- Email: [email protected]
positive margins after breast-conserving therapy: Additional resection or no resection?
The Breast 22 (2013) S115eS117
Contents lists available at SciVerse ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Close/positive margins after breast-conserving therapy: Additional resection or no resection? William C. Wood* Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road NE, Room 5004, Atlanta, GA 30322, USA
a b s t r a c t Keywords: Breast conserving therapy Re-excision Margins
The primary goal of breast conserving surgery or mastectomy is the prevention of recurrent breast cancer. The distinguishing goal of breast conserving surgery is preservation of a breast as normal in appearance as possible. If the margins of the excised breast cancer extend to the border of the excised specimen one cannot determine the amount of gross tumor that was not excised. Retrospective analyses of surgical series show a 2e3 fold increase in local recurrence of the breast tumor if the margin is positive under the microscope, even when the surgeon believed it to be clear on gross examination [1]. This fact has led to a variety of techniques attempting to ensure that the margins of the excised specimen are free of obvious tumor including pre-operative and specimen imaging and mapping, neo-adjuvant therapy to shrink the primary tumor, touch-prep and frozen section of the specimen margins during the procedure, shaving additional margins about the specimen at the closest aspects grossly or on all six surfaces, and examinations of the in situ walls of the remaining breast with new instrumentation. An obvious approach to diminishing the likelihood of positive specimen margins is taking a wider margin of normal tissue. As the volume of resected breast increases by the cube of the radius of excised tissue, this tracks all too well with diminishing cosmetic results and patient approval of the conserved breast. The question posed regards the finding of a positive or close margin after the surgical procedure. The finding of a positive margin can be parsed to a microscopic focus of tumor at the margin vs. the margin inking on a tumor surface. The latter demands re-excision despite the morbidity involved barring an extraordinary contra-indication or patient refusal. It represents the very real possibility of sufficient residual gross tumor in the breast that even with systemic therapy and breast irradiation the tumor will be un-controlled. A microscopic focus separated from the bulk of the primary tumor and adjacent to a margin has not been shown to carry such risk. The margin of normal tissue beyond the primary tumor that significantly reduces the risk of local recurrence remains undefined. Sufficient data are available to say that in the era of systemic therapy, excellent radiation therapy techniques, and boost doses when indicated, no margin of normal breast tissue beyond the tumor has been shown to be clearly superior to a layer of cells between the ink and the tumor. The larger the tumor and the more aggressive its biology is judged to be the lower the confidence that a single layer of cells at the point of histologic study accurately represents a clear margin. As in all medical decisions wise judgment must integrate all of the known factors to reach the best recommendation. There are few circumstances that would warrant a second surgical procedure for a close but clear margin today. Ó 2013 Elsevier Ltd. All rights reserved.
An apparent tension exists between the primary goal of breast cancer therapy, the prevention of recurrence and mortality, and the defining goal of breast conservation therapy [BCT], the preservation of a breast normal in appearance. The very familiar six randomized trials and a subsequent series of consensus conferences and meta-
* Tel.: þ1 404 778 3301; fax: þ1 404 778 4490. E-mail address: [email protected]. 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.07.022
analyses demonstrating equivalent survival without loss of the breast opened the dialog that persists today regarding how much less than mastectomy is best [2]. The premise of BCT is that irradiation of the breast at clinically tolerable dose levels will control sub-clinical volumes of residual breast cancer, and surgical excision of the primary tumor mass will deal with a volume of partially hypoxic tumor that would require very high dose irradiation to control at best. The NSABP [National Surgical Breast and Bowel Program] B-06 trial required inked specimens and clear margins,
S116
W.C. Wood / The Breast 22 (2013) S115eS117
