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Innovations in Reduction of Positive Margins during Breast Conserving Surgery
Akiko Chiba1*, Marissa Howard-McNatt1 and Lacey R McNally2
1Department of Surgical Oncology, Wake Forest University School of Medicine, Winston-Salem, USA

2Department of Cancer Biology, Wake Forest Comprehensive Cancer Center, Winston-Salem, USA

ABSTRACT
Assessment of margins during Breast Conserving Surgery (BCS) remains imperfect despite advancement in surgical, pathologic, and imaging technique. Reoperation after BCS is recommended when tumor is present at the margin, which has significant negative implications for the patients. This article aims to review current strategies for minimizing the rate of positive margin.
KEYWORDS
Breast cancer; Breast conserving surgery; Lumpectomy; Margins

Introduction
Breast Conserving Surgery (BCS) which includes lumpectomy with radiation has demonstrated equivalent outcomes to mastectomy in patients with localized breast cancer. Surveillance, Epidemiology, and End Results (SEERs) database estimates 252,710 new breast cancer cases in the US in 2017, and approximately two-thirds of operable breast cancer cases are suitable for BCS. Recent studies indicated improved overall survival in patients undergoing BCS with whole breast radiation compared with patient undergoing mastectomy [1,2]. In order for BCS to be successful, negative margins should be obtained because patients with positive margins have higher rates of recurrence [3]. Despite advancement in surgical, pathologic and imaging techniques, the ability to achieve negative margins for BCS remains imperfect. The rate of second operation performed in the US to achieve negative margins vary widely in the literature, but are reported to range from 21 to 50% [4]. Society for surgical oncology and the American Society for radiation oncology released a consensus guideline on adequate margins for BCS with whole-breast irradiation in February 2014. This guideline endorsed “no ink on tumor” as the standard for a negative margin which decreased the rate of reoperation [5]. Re-excision has multiple negative morbidities including delay in initiation of adjuvant therapy, negative psychological impact to the patient, increased postoperative infection rate, poor cosmesis, and increased cost [6,7]. It is evident that further advancement in surgical, pathologic and imaging technique is necessary to improve breast conserving surgery to decrease or avoid second surgery to achieve negative margin.
Current Options for Reducing Positive Margin Rate
There have been few methods to date to assess resection margins intraoperatively. These methods include frozen section, MarginProbe, spectroscopy, Near-Infrared (NIR) imaging, and MRI. Surgical technique such as full-cavity shaving has also been utilized. None of these methods are routinely used as standard methods as these procedures are time consuming, imperfect, expensive, require specialized training, and/or are experimental.
Frozen Section
The frozen section technique was developed at the Mayo Clinic more than 100 years ago. In this technique, tissue sections are cut from fresh tissue blocks by using open-air freezing platform called microtomes. The stage is rapidly cooled and chills the tissue. Tissue is then cut using microtome blade to sections approximately of 8 to 10 µm. The frozen section tissue is immersed in a toluidine blue stain for a few seconds then rinsed with clean water. The stained tissue is rolled onto a glass slide and covered with cover slip [8]. This technique is still used for intraoperative margin assessment for many oncologic surgeries. However, it is infrequently used for assessing lumpectomy margins. The Mayo clinic reported their positive margin rate of 3.6% compared to 13.2% nationally using the National Surgical Quality Improvement Program (NSQUIP) database. National Surgical Quality Improvement Program (NSQUIP) database is a validated outcomes-based database designed to assist participating hospitals develop quality initiatives and improve the quality of surgical care. Since 2012, the NSQIP database has collected detailed information on return to the operating room within 30 days of a procedure. Significant low-rate of positive margins was attributed to the use of frozen section analysis intraoperatively [9]. However, this technique is time consuming and labor intensive leading to prolonged operative time. Frozen section of lumpectomy specimen may be unreliable when performed by inexperienced pathologist. In most institutions, this method is not practical for routine use due to significant institutional resources required.
MarginProbe
The MarginProbe system is an intra-operative devise for identifying positive margin at margins of excised lumpectomy specimens. This system uses near-field radiofrequency spectroscopy signal to differentiate between dielectric properties of malignant and normal breast tissue for intraoperative assessment to guide re-excision of positive margins [10]. A recently published study using MarginProbe reported reduction of re-excision rates by more than 50% [11]. The drawback of this devise is that this devise adds an additional cost to the procedure. Further the device was designed with emphasis on sensitivity to increase detection of all positive margins, which reduced specificity and increased false-positive results. Excision of additional non-malignant tissue may lead to poor cosmetic outcome.
Full Lumpectomy Cavity Shavings
Some studies have demonstrated 48% reduction in re-excision rates when additional shaved margin is routinely removed from all six sides of the lumpectomy cavity [12,13]. However, there has been conflicting result reported in the current literature. A study from Massachusetts General Hospital showed no difference in re-excision rates in patients undergoing BCS alone or BCS with full-cavity shavings [14]. Due to conflicting result and concern for additional non-malignant tissues removed causing poor cosmesis, full-cavity shaving techniques has not been routinely used by many breast surgeons.
Spectroscopy
Intraoperative assessment of margins using spectroscopy is under development. Optical fiber probe-based diffuse reflectance spectroscopy and Intrinsic Fluorescence Spectroscopy (IFS) are being considered as tools for the intraoperative imaging of malignancy. DRS and IFS depend on the inherent optical properties of tissue for imaging without the use of exogenous contrast agents. The combination of DRS and IFS provides information regarding metabolic, biochemical and morphology of the tissue which is then translated into disease diagnosis. One of the drawbacks of this technique is that the tissue penetration is relatively shallow at ≤ 1mm. The benefit of this kind of imaging is that spectroscopic imaging can examine the entire margin of the excised tissue which reduces the sampling limitations which can be seen in frozen section pathologic examination. Few studies have demonstrated real-time assessment of surgical margins, however, these devises still remain an experimental technique [15,16].
Optical Imaging
Optical imaging has been gaining attention in the image-guided surgery coupled with near-infrared fluorophores. However, inevitable limitations have been identified with this method as these agents can only penetrate up to 1cm depth [17]. Another pitfall of this method includes photo bleaching limiting the number of images which can be obtained and the need for fluorescent camera system for detection, which requires operating room lights to be turned off. The requirements of turning off operating room lights during surgery is not practical and is a major limitation.
MRI
MRI guided breast conserving surgery has been evaluated where patients received 3D MRI under general anesthesia followed by standard breast conserving surgery with sentinel lymph node biopsy. If residual disease was seen following intraoperative MRI imaging, additional margins were excised [18]. Although the study concluded MRI guided BCS is feasible in the 8 patients enrolled in the study, obtaining MRI before and after surgery while the patient is under general anesthesia may not be practical. This process will result in prolonged operating time, longer anesthesia time, and additional equipment cost. Handful of institutions has the capability of intraoperative MRI, however, this technology is mostly used for neurosurgery to improve the extent of resection of brain tumor while avoiding neurological deficits.
Discussion
The rate of re-operation is reported to be ranging from 21 to 50%, which is not insignificant. Re-excision has multiple negative implications including delay in initiation of adjuvant therapy, negative psychological impact to the patient, increased postoperative infection rate, poor cosmesis, and increased cost. None of the modalities mentioned in this article are the current standard for evaluating the margin status intraoperatively. It is clear that there is an unmet need for a reliable and practical technology to localize the tumor and assess the excision margins intraoperatively. Although imaging modalities, such as MRI, mammography, and ultrasound have been of immense advantage in tumor detection, the need for accurate intraoperative imaging with the ability to function with standard operating room lights and to detect cancer based upon molecular features of the tumor would be ideal for successful cancer surgery. Even though the success of BCT depends on obtaining negative margins, intraoperative assessment of surgical margin has been inadequately addressed to date.

