus of ductal carcinoma in situ, 1.4 cm in maximal extent. Despite the absence of histological evidence of uninvolved intervening parenchyma, she was classified as having multifocal breast cancer. The final cosmetic result for this patient with double-A cup-sized breast tissue volume is depicted in Figure 1d.
predominantly Chinese community, where more women with SVB are expected.
Methods A retrospective analysis was performed on all patients with breast malignancies who underwent operative treatment at the authors’ centre between January 2009 and December 2011. Initial evaluation consisted of clinical examination, mammography and ultrasonography. Diagnosis was made preoperatively where possible using percutaneous needle biopsies. Where there were technical limitations, surgical diagnostic procedures were performed. Eligibility for BCT was based on the surgeon’s assessment that the combined volume of tissue excised would not exceed 25% of total breast volume. Patients considered eligible were given an option of an attempt at BCT or mastectomy, with or without reconstruction. Those with large lesions were treated with neoadjuvant medical therapy following placement of radio-opaque clip(s). Preoperative breast magnetic resonance imaging (MRI) was not routinely used in this cohort of patients. Multifocal tumours were defined as the presence of more than one focus of tumour within the same segment of the breast. Multicentric tumours were defined as separate malignant foci in different segments of the breast. Based on the ‘sick lobe theory’,16 this classification facilitates surgical planning. Multiple tumours were defined based on preoperative workup. Pathological confirmation of tumour foci was made when clinical and imaging findings were suspicious of multiple malignancies. However, intervening normal tissue was not always demonstrable for MFMCBC patients who underwent neoadjuvant chemotherapy and had pathological complete response for at least one of the lesions (Fig. 1a–d). Incidental findings of multifocal lesions following histological examination of wide excision or mastectomy specimens were not classified as MFMCBC. Where indicated, localizations of non-palpable foci were performed, and patients underwent sentinel node biopsy using blue dye based on the dominant lesion. An axillary clearance up to level III was
performed if there was lymph node positivity. For purposes of staging and analysis, calculations were made based only on the larger, dominant lesion. All patients underwent en bloc wide excisions of MFMCBC through a single incision, usually a boomerang incision or its modifications.17 This approach was most suitable for patients with at least one lesion in close proximity to the nipple-areolar complex (NAC) (Fig. 1a,b). In cases where the tumours were remote from the nipple, another appropriate incision design was used. For example, tumours in the upper outer quadrant of the breast were approached with a modification of the boomerang incision18 (Fig. 2a–f). This allows for adequate exposure for multisegment wide excision, remodelling and axillary surgery through a single incision and avoids significant deviation of the nipple without the need for de-epithelization to reposition the NAC.19 Tumour excision for multicentric lesions was performed with a multisegment resection pattern, consisting of elliptically shaped limbs around each focus, with the long axis oriented radially and connected centrally (Fig. 2). This allowed an en bloc resection through a single incision in conformity to guideline recommendations.20 After tumour extirpation, the partial mastectomy defect was repaired using only local tissue rearrangement techniques. Full thickness parenchymal flaps were mobilized off the pectoralis fascia, the tissue pillars advanced and apposed with sutures. This approach does not preclude BCT for malignancies on opposite quadrants of the breast. Volume replacement techniques with autologous flaps or implants were not used. Intraoperative frozen section analysis (IFSA) was used for margins status for each patient undergoing BCT. Further margins were taken where necessary until proven negative intraoperatively. Successful BCT of MFMCBC was defined as operative attainment of clear margins (no ink on tumour)2 on paraffin sections and an acceptable cosmetic outcome. The incision was planned such that at least one of the tumour foci was located beneath the scar to facilitate radiotherapy. Tumour beds more than 2 cm from the scar were © 2014 Royal Australasian College of Surgeons
Breast conservation for multiple cancers
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Fig. 2. (a–f) A modification of the boomerang incision is used when at least one of the lesions is close to the nipple–areolar complex (localized) and the other (palpable) is distant, in the upper outer quadrant of the breast. A multi-segment resection is performed and parenchymal pillars mobilized to repair the defect to obtain a cosmetic result shown in Figure 2e,f.
marked by a liga clip. Whole breast external beam radiation was delivered in divided doses with electron boosts according to the preference of the radiation oncologist. If a reasonable cosmesis was thought to be unattainable, or if patients elected against BCT, a mastectomy was performed. Anticipating the possibility that BCT was feasible for MFMCBC, the null hypothesis was that there would be no difference between conservation rates for MFMCBC and unifocal lesions. Comparisons with unifocal cancers were made where appropriate, and analyses were performed using Statistical Package for the Social Sciences (SPSS, Inc., Chicago, IL, USA) version 11 advanced statistical software module.
