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Optimizing Surgical Margins in Breast Conservation

Optimizing Surgical Margins in Breast Conservation Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2012, Article ID 585670, 9 pages doi:10.1155/2012/585670 Review Article 1 1 2 Preya Ananthakrishnan, Fatih Levent Balci, and Joseph P. Crowe Breast Surgery Division, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA Department of General Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA Correspondence should be addressed to Preya Ananthakrishnan, pa2325@columbia.edu Received 2 October 2012; Accepted 31 October 2012 Academic Editor: Eisuke Fukuma Copyright © 2012 Preya Ananthakrishnan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Adequate surgical margins in breast-conserving surgery for breast cancer have traditionally been viewed as a predictor of local recurrence rates. There is still no consensus on what constitutes an adequate surgical margin, however it is clear that there is a trade-off between widely clear margins and acceptable cosmesis. Preoperative approaches to plan extent of resection with appropriate margins (in the setting of surgery first as well as after neoadjuvant chemotherapy,) include mammography, US, and MRI. Improvements have been made in preoperative lesion localization strategies for surgery, as well as intraoperative specimen assessment, in order to ensure complete removal of imaging findings and facilitate margin clearance. Intraoperative strategies to accurately assess tumor and cavity margins include cavity shave techniques, as well as novel technologies for margin probes. Ablative techniques, including radiofrequency ablation as well as intraoperative radiation, may be used to extend tumor-free margins without resecting additional tissue. Oncoplastic techniques allow for wider resections while maintaining cosmesis and have acceptable local recurrence rates, however often involve surgery on the contralateral breast. As systemic therapy for breast cancer continues to improve, it is unclear what the importance of surgical margins on local control rates will be in the future. 1. Introduction It is well accepted that complete removal of tumor is necessary, however, there is aconsiderable debate regarding Breast-conservation therapy (BCT), including lumpectomy what margin of normal tissue surrounding the tumor con- and sentinel lymph node biopsy followed by radiation ther- stitutes a negative margin. Definitions range from no ink on apy, is the treatment of choice for women with early stage tumor surface (NSABP B-06) to 1 cm or more [8]. Blair et al. breast cancer. Randomized trials have shown that overall sur- sent a survey to nearly 1000 breast cancer surgeons, and vival of women undergoing BCT is equivalent to mastectomy found that 15% defined a negative margin as no tumor on [1, 2]. The goal of lumpectomy is to completely excise the inked margin, 21% accepted a 1 mm margin, 50% accepted tumor with negative margins while maintaining acceptable a 2 mm margin, 12% accepted a 5 mm margin, and 3% cosmesis. Rates of margin positivity at initial lumpectomy accepted a 1 cm margin [9]. A meta-analysis by Wang et al. have been reported ranging from 15% to 47% [3–6]. Positive found that wider margins minimize the risk of ipsilateral margins are usually addressed with surgical reexcision, since local recurrence, with lowest recurrence rates achieved with the risk of local recurrence associated with a positive margin a negative margin larger than 10 mm rather than 2 mm. This is approximately 2 to 3 times that compared with a negative finding was independent of whether or not the patient margin [7]. Reexcision can include reoperative lumpectomy received radiation [10]. or possibly mastectomy. This additional surgical reoperative In another meta-analysis of 21 retrospective studies procedure can result in increased psychological trauma to the which included 14,571 patients, Houssami et al. demon- patient, delay of adjuvant therapy, worsened cosmesis, and strated an odds ratio for local recurrence of 2.42 (P< 0.001) increased cost [7]. with positive margins. This meta-analysis did not identify 2 International Journal of Surgical Oncology a statistically significant difference in local recurrence asso- multidisciplinary management, including improvements in ciated with margin widths of more than 1 mm, more than pathologic evaluation and systemic therapy, could be cred- 2 mm, or more than 5 mm after adjustment for a radiation ited for the improvement in IBTR. boost and endocrine therapy [11]. This suggests that a 2 or Further evidence supports the fact that systemic treat- 5 mm margin is not necessarily better than a 1 mm margin. ments not only reduce the risk of distant metastases but When considering optimal margin width, it is useful to also reduce the risk of local recurrence. In the NSABP B- remember that a “negative” margin does not indicate the 14 trial, women with node-negative, estrogen-receptor (ER)- absence of residual unresected tumor in the breast [12]. It positive tumors were randomly assigned to tamoxifen or simply suggests that the residual tumor burden is probably placebo [26]. The 10-year rate of local recurrence after low enough to be controlled with radiotherapy. Even the breast-conserving surgery was reduced from 14.7% in the widest margins resulting from mastectomy do not eliminate placebo group to 4.3% in the tamoxifen group. Similarly, risk of local recurrence. This indicates that residual disease in the NSABP B-13 trial, women with node-negative, ER- burden is not totally eliminated by local surgery and that negative tumors were randomly assigned to methotrexate tumor biology, radiation therapy, and systemic therapy may and fluorouracil or to no treatment [27]. A reduction was play an important role in controlling local recurrence [13]. noted in the 10-year local recurrence rate from 13.4% in the In further defining this idea of residual disease burden, no-treatment group to 2.6% in the treatment group. In both Margenthaler et al. have proposed calculating a “margin studies, the NSABP definition of no ink on tumor was used index” as a predictive tool for residual disease after breast- to define a negative margin. conservation surgery [14]. This margin index is calculated Studies examining the effect of adding trastuzumab to by dividing the closest margin (in mm) by the tumor size (in adjuvant chemotherapy in women with human epidermal mm)× 100. They found that with a margin index >5, the risk growth factor receptor 2 (HER2)-overexpressing tumors of residual disease was 3.2%. With a margin index of 20, no have shown an additional 40% reduction in the risk of residual disease was found in the reexcision specimen. local recurrence over a median follow-up of 1.5 to 2.0 years The NSABP B-06 study showed that in 1851 patients who [28]. Triple negative tumors have the highest risk of local underwent breast conservation, the positive margin rate was recurrence after both breast-conserving therapy and mas- 6.8% and the in-breast tumor recurrence rate was 14.2% over tectomy [29–31], and retrospective studies do not show an 20 years of followup [1]. Other randomized controlled trials improvement in local control after mastectomy as compared described a range of local recurrences rates from 5.9% at with lumpectomy and radiation in this subgroup of patients 20 years to 19.7% at 13 years [22]. These randomized trials with biologically aggressive tumors [32, 33]. do not explicitly define margin width, which ranged from no The effect of tumor biology on local recurrence was ink on tumor to 1 cm gross margin. While the B-06 trial was clearly shown in a study examining the usefulness of the 21- conducted in the 1970s, several subsequent NSABP trials in gene recurrence score (Oncotype DX) in predicting local and the 1990s showed improvement in 10-year local recurrence regional recurrence [34]. The recurrence score was developed rates ranging from 3.5% to 6.5% [23]. Although devel- to predict the likelihood of distant metastases in patients opments in breast imaging and pathological evaluation with ER-positive, node-negative breast cancer who received of lumpectomy specimens probably contributed to these tamoxifen [35]. Mamounas et al. found that without sys- improvements, significant strides were also made in systemic temic therapy, 18.4% of