References
  1. Hwang ES, Lichtensztajn DY, Gomez SL, Fowble B, Clarke CA (2013) Survival after lumpectomy and mastectomy for early stage invasive breast cancer: the effect of age and hormone receptor status. Cancer 119: 1402-1411.
  2. van Maaren MC, de Munck L, de Bock GH, Jobsen JJ, van Dalen T, et al. (2016) 10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study. Lancet Oncol 17: 1158-1170.
  3. Singletary SE (2002) Surgical margins in patients with early-stage breast cancer treated with breast conservation therapy. Am J Surg 184: 383-393.
  4. McLaughlin SA, Ochoa-Frongia LM, Patil SM, Cody HS, Sclafani LM (2008) Influence of frozen-section analysis of sentinel lymph node and lumpectomy margin status on reoperation rates in patients undergoing breast-conservation therapy. J Am Coll Surg 206: 76-82.
  5. Buchholz TA, Somerfield MR, Griggs JJ, El-Eid S, Hammond ME, et al. (2014) Margins for breast-conserving surgery with whole-breast irradiation in stage I and II invasive breast cancer: American Society of Clinical Oncology endorsement of the Society of Surgical Oncology/American Society for Radiation Oncology consensus guideline. J Clin Oncol 32: 1502-1506.
  6. Russo AL, Arvold ND, Niemierko A, Wong N, Wong JS, et al. (2013) Margin status and the risk of local recurrence in patients with early-stage breast cancer treated with breast-conserving therapy. Breast Cancer Res Treat 140: 353-361.
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  8. Ferreiro JA, Myers JL, Bostwick DG (1995) Accuracy of frozen section diagnosis in surgical pathology: review of a 1-year experience with 24,880 cases at Mayo Clinic Rochester. Mayo Clin Proc 70: 1137-1141.
  9. Boughey JC, Hieken TJ, Jakub JW, Degnim AC, Grant CS, et al. (2014) Impact of analysis of frozen-section margin on reoperation rates in women undergoing lumpectomy for breast cancer: evaluation of the National Surgical Quality Improvement Program data. Surgery 156: 190-197.
  10. Pappo I, Spector R, Schindel A, Morgenstern S, Sandbank J, et al. (2010) Diagnostic Performance of a Novel Device for Real-Time Margin Assessment in Lumpectomy Specimens. J Surg Res 160: 277-281.
  11. Allweis TM, Kaufman Z, Lelcuk S, Pappo I, Karni T, et al. (2008) A prospective, randomized, controlled, multicenter study of a real-time, intraoperative probe for positive margin detection in breast-conserving surgery. Am J Surg 196: 483-489.
  12. Jacobson AF, Asad J, Boolbol SK, Osborne MP, Boachie-Adjei K, et al. (2008) Do additional shaved margins at the time of lumpectomy eliminate the need for re-excision? Am J Surg 196: 556-558.
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  14. Coopey SB, Buckley JM, Smith BL, Hughes KS, Gadd MA, et al. (2011) Lumpectomy cavity shaved margins do not impact re-excision rates in breast cancer patients. Ann Surg Oncol 18: 3036-3040.
  15. Keller MD, Vargis E, de Matos Granja N, Wilson RH, Mycek MA, et al. (2011) Development of a spatially offset Raman spectroscopy probe for breast tumor surgical margin evaluation. J Biomed Opt 16: 077006.
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  18. Golshan M, Sagara Y, Wexelman B, Aydogan F, Desantis S, et al. (2014) Pilot study to evaluate feasibility of image-Guided breast-conserving therapy in the advanced multimodal image-guided operating (AMIGO) suite. Ann Surg Oncol 21: 3356-3357.

