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CME TopicSurgical Margins in Breast ConservationTherapy: How Much Should We Excise?Tsz Ting Law,              MBBS,     an...
CME Topicgroups, respectively.13 However, in examining the LR rates                        mammography; as a result, a wid...
Law and Kwong • How Much Should We Excise?As a result a “safe” margin could not be concluded from these        Table 2. In...
CME Topic 3. Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with           21. Vargas C, Kestin L, Go N, et...
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Surgical margins in_breast_conservation_therapy_.16

  1. 1. CME TopicSurgical Margins in Breast ConservationTherapy: How Much Should We Excise?Tsz Ting Law, MBBS, and Ava Kwong, FRCS some authors to obtain good results in terms of LR althoughBackground: Breast conservation therapy (BCT) has become thestandard of treatment for early stage breast cancer, and the surgical others would accept a much smaller margin.margin was one of the important factors that affected risk of localrecurrence. This review looks at the safe margin for BCT in early stage Margins for Invasive Breast Cancerinvasive breast cancer and ductal carcinoma in situ (DCIS). The definition of a free margin varies. According to the National Surgical Adjuvant Breast and Bowel ProjectMethods: Published literature abstracted in Medline was searched (NSABP),2 a margin is positive if tumor cells are present atusing the gateway site from the US National Library of Medicine. the edge of resection on inked histology section. Quadrante-Conclusions: A positive margin is associated with increased risk of ctomy described in the Milan trial involved excision of 2–3local recurrence after BCT for invasive breast cancer and DCIS. How- cm of normal tissue around the tumor7; the European Orga-ever there was no cut off for the margin width and the significance of nization for Research and Treatment of Cancer (EORTC) triala close margin remains controversial. It was generally accepted that the considered 1 cm gross as free margin.8risk of local recurrence was low if the margin was 10 mm while There was no quantitative definition of a negative margin inmargins that were 2 mm were considered inadequate. The surgeon some studies,9,10 while others quantitatively defined negativeneeds to balance the risk between local recurrence and cosmesis in margin as no tumor cells within a fixed distance of the cut edgeplanning BCT so that the prognosis is not compromised. of the surgical specimen, for example, 1 mm, 2 mm, 3 mm, and so forth.11,12 Controversies exist in the literature regarding theKey Words: breast conservation therapy, local recurrence, surgical meaning of a close margin. In general a close margin is definedmargin as cancer cells being within 1 mm of the inked margin. The majority of studies show that positive margins resultW ith the increasing use of screening mammography, the majority of breast tumors are detected when they aresmall. Breast conservation therapy (BCT), which includes in an increased rate of LR. A review by Singletary13 showed that patients with positive margins had increased incidence of LR with increasing follow-up times, using 2 mm as a nega-local excision and radiation treatment to the breast, has be- tive margin. When studies were grouped according to howcome the treatment standard for early invasive breast cancers the negative margin was defined (ie positive versus negative,(stages I & II).1,2 The rate of local recurrence (LR) following 1 mm and 2 mm, respectively), the differences in LR betweenBCT varies between 5 and 10%.1,2 Surgical margin status is positive and negative margins were highly significant forconsidered to be one of the factors which increases risk for each group. For a negative margin defined as 1 mm, LRLR, and to date there is no consensus on a safe margin. was 3–7% in negative margin group versus 16 –22% in theMargins for Ductal Carcinoma In Situ positive margin group; whereas the negative margin was de- BCT is an established treatment for ductal carcinoma fined as 2 mm, LR was 2–7% versus 8 –22% in the twoin-situ.3– 6 A wide margin up to 10 mm had been suggested byFrom the Division of Breast Surgery, Department of Surgery, The University Key Points of Hong Kong Li Ka Shing Faculty of Medicine, Queen Mary Hospital, • There is no cut off regarding a safe margin width for Hong Kong SAR. breast conservation therapy in the literature.Reprint requests to Dr. Ava Kwong, Chief of Breast Surgery Division, Department • It is generally accepted that the risk of local recur- of Surgery, The University of Hong Kong Li Ka Shing Faculty of Medicine, Queen Mary Hospital, Hong Kong SAR. Email: avakwong@hkucc.hku.hk rence is low if the margin is 10 mm while marginsNeither Dr. Law or Dr. Kwong have any disclosures to declare or conflicts 2 mm are considered inadequate. of interest to report. • The surgeon needs to balance the risk between localAccepted July 10, 2009. recurrence and cosmesis in planning breast conserva-Copyright © 2009 by The Southern Medical Association tion therapy so that prognosis is not compromised.0038-4348/0 2000/10200-12341234 © 2009 Southern Medical Association