Results Forty-one of 160 (25.6%) patients assessed had clinical evidence of more than one focus of malignancy on preoperative evaluation. Twenty-six (16.3%) had multifocal and 15 (9.4%) had multicentric disease, proportions similar to another larger series.21 A summary of the clinicopathological characteristics of the study cohort is given in Table 1. Of the 119 patients with unifocal lesions, 102 (85.7%) underwent BCT. Twenty-two of 26 patients (84.6%) with multifocal lesions and 13 of 15 (86.7%) with multicentric cancers underwent BCT. Four of 26 (15.4%) patients with multifocal cancers underwent mastectomy, of whom two elected for the procedure against recommendations for a trial of BCT. Two of 15 (13.3%) patients with multicentric cancers underwent mastectomy as recommended. There was no significant difference between the BCT rate for unifocal lesions and MFMCBC with successful BCT (P = 0.83). Of note, 66.3% of the patients were Chinese, and expected to have SVB, while 22.5% were of other Asian origins and 11.2% were Caucasian. Twenty-four of 29 (82.8%) Chinese women with MFMCBC underwent BCT. Among those with MFMCBC, there was no significant difference in BCT rates based on ethnicity (P = 0.30). Of the 21 Chinese women with multifocal disease, 17 (81%) had BCT. Seven of eight (87.5%) Chinese women with multicentric disease © 2014 Royal Australasian College of Surgeons
underwent BCT. Of note, there was a significantly higher proportion of women with multicentric lesions who underwent neoadjuvant chemotherapy for a trial of BCT. Four patients required reoperation, one for a false-negative IFSA of the sentinel lymph node (SLN), who underwent completion axillary dissection prior to a change in axillary staging practices,22 and three for multicentric disease only detected on postoperative review. Of the patients with MFMCBC who underwent a re-operation, the mean pathological dimension of the dominant tumour was 36.3 mm (standard deviation (SD) 18.0 mm). This is in comparison with 18.3 mm (SD 13 mm), which is the mean of the largest tumour size for those who did not need another surgical procedure. All patients who underwent re-operations are currently well with no signs of local recurrence or distant disease. All patients had their margins subject to IFSA and negative margin status was confirmed on paraffin sections. At a median follow-up of 45 months, none of the patients with MFMCBC developed local recurrence. However, two have succumbed to metastatic disease, the first of whom underwent mastectomy and died 53 months after surgery while the second had BCT and died 14 months after surgery.
Discussion Although multiple ipsilateral tumour foci may occur in up to 63% of mastectomy specimens,23 equivalent survival outcomes were observed in prospective trials comparing BCT and mastectomy for clinically unifocal lesions, suggesting that the majority of these foci are not, or do not become, biologically relevant or clinically significant with appropriate treatment. Recent data on axillary treatment have also demonstrated a similar phenomenon where less surgery does not necessarily lead to inferior local control or survival outcomes.22 The concept of BCT for MFMCBC would thus be concordant with current treatment policies for unifocal tumours and axillary staging. In line with this philosophy, a recent expert consensus considered MFMCBC as a relative contraindication, rather than an
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Table 1 Summary of demographic, clinicopathological and outcome data for study population Clinicopathological characteristic
Age in years Median (range) Mean (SD) Ethnicity Chinese Malay/Indonesian Indian Other Asian Caucasian Mode of presentation Symptomatic tumours Screen detected lesions Tumour size in mm (range) Median (range) Mean (SD) T1 T2 T3 T4 Pathological stage 0 I II III IV Histological type DCIS Invasive ductal Invasive lobular Other invasive Grade DCIS 1 2 3 Unknown Neoadjuvant medical therapy Yes No Surgical procedure BCT Mastectomy by need Mastectomy by choice Re-operations Axillary dissection Missed multicentric Recurrence Local recurrence Distant disease/death Median follow-up (months) (range)
Unifocal (n = 119)
49 (30–78) 49.7 (9.8)
MFMCBC (n = 41)
P value
%
MF (26)
%
MC (15)
%
— —
46.5 (31–67) 47.62 (10.8)
— —
44 (28–52) 43.7 (6.3)
— —
77 7 9 9 17
64.7 5.9 7.6 7.6 14.3
21 0 2 3 0
80.8 0.0 7.7 11.5 —
8 2 2 2 1
53.3 13.3 13.3 13.3 6.7
86 33
72.3 27.7
20 6
76.9 23.1
10 5
66.7 33.3
18.0 (2–97) 22.2 (16.3) 76 35 6 2