defined as “no ink on tumor.” The other early, randomized trials described either grossly or microscopically clear margins. In all surgery for cancer, pathology reports stating that margins “are widely clear” delight surgeon and patient as in many solid tumors surgery is the only very effective treatment modality. In breast cancer careful studies of mastectomy specimens using Egan’s whole-breast-mount technique have demonstrated multifocality in most breast cancers and that margins of 2 cm. would leave multifocal sites behind in 42e47% [3,4] of breast cancer excisions. The inbreast recurrences in women treated by tumor excision alone e without breast irradiation e in trials such as NSABP B-06 are consonant with these pathological findings [5]. The diminishing incidence of local failure of BCT with the refinement in techniques of irradiation including boost, and the addition of systemic therapy when indicated, show that multicentric foci too small to be detected by diagnostic mammography and ultrasound examination appear to be controlled [6]. The addition of magnetic resonance imaging to detect such small foci of multicentric breast cancer has not proved to be beneficial, providing further evidence of the effectiveness of BCT in best practice today [7,8]. The question of the target margin of excision is complex. A cancer 1.6 cm in diameter has a volume of 2.1 cc. To excise this volume with 3 mm margins would yield a specimen volume of 5.6 cc. To excise with 10 mm margins would increase the volume to 24.4 cc, more than a four-fold volume increase. The volume excised from the breast is the main determinant of cosmetic outcome in BCT [9]. Clearly this relates to the ratio between excision volume, breast size, and the depth of the tumor site within the breast. The pathologic finding of a positive margin with the inked surface directly on tumor indicates no information whatever regarding the extent of the cancer in the remaining breast. The surgeon may have magically divided malignant cells from normal ones perfectly, leaving no cancer behind, but that is highly unlikely. A meta-analysis of 21 retrospective studies performed by Houssami and colleagues demonstrated that positive margins (tumor at inked surface) were associated with more than a doubling of risk for local recurrence [1]. Park and colleagues demonstrated that the amount of tumor at the margin related to the risk: 7% local failure with negative margins, 18 % with positive margins, but 27% if extensively positive vs. 14% if only focally positive. That is still twice the risk when negative. Interestingly, they found the same 7% risk of local failure with negative margins >1 mm or close margins 1 mm or less [10]. What should be the target margin when performing an excision of a cancer for breast conservation? Ideally, remove all of the tumor, a cell layer of normal tissue to take the pathologists margin ink, and no other normal breast tissue. As that is not feasible, several mm of normal tissue should cover the surface of the tumor. Numerous techniques have been attempted to idealize this. The first is the use of neo-adjuvant chemotherapy (after clip placement), for anyone who will require chemotherapy, to take advantage of the volume reduction seen in 70e80% of tumors so treated, 30% with clinical complete response. The incidence of positive resection margins rises with the tumor diameter [11].A lower rate of re-excision has been reported after neo-adjuvant treatment as well as the diminished resection volume providing a better esthetic result [12]. Aiming to remove 3e5 mm of normal breast about the margin of T1-2 tumor, coupled with careful examination of the oriented specimen to see if any margin appears close for an immediate shave margin is one approach. Another, frequently used at our institution, involves taking narrow additional oriented margins after the primary excision. This has demonstrated a higher rate of negative margins [13]. A study from the Massachusetts General Hospital found the same frequency of re-excisions with this technique, but they removed significantly (p < 0.001) less volume of tissue with