patients with a high recurrence score therapy during this time. This suggests that the likelihood of (≥31) had a recurrence of local or regional disease [34]. The local recurrence is related to not only the surgical margin addition of tamoxifen had a minimal effect on the rate of width as well, but also to the underlying tumor biology as local and regional recurrence, with a decrease to 15.8%. In well as the effectiveness of adjuvant therapy. contrast, the combination of chemotherapy and tamoxifen Multiple retrospective studies have attempted to define was associated with a reduction in the local recurrence rate predictors of a positive margin at lumpectomy. These studies to 7.8%. identified a number of independent predictors of local recur- Interestingly, the majority of the studies describing local rence including age less than 40 years, microcalcifications recurrence rates do not make the distinction between true on mammography, palpable tumors, large tumors, multi- local recurrences and new ipsilateral primary tumors. Yi et al. centricity, presence of DCIS or lobular histology, and lym- suggested that approximately 50% of IBTRs are actually new phovascular invasion [24]. While these studies showed that primary cancers as differentiated by histologic subtype and 1-2 mm margins were associated with decreased local recur- receptor status [36]. This would lead us to expect that the rence rates, it is unclear what the impact of improved sys- true localrecurrenceratemay be half of what is reported in temic therapy and boost radiation therapy is on these results. the above studies, if in fact half of in-breast recurrences are Cabioglu retrospectively assessed patient and tumor charac- new primaries. These new primary tumors therefore would teristics as well as IBTR rates in two cohorts of patients (those notbeexpectedtobeaffected by margin width. treated from 1970 to 1993, and those treated from 1994 to 1996) [25]. Patients treated after 1994 were less likely to have 2. Preoperative Imaging and positive or unknown margin status (2.9% compared to Treatment Strategies 24.1% before 1994,) and the 5-year IBTR rate was lower in patients treated after 1994 (1.3% compared to 5.7% in those Thorough preoperative imaging is necessary to plan the treated before 1994). These investigators postulated that extent of resection while minimizing positive margins. International Journal of Surgical Oncology 3 Standard preoperative imaging includes mammography and predicting residual tumor extent for triple-negative breast ultrasound, and often MRI. Mammography can delineate tumors, and least accurate in the Luminal A subtype (Pearson tumor size and borders, as well as identify extent of micro- correlation coefficient of 0.754 and 0.531.) calcifications, presence of multifocality, and multicentricity. Multivariate analysis suggested that ER status was an Mammography is also important for assessment of the con- independent factor which influenced the accuracy of MRI. tralateral breast. Compared to mammography, ultrasonog- In HER2 amplified tumors, the use of HER2-targeted agents raphy can often give more accurate estimation of tumor size was associated with a less accurate MRI prediction of residual and borders, particularly in patients of young age with dense tumor extent. breasts. Huang et al. proposed a prognostic index score for MRI is a more sensitive test that can detect additional foci patients receiving neoadjuvant chemotherapy composed of of disease not appreciated on mammogram and ultrasound. four points: (1) clinical N2 to N3 disease, (2) lymphovascular Houssami et al., in a metaanalysis of 19 studies, found that invasion, (3) pathologic size >2 cm, and (4) multifocal resid- MRI detected additional disease in 16% and led to more ual disease [43]. Patients with an index of 0 or 1 had similar extended surgery in 5.5% with a change from lumpectomy LRR rates between mastectomy and BCT. Patients with to mastectomy in 1.1% [37]. Crowe et al. demonstrated that a score of 2 had a trend towards less LRR that was not sig- MRI identified occult or separate tumors in 13% of patients nificant (12% after mastectomy versus 28% after BCT), and [38]. MRI has a high false-positive rate, so it is clear that patients with a score of 3 or 4 had a significant difference additional lesions identified on MRI must be biopsied to (19% after mastectomy versus 61% after BCT.) This index demonstrate malignancy prior to changes in surgical plan- provides a framework in which to guide surgery selection ning. Of note, the clinical consequence of detecting these after neoadjuvant chemotherapy, however, does not explic- additional lesions on MRI is unknown since no study has itly address the impact of margin status on LRR rates. demonstrated that use of MRI translates into improved local Other novel preoperative imaging strategies include opti- recurrence rates or survival. cal spectroscopy and molecular vibrational imaging. Optical Another theoretical advantage of MRI is the potential spectroscopy uses properties of tissue microstructure and to better define the extent of the index lesion in order to biochemical composition to characterize tissue. It can dif- better plan surgical resection. However, Bleicher et al. in a ferentiate normal from malignant tissue by distinguishing retrospective review of 577 patients (130 of which had pre- deoxy-hemoglobin, oxy-hemoglobin, water, and lipids, and operative MRI) failed to demonstrate a difference in margin thus is not limited by mammographic tissue density. This has positivity or the need to convert from breast conservation also shown promise in assessing tumor response to neoad- to mastectomy in the group who had MRI [39]. At this juvant chemotherapy [44]. This technology is limited in time, preoperative MRI does not improve surgical planning distinguishing DCIS from normal tissue. Molecular vibra- and does not reduce the need for reexcision. Furthermore, tional imaging is another quantitative imaging technology Shin et al. in a retrospective analysis showed that breast MRI that uses Coherent anti-Stokes Raman scattering (CARS) provided more accurate estimation of tumor size in compar- microscopy to visualize cellular and tissue features. This tech- ison to ultrasound for both invasive and in situ breast cancer. nology shows promise in differentiating invasive ductal from However, no clear benefit in terms of lower reexcision rate, invasive lobular lesions, as well as DCIS from normal tissue. higher rate of success of breast conservation, or reduced rate of local recurrence emerged with routine use of breast MRI before BCT [40]. 3. Lesion Localization, Margin Assessment, There is some suggestion that MRI may be better at and Intraoperative Techniques assessing DCIS than conventional imaging. Kropcho et al. prospectively evaluated patients diagnosed with DCIS with Preoperative tumor localization for nonpalpable lesions was and without MRI [41]. In this study, the correlation between traditionally performed by the radiologist with either a MRI and tumor size was found to be significantly higher; mammographically or sonographically guided wire place- however, no significant difference was found in between- ment into the tumor. The limitation of this technique is group analysis of the incidence of margin involvement with that it identifies the lesion in one plane only, with limited MRI versus without MRI (30% versus 24.7%, P = 0.414, ability to guide a three-dimensional resection of the lesion. resp.). Lesion bracketing with multiple guidewires as opposed to Neoadjuvant chemotherapy can often shrink larger a single wire would theoretically improve margin clearance tumors to allow for breast conservation. Sweeting et al. by facilitating complete resection of an imaging abnormality. demonstrated that over 6-year median followup in young However, Liberman et al. found that while bracketing a lesion women <age 45, locoregional recurrence rates were no differ- (particularly if the lesion was a large area of calcifications) ent after breast conservation than mastectomy (13% versus with multiple wires may help to ensure removal of the entire 18%) in patients who underwent neoadjuvant chemotherapy mammographic lesion, it still did not improve on rates of [42]. Higher posttreatment, but not pretreatment, stage margin positivity [45]. was associated with higher locoregional recurrence rates. Intraoperative specimen radiography using the Faxitron Recently, Moon et al demonstrated that the accuracy of MRI can be done immediately after specimen excision. The Fax- after neoadjuvant chemotherapy is influenced by the molec- itron allows the surgeon to visualize an eccentric location of ular subtype of the tumor. MRI was most accurate in a tumor or clip so that additional tissue can be removed. 