  2. 2. CME Topicgroups, respectively.13 However, in examining the LR rates mammography; as a result, a wide margin is recommendedin patients with negative margin, no clear cut differences for excision. Randomized controlled trials, namely NSABPbased on the exact margin width were found. Whether pa- B-17,3 UKCCCR,6 and EOTRC 108534,5 showed that BCTtients with close margin had a LR rate equivalent to those followed by radiotherapy reduced the risk of noninvasive andwith a positive margin, negative margin, or intermediate mar- invasive recurrences in the ipsilateral breast when comparedgin was unclear. with local excision alone. The incidence of invasive ipsilat- eral breast recurrence in patients who received radiotherapyMargins for DCIS was 3.9% and 5.8% at 5 yrs in NSABP B-17 trial and EORTC DCIS is a local disease lacking stromal invasion and 10853 trial, respectively, which was lower than the excisiondistant metastases. The presentation varies from a palpable group. Data from the pathological review of NSABP B-17mass to microcalcifications on mammography. The work by and EORTC 10853 trials showed that the risk of LR wasHolland showed that the histological size of DCIS might not higher in patients who did not have free margins.5,16 Unfor-correlate with mammographic findings.14,15 The reliability of tunately, the trial eligibility criteria did not require reportingmammography in assessing tumor size was related to both the of margin widths in all 3 trials. Only 5% of the pathologicalhistological type and the type of microcalcifications seen on reports did specify the exact distance in the EORTC trial.4,5Table 1. Summary of reported rates of local recurrence after breast-conserving therapy for ductal carcinoma insituaAuthor Margin (mm) N Management LR (%) Follow-up (mo) ConclusionSilverstein23 10 mm 93 Excision 2.2 Mean 81 No reduction in probability of LR with addition of postop RT if margin is 10 mm 10 mm 40 Excision RT 2.5 — —Kestin24 2b 44 Excision RT 5.9 Median 84 Margin status alone may not predict complete tumor extirpation adequately 2 88 Excision RT 15.1 — —Chan17 1 66 Excisionc 37.9 Median 47 Margins greater than 1 mm regardless of width of clearance was associated with a low LR 1.1–5 89 — 3.5 — — 5.1–10 28 — 7.1 — — 10 22 — 4.5 — —Vicini25 2 46 Excision RT 11.0 Median 87 Margin status alone may be suboptimal in accurately defining excision adequacy 2 99 Excision RT 2.0 — —Vargas21 2 34 Excision 13.0 Median 73 Margins 2 mm are shown to be an independent predictor of LR 2 198 Excision 4.0 — —MacDonald22 0 (transected) 32 Excision 46.7 Median 57 Margin width is the single most important factor in predicting LR after excision alone for DCIS 0.1–0.9 53 Excision 34.0 — — 1.0–1.9 20 Excision 35.0 — — 2.0–2.9 82 Excision 24.4 — — 3.0–5.9 39 Excision 20.5 — — 6.0–9.9 22 Excision 9.1 — — 10 197 Excision 4.6 — —MacDonald18 10 212 Excision 5.7 Median 53 Low risk of LR after excision alone for DCIS with margins 10 mm 10 60 Excision RT 1.7 — —West19 5 82 Excision RT 1.4 Median 97 5 mm margin plus radiation results in low rates of recurrence 10 71 Excision 6.0 — —a RT, radiotherapy; LR, local recurrence; DCIS, ductal carcinoma in situ.b Includes uncertain margin (n 3).c Majority of patients received excision only, other patient received adjuvant radiotherapy tamoxifen.Southern Medical Journal • Volume 102, Number 12, December 2009 1235
  3. 3. Law and Kwong • How Much Should We Excise?As a result a “safe” margin could not be concluded from these Table 2. Intraoperative margin assessment techniquesstudies. Nevertheless, margin status was consistently found tobe an important risk factor for recurrence in many nonran- Advantages Disadvantagesdomized trials. There was a low risk of recurrence after ex- Gross evaluation Rapid Gross evaluation onlycision alone for DCIS with surgical margins of more than 10 of specimenmm,17–19 whereas a close margin ( 2 mm) was associated Pathologicwith an increase risk of residual disease. The study of residual evaluationDCIS in re-excision specimens showed that initial excision Frozen section Accurate Loss of tissuemargin significantly predicted for residual tumor in re-exci- Histologic artifactssion specimens.20 Margin status was shown to be an inde- related to tissue preparationpendent predictor of LR.21 Results from a retrospective study Increased operation timeof 445 patients with pure DCIS treated by excision alone Touch Rapid Could not assess closeindicated that margin width was the most important indepen- preparation margindent predictor of LR.22 cytology No tissue loss Cytopathology training