their cavity shaved margin group than in the simple excision group, so it is not surprising that they had a similar frequency of additional resection [14]. Mayo Clinic investigated waiting in the operating room for routine frozen-section analysis of breast margins, compared with later reoperation for positive margins. They found that this approach became cost-effective when the re-operation rate exceeded 36% [15]. Costs aside, it may be a preferable approach from the patient’s perspective. Dr. Nicole Krekel of Amsterdam presented results from a Dutch randomized trial that demonstrated a 3.3% incidence of positive margins in excisions guided by intra-operative ultrasound vs. 16.4% in those randomized to surgery guided only by palpation [16]. Electro-magnetic margin probes are also under investigation. Dr. Klimberg and colleagues continue to study the use of radiofrequency ablation of the margins remaining in the breast [17]. Such innovations may significantly change this conversation in the next few years. The specific question addressed by this paper arises subsequent to these considerations. Should additional resection be performed for close or positive margins after the primary excision has been performed? I will contend that re-excision is under-performed for positive margins, and over-performed for close ones. When a tumor margin is truly positive, not just a few cells isolated from the primary tumor at the site of an excision margin, one cannot know what volume of tumor remains in the breast that was cut through by the surgeon. Effective as modern radiation therapy techniques are in combination with systemic therapies in controlling microscopic disease, their inability to always control macroscopic disease is demonstrated by the greatly increased failure rate with positive margins cited above. Barring patient refusal or extraordinary contra-indications to proceeding, such margins should always be re-excised. Careful orientation of the primary excision specimen and painting each of the six faces with a different color ink identifies the area of breast to be addressed. The anxiety of the patient and possible diminution in cosmetic outcome cannot outweigh the risk associated with inaction. A recent series from four high-volume breast centers observed variation from 74% to 94% in re-excision for positive margins [11]. The case-specifics cannot be known, but such variation suggests that the clear evidence supporting re-excision for positive margins is not always followed. If positive margins are sometimes under-treated, clear but close margins are probably greatly over-treated. In careful reviews by Singletary [18], Houssami [1], and Revesz [19] the case is clearly made that there is no evidence that a specific margin beyond ‘no ink on tumor’ is ideal. This argument was pursued by Morrow and colleagues in a Sounding Board editorial in the New England Journal of Medicine last year [20]. Several major issues render it unlikely a priori that a specific margin width would prove definitive. Tumor biology relates powerfully to the risk of local failure with such features as grade, multifocality, stage, and genomic parameters [21,22]. Secondly, the margins seen by the pathologist are from a flattened, ‘hamburger patty’ specimen after the effects of gravity and, sometimes, compression in breast imaging on a surgically removed sphere of tissue. Finally, the margins are descriptions of tissue removed from the patient and no longer exerting effects, unlike the remaining breast tissue and residual foci of tumor for which they are weak surrogates. It is not surprising that the measured margin width beyond tumor have not proved predictive of local failure, given the presence of multifocality. This is not to say that a thoughtful approach to surgical resection should not include considerable thought as to the margin goal. A larger tumor is more likely to have a positive margin, so a more generous margin than a smaller tumor will avoid some re-excisions for positive margins. A younger patient, especially under 45 years,
W.C. Wood / The Breast 22 (2013) S115eS117
is at greater risk of local recurrence [23] as is a patient with “triple negative features.” It is appealing to attempt a slightly larger margin in such patients, but one must not imagine that decision to be based on evidence of benefit from the larger margin. Multifocal tumors and those with extensive DCIS are more likely to extend beyond the apparent border [24], and either of these giving a positive margin should be re-excised. LCIS found at the margin is not predictive of risk and may be ignored [25].
[7]
[8] [9]
[10]
Conclusion The goal of breast conserving therapy is best served by excision after the diagnosis is made by core biopsy. The margin desired is a differential equation involving tumor size, tumor biology, patient age, multifocality, breast size, and location within the breast. It does not lend itself to a nomogram. Increasingly, neo-adjuvant chemotherapy or hormonal therapy will precede the excision and the response or non-response or patchy response will further influence the surgical approach. If the resected margins are clear e no ink on tumor, there is no evidence that benefit would accrue from a wider re-excision. If the margin(s) are frankly positive, re-excision is definitely indicated.
