Intraoperative margin assessment techniques in breast-conserving surgery: current status and advances

doi:10.16139/j.1007-9610.2025.02.14

Abstract

Abstract:

In breast-conserving surgery, timely and accurate intraoperative margin assessment is crucial for ensuring surgical success and reducing local recurrence rates. This review first outlined the current methods for intraoperative margin evaluation, including rapid pathological examination and specimen imaging techniques. According to the technical classification, this review systematically introduced emerging technologies that have advanced significantly in recent years, encompassing advanced microscopy, advancements in conventional imaging technologies, novel imaging technologies, and techniques based on biochemical and electrical property contrasts of tissues. Finally, the review summarized and compared these technologies horizontally, and proposed several assessment dimensions aligned with surgical clinical needs, aiming to support the optimization and clinical translation of intraoperative margin assessment techniques. Despite the vigorous development of new technologies, further clinical research and technical refinement remain necessary to achieve continuous improvement and innovation, ultimately providing better options for the patients.

Key words: Margins, Intraoperative margin assessment, Breast-conserving surgery, Breast Cancer

CLC Number:

R737.9

JIN Xiaoding, ZOU Qiang, JIN Yiting. Intraoperative margin assessment techniques in breast-conserving surgery: current status and advances[J]. Journal of Surgery Concepts & Practice, 2025, 30(2): 176-182.