It is not clear whether there is a subgroup of low risk Imagingpatients who do not require radiotherapy. Silverstein et al23 Intraoperative Real time Limited role inshowed that excellent local control was achieved in a sub- ultrasonography Performed by surgeon nonpalpable lesionsgroup of patients with margin widths of 10 mm or greater Specimen Assessed margin in Time consumingwith excision alone and hypothesized that radiation did not radiography nonpalpable lesionshave significant benefit in this group of patients. Besides margin status, a number of clinical and patho-logical factors for recurrences include patient age, nuclear and slides reviewed by cytopathologists. Early results weregrade, histologic type and the presence of necrosis; they must promising.33,34 Intraoperative ultrasound showed significantbe added into consideration in the clinical management.24,25 reduction of pathologically positive margins in palpable tu-The Van Nuys prognostic index (VNPI) is a tool that quan- mors.35 Specimen radiography was mandatory for resectiontifies 4 measurable prognostic factors: tumor size, margin of nonpalpable lesions.36width, nuclear grade, and the presence or absence of come-donecrosis.26 A fifth factor, patient age, was added by inves-tigators from the University of South California (USC) and Oncoplastic Surgerybecame the USC/VNPI.27 Patients are stratified into different The balance between oncological control and cosmeticrisk groups for LR according to the score with the aim of outcome is always a concern in BCT. The use of plasticaiding clinical decision making. The validity of VNPI needs surgery techniques following lumpectomy, “oncoplastic sur-to be further confirmed by other groups. Table 1 summarizes gery,” is widely practiced in Europe.37 The margin of exci-the LR rate after BCT in DCIS using different margin cutoffs. sion is frequently wider as the tumor is removed en bloc with the tissue removed for mammoplasty.37 Short term oncolog- ical results in terms of LR and distant metastases is compa-Management of Positive Margin rable with the results of BCT randomized trials,38,39 yet long For both invasive breast cancer and DCIS, re-excision(s) term oncological safety needs further investigation.was recommended for positive margins in order to reduce therisk of LR.28 Treatment options for patients with close or focally Conclusionpositive margins should be individualized as the chance of hav- A positive margin is associated with increased risk of LRing significant residual tumor is not high.29 Personalized radio- after BCT for invasive breast cancer and DCIS. There is notherapy is the treatment of choice in some centers.30 cut off for the margin width and the significance of a close margin remains controversial.40,41 The surgeon needs to bal-Intraoperative Assessment of Margin Status ance the risk between LR and cosmesis in planning BCT so Intraoperative margin assessment techniques are de- that prognosis is not compromised.scribed in Table 2. Staining could be used to stain the entirecut surface of the specimen, with placement of one or more Referencessutures for directional orientation. Intraoperative frozen sec- 1. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow up of ation allowed immediate resection of suspicious or positive randomized study comparing breast-conserving surgery with radical mas- tectomy for early breast cancer. N Engl J Med 2002;347:1227–1232.margins and resulted in low rates of re-excisions.31,32 Touch 2. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a ran-preparation cytology is another technique for sampling the domized trial comparing total mastectomy, lumpectomy, and lumpec-margins: tumor cells will stick to a clean glass surface, while tomy plus radiation for the treatment of breast cancer. N Engl J Medfat cells will not. The touch slides were subjected to staining 2002;347:1233–1241.1236 © 2009 Southern Medical Association
  4. 4. CME Topic 3. Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with 21. Vargas C, Kestin L, Go N, et al. Factors associated with local recurrence lumpectomy and radiation therapy for the treatment of intraductal breast and cause-specific survival in patients with ductal carcinoma in situ of cancer. N Engl J Med 1993;328:1581–1586. the breast treated with breast-conserving therapy or mastectomy. Int J 4. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserv- Radiat Oncol Biol Phys 2005;63:1514 –1521. ing treatment for ductal carcinoma in situ: first results of the EORTC 22. MacDonald HR, Silverstein MJ, Mabry H, et al. Local control in ductal randomised phase III trial 10853. EORTC Breast Cancer Cooperative carcinoma in situ treated by excision alone: incremental benefit of larger Group and EORTC Radiotherapy Group. Lancet 2000;355:528 –533. margins. Am J Surg 2005;190:521–525. 