[11] [12]
[13]
[14]
[15]
[16]
Conflict of interest statement [17]
I have no conflicts of interest to declare. References
[18] [19]
[1] Houssami N, Macaskill P, Marinovich ML, et al. Meta-analysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. Eur J Cancer 2010;46: 3219e32. [2] conf and panel chair NIH Consensus Conference Report, Wood WC. Treatment of early-stage breast cancer. J Am Med Assoc 1991;265:391e5. [3] Vaidya JS, Vyas JJ, Chinoy RF, Merchant N, Sharma OP, Mittra I. Multicentricity of breast cancer: whole-organ analysis and clinical implications. Br J of Cancer 1996;74:820e4. [4] Holland R, Veling S, Mravunac M, Hendrics JHCL. Histologic multifocality of Tis, T1-2 breast carcinomas: implications for clinical trials of breast conserving surgery. Cancer 1985;56:979e90. [5] Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347: 1233e41. [6] Anderson SJ, Wapnir I, Dignam JJ, et al. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by
[20] [21]
[22]
[23]
[24]
[25]
S117
breast-conserving therapy in five NSABP protocols of node-negative breast cancer. J Clin Oncol 2009;27:2466e73. Turnbull L, Brown S, Harvey I, et al. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomized controlled trial. Lancet 2010;375: 563e71. Miller BT, Abbott AM, Tuttle TM. The influence of preoperative MRI on breast cancer treatment. Ann Surg Oncol 2012;19:536e40. Krekel N, Zonderhuis B, Muller S, et al. Excessive resections in breastconserving surgery: a retrospective multicenter study. Breast J 2011;17: 602e9. Park CP, Misumori M, Nixon A, et al. Outcome at 8 years after breastconserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence. J Clin Oncol 2000;18:1668e75. McCahill LE, Single RM, Bowles EJA, et al. Variability in reexcision following breast conservation surgery. J Am Med Assoc 2012;307:467e75. Christy CJ, Thorsteinsson D, Grube BJ, et al. Preoperative chemotherapy decreases the need for re-excision of breast cancers between 2 and 4 cm diameter. Ann Surg Oncol 2009;16:697e702. Rizzo M, Iyengar R, Gabram SGA, et al. The effects of additional tumor cavity sampling at the time of breast-conserving surgery on final margin status, volume of resection, and pathologist workload. Ann Surg Oncol 2010;17:228e34. Coopey SB, Buckley JM, Bl Smith, et al. Lumpectomy cavity shaved margins do not impact re-excision rates in breast cancer patients. Ann Surg Oncol 2011;18:3036e40. Osborn JB, Keeney GL, Jakub JW, Degnim AC, Boughey JC. Cost-effectiveness analysis of routine frozen-section analysis of breast margins compared with reoperation for positive margins. Ann Surg Oncol 2011;18:3204e9. Krekel NM, Haloua MH, Lopes Cardozo AM, et al. Intraoperative ultrasound guidance for palpable breast cancer excision (COBALT trial): a multicenter, randomized controlled trial. Lancet Oncol 2013;14:48e54. Klimberg VS, Boneti C, Adkins LL, et al. Feasibility of percutaneous excision followed by ablation for local control in breast cancer. Ann Surg Oncol 2011;18:3079e87. Singletary SE. Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg 2002;184:383e93. Revesz E, Khan SA. What are safe margins of resection for invasive and in situ breast cancer? Oncology 2011;25:890e5. Morrow M, Harris JR, Schnitt SJ. Surgical margins in lumpectomy for breast cancerdbigger is not better. N Engl J Med 2012;367:79e82. Mamounas EP, Anderson SJ, Dignam JJ, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of NSABP B-18 and B-27. J Clin Oncol 2012;30:3960e6. Dimirci S, Broadwater G, Marks LB, Clough R, Prosnitz LR. Breast conservation therapy: the influence of molecular subtype and margins. Int J Radiat Oncol Biol Phys 2012;83:814e20. Aziz D, Rawlinson E, Narod SA, et al. The role of reexcision for positive margins in optimizing local disease control after breast e conserving surgery for cancer. Breast J 2006;12:331e7. Jung W, Kang E, Kim SM, et al. Factors associated with re-excision after breast conserving surgery for early-stage breast cancer. J Breast Cancer 2012;15: 412e9. Ciocca RM, Li T, Freedman GM, Morrow M. Presence of lobular carcinoma in situ does not increase local recurrence in patients treated with breastconserving therapy. Ann Surg Oncol 2008;15:2263e71.