— — 63.9 29.4 5.0 1.7
18.5 (3–72) 20.7 (16.2) 15 8 2 1
— — 57.7 30.8 7.7 3.8
20.0 (5–28) 17.7 (8.2) 9 6 0 0
— — 60.0 40.0 — —
— 0.04 0.30 — — — — — 0.77 — — — 0.60 0.86 — — — 0.05 — — — — — 0.28 — — — — 0.02 — — — — —
15 54 36 13 1
12.6 45.4 30.3 10.9 0.8
5 9 7 5 0
19.2 34.6 26.9 19.2 0.0
0 4 11 0 0
0.0 26.7 73.3 0.0 0.0
15 93 3 8
12.6 78.2 2.5 6.7
5 20 1 0
19.2 76.9 3.8 0.0
0 11 3 1
0.0 73.3 20.0 6.7
15 22 45 34 3
12.6 18.5 37.8 28.6 2.5
5 3 4 14 0
19.2 11.5 15.4 53.9 0.0
0 3 9 2 1
0.0 20.0 60.0 13.3 6.7
12 107
10.1 89.9
5 21
19.2 80.8
9 6
60.0 40.0
102 11 6
85.7 9.2 5.0 0.0 — —
22 2 2
84.6 7.7 7.7
13 0 2
86.7 0.0 13.3
1 0
6.7 —
0 3
— 20.0
0.006 — 0.83 — — — 0.01 — —
1.7 1.7
0 2
— —
— —
0.52 0.45
— — 2 2 —
—
— 0 45 (18–64)
BCT, breast conservation treatment; DCIS, ductal carcinoma in situ; MFMCBC, multifocal and multicentric breast cancer; SD, standard deviation.
absolute contraindication to BCT.2 This status paves the way for developing means to increase both eligibility and utilization of BCT in MFMCBC. Quality of life issues have become increasingly important with improved survivorship.24 Mastectomy results in negative body stigma, which reconstruction may not completely overcome.6,7 BCT offers an advantage with superior body image outcomes.6,7 Despite these benefits, BCT rates for early breast cancer in predominantly Chinese communities are unfortunately well below 70%,8–12 the level that may be viewed as the optimum threshold for ideal survival outcomes based on recent data.3,4 These low BCT rates, thought to be
contributed by socio-cultural attitudes, surgeon preferences and physical attributes,12 are now an issue of concern because of the potential for suboptimal cancer-specific survival on a population basis. Some of these factors may be surmounted by certain technical manoeuvres to allow improved eligibility for BCT in MFMCBC for women with SVB. However, there is a paucity in the literature on specific techniques for these circumstances. The use of double lumpectomies and oncoplastic techniques has been described for MFMCBC.25,26 The former approach may violate guidelines,20 while the latter are reported to have higher complication rates than techniques with direct parenchymal closure.14,27 The surgical approach © 2014 Royal Australasian College of Surgeons
Breast conservation for multiple cancers
used in this study differs in essentials from double lumpectomy and conventional oncoplastic techniques. All patients who underwent BCT had en bloc multiple tumour excisions through a single incision, followed by local tissue arrangement procedures. In order to achieve this outcome, specific incision designs were selected. MFMCBC not involving the skin, with at least one lesion in close proximity to the nipple–areolar complex, were approached using a boomerang incision or its modifications17 (Figs 1,2). Other incisions, like a radial incision with an eccentric ellipse,18 or conventional skin-crease incisions, were applied for lesions further away from the nipple. Modifications of skin incision design from conventional recommendations may be necessary to achieve complete tumour excision as patient’s individual circumstances demand. Paradoxically, violating one set of guidelines advising skin-crease incisions28 is needed for compliance with another set of guidelines demanding excision of all lesions through a single incision.20 Innovative surgical manoeuvres may be necessary to effect a concept change in BCT utilization for MFMCBC. In contradistinction to prior definitions where multifocality and multicentricity were quadrant-based,15 definitions were segmentbased in this study. Multifocal lesions were defined as those occurring in what is expected to be the same segment, and multicentric lesions were defined as malignancies occurring in what may be expected to be a different segment, regardless of position within the quadrant. This was to allow surgical and spatial planning. An extended single segmental removal was applied for multifocal lesions,17 and a multisegment resection pattern was used for multicentric lesions (Fig. 2a–f). Multisegment resection allowed tissue from the intervening segment(s) to be incorporated into the tissue repair, which if sacrificed may have necessitated either a mastectomy or volume replacement with implants or autologous flaps in SVB. Tumour extirpation in this fashion, whether through an extended segment or multisegment resection, created a unique pattern of residual uninvolved parenchyma, which when mobilized and