Figures


Figure 1: (a) Chemical structures of PAMPS48-PEG227-PAMPS48 (AEA) and PEG47-PMAPTACm (EMm, m = 27,53, and 106).
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.



Figure 2: Time-conversion (?) and the first-order kinetic plots (?) for the polymerization of AMPS in the presence of CPD-PEG-CPD in water at 70oC.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.



Figure 3: GPC elution curves for a sample of HO-PEG-OH (Mn = 9.40 ? 103; Mw/Mn = 1.06) (----) and triblock copolymer of PAMPS48-PEG227-PAMPS48 (AEA, Mn = 2.32 × 104; Mw/Mn = 1.42) (--).
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.



Figure 4: 1H NMR spectra for (a) EM53, (b) AEA, and (c) AEA/EM53 micelle in D2O containing 0.1 M NaCl at 20°C. Assignments are indicated for the resonance peaks.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.



Figure 5: (a) Light scattering intensities and (b) Rh for PIC micelles of AEA/EM106 (?), AEA/EM53 (?), and AEA/M27 (?) as a function of fAMPS (= [AMPS]/([AMPS] + [MAPTAC])) in 0.1 M NaCl aqueous solutions. [AMPS] and [MAPTAC] represent the concentrations of the AMPS and MAPTAC units, respectively. The total polymer concentration was kept constant at 1 g/L.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.



Figure 6: (a) Distributions of Rh for the PIC micelles of AEA/EM106 (?), AEA/EM53 (?), and AEA/EM27 (?) in 0.1 M NaCl aqueous solutions. (b) Relationship between relaxation rate (G) and square of the magnitude of the scattering vector (q2). (c) Plots of Rh as a function of Cp.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.



Figure 7: A typical example of Zimm plots for AEA/EM106 micelle in 0.1 M NaCl aqueous solution.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.



Figure 8: TEM images for (a) AEA/EM27, (b) AEA/EM53, and (c) AEA/EM106 micelles.
[M]0 and [M] represent the concentrations of the monomer at polymerization time = 0 and the corresponding time, respectively.

Tables
SamplesMn(theo)a × 10-4Mn(NMR)b ×10-4Mn(GPC)c ×10-4Mw/MncRhd (nm)?-potential (mV)
EM270.780.830.821.034.518.2
EM531.361.411.111.024.324.2
EM1062.522.581.511.026.125.4
AEA3.213.262.321.426.1-14.4
Table 1: Number-average Molecular weight (Mn), Molecular weight distribution (Mw/Mn), hydrodynamic radius (Rh), and ?-potential for the polymers.
aCalculated from Equation (2), bEstimated from 1H NMR, cEstimated from GPC, dEstimated from DLS.

PIC micelles Mwa × 10-5 Rga Rhb Rg/Rh Naggc dPICd

?-potential

(mV)
(nm) (nm)
AEA/EM27 8.48 15.1 15.2 0.99 50 0.096 -0.88
AEA/EM53 189 36.6 41.0 0.89 735 0.109 -0.53
AEA/EM106 111 28.6 32.4 0.88 302 0.129 -0.20
Table 2: Dynamic and static light scattering data for PIC micelles in 0.1 M NaCl.
aEstimated by SLS in 0.1 M NaCl, bEstimated by DLS in 0.1 M NaCl, cAggregation number of PIC micelles calculated from Mw(SLS) of PIC micelles determined by SLS and Mw of the corresponding unimers determined by 1H NR and GPC, dDensity calculated from Equation (3).

Citation: Chiba A, Howard-McNatt M, McNally LR (2017) Innovations in Reduction of Positive Margins during Breast Conserving Surgery. J Surg Curr Trend Innov 1: 002.