Contents lists available at SciVerse ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Close/positive margins after breast-conserving therapy: Additional resection or no resection? William C. Wood* Winship Cancer Institute, Emory University School of Medicine, 1365C Clifton Road NE, Room 5004, Atlanta, GA 30322, USA
a b s t r a c t Keywords: Breast conserving therapy Re-excision Margins
The primary goal of breast conserving surgery or mastectomy is the prevention of recurrent breast cancer. The distinguishing goal of breast conserving surgery is preservation of a breast as normal in appearance as possible. If the margins of the excised breast cancer extend to the border of the excised specimen one cannot determine the amount of gross tumor that was not excised. Retrospective analyses of surgical series show a 2e3 fold increase in local recurrence of the breast tumor if the margin is positive under the microscope, even when the surgeon believed it to be clear on gross examination [1]. This fact has led to a variety of techniques attempting to ensure that the margins of the excised specimen are free of obvious tumor including pre-operative and specimen imaging and mapping, neo-adjuvant therapy to shrink the primary tumor, touch-prep and frozen section of the specimen margins during the procedure, shaving additional margins about the specimen at the closest aspects grossly or on all six surfaces, and examinations of the in situ walls of the remaining breast with new instrumentation. An obvious approach to diminishing the likelihood of positive specimen margins is taking a wider margin of normal tissue. As the volume of resected breast increases by the cube of the radius of excised tissue, this tracks all too well with diminishing cosmetic results and patient approval of the conserved breast. The question posed regards the finding of a positive or close margin after the surgical procedure. The finding of a positive margin can be parsed to a microscopic focus of tumor at the margin vs. the margin inking on a tumor surface. The latter demands re-excision despite the morbidity involved barring an extraordinary contra-indication or patient refusal. It represents the very real possibility of sufficient residual gross tumor in the breast that even with systemic therapy and breast irradiation the tumor will be un-controlled. A microscopic focus separated from the bulk of the primary tumor and adjacent to a margin has not been shown to carry such risk. The margin of normal tissue beyond the primary tumor that significantly reduces the risk of local recurrence remains undefined. Sufficient data are available to say that in the era of systemic therapy, excellent radiation therapy techniques, and boost doses when indicated, no margin of normal breast tissue beyond the tumor has been shown to be clearly superior to a layer of cells between the ink and the tumor. The larger the tumor and the more aggressive its biology is judged to be the lower the confidence that a single layer of cells at the point of histologic study accurately represents a clear margin. As in all medical decisions wise judgment must integrate all of the known factors to reach the best recommendation. There are few circumstances that would warrant a second surgical procedure for a close but clear margin today. Ó 2013 Elsevier Ltd. All rights reserved.
An apparent tension exists between the primary goal of breast cancer therapy, the prevention of recurrence and mortality, and the defining goal of breast conservation therapy [BCT], the preservation of a breast normal in appearance. The very familiar six randomized trials and a subsequent series of consensus conferences and meta-
* Tel.: þ1 404 778 3301; fax: þ1 404 778 4490. E-mail address: [email protected]. 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.07.022
analyses demonstrating equivalent survival without loss of the breast opened the dialog that persists today regarding how much less than mastectomy is best [2]. The premise of BCT is that irradiation of the breast at clinically tolerable dose levels will control sub-clinical volumes of residual breast cancer, and surgical excision of the primary tumor mass will deal with a volume of partially hypoxic tumor that would require very high dose irradiation to control at best. The NSABP [National Surgical Breast and Bowel Program] B-06 trial required inked specimens and clear margins,
S116
W.C. Wood / The Breast 22 (2013) S115eS117
