INTRODUCTION — Breast-conserving surgery achieves equivalent local control and disease-specific survival as mastectomy in early-stage breast cancer [1] and is often the preferred technique for primary tumor extirpation for breast cancer patients [2]. Optimal results with breast-conserving surgery require achieving "clear" or negative margins as positive margins have been associated with a twofold increase in local recurrence rate [3].
Neither radiotherapy nor systemic therapy can substitute for re-excision to clear margins. After initial surgery, reoperation is frequently necessary to obtain negative margins. In the United States, breast-conserving surgery has an aggregate reoperation rate of 21.6 percent even with contemporary imaging methods [4], at a per annum cost of 228 million dollars [5].
Techniques that can be used to reduce positive margin rates in breast-conserving surgery are presented here. The indications, techniques, complications, and outcomes of breast-conserving surgery are discussed elsewhere. (See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer", section on 'Breast-conserving therapy' and "Breast-conserving therapy".)
DEFINITION OF A POSITIVE MARGIN
Invasive disease — The definition of an acceptable margin has been the source of historical controversy. A 2014 consensus statement between several professional organizations has suggested that, for patients with invasive disease, a positive margin should be considered as "tumor at ink" [6] (ie, that even a distance of less than 1 millimeter of histologically normal tissue between the tumor and the resected edge is acceptable and therefore does not warrant re-excision as long as there is no tumor at the edge). This consensus also considered this margin appropriate for patients with both invasive and in situ disease as long as the intraductal component was not "extensive" (ie, more than 25 percent of the tumor). (See "Breast-conserving therapy", section on 'Margins for invasive cancer'.)
The deployment of this definition alone can result in a reduction of re-excision rates as many surgeons had previously required a larger margin to deem a patient as having clear margins [7]. Indeed, in a meta-analysis of 21 nonrandomized studies, pooled odds ratios (ORs) of reoperations were reduced after the publication of the Society of Surgical Oncology-American Society for Radiation Oncology (SSO-ASTRO) margin guideline, albeit to a greater extent in institution-based studies than in population-based studies (OR 0.62, 95% CI 0.52-0.74 versus OR 0.76, 95% CI 0.72-0.80) [8]. However, such retrospective studies cannot prove that adoption of the margin guideline reduced re-excision rates (eg, as opposed to surgeons becoming more proficient at obtaining negative margins with techniques to be discussed below) [9].
In situ disease — For patients who have ductal carcinoma in situ (DCIS) alone, a 2016 consensus statement advocated a margin of 2 mm (ie, wider than that for invasive cancer) [10], given that DCIS tends to be multifocal. However, the consensus was less adamant on this mandate, stating that a less than 2 mm margin should not, in and of itself, be an indication for a patient to undergo mastectomy. Given that the National Comprehensive Cancer Network (NCCN) guidelines had previously suggested a margin of ≥1 mm for DCIS [11], the new margin guidelines may increase re-excision rates. This has not yet been well studied. (See "Breast-conserving therapy", section on 'Margins for DCIS'.)
PREOPERATIVE IMAGING — While positive margins may be associated with factors beyond the surgeon's control (eg, tumor biology, multifocal disease with ductal carcinoma in situ [DCIS]), some have suggested that preoperative imaging may help gauge the extent of disease, which may allow surgeons to better plan their surgery and lead to fewer positive margins.
Prior to breast-conserving surgery, one should perform routine standard imaging with mammography and/or ultrasound, along with clinical examination, to determine the extent of disease. (See "Diagnostic evaluation of suspected breast cancer".)
Role of MRI — Given that magnetic resonance imaging (MRI) is highly sensitive, some have investigated the use of this technology in reducing positive margin rates. Two randomized controlled trials have evaluated the impact of preoperative MRI on margin positivity; neither the COMICE nor the MONET trial found a benefit associated with MRI (table 1) [12,13]. Choosing Wisely campaign guidelines now suggest that MRI should not be routinely performed in all newly diagnosed breast cancer patients [14], as this does not reduce positive margin rates. Rather, preoperative MRI has been associated with higher patient anxiety, more biopsies, and higher mastectomy rates, without any evidence of benefit. (See "MRI of the breast and emerging technologies", section on 'Preoperative evaluation of newly diagnosed breast cancer patients'.)