advanced allowed the corresponding pillars to dovetail and ‘lock’ when apposed with sutures. This approach allowed BCT to be achieved for women with SVB and MFMCBC without vitiating the final cosmetic outcome. Compared with unifocal lesions, multifocality and multicentricity have been shown to be associated with a higher risk of positive margin status requiring re-excision.29 In this study, through the use of routine IFSA, there were no patients who required a re-excision on the basis of positive margins, whether unifocal or multiple cancers. The routine use of IFSA is controversial. Opponents to its implementation have argued for an individualized approach to margin status to reduce re-excisions and the associated costs.30 On the other hand, advocates for its regular use cite fourfold higher 30-day re-operation rates in a national database when compared with an institution applying routine IFSA.31 The current study was conducted in a private healthcare facility where frozen section costs are between $457 and 985 for a single surgical procedure, compared with the expected hospital costs of between $2675 and 3645 for a repeat breast surgical procedure. Based on the data from the study by Boughey et al.31 and the cost differential at our centre, the authors perform routine IFSA in an effort to reduce both re-excision rates and costs. © 2014 Royal Australasian College of Surgeons
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In spite of IFSA, there were four patients who required a re-operation in this entire cohort. Although margin status was not the indication for re-operation in any of these cases, all four patients had MFMCBC. Three had undetected multicentric disease prior to their primary procedure. It may be argued that the use of breast MRI might have reduced the need for re-excision. However, recent data found that its routine use increases the odds of having a mastectomy without significant reduction in re-excision rates or mortality.32 Routine preoperative MRI would thus be in conflict with the objective of optimizing BCT rates for MFMCBC, and was avoided in this cohort. If MRI is not routinely done, there might be occasions when ipsilateral synchronous tumours are missed. These are rare occurrences and it is the authors’ opinion that the low possibility does not warrant a policy of routine preoperative MRI. Nevertheless, further investigations may be needed to select appropriate candidates for MRI. As two of these four patients had ductal carcinoma in situ components with microcalcification in excess of 40 mm associated, this could form an indication for preoperative MRI. The majority of patients (66.3%) in the present study cohort were of Chinese ethnicity, and most of these who had MFMCBC underwent successful BCT. This suggests that despite having SVB, BCT rates for MFMCBC in women of Chinese ethnicity is similar to those of other ethnic origin. Of the entire cohort with MFMCBC, 85.4% underwent successful BCT, without any significant difference between multifocal (84.6%) and multicentric tumours (86.7%). All these rates, individually and collectively, are higher than the 70% threshold for potentially superior survival outcomes with BCT.3 Hence, the data suggest that the physical attributes of Chinese or Asian women do not serve as an impediment to successful BCT in MFMCBC. Applying surgical techniques described herein could improve utilization of BCT in women with SVB who have MFMCBC. In a surgical era where there is a trend towards performing less invasive procedures for equivalent treatment outcomes, as in percutaneous breast biopsies and SLN biopsies, it is timely to consider therapeutic operations of a less extensive nature for the breast. While MFMCBC conventionally is an indication for mastectomy, there is contemporary evidence from retrospective studies that BCT offers acceptable local control and survival outcomes.21,25,26 Data from this study add to the growing body of evidence that BCT is feasible in the majority of patients with MFMCBC regardless of breast tissue volume, and can be achieved without compromising cosmesis or local control through attention to appropriate patient selection and surgical technique. As the small cohort size and retrospective nature of data collection serve as a limitation for the study, further investigation is warranted to confirm the findings.
Acknowledgement The authors wish to thank Dr Sitoh Yih Yiow for his invaluable help with the paper.
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