4 International Journal of Surgical Oncology Bathla et al. demonstrated a reexcision rate of 14.3% when margin positivity. Traditional margin assessment intraoper- 2-dimensional Faxitron was used to guide further tissue atively consists of either frozen section histology or imprint removal at the time of initial lumpectomy [46]. In this study, cytology. Frozen section histology, while relatively accurate 95.8% of patients who would have required subsequent in reflecting margin status, is limited due to time, cost, and reexcision were spared further surgery since additional loss of tissue for permanent section evaluation. Furthermore margins were taken at the time of lumpectomy based on this method is very labor intensive and can only examine a Faxitron imaging findings. limited amount of tissue, with false negative rates reported Intraoperative ultrasonography allows for improved gui- in 19% of patients [52]. Imprint cytology or “touch prep” dance on extent of resection. This technique is quite promis- involves touching the lumpectomy margins to a glass slide, ing for lesions that can be visualized with ultrasound. This then fixing and staining them based on the principle that was demonstrated by Rahusen et al. in a randomized clinical cancer cells will stick to the slide and fat cells will not. This study comparing ultrasound guided lumpectomy of nonpal- method only assesses tumor cells at the lumpectomy surface pable breast cancer to wire-guided resection. Using ultra- and does not indicate when margins are close. The accuracy sound to localize the cancer improved rates of margin pos- is extremely variable and experience dependant, with positive itivity from 45% with wire guided localization alone to 11% predictive values ranging from 21% to 73.6% [53, 54]. In with intraoperative US localization [47]. However, many addition, both of these pathologic techniques are limited in lesions are not visualized on ultrasound; in particular DCIS their ability to predict invasive lobular cancer as well as DCIS lesions which are diagnosed as calcifications on mammogra- at the margins [52]. phy often have no ultrasound correlate. For this reason, it is Besides pathologic techniques to assess margins, sig- essential for the surgeon to document presence of the lesion nificant efforts have been directed towards intraoperative on ultrasound preoperatively to ensure visualization. margin probes to assess the lumpectomy specimen margins For lesions not visible on ultrasound, a hydrogel based- at the time of surgery. The MarginProbe (TM, Dune Medical breast biopsy clip can be placed at the time of biopsy. This Devices) uses radiofrequency spectroscopy to assess margin clip is visible on ultrasound and enables the surgeon to use status. Using this probe, Allweis et al. reported a decrease US guidance rather than preoperative wire localization for in reexcision rate from 12.7% to 5.6% [55]. High frequency excision of sonographically occult lesions. However, this ultrasound probes have also been developed for intraopera- approach has limitations. Klein et al. reported that while the tive margin assessment [56]. This technology may have the clip was very well visualized with intraoperative US, there ability to differentiate carcinomas and precancerous lesions was a high rate of clip migration either prior to the procedure such as ADH from normal tissue. It can also differentiate (6.4%) or when the biopsy cavity was transected (45.2%) invasive lobular cancer from normal tissue, which is a [48]. limitation of other techniques. Another technique to enable use of intraoperative ultra- Dooley et al. described ductoscopy-assisted lumpectomy sound for lesion excision involves cryoprobe assisted local- based on the “sick lobe” hypothesis, with the idea that ization (CAL), in which an ultrasound-guided cryoprobe is the entire lobe of the breast containing disease should be placed into the tumor to freeze it. This enables the tumor evaluated and all affected areas should be removed in order to be easily palpable and visible on ultrasound. Tafra et al. to minimize local recurrence rates [57]. His nonrandomized demonstrated that although similar rates of margin posi- series showed a lower rate of local failure in those patients tivity (28% with CAL compared to 31% with wire guided who had ductoscopy assisted surgical excision. Furthermore, localization) and reexcision (19% and 21%) were noted, the 42% of patients were noted to have extensive disease within cosmetic outcome was improved with CAL since less healthy the affected lobe. surrounding tissue around the tumor was removed [49]. Since a primary drawback of large excisions to achieve Another technique that is showing promise in improving negative margins is due to removal of excess volume of margin clearance is radioguided occult lesion localization tissue and resultant cosmetic deformity, several ablative (ROLL). This involves placement of a small radioactive seed methods have been investigated to provide a larger perimeter under imaging guidance. This seed can be detected with a of margin clearance without resecting additional tissue. hand-held gamma probe at the time of surgery. A recent Manenti et al. demonstrated that cryoablation of unifocal metaanalysis of four randomized controlled trials including small malignant tumors led to complete necrosis in 14 of 15 449 patients comparing radioguided seed localization to patients [58]. Laser ablation has been demonstrated to ablate wire guided localization showed improvement in margin mammographically detected breast cancer [59]. Klimberg statusaswellasreoperation rateswiththe ROLL technique et al. have demonstrated that radiofrequency ablation at the [50]. However, when Krekel et al. compared wire guided time of surgical excision (eRFA) creates a 5–10 mm zone localization, intraoperative US localization, and the ROLL of ablation around the resected tumor, without removing technique, the rate of positive margins was the lowest in the excess of volume of tissue to achieve the same result [60]. intraoperativeUSgroup [51]. These technologies hold promise in achieving wider margins These studies suggest that the ability to visualize the without compromising cosmesis. lesion in multiple dimensions facilitates complete removal, Since most true in-breast recurrences occur at or near however, rates of margin positivity may still be unchanged. the initial lumpectomy cavity, partial breast intraoperative Therefore, efforts have been focused on methods of eval- radiation has been investigated as an alternative to traditional uating the lumpectomy specimen intraoperatively to assess external beam. The use of a single dose of intraoperative International Journal of Surgical Oncology 5 radiation using a spherical applicator placed in the surgical Pathologic processing includes inking with close atten- cavity was compared to traditional external beam radiation tion so that ink does not run into cut surfaces. Multiple sam- in the TARGIT-A trial [61]. This trial showed that at 4 ples are taken perpendicular to each inked surface, with years of followup in selected patients, a single intraoperative additional samples taken based on gross appearance of the radiation dose is an acceptable alternative to external beam tissue [67]. In order to more accurately orient the specimen radiotherapy. for the pathologist and to help guide reexcision, Singh et al. compared standard inking by the pathologist after lump- ectomy versus intraoperative inking with surgeon input [68]. 