LOCALIZATION OF NONPALPABLE LESIONS — Many breast cancers diagnosed in the Western world are not palpable and are only found on screening mammography. In order to remove these tumors, a localization technique is required to guide the surgeon to the lesion in question. While there have been a number of techniques described (table 2) [15], few randomized controlled trials have compared them [16].
Needle localization — One of the oldest techniques to localize nonpalpable tumors, which is often considered the historic standard of care, is needle localization. In this technique, a nonpalpable lesion is localized using a fine wire inserted percutaneously under either mammographic or ultrasonographic guidance. The margin clearance rate associated with needle/wire localization is 54 to 90 percent (table 2) [15,17-22]. This is generally the standard to which all other techniques are compared.
Role of bracketing — For patients with a wider span of calcifications, or a larger extent of disease, radiologists can often place more than one wire to "bracket" the area in question. Whether this technique provides better margin clearance remains unclear [23]. Bracketing can also be accomplished with one of the non-wire localization techniques described below.
Radioactive seed localization — Radioactive seed localization (RSL) has emerged as an alternative to needle localization for nonpalpable lesions. While this technique offers the ability to place the radioactive seed marker up to one week prior to the operative procedure, obviating the need for wire placement the morning of surgery and thereby a later surgical start time, there are some disadvantages to this technique as well. Because this involves a radioactive seed, radiation safety protocols must be followed, with a diligent record kept of the "chain of possession" of the radioactive seed, from being implanted in the breast, to the removal with the specimen, to the appropriate disposal of the seed. It is also imperative that personnel in the pathology department not cut through the seed while grossing the specimen. Some surgeons have noted some issues with depth perception of the seed marker intraoperatively.
Many surgeons, particularly those who are experienced with sentinel node biopsy, have found that this technique is easy to master and improves surgical workflow. In terms of margin clearance, however, there are no consistent data to suggest the superiority of either RSL or needle localization (table 3) [24-30]. The margin clearance rate associated with RSL is 74 to 96 percent (table 2).
Radio-occult lesion localization — Radio-occult lesion localization (ROLL) uses the injection of a radioactive isotope to localize nonpalpable lesions. The short half-life of the isotopes requires injection the morning of surgery and therefore may delay surgery start times. However, ROLL, like RSL, does not require placement of a wire external to the breast.
A randomized trial evaluating ROLL versus needle localization found more tissue excised using ROLL than with needle localization (71 versus 64 cm3) but no difference in the positive margin rate [23]. Similarly, other studies have found no difference in margin positivity rates between ROLL and needle localization or RSL (table 3) [31-33]. The margin clearance rate associated with ROLL is 66.7 to 87 percent (table 2).
Novel localization technologies — Several novel tools have been developed to localize nonpalpable lesions with infrared radar (eg, SaviScout), magnetic seeds (eg, MAGSEED), or radiofrequency identification tags. These tools can be implanted days prior to surgery and do not require the use of any radioactive material. While the positive margin rates of the newer tools appear comparable to other methods of nonpalpable lesion localization (table 2) [34,35], data are limited and not from randomized trials.
Intraoperative ultrasound — The use of intraoperative ultrasound (IOUS) has been found to aid localization of both palpable and ultrasonographically visible nonpalpable tumors, improving margin clearance rates beyond palpation or needle localization alone (table 4) [36-43]. However, most authorities consider IOUS an adjunct to, rather than a stand-alone substitute for, other more established localization techniques such as needle localization, RSL, or ROLL [16,44].
INTRAOPERATIVE MARGIN ASSESSMENT — Intraoperative margin assessment techniques are employed to determine the oncological status of the resection margins while the patient is still in the operating room, thereby facilitating immediate margin re-excision when necessary.
Specimen radiography — One of the most commonly utilized techniques of intraoperative margin assessment, particularly for nonpalpable tumors, is specimen radiography (image 1), which can confirm that the lesion in question, plus any preoperatively placed radio-opaque markers identifying the location of the tumor, have been removed. This technique can also identify whether the tumor and/or calcifications extend close to an edge of the specimen such that additional tissue may be resected in that area to lower the risk of a positive margin. (See 'Selective margin excision' below.)