defined as “no ink on tumor.” The other early, randomized trials described either grossly or microscopically clear margins. In all surgery for cancer, pathology reports stating that margins “are widely clear” delight surgeon and patient as in many solid tumors surgery is the only very effective treatment modality. In breast cancer careful studies of mastectomy specimens using Egan’s whole-breast-mount technique have demonstrated multifocality in most breast cancers and that margins of 2 cm. would leave multifocal sites behind in 42e47% [3,4] of breast cancer excisions. The inbreast recurrences in women treated by tumor excision alone e without breast irradiation e in trials such as NSABP B-06 are consonant with these pathological findings [5]. The diminishing incidence of local failure of BCT with the refinement in techniques of irradiation including boost, and the addition of systemic therapy when indicated, show that multicentric foci too small to be detected by diagnostic mammography and ultrasound examination appear to be controlled [6]. The addition of magnetic resonance imaging to detect such small foci of multicentric breast cancer has not proved to be beneficial, providing further evidence of the effectiveness of BCT in best practice today [7,8]. The question of the target margin of excision is complex. A cancer 1.6 cm in diameter has a volume of 2.1 cc. To excise this volume with 3 mm margins would yield a specimen volume of 5.6 cc. To excise with 10 mm margins would increase the volume to 24.4 cc, more than a four-fold volume increase. The volume excised from the breast is the main determinant of cosmetic outcome in BCT [9]. Clearly this relates to the ratio between excision volume, breast size, and the depth of the tumor site within the breast. The pathologic finding of a positive margin with the inked surface directly on tumor indicates no information whatever regarding the extent of the cancer in the remaining breast. The surgeon may have magically divided malignant cells from normal ones perfectly, leaving no cancer behind, but that is highly unlikely. A meta-analysis of 21 retrospective studies performed by Houssami and colleagues demonstrated that positive margins (tumor at inked surface) were associated with more than a doubling of risk for local recurrence [1]. Park and colleagues demonstrated that the amount of tumor at the margin related to the risk: 7% local failure with negative margins, 18 % with positive margins, but 27% if extensively positive vs. 14% if only focally positive. That is still twice the risk when negative. Interestingly, they found the same 7% risk of local failure with negative margins >1 mm or close margins 1 mm or less [10]. What should be the target margin when performing an excision of a cancer for breast conservation? Ideally, remove all of the tumor, a cell layer of normal tissue to take the pathologists margin ink, and no other normal breast tissue. As that is not feasible, several mm of normal tissue should cover the surface of the tumor. Numerous techniques have been attempted to idealize this. The first is the use of neo-adjuvant chemotherapy (after clip placement), for anyone who will require chemotherapy, to take advantage of the volume reduction seen in 70e80% of tumors so treated, 30% with clinical complete response. The incidence of positive resection margins rises with the tumor diameter [11].A lower rate of re-excision has been reported after neo-adjuvant treatment as well as the diminished resection volume providing a better esthetic result [12]. Aiming to remove 3e5 mm of normal breast about the margin of T1-2 tumor, coupled with careful examination of the oriented specimen to see if any margin appears close for an immediate shave margin is one approach. Another, frequently used at our institution, involves taking narrow additional oriented margins after the primary excision. This has demonstrated a higher rate of negative margins [13]. A study from the Massachusetts General Hospital found the same frequency of re-excisions with this technique, but they removed significantly (p < 0.001) less volume of tissue with
their cavity shaved margin group than in the simple excision group, so it is not surprising that they had a similar frequency of additional resection [14]. Mayo Clinic investigated waiting in the operating room for routine frozen-section analysis of breast margins, compared with later reoperation for positive margins. They found that this approach became cost-effective when the re-operation rate exceeded 36% [15]. Costs aside, it may be a preferable approach from the patient’s perspective. Dr. Nicole Krekel of Amsterdam presented results from a Dutch randomized trial that demonstrated a 3.3% incidence of positive margins in excisions guided by intra-operative ultrasound vs. 16.4% in those randomized to surgery guided only by palpation [16]. Electro-magnetic margin probes are also under investigation. Dr. Klimberg and colleagues continue to study the use of radiofrequency ablation of the margins remaining in the breast [17]. Such innovations may significantly change this conversation in the next few years. The specific question addressed by this paper arises subsequent to these considerations. Should additional resection be performed for close or positive margins after the primary excision has been performed? I will contend that re-excision is under-performed for positive margins, and over-performed for close ones. When a tumor margin is truly positive, not just a few