4. Pathologic Assessment This study demonstrated a decrease in margin positivity rate There is no universally accepted pathology standard for from 46% to 23%, as well as a decrease in reexcision rates assessing breast specimens, and translation of intraoperative from 38% to 19% when the surgeon was responsible for findings to the pathology lab can be quite difficult. After a inking the margin. Importantly, residual disease at the time lumpectomy specimen is removed from the breast, there may of reexcision was noted to be 67% in the group inked by be distortion of the margins due to compression of the spec- the surgeon (as opposed to 23% in the group inked by imen for radiographic lesion confirmation. The breast tissue the pathologist). This simple technique of surgeon staining is fatty, and often with compression of the tissue for specimen the lumpectomy specimen with 6 different ink colors at the time of lumpectomy can enable orientation to be main- radiograph to confirm lesion excision, the specimen flattens out or “pancakes,” resulting in distortion of the specimen tained when evaluating the margins. Furthermore, directed and spurious positive margins [62]. Furthermore, even with reexcision also decreases the volume of tissue excised when compared to the whole cavity reexcision [69]. minimal handling, the breast tissue is fatty and often slides off a tumor which remains firm. Therefore, in addition to assessing the lumpectomy spec- imen margins, surgeons often submit additional tissue from 5. Oncoplastic Surgery to Achieve the cavity margins once the primary specimen has been Wider Margins removed (cavity shave margins). Assessing the cavity margins rather than lumpectomy margins is likely a better indicator Oncoplastic breast surgery combines the principles of cancer of presence of residual disease in the cavity since it avoids the resection with plastic surgery to achieve wide tumor-free issues of compression and specimen processing artifact. The margins in such a manner as to maximize resection volume technique involves resecting thin samples of tissue from all 6 while optimizing cosmetic outcome. The two main tech- margins (superior, inferior, medial, lateral, anterior, and pos- niques used involve volume displacement and volume terior) for pathology evaluation. This technique can direct replacement. Volume displacement techniques combine the surgeon to the exact location of a positive margin in the resection with a variety of different breast-reshaping and event that reexcision is necessary; however, the drawback is breast-reduction techniques and include radial ellipse seg- that it further increases resection volume [63]. Although the mentectomy and circumareolar approach. Lesions in the volume of tissue resected is increased, Rizzo et al. demon- upper or central breast can be resected with the crescent strated a higher rate of pathologic margin negativity and mastopexy, batwing incision, donut mastopexy, and central therefore a lower rate of reoperation with this technique [64]. quadrantectomy. Lesions of the lower breast can be resected While there is a cost savings associated with fewer reopera- with the triangle incision, inframammary incision, and tions, there is additional time required by pathology to assess reduction mastopexy [70]. the extra tissue removed and may adversely impact cosmesis. These procedures can be done by the breast surgeon and/ Another challenge as the lumpectomy specimen moves or plastic surgeon at the time of cancer resection. Of note, the from the operating room to the pathology lab is specimen three dimensional orientation of the tumor bed is frequently orientation. Marking sutures have traditionally been placed altered with these techniques so that identification of the on 2 or more of the 6 surfaces of a lumpectomy specimen by initial resection cavity for postoperative radiation therapy is the surgeon in the operating room, followed by inking of all not possible. At the very least, placement of surgical clips 6 margins done by the pathologist in the lab. Molina et al. after tumor resection and before oncoplastic reconstruction demonstrated that with 2 marking sutures placed by the sur- may be the most accurate method to localize the RT local geon, there was a 20% rate of discordance between surgeon boost field. Additionally, oncoplastic techniques commonly and pathologist interpretation of the margins in specimens prevent a simple further excision in the event of positive mar- larger than 20 square cm [65]. In smaller specimens less than gins, so that most patients with involved margins will need 20 square cm, the discordance was as high as 78%. amastectomy[71]. Oncoplastic procedures for cancer often Particularly disturbing for the surgeon are cases where a result in the need for a contralateral symmetry procedure. positive margin is noted on pathology from the initial lum- The contralateral procedure can be done at the same time as pectomy, and no further disease is evident on reexcision, the cancer resection, or at a later time. since it is unclear whether the reexcision removed the correct Volume replacement techniques are performed less fre- area. Dooley and Parker demonstrated that when a single quently, and involve autologous tissue flap placement when margin was close or positive, reexcision showed tumor in there is insufficient tissue for a satisfactory cosmetic result. only 35% of cases [66]. When multiple margins were close or These procedures can retain the volume and shape of the positive, reexcision showed tumor in 47% of cases. breast and avoid contralateral breast surgery. However, these 6 International Journal of Surgical Oncology Table 1: Oncoplastic surgery and margin involvement, local recurrence rates, and survival rates. Close/involved Number of Weight (g)/volume Local Median followup Author Year margins Survival rate patients of specimen recurrence rate (months) (reexcision/mastectomy) Clough et al. [15] 2003 101 222 9.4% 95.7% 44 Kaur et al. [16] 2005 30 200 16% Rietjens et al. [17] 148 198 2.02% 3% 92.47% 74 Giacalone et al. [18] 2006 31 190 21% Meretoja et al. [19] 90 12.2% 0% 26 Fitoussi et al. [20] 540 187.7 18.9% 6.8% 92.6% 49 Chakravorty et al. [21] 146 67 (11–1050) 2.7% 4.3% 28 techniques are more complex, require a donor site, and It appears that oncoplastic breast surgery extends the lead to increased recovery time following autologous tissue indications of breast conservation and allows for achieve- harvesting. Autologous flaps for volume replacement include ment of large resection volumes with good cosmesis. How- transverse rectus abdominus (TRAM), adipofascial flap, ever, drawbacks include frequent necessity to operate on the a lateral thoracodorsal flap, a thoracoepigastric flap, an contralateral healthy breast, increased cost, and increased intercostal artery perforator (ICAP) flap, a thoracodorsal possibility of complications delaying adjuvant therapy. While artery perforator (TDAP) flap, and a latissimus dorsi (LD) there has been some concern that oncoplastic surgery could myocutaneous flap [72]. confound subsequent mammographic imaging, Roberts et al. demonstrated that in patients who underwent reduction Oncoplastic breast conserving surgery (oBCS) has the mammoplasty, no increase in subsequent imaging or diag- potential to improve the aesthetic outcome of BCS as well as nostic interventions was noted [76]. extending the role of BCS in situations previously considered unsuitable for conservation (large tumors relative to breast size, central and lower pole tumor location, or multifocal- 6. Looking Forward ity). While tumor size, or more precisely tumor-to-breast volume, is a key indication for oBCS, tumor location is an Trends in breast cancer care continue to progress towards less equally important consideration. However, the application invasive surgical treatment. Recent data from the ACOSOG of aesthetic techniques for therapeutic purposes must never Z11 trial suggests that axillary dissection may not be of ben- compromise the main objective of breast cancer surgery: efit in node positive patients who receive maximal systemic clear margins with good local disease control [72]. therapy and radiation. As systemic therapy improves, and There is now agrowing evidence through prospective individualized and targeted approaches evolve, it is unclear series that oncoplastic techniques offer patients a safe onco- what role surgery will play in achieving local control. Primary logical outcome (Table 1). Clough et al. from Institute Curie ablative therapies may make questions of margins obsolete, published their first evaluation of 101 patients and concluded in that if a tumor is ablated and resolves on imaging, then that oncoplastic techniques allow larger resections, however surgical excision may not be necessary. a recurrence rate of 9% was reported with median followup of 5 years [15]. Kaur et al. found that a larger volume excision References is possible in a subset of patients treated by oncoplastic techniques however; this series reported a re-excision rate [1] B. Fisher, S. Anderson, J. Bryant et al., “Twenty-year follow-up of 16% [16]. 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Optimizing Surgical Margins in Breast Conservation