Specimen orientation — In order to guide further intraoperative excision based on the specimen radiograph, it is critical to appropriately orient the specimen with at least two orthogonal markers [45]. Many surgeons designate the faces of the specimen with a short stitch marking superior and a long stitch marking lateral. Other surgeons mark additional margins, either with charms (such as MarginMap) or by inking the specimen themselves with commercially available inking kits such as MarginMarker. Proper orientation of the specimen is also crucial to planning re-excision based on the final pathology.
Role for 3D specimen radiography — Given that traditional specimen radiography produces a two-dimensional image of a three-dimensional specimen, there has been concern that while a specimen may appear to have the lesion in its center, the lesion may actually be on the edge of the specimen if assessed with an orthogonal image. In order to address this concern, systems are available to obtain orthogonal images (eg, the Wedge) or use tomosynthesis technology to obtain fine slices from one end of the specimen to the other, which permits a three-dimensional reconstruction. However, one study that evaluated the impact of taking orthogonal specimen radiographs found that this technology did not dramatically reduce the positive margin rate [46]. Others have also found that tomosynthesis did not significantly improve margin status [47,48].
Frozen section and/or touch imprint cytology — Some centers perform intraoperative pathologic evaluation of margins with either frozen section and/or touch imprint cytology. In a 2017 meta-analysis, frozen section and imprint cytology had pooled sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC) values of 86 percent, 96 percent, and 0.96 (9 studies), and 91 percent, 95 percent, and 0.98 (11 studies), respectively [49]. Some, but not all, studies have also found that such techniques reduced the final margin positivity rate (table 5) [50-55].
However, most surgeons (including the author of this topic) do not routinely use frozen section or touch imprint cytology for breast-conserving surgery [56]. A number of concerns beyond reducing positive margin rate should be considered before utilizing this strategy [45]. The first is the availability of appropriately trained pathologists to render a timely evaluation of the margins intraoperatively. If assessment is done using touch imprint cytology, expertise in cytopathology is required. The second issue is that it is impossible to sample the full surface area of a partial mastectomy specimen intraoperatively to provide a comprehensive margin assessment. Frequently, the specimen is grossly evaluated, and the areas that are the most suspicious are sampled for intraoperative assessment. Hence, there remains a false negative rate associated with this procedure. For margin assessment with frozen section, there has been some concern that fatty tissue that has not been properly fixed does not freeze well, and valuable tissue may be lost in the cryostat. Finally, how one assesses the margin, whether tangentially or en face, is a consideration if one wants a margin distance, rather than a qualitative binary judgment of whether there is tumor at the edge of the specimen.
Novel technologies of intraoperative margin assessment
MarginProbe — There has been significant expansion in the field of devices used to predict positive margins intraoperatively. One of the oldest, and hence most studied, of these is MarginProbe, which utilizes radiofrequency spectroscopy to detect cancer cells at the edge of a specimen. In general, studies have associated the use of this device with a lower positive margin rate and re-excision rate (table 6) [57-60]. Disadvantages of the use of this technology include the capital cost of both the console as well as the disposable probes. The author of this topic currently does not use this device, given its cost and the lack of evidence that it improves positive margin rates beyond the reduction seen with cavity shave margins and other techniques. (See 'Cavity shaving' below.)
Lumicell — This technology utilizes a protease-activated fluorescent probe that can be used to evaluate the cavity after resection of a tumor to guide further resection of residual disease. While preliminary studies have suggested that this technology holds promise for lowering positive margin rates [61], larger clinical trials are ongoing to evaluate this [62]. Disadvantages of this technology include cost and potential allergic reactions as well as the fact that the LUM015 imaging agent needs to be injected two to six hours prior to the surgical procedure.
Others — A number of other intraoperative margin assessment technologies are being developed to optimize margin control and reduce re-excision rate. These technologies rely on imaging, optical spectroscopy, bioimpedance, or mass spectrometry [63].
CAVITY SHAVING
Selective margin excision — Following visualization of the tumor and determination of how close it approaches the edge of the specimen with one of the techniques discussed above, selective margin excision can be performed for removal of an area of the cavity that is most likely to harbor additional cancer.
In the SHAVE trial, in which surgeons were instructed to perform their best partial mastectomy prior to randomization, it was found that those patients who had selective margins excised did not have a significantly lower rate of positive margins than those who did not (38.1 versus 33.7 percent, p = 0.53) [64].