5. Bijker N, Peterse JL, Duchateau L, et al. Risk factors for recurrence and 23. Silverstein MJ, Lagios MD, Groshen S, et al. The influence of margin metastasis after breast-conserving therapy for ductal carcinoma-in-situ: width on local control of ductal carcinoma in situ of the breast. N Engl analysis of European Organization for Research and Treatment of Can- J Med 1999;340:1455–1461. cer Trial 10853. J Clin Oncol 2001;19:2263–2271. 24. Kestin LL, Goldstein NS, Lacerna MD, et al. Factors associated with 6. Houghton J, George WD, Cuzick J, et al; UK Coordinating Committee local recurrence of mammographically detected ductal carcinoma in situ on Cancer Research; Ductal Carcinoma in situ Working Party; DCIS in patients given breast-conserving therapy. Cancer 2000;88:596 – 607. trialists in the UK, Australia, and New Zealand. Radiotherapy and ta- 25. Vicini FA, Kestin LL, Goldstein NS, et al. Relationship between exci- moxifen in women with completely excised ductal carcinoma in situ of sion volume, margin status and tumor size with the development of local the breast in the UK, Australia, and New Zealand: Randomised con- recurrence in patients with ductal carcinoma in situ treated with breast- trolled trial. Lancet 2003;362:95–102. conserving therapy. J Surg Oncol 2001;76:245–254. 7. Veronesi U, Volterrani F, Luini A, et al. Quadrantectomy versus lumpec- 26. Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for tomy for small size breast cancer. Eur J Cancer 1990;26:671– 673. ductal carcinoma in situ of the breast. Cancer 1996;77:2267–2274. 8. van Dongen JA, Bartelink H, Fentiman IS, et al. Factors influencing 27. Silverstein MJ. The University of Southern California/Van Nuys prog- local relapse and survival and results of salvage treatment after breast- nostic index for ductal carcinoma in situ of the breast. Am J Surg 2003; conserving therapy in operable breast cancer: EORTC trial 10801, breast 186:337–343. conservation compared with mastectomy in TNM stage I and II 28. National Comprehensive Cancer Network. Clinical Practice Guidelines breast cancer. Eur J Cancer 1992;28A:801– 805. in oncology–Breast Cancer, v2.2008 [PDF on Internet]. Available at: 9. DiBiase SJ, Komarnicky LT, Schwartz GF, et al. The number of positive www.nccn.org. Accessed April 3, 2008. margins influences the outcome of women treated with breast preserva- 29. Papa MZ, Zippel D, Koller M, et al. Positive margins of breast biopsy: tion for early stage breast carcinoma. Cancer 1998;82:2212–2220. is reexcision always necessary? J Surg Oncol 1999;70:167–171.10. Mansfield CM, Komarnicky LT, Schwartz GF, et al. Ten-year results in 30. Luini A, Rososchansky J, Gatti G, et al. The surgical margin after 1070 patients with stages I and II breast cancer treated by conservative breast-conserving surgery: discussion of an open issue. Breast Cancer surgery and radiation therapy. Cancer 1995;75:2328 –2336. Res Treat 2009;113:397– 402.11. Gage I, Schnitt SJ, Nixon AJ, et al. Pathologic margin involvement and 31. Cabioglu N, Hunt KK, Sahin AA, et al. Role of intraoperative margin the risk of recurrence in patients treated with breast conserving therapy. assessment in patients undergoing breast-conserving surgery. Ann Surg Cancer 1996;78:1921–1928. Oncol 2007;14:1458 –1471.12. Peterson ME, Schultz DJ, Reynolds C, et al. Outcomes in breast cancer 32. Olson TP, Harter J, Munoz A, et al. Frozen section analysis for intra- ˜ patients relative to margin status after treatment with breast-conserving operative margin assessment during breast-conserving surgery results in surgery and radiation therapy: the University of Pennsylvania experi- low rates of re-excision and local recurrence. Ann Surg Oncol 2007;14: ence. Int J Radiat Oncol Biol Phys 1999;43:1029 –1035. 2953–2960.13. Singletary SE. Surgical margins in patients with early-stage breast can- 33. Weinberg E, Cox C, Dupont E, et al. Local recurrence in lumpectomy cer treated with breast conservation therapy. Am J Surg 2002;184:383– patients after imprint cytology margin evaluation. Am J Surg 2004;188: 393. 349 –54.14. Holland R, Hendriks JH, Vebeek AL, et al. Extent, distribution, and 34. Bakhshandeh M, Tutuncuoglu SO, Fischer G, et al. Use of imprint mammographic/histological correlations of breast ductal carcinoma in cytology for assessment of surgical margins in lumpectomy specimens situ. 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Margin status after breast-conserving treatment of breast 532–534. cancer: how much free margin is enough? J Surg Oncol 2008;98:585–587.20. Neuschatz AC, DiPetrillo T, Steinhoff M, et al. The value of breast 41. Meijnen P, Gilhuijs KG, Rutgers EJ. The effects of margins on the lumpectomy margin assessment as a predictor of residual tumor burden clinical management of ductal carcinoma in situ of the breast. J Surg in ductal carcinoma in situ of the breast. Cancer 2002;94:1917–1924. Oncol 2008;98:579 –584.Southern Medical Journal • Volume 102, Number 12, December 2009 1237