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Copyright © 2012 Preya Ananthakrishnan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2012, Article ID 585670, 9 pages doi:10.1155/2012/585670 Review Article 1 1 2 Preya Ananthakrishnan, Fatih Levent Balci, and Joseph P. Crowe Breast Surgery Division, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA Department of General Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA Correspondence should be addressed to Preya Ananthakrishnan, pa2325@columbia.edu Received 2 October 2012; Accepted 31 October 2012 Academic Editor: Eisuke Fukuma Copyright © 2012 Preya Ananthakrishnan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Adequate surgical margins in breast-conserving surgery for breast cancer have traditionally been viewed as a predictor of local recurrence rates. There is still no consensus on what constitutes an adequate surgical margin, however it is clear that there is a trade-off between widely clear margins and acceptable cosmesis. Preoperative approaches to plan extent of resection with appropriate margins (in the setting of surgery first as well as after neoadjuvant chemotherapy,) include mammography, US, and MRI. Improvements have been made in preoperative lesion localization strategies for surgery, as well as intraoperative specimen assessment, in order to ensure complete removal of imaging findings and facilitate margin clearance. Intraoperative strategies to accurately assess tumor and cavity margins include cavity shave techniques, as well as novel technologies for margin probes. Ablative techniques, including radiofrequency ablation as well as intraoperative radiation, may be used to extend tumor-free margins without resecting additional tissue. Oncoplastic techniques allow for wider resections while maintaining cosmesis and have acceptable local recurrence rates, however often involve surgery on the contralateral breast. As systemic therapy for breast cancer continues to improve, it is unclear what the importance of surgical margins on local control rates will be in the future. 1. Introduction It is well accepted that complete removal of tumor is necessary, however, there is aconsiderable debate regarding Breast-conservation therapy (BCT), including lumpectomy what margin of normal tissue surrounding the tumor con- and sentinel lymph node biopsy followed by radiation ther- stitutes a negative margin. Definitions range from no ink on apy, is the treatment of choice for women with early stage tumor surface (NSABP B-06) to 1 cm or more [8]. Blair et al. breast cancer. Randomized trials have shown that overall sur- sent a survey to nearly 1000 breast cancer surgeons, and vival of women undergoing BCT is equivalent to mastectomy found that 15% defined a negative margin as no tumor on [1, 2]. The goal of lumpectomy is to completely excise the inked margin, 21% accepted a 1 mm margin, 50% accepted tumor with negative margins while maintaining acceptable a 2 mm margin, 12% accepted a 5 mm margin, and 3% cosmesis. Rates of margin positivity at initial lumpectomy accepted a 1 cm margin [9]. A meta-analysis by Wang et al. have been reported ranging from 15% to 47% [3–6]. Positive found that wider margins minimize the risk of ipsilateral margins are usually addressed with surgical reexcision, since local recurrence, with lowest recurrence rates achieved with the risk of local recurrence associated with a positive margin a negative margin larger than 10 mm rather than 2 mm. This is approximately 2 to 3 times that compared with a negative finding was independent of whether or not the patient margin [7]. Reexcision can include reoperative lumpectomy received radiation [10]. or possibly mastectomy. This additional surgical reoperative In another meta-analysis of 21 retrospective studies procedure can result in increased psychological trauma to the which included 14,571 patients, Houssami et al. demon- patient, delay of adjuvant therapy, worsened cosmesis, and strated an odds ratio for local recurrence of 2.42 (P< 0.001) increased cost [7]. with positive margins. This meta-analysis did not identify 2 International Journal of Surgical Oncology a statistically significant difference in local recurrence asso- multidisciplinary management, including improvements in ciated with margin widths of more than 1 mm, more than pathologic evaluation and systemic therapy, could be cred- 2 mm, or more than 5 mm after adjustment for a radiation ited for the improvement in IBTR. boost and endocrine therapy [11]. This suggests that a 2 or Further evidence supports the fact that systemic treat- 5 mm margin is not necessarily better than a 1 mm margin. ments not only reduce the risk of distant metastases but When considering optimal margin width, it is useful to also reduce the risk of local recurrence. In the NSABP B- remember that a “negative” margin does not indicate the 14 trial, women with node-negative, estrogen-receptor (ER)- absence of residual unresected tumor in the breast [12]. It positive tumors were randomly assigned to tamoxifen or simply suggests that the residual tumor burden is probably placebo [26]. The 10-year rate of local recurrence after low enough to be controlled with radiotherapy. Even the breast-conserving surgery was reduced from 14.7% in the widest margins resulting from mastectomy do not eliminate placebo group to 4.3% in the tamoxifen group. Similarly, risk of local recurrence. This indicates that residual disease in the NSABP B-13 trial, women with node-negative, ER- burden is not totally eliminated by local surgery and that negative tumors were randomly assigned to methotrexate tumor biology, radiation therapy, and systemic therapy may and fluorouracil or to no treatment [27]. A reduction was play an important role in controlling local recurrence [13]. noted in the 10-year local recurrence rate from 13.4% in the In further defining this idea of residual disease burden, no-treatment group to 2.6% in the treatment group. In both Margenthaler et al. have proposed calculating a “margin studies, the NSABP definition of no ink on tumor was used index” as a predictive tool for residual disease after breast- to define a negative margin. conservation surgery [14]. This margin index is calculated Studies examining the effect of adding trastuzumab to by dividing the closest margin (in mm) by the tumor size (in adjuvant chemotherapy in women with human epidermal mm)× 100. They found that with a margin index >5, the risk growth factor receptor 2 (HER2)-overexpressing tumors of residual disease was 3.2%. With a margin index of 20, no have shown an additional 40% reduction in the risk of residual disease was found in the reexcision specimen. local recurrence over a median follow-up of 1.5 to 2.0 years The NSABP B-06 study showed that in 1851 patients who [28]. Triple negative tumors have the highest risk of local underwent breast conservation, the positive margin rate was recurrence after both breast-conserving therapy and mas- 6.8% and the in-breast tumor recurrence rate was 14.2% over tectomy [29–31], and retrospective studies do not show an 20 years of followup [1]. Other randomized controlled trials improvement in local control after mastectomy as compared described a range of local recurrences rates from 5.9% at with lumpectomy and radiation in this subgroup of patients 20 years to 19.7% at 13 years [22]. These randomized trials with biologically aggressive tumors [32, 33]. do not explicitly define margin width, which ranged from no The effect of tumor biology on local recurrence was ink on tumor to 1 cm gross margin. While the B-06 trial was clearly shown in a study examining the usefulness of the 21- conducted in the 1970s, several subsequent NSABP trials in gene recurrence score (Oncotype DX) in predicting local and the 1990s showed improvement in 10-year local recurrence regional recurrence [34]. The recurrence score was developed rates ranging from 3.5% to 6.5% [23]. Although devel- to predict the likelihood of distant metastases in