Cavity shave margin excision — There has been consistent evidence from retrospective [65-69] and prospective randomized controlled trials [64,70,71] that routine excision of cavity shave margins (ie, removal of a small rim of tissue circumferentially from the partial mastectomy cavity) results in at least a 50 percent reduction in the positive margin rate (table 7). This technique takes 10 minutes or less in the operating room and does not appear to be associated with an increase in complications or worse cosmetic outcome [64]. It can reduce the frequency of reoperation.
The author of this topic routinely takes cavity shave margins circumferentially around the cavity and orients these to indicate their locations and the aspect of the specimen that is the true margin.
AMERICAN SOCIETY OF BREAST SURGEONS "TOOLBOX" — In 2015, an American Society of Breast Surgeons consensus conference developed a "toolbox" with the purpose of reducing lumpectomy reoperations and improving cosmetic outcome in breast cancer patients [45]. Most of the "tools" contained in that "toolbox" are discussed above. Individual surgeons may choose from this menu of "tools" based upon their experience and available local resources.
Available evidence suggests that the impact of intraoperative margin assessment is greater when the baseline positive margin rate is greater than 20 percent [44].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast surgery" and "Society guideline links: Breast cancer".)
SUMMARY AND RECOMMENDATIONS
●Breast-conserving surgery is equivalent to mastectomy in terms of survival. Positive margins at the time of breast-conserving surgery have been associated with a twofold increase in local recurrence rate. (See 'Introduction' above.)
●A 2014 consensus statement suggested a positive margin to be "tumor at ink" for patients with invasive disease. The same margin is appropriate for patients with both invasive and in situ disease, as long as the intraductal component is not "extensive" (ie, more than 25 percent of the tumor). (See 'Invasive disease' above and "Breast-conserving therapy", section on 'Margins for invasive cancer'.)
●A 2016 consensus statement advocated a wider margin of 2 mm for patients with ductal carcinoma in situ (DCIS) only, given that DCIS tends to be multifocal. However, this consensus leaves room for clinical judgment and does not consider a <2 mm margin per se to be an indication for mastectomy. (See 'In situ disease' above and "Breast-conserving therapy", section on 'Margins for DCIS'.)
●Standard preoperative imaging with mammography and/or ultrasound, along with clinical examination, should be performed to gauge the extent of disease. Breast magnetic resonance imaging (MRI) should not be performed routinely for all newly diagnosed breast cancer, as it does not reduce positive margin rates (table 1) and has been associated with higher patient anxiety, more biopsies, and a higher mastectomy rate. (See 'Preoperative imaging' above.)
●For nonpalpable lesions, localization is critical, but no technique is necessarily superior to another. Standard methods include needle/wire location, radioactive seed localization (RSL), and radio-occult lesion localization (ROLL). Newer techniques include infrared radar (eg, SaviScout), magnetic seeds (eg, MAGSEED), and radiofrequency identification tags (table 2). (See 'Localization of nonpalpable lesions' above.)
●Intraoperative ultrasound may be helpful to reduce positive margin rates if the lesion is ultrasonographically visible but should not be used as a stand-alone localization technique (table 4). (See 'Intraoperative ultrasound' above.)
●Following excision, the specimen should be oriented with at least two orthogonal markers, and intraoperative specimen radiographs should be performed to verify that the lesion has been completely excised. There is no evidence that three-dimensional specimen radiography reduces positive margin rate. (See 'Specimen radiography' above.)
●Some centers use frozen section and/or touch imprint cytology to evaluate margins intraoperatively. However, this technique has not been universally found to reduce positive margin rate (table 5) and could produce false negative results. (See 'Frozen section and/or touch imprint cytology' above.)
●Although there has been significant expansion in the field of devices used to predict positive margins intraoperatively, most intraoperative margin assessment devices remain investigational. (See 'Novel technologies of intraoperative margin assessment' above.)
●Shaving of the cavity wall following breast-conserving surgery can be performed selectively or circumferentially. We suggest routine circumferential cavity shaving rather than selective or no cavity shaving (Grade 2B). Data suggest that circumferential, but not selective, cavity shaving reduces the rate of positive margins (table 7). (See 'Cavity shaving' above.)
●A "toolbox" of available techniques has been developed by a 2015 American Society of Breast Surgeons Consensus Conference [45]. Available evidence suggests that the impact of intraoperative margin assessment is greater when the baseline positive margin rate is greater than 20 percent. (See 'American Society of Breast Surgeons "toolbox"' above.)
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