cells isolated from the primary tumor at the site of an excision margin, one cannot know what volume of tumor remains in the breast that was cut through by the surgeon. Effective as modern radiation therapy techniques are in combination with systemic therapies in controlling microscopic disease, their inability to always control macroscopic disease is demonstrated by the greatly increased failure rate with positive margins cited above. Barring patient refusal or extraordinary contra-indications to proceeding, such margins should always be re-excised. Careful orientation of the primary excision specimen and painting each of the six faces with a different color ink identifies the area of breast to be addressed. The anxiety of the patient and possible diminution in cosmetic outcome cannot outweigh the risk associated with inaction. A recent series from four high-volume breast centers observed variation from 74% to 94% in re-excision for positive margins [11]. The case-specifics cannot be known, but such variation suggests that the clear evidence supporting re-excision for positive margins is not always followed. If positive margins are sometimes under-treated, clear but close margins are probably greatly over-treated. In careful reviews by Singletary [18], Houssami [1], and Revesz [19] the case is clearly made that there is no evidence that a specific margin beyond ‘no ink on tumor’ is ideal. This argument was pursued by Morrow and colleagues in a Sounding Board editorial in the New England Journal of Medicine last year [20]. Several major issues render it unlikely a priori that a specific margin width would prove definitive. Tumor biology relates powerfully to the risk of local failure with such features as grade, multifocality, stage, and genomic parameters [21,22]. Secondly, the margins seen by the pathologist are from a flattened, ‘hamburger patty’ specimen after the effects of gravity and, sometimes, compression in breast imaging on a surgically removed sphere of tissue. Finally, the margins are descriptions of tissue removed from the patient and no longer exerting effects, unlike the remaining breast tissue and residual foci of tumor for which they are weak surrogates. It is not surprising that the measured margin width beyond tumor have not proved predictive of local failure, given the presence of multifocality. This is not to say that a thoughtful approach to surgical resection should not include considerable thought as to the margin goal. A larger tumor is more likely to have a positive margin, so a more generous margin than a smaller tumor will avoid some re-excisions for positive margins. A younger patient, especially under 45 years,
W.C. Wood / The Breast 22 (2013) S115eS117
is at greater risk of local recurrence [23] as is a patient with “triple negative features.” It is appealing to attempt a slightly larger margin in such patients, but one must not imagine that decision to be based on evidence of benefit from the larger margin. Multifocal tumors and those with extensive DCIS are more likely to extend beyond the apparent border [24], and either of these giving a positive margin should be re-excised. LCIS found at the margin is not predictive of risk and may be ignored [25].
[7]
[8] [9]
[10]
Conclusion The goal of breast conserving therapy is best served by excision after the diagnosis is made by core biopsy. The margin desired is a differential equation involving tumor size, tumor biology, patient age, multifocality, breast size, and location within the breast. It does not lend itself to a nomogram. Increasingly, neo-adjuvant chemotherapy or hormonal therapy will precede the excision and the response or non-response or patchy response will further influence the surgical approach. If the resected margins are clear e no ink on tumor, there is no evidence that benefit would accrue from a wider re-excision. If the margin(s) are frankly positive, re-excision is definitely indicated.
[11] [12]
[13]
[14]
[15]
[16]
Conflict of interest statement [17]
I have no conflicts of interest to declare. References
[18] [19]
[1] Houssami N, Macaskill P, Marinovich ML, et al. Meta-analysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. Eur J Cancer 2010;46: 3219e32. [2] conf and panel chair NIH Consensus Conference Report, Wood WC. Treatment of early-stage breast cancer. J Am Med Assoc 1991;265:391e5. [3] Vaidya JS, Vyas JJ, Chinoy RF, Merchant N, Sharma OP, Mittra I. Multicentricity of breast cancer: whole-organ analysis and clinical implications. Br J of Cancer 1996;74:820e4. [4] Holland R, Veling S, Mravunac M, Hendrics JHCL. Histologic multifocality of Tis, T1-2 breast carcinomas: implications for clinical trials of breast conserving surgery. Cancer 1985;56:979e90. [5] Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347: 1233e41. [6] Anderson SJ, Wapnir I, Dignam JJ, et al. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by
[20] [21]
[22]
[23]
[24]
[25]
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