patients opments in breast imaging and pathological evaluation with ER-positive, node-negative breast cancer who received of lumpectomy specimens probably contributed to these tamoxifen [35]. Mamounas et al. found that without sys- improvements, significant strides were also made in systemic temic therapy, 18.4% of patients with a high recurrence score therapy during this time. This suggests that the likelihood of (≥31) had a recurrence of local or regional disease [34]. The local recurrence is related to not only the surgical margin addition of tamoxifen had a minimal effect on the rate of width as well, but also to the underlying tumor biology as local and regional recurrence, with a decrease to 15.8%. In well as the effectiveness of adjuvant therapy. contrast, the combination of chemotherapy and tamoxifen Multiple retrospective studies have attempted to define was associated with a reduction in the local recurrence rate predictors of a positive margin at lumpectomy. These studies to 7.8%. identified a number of independent predictors of local recur- Interestingly, the majority of the studies describing local rence including age less than 40 years, microcalcifications recurrence rates do not make the distinction between true on mammography, palpable tumors, large tumors, multi- local recurrences and new ipsilateral primary tumors. Yi et al. centricity, presence of DCIS or lobular histology, and lym- suggested that approximately 50% of IBTRs are actually new phovascular invasion [24]. While these studies showed that primary cancers as differentiated by histologic subtype and 1-2 mm margins were associated with decreased local recur- receptor status [36]. This would lead us to expect that the rence rates, it is unclear what the impact of improved sys- true localrecurrenceratemay be half of what is reported in temic therapy and boost radiation therapy is on these results. the above studies, if in fact half of in-breast recurrences are Cabioglu retrospectively assessed patient and tumor charac- new primaries. These new primary tumors therefore would teristics as well as IBTR rates in two cohorts of patients (those notbeexpectedtobeaffected by margin width. treated from 1970 to 1993, and those treated from 1994 to 1996) [25]. Patients treated after 1994 were less likely to have 2. Preoperative Imaging and positive or unknown margin status (2.9% compared to Treatment Strategies 24.1% before 1994,) and the 5-year IBTR rate was lower in patients treated after 1994 (1.3% compared to 5.7% in those Thorough preoperative imaging is necessary to plan the treated before 1994). These investigators postulated that extent of resection while minimizing positive margins. International Journal of Surgical Oncology 3 Standard preoperative imaging includes mammography and predicting residual tumor extent for triple-negative breast ultrasound, and often MRI. Mammography can delineate tumors, and least accurate in the Luminal A subtype (Pearson tumor size and borders, as well as identify extent of micro- correlation coefficient of 0.754 and 0.531.) calcifications, presence of multifocality, and multicentricity. Multivariate analysis suggested that ER status was an Mammography is also important for assessment of the con- independent factor which influenced the accuracy of MRI. tralateral breast. Compared to mammography, ultrasonog- In HER2 amplified tumors, the use of HER2-targeted agents raphy can often give more accurate estimation of tumor size was associated with a less accurate MRI prediction of residual and borders, particularly in patients of young age with dense tumor extent. breasts. Huang et al. proposed a prognostic index score for MRI is a more sensitive test that can detect additional foci patients receiving neoadjuvant chemotherapy composed of of disease not appreciated on mammogram and ultrasound. four points: (1) clinical N2 to N3 disease, (2) lymphovascular Houssami et al., in a metaanalysis of 19 studies, found that invasion, (3) pathologic size >2 cm, and (4) multifocal resid- MRI detected additional disease in 16% and led to more ual disease [43]. Patients with an index of 0 or 1 had similar extended surgery in 5.5% with a change from lumpectomy LRR rates between mastectomy and BCT. Patients with to mastectomy in 1.1% [37]. Crowe et al. demonstrated that a score of 2 had a trend towards less LRR that was not sig- MRI identified occult or separate tumors in 13% of patients nificant (12% after mastectomy versus 28% after BCT), and [38]. MRI has a high false-positive rate, so it is clear that patients with a score of 3 or 4 had a significant difference additional lesions identified on MRI must be biopsied to (19% after mastectomy versus 61% after BCT.) This index demonstrate malignancy prior to changes in surgical plan- provides a framework in which to guide surgery selection ning. Of note, the clinical consequence of detecting these after neoadjuvant chemotherapy, however, does not explic- additional lesions on MRI is unknown since no study has itly address the impact of margin status on LRR rates. demonstrated that use of MRI translates into improved local Other novel preoperative imaging strategies include opti- recurrence rates or survival. cal spectroscopy and molecular vibrational imaging. Optical Another theoretical advantage of MRI is the potential spectroscopy uses properties of tissue microstructure and to better define the extent of the index lesion in order to biochemical composition to characterize tissue. It can dif- better plan surgical resection. However, Bleicher et al. in a ferentiate normal from malignant tissue by distinguishing retrospective review of 577 patients (130 of which had pre- deoxy-hemoglobin, oxy-hemoglobin, water, and lipids, and operative MRI) failed to demonstrate a difference in margin thus is not limited by mammographic tissue density. This has positivity or the need to convert from breast conservation also shown promise in assessing tumor response to neoad- to mastectomy in the group who had MRI [39]. At this juvant chemotherapy [44]. This technology is limited in time, preoperative MRI does not improve surgical planning distinguishing DCIS from normal tissue. Molecular vibra- and does not reduce the need for reexcision. Furthermore, tional imaging is another quantitative imaging technology Shin et al. in a retrospective analysis showed that breast MRI that uses Coherent anti-Stokes Raman scattering (CARS) provided more accurate estimation of tumor size in compar- microscopy to visualize cellular and tissue features. This tech- ison to ultrasound for both invasive and in situ breast cancer. nology shows promise in differentiating invasive ductal from However, no clear benefit in terms of lower reexcision rate, invasive lobular lesions, as well as DCIS from normal tissue. higher rate of success of breast conservation, or reduced rate of local recurrence emerged with routine use of breast MRI before BCT [40]. 3. Lesion Localization, Margin Assessment, There is some suggestion that MRI may be better at and Intraoperative Techniques assessing DCIS than conventional imaging. Kropcho et al. prospectively evaluated patients diagnosed with DCIS with Preoperative tumor localization for nonpalpable lesions was and without MRI [41]. In this study, the correlation between traditionally performed by the radiologist with either a MRI and tumor size was found to be significantly higher; mammographically or sonographically guided wire place- however, no significant difference was found in between- ment into the tumor. The limitation of this technique is group analysis of the incidence of margin involvement with that it identifies the lesion in one plane only, with limited MRI versus without MRI (30% versus 24.7%, P = 0.414, ability to guide a three-dimensional resection of the lesion. resp.). Lesion bracketing with multiple guidewires as opposed to Neoadjuvant chemotherapy can often shrink larger a single wire would theoretically improve margin clearance tumors to allow for breast conservation. Sweeting et al. by facilitating complete resection of an imaging abnormality. demonstrated that over 6-year median followup in young However, Liberman et al. found that while bracketing a lesion women <age 45, locoregional recurrence rates were no differ- (particularly if the lesion was a large area of calcifications) ent after breast conservation than mastectomy (13% versus with multiple wires may help to ensure removal of the entire 18%) in patients who underwent neoadjuvant chemotherapy mammographic lesion, it still did not improve on rates of [42]. Higher posttreatment, but not pretreatment, stage margin positivity [45]. was associated with higher locoregional recurrence rates. Intraoperative specimen radiography using the Faxitron Recently, Moon et al demonstrated that the accuracy of MRI can be done immediately after specimen excision. The Fax- after neoadjuvant chemotherapy is influenced by the molec- itron allows the surgeon to visualize an eccentric location of ular subtype of the tumor. MRI was most accurate in a tumor or clip so that additional tissue can be removed. 4 International Journal of Surgical Oncology Bathla et al. demonstrated a reexcision rate of 14.3% when margin positivity. Traditional margin assessment intraoper- 2-dimensional Faxitron was used to guide further tissue atively consists of either frozen section histology or imprint removal at the time of initial lumpectomy [46]. In this study, cytology. Frozen section histology, while relatively accurate 95.8% of patients who would have required subsequent in reflecting margin status, is limited due to time, cost, and reexcision were spared further surgery since additional loss of tissue for permanent section evaluation. Furthermore margins were taken at the time of lumpectomy based on this method is very labor intensive and can only examine a Faxitron imaging findings. limited amount of tissue, with false negative rates reported Intraoperative ultrasonography allows for improved gui- in 19% of patients [52]. Imprint cytology or “touch prep” dance on extent of resection. This technique is quite promis- involves touching the lumpectomy margins to a glass slide, ing for lesions that can be visualized with ultrasound. This then fixing and staining them based on the principle that was demonstrated by Rahusen et al. in a randomized clinical cancer cells will stick to the slide and fat cells will not. This study comparing ultrasound guided lumpectomy of nonpal- method only assesses tumor cells at the lumpectomy surface pable breast cancer to wire-guided resection. Using ultra- and does not indicate when margins are close. The accuracy sound to localize the cancer improved rates of margin pos- is extremely variable and experience dependant, with positive itivity from 45% with wire guided localization alone to 11% predictive values ranging from 21% to 73.6% [53, 54]. In with intraoperative US localization [47]. However, many addition, both of these pathologic techniques are limited in lesions are not visualized on ultrasound; in particular DCIS their ability to predict invasive lobular cancer as well as DCIS lesions which are diagnosed as calcifications on mammogra- at the margins [52]. phy often have no ultrasound correlate. For this reason, it is Besides pathologic techniques to assess margins, sig- essential for the surgeon to document presence of the lesion nificant efforts have been directed towards intraoperative on ultrasound preoperatively to ensure visualization. margin probes to assess the lumpectomy specimen margins For lesions not visible on ultrasound, a hydrogel based- at the time of surgery. The MarginProbe (TM, Dune Medical breast biopsy clip can be placed at the time of biopsy. This Devices) uses radiofrequency spectroscopy to assess margin clip is visible on ultrasound and enables the surgeon to use status. Using this probe, Allweis et al. reported a decrease US guidance rather than preoperative wire localization for in reexcision rate from 12.7% to 5.6% [55]. High frequency excision of sonographically occult lesions. However, this ultrasound probes have also been developed for intraopera- approach has limitations. Klein et al. reported that while the tive margin assessment [56]. This technology may have the clip was very well visualized with intraoperative US, there ability to differentiate carcinomas and precancerous lesions was a high rate of clip migration either prior to the procedure such as ADH from normal tissue. It can also differentiate (6.4%) or when the biopsy cavity was transected (45.2%) invasive lobular cancer from normal tissue, which is a [48]. limitation of other techniques. Another technique to enable use of intraoperative ultra- Dooley et al. described ductoscopy-assisted lumpectomy sound for lesion excision involves cryoprobe assisted local- based on the “sick lobe” hypothesis, with the idea that ization (CAL), in which an ultrasound-guided cryoprobe is the entire lobe of the breast containing disease should be placed into the tumor to freeze it. This enables the tumor evaluated and all affected areas should be removed in order to be easily palpable and visible on ultrasound. Tafra et al. to minimize local recurrence rates [57]. His nonrandomized demonstrated that although similar rates of margin posi- series showed a lower rate of local failure in those patients tivity (28% with CAL compared to 31% with wire guided who had ductoscopy assisted surgical excision. Furthermore, localization) and reexcision (19% and 21%) were noted, the 42% of patients were noted to have extensive disease within cosmetic outcome was improved with CAL since less healthy the affected lobe. surrounding tissue around the tumor was removed [49]. Since a primary drawback of large excisions to achieve Another technique that is showing promise in improving negative margins is due to removal of excess volume of margin clearance is radioguided occult lesion localization tissue and resultant cosmetic deformity, several ablative (ROLL). This involves placement of a small radioactive seed methods have been investigated to provide a larger perimeter under imaging guidance. This seed can be detected with a of margin clearance without resecting additional tissue. hand-held gamma probe at the time of surgery. A recent Manenti et al. demonstrated that cryoablation of unifocal metaanalysis of four randomized controlled trials including small malignant tumors led to complete necrosis in 14 of 15 449 patients comparing radioguided seed localization to patients [58]. Laser ablation has been demonstrated to ablate wire guided localization showed improvement in margin mammographically detected breast cancer [59]. Klimberg statusaswellasreoperation rateswiththe ROLL technique et al. have demonstrated that radiofrequency ablation at the [50]. However, when Krekel et al. compared wire guided time of surgical excision (eRFA) creates a 5–10 mm zone localization, intraoperative US localization, and the ROLL of ablation around the resected tumor, without removing technique, the rate of positive margins was the lowest in the excess of volume of tissue to achieve the same result [60]. intraoperativeUSgroup [51]. These technologies hold promise in achieving wider margins These studies suggest that the ability to visualize the without compromising cosmesis. lesion in multiple dimensions facilitates complete removal, Since most true in-breast recurrences occur at or near however, rates of margin positivity may still be unchanged. the initial lumpectomy cavity, partial breast intraoperative Therefore, efforts have been focused on methods of eval- radiation has been investigated as an alternative to traditional uating the lumpectomy specimen intraoperatively to assess external beam. The use of a single dose of intraoperative International Journal of Surgical Oncology 5 radiation using a spherical applicator placed in the surgical Pathologic processing includes inking with close atten- cavity was compared to traditional external beam radiation tion so that ink does not run into cut surfaces. Multiple sam- in the TARGIT-A trial [61]. This trial showed that at 4 ples are taken perpendicular to each inked surface, with years of followup in selected patients, a single intraoperative additional samples taken based on gross appearance of the radiation dose is an acceptable alternative to external beam tissue [67]. In order to more accurately orient the specimen radiotherapy. for the pathologist and to help guide reexcision, Singh et al. compared standard inking by the pathologist after lump- ectomy versus intraoperative inking with surgeon input [68]. 4. Pathologic Assessment This study demonstrated a decrease in margin positivity rate There is no universally accepted pathology standard for from 46% to 23%, as well as a decrease in reexcision rates assessing breast specimens, and translation of intraoperative from 38% to 19% when the surgeon was responsible for findings to the pathology lab can be quite difficult. After a inking the margin. Importantly, residual disease at the time lumpectomy specimen is removed from the breast, there may of reexcision was noted to be 67% in the group inked by be distortion of the margins due to compression of the spec- the surgeon (as opposed to 23% in the group inked by imen for radiographic lesion confirmation. The breast tissue the pathologist). This simple technique of surgeon staining is fatty, and often with compression of the tissue for specimen the lumpectomy specimen with 6 different ink colors at the time of lumpectomy can enable orientation to be main- radiograph to confirm lesion excision, the specimen flattens out or “pancakes,” resulting in distortion of the specimen tained when evaluating the margins. Furthermore, directed and spurious positive margins [62]. Furthermore, even with reexcision also decreases the volume of tissue excised when compared to the whole cavity reexcision [69]. minimal handling, the breast tissue is fatty and often slides off a tumor which remains firm. Therefore, in addition to assessing the lumpectomy spec- imen margins, surgeons often submit additional tissue from 5. Oncoplastic Surgery to Achieve the cavity margins once the primary specimen has been Wider Margins removed (cavity shave margins). Assessing the cavity margins rather than lumpectomy margins is likely a better indicator Oncoplastic breast surgery combines the principles of cancer of presence of residual disease in the cavity since it avoids the resection with plastic surgery to achieve wide tumor-free issues of compression and specimen processing artifact. The margins in such a manner as to maximize resection volume technique involves resecting thin samples of tissue from all 6 while optimizing cosmetic outcome. The two main tech- margins (superior, inferior, medial, lateral, anterior, and pos- niques used involve volume displacement and volume terior) for pathology evaluation. This technique can direct replacement. Volume displacement techniques combine the surgeon to the exact location of a positive margin in the resection with a variety of different breast-reshaping and event that reexcision is necessary; however, the drawback is breast-reduction techniques and include radial ellipse seg- that it further increases resection volume [63]. Although the mentectomy and circumareolar approach. Lesions in the volume of tissue resected is increased, Rizzo et al. demon- upper or central breast can be resected with the crescent strated a higher rate of pathologic margin negativity and mastopexy, batwing incision, donut mastopexy, and central therefore a lower rate of reoperation with this technique [64]. quadrantectomy. Lesions of the lower breast can be resected While there is a cost savings associated with fewer reopera- with the triangle incision, inframammary incision, and tions, there is additional time required by pathology to assess reduction mastopexy [70]. the extra tissue removed and may adversely impact cosmesis. These procedures can be done by the breast surgeon and/ Another challenge as the lumpectomy specimen moves or plastic surgeon at the time of cancer resection. Of note, the from the operating room to the pathology lab is specimen three dimensional orientation of the tumor bed is frequently orientation. Marking sutures have traditionally been placed altered with these techniques so that identification of the on 2 or more of the 6 surfaces of a lumpectomy specimen by initial resection cavity for postoperative radiation therapy is the surgeon in the operating room, followed by inking of all not possible. At the very least, placement of surgical clips 6 margins done by the pathologist in the lab. Molina et al. after tumor resection and before oncoplastic reconstruction demonstrated that with 2 marking sutures placed by the sur- may be the most accurate method to localize the RT local geon, there was a 20% rate of discordance between surgeon boost field. Additionally, oncoplastic techniques commonly and pathologist interpretation of the margins in specimens prevent a simple further excision in the event of positive mar- larger than 20 square cm [65]. In smaller specimens less than gins, so that most patients with involved margins will need 20 square cm, the discordance was as high as 78%. amastectomy[71]. Oncoplastic procedures for cancer often Particularly disturbing for the surgeon are cases where a result in the need for a contralateral symmetry procedure. positive margin is noted on pathology from the initial lum- The contralateral procedure can be done at the same time as pectomy, and no further disease is evident on reexcision, the cancer resection, or at a later time. since it is unclear whether the reexcision removed the correct Volume replacement techniques are performed less fre- area. Dooley and Parker demonstrated that when a single quently, and involve autologous tissue flap placement when margin was close or positive, reexcision showed tumor in there is insufficient tissue for a satisfactory cosmetic result. only 35% of cases [66]. When multiple margins were close or These procedures can retain the volume and shape of the positive, reexcision showed tumor in 47% of cases. breast and avoid contralateral breast surgery. However, these 6 International Journal of Surgical Oncology Table 1: Oncoplastic surgery and margin involvement, local recurrence rates, and survival rates. Close/involved Number of Weight (g)/volume Local Median followup Author Year margins Survival rate patients of specimen recurrence rate (months) (reexcision/mastectomy) Clough et al. [15] 2003 101 222 9.4% 95.7% 44 Kaur et al. [16] 2005 30 200 16% Rietjens et al. [17] 148 198 2.02% 3% 92.47% 74 Giacalone et al. [18] 2006 31 190 21% Meretoja et al. [19] 90 12.2% 0% 26 Fitoussi et al. [20] 540 187.7 18.9% 6.8% 92.6% 49 Chakravorty et al. [21] 146 67 (11–1050) 2.7% 4.3% 28 techniques are more complex, require a donor site, and It appears that oncoplastic breast surgery extends the lead to increased recovery time following autologous tissue indications of breast conservation and allows for achieve- harvesting. Autologous flaps for volume replacement include ment of large resection volumes with good cosmesis. How- transverse rectus abdominus (TRAM), adipofascial flap, ever, drawbacks include frequent necessity to operate on the a lateral thoracodorsal flap, a thoracoepigastric flap, an contralateral healthy breast, increased cost, and increased intercostal artery perforator (ICAP) flap, a thoracodorsal possibility of complications delaying adjuvant therapy. While artery perforator (TDAP) flap, and a latissimus dorsi (LD) there has been some concern that oncoplastic surgery could myocutaneous flap [72]. confound subsequent mammographic imaging, Roberts et al. demonstrated that in patients who underwent reduction Oncoplastic breast conserving surgery (oBCS) has the mammoplasty, no increase in subsequent imaging or diag- potential to improve the aesthetic outcome of BCS as well as nostic interventions was noted [76]. extending the role of BCS in situations previously considered unsuitable for conservation (large tumors relative to breast size, central and lower pole tumor location, or multifocal- 6. Looking Forward ity). While tumor size, or more precisely tumor-to-breast volume, is a key indication for oBCS, tumor location is an Trends in breast cancer care continue to progress towards less equally important consideration. However, the application invasive surgical treatment. Recent data from the ACOSOG of aesthetic techniques for therapeutic purposes must never Z11 trial suggests that axillary dissection may not be of ben- compromise the main objective of breast cancer surgery: efit in node positive patients who receive maximal systemic clear margins with good local disease control [72]. therapy and radiation. As systemic therapy improves, and There is now agrowing evidence through prospective individualized and targeted approaches evolve, it is unclear series that oncoplastic techniques offer patients a safe onco- what role surgery will play in achieving local control. Primary logical outcome (Table 1). 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