Figures/Tables 1

References 54

[1]	MORROW M, HARRIS J R, SCHNITT S J. Surgical margins in lumpectomy for breast cancer - bigger is not better[J]. N Engl J Med, 2012, 367(1):79-82.
[2]	ST JOHN E R, AL-KHUDAIRI R, ASHRAFIAN H, et al. Diagnostic accuracy of intraoperative techniques for margin assessment in breast cancer surgery: a meta-analysis[J]. Ann Surg, 2017, 265(2):300-310. doi: 10.1097/SLA.0000000000001897 pmid: 27429028
[3]	RIEDL O, FITZAL F, MADER N, et al. Intraoperative frozen section analysis for breast-conserving therapy in 1016 patients with breast cancer[J]. Eur J Surg Oncol, 2009, 35(3):264-270. doi: 10.1016/j.ejso.2008.05.007 pmid: 18706785
[4]	D'HALLUIN F, TAS P, ROUQUETTE S, et al. Intra-operative touch preparation cytology following lumpectomy for breast cancer: a series of 400 procedures[J]. Breast, 2009, 18(4):248-253. doi: 10.1016/j.breast.2009.05.002 pmid: 19515566
[5]	RAMOS M, DíAZ J C, RAMOS T, et al. Ultrasound-guided excision combined with intraoperative assessment of gross macroscopic margins decreases the rate of reoperations for non-palpable invasive breast cancer[J]. Breast, 2013, 22(4):520-524. doi: 10.1016/j.breast.2012.10.006 pmid: 23110817
[6]	TAO Y K, SHEN D, SHEIKINE Y, et al. Assessment of breast pathologies using nonlinear microscopy[J]. Proc Natl Acad Sci USA, 2014, 111(43):15304-15309. doi: 10.1073/pnas.1416955111 pmid: 25313045
[7]	CAHILL L C, GIACOMELLI M G, YOSHITAKE T, et al. Rapid virtual hematoxylin and eosin histology of breast tissue specimens using a compact fluorescence nonlinear microscope[J]. Lab Invest, 2018, 98(1):150-160. doi: 10.1038/labinvest.2017.116 pmid: 29131161
[8]	TOGAWA R, HEDERER J, RAGAZZI M, et al. Imaging of lumpectomy surface with large field-of-view confocal laser scanning microscopy 'Histolog^® scanner' for breast margin assessment in comparison with conventional specimen radiography[J]. Breast, 2023,68:194-200.
[9]	CHANG T P, LEFF D R, SHOUSHA S, et al. Imaging breast cancer morphology using probe-based confocal laser endomicroscopy: towards a real-time intraoperative imaging tool for cavity scanning[J]. Breast Cancer Res Treat, 2015, 153(2):299-310.
[10]	ZHANG Y, XIE M, XUE R, et al. A novel cell morpho-logy analyzer application in head and neck cancer[J]. Int J Gen Med, 2021,14:9307-9314.
[11]	CHEN J J, YU B H, SHEN T J, et al. A prospective comparison of a modified miniaturised hand-held epifluorescence microscope and touch imprint cytology for evaluation of axillary sentinel lymph nodes intraoperatively in breast cancer patients[J]. Cytopathology, 2024, 35(1):136-144.
[12]	YOSHITAKE T, GIACOMELLI M G, QUINTANA L M, et al. Rapid histopathological imaging of skin and breast cancer surgical specimens using immersion microscopy with ultraviolet surface excitation[J]. Sci Rep, 2018, 8(1):4476. doi: 10.1038/s41598-018-22264-2 pmid: 29540700
[13]	YANG Y, LIU Z, HUANG J, et al. Histological diagnosis of unprocessed breast core-needle biopsy via stimulated Raman scattering microscopy and multi-instance learning[J]. Theranostics, 2023, 13(4):1342-1354.
[14]	ORRINGER D A, PANDIAN B, NIKNAFS Y S, et al. Rapid intraoperative histology of unprocessed surgical specimens via fibre-laser-based stimulated Raman scattering microscopy[J]. Nat Biomed Eng,2017, 1:0027
[15]	FU H L, MUELLER J L, JAVID M P, et al. Optimization of a widefield structured illumination microscope for non-destructive assessment and quantification of nuclear features in tumor margins of a primary mouse model of sarcoma[J]. PLoS One, 2013, 8(7):e68868.
[16]	MCCLATCHY D M, RIZZO E J, MEGANCK J, et al. Calibration and analysis of a multimodal micro-CT and structured light imaging system for the evaluation of excised breast tissue[J]. Phys Med Biol, 2017, 62(23):8983-9000. doi: 10.1088/1361-6560/aa94b6 pmid: 29048330
[17]	TANG R, COOPEY S B, BUCKLEY J M, et al. A pilot study evaluating shaved cavity margins with micro-computed tomography: a novel method for predicting lumpectomy margin status intraoperatively[J]. Breast J, 2013, 19(5):485-489.
[18]	THILL M, SZWARCFITER I, KELLING K, et al. Magnetic resonance imaging system for intraoperative margin assessment for DCIS and invasive breast cancer using the ClearSight™ system in breast-conserving surgery-results from a postmarketing study[J]. J Surg Oncol, 2022, 125(3):361-368.
[19]	WATANABE G, ITOH M, DUAN X, et al. ¹⁸F-fluorodeoxyglucose specimen-positron emission mammography delineates tumour extension in breast-conserving surgery: preliminary results[J]. Eur Radiol, 2018, 28(5):1929-1937. doi: 10.1007/s00330-017-5170-8 pmid: 29218614
[20]	GROOTENDORST M R, CARIATI M, PINDER S E, et al. Intraoperative assessment of tumor resection margins in breast-conserving surgery using ¹⁸F-FDG cerenkov luminescence imaging: a first-in-human feasibility study[J]. J Nucl Med, 2017, 58(6):891-898.
[21]	NGUYEN F T, ZYSK A M, CHANEY E J, et al. Intra-operative evaluation of breast tumor margins with optical coherence tomography[J]. Cancer Res, 2009, 69(22):8790-8796.
[22]	ALLEN W M, FOO K Y, ZILKENS R, et al. Clinical feasibility of optical coherence micro-elastography for imaging tumor margins in breast-conserving surgery[J]. Biomed Opt Express, 2018, 9(12):6331-6349. doi: 10.1364/BOE.9.006331 pmid: 31065432
[23]	SOUTH F A, CHANEY E J, MARJANOVIC M, et al. Differentiation of ex vivo human breast tissue using polarization-sensitive optical coherence tomography[J]. Biomed Opt Express, 2014, 5(10):3417-3426.
[24]	ERICKSON-BHATT S J, NOLAN R M, SHEMONSKI N D, et al. Real-time imaging of the resection bed using a handheld probe to reduce incidence of microscopic positive margins in cancer surgery[J]. Cancer Res, 2015, 75(18):3706-3712.
[25]	KHO E, DE BOER L L, VAN DE VIJVER K K, et al. Hyperspectral imaging for resection margin assessment during cancer surgery[J]. Clin Cancer Res, 2019, 25(12):3572-3580. doi: 10.1158/1078-0432.CCR-18-2089 pmid: 30885938
[26]	FITZGERALD A J, WALLACE V P, JIMENEZ-LINAN M, et al. Terahertz pulsed imaging of human breast tumors[J]. Radiology, 2006, 239(2):533-540. pmid: 16543586
[27]	GROOTENDORST M R, FITZGERALD A J, BROUWER DE KONING S G, et al. Use of a handheld terahertz pulsed imaging device to differentiate benign and malignant breast tissue[J]. Biomed Opt Express, 2017, 8(6):2932-2945. doi: 10.1364/BOE.8.002932 pmid: 28663917
[28]	SADEGHI A, NAGHAVI S M H, MOZAFARI M, et al. Nanoscale biomaterials for terahertz imaging: a non-invasive approach for early cancer detection[J]. Transl Oncol,2023, 27:101565
[29]	NYAYAPATHI N, XIA J. Photoacoustic imaging of breast cancer: a mini review of system design and image features[J]. J Biomed Opt, 2019, 24(12):1-13. doi: 10.1117/1.JBO.24.12.121911 pmid: 31677256
[30]	LI R, LAN L, XIA Y, et al. High-speed intraoperative assessment of breast tumor margins by multimodal ultrasound and photoacoustic tomography[J]. Med Devices Sens, 2018, 1(3):e10018.
[31]	EGLOFF-JURAS C, BEZDETNAYA L, DOLIVET G, et al. NIR fluorescence-guided tumor surgery: new strategies for the use of indocyanine green[J]. Int J Nanomedicine, 2019,14:7823-7838.
[32]	TUMMERS Q R, VERBEEK F P, SCHAAFSMA B E, et al. Real-time intraoperative detection of breast cancer using near-infrared fluorescence imaging and methylene blue[J]. Eur J Surg Oncol, 2014, 40(7):850-858. doi: 10.1016/j.ejso.2014.02.225 pmid: 24862545
[33]	LAMBERTS L E, KOCH M, DE JONG J S, et al. Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: a phase -Ⅰ feasibility study[J]. Clin Cancer Res, 2017, 23(11):2730-2741.
[34]	DINTZIS S M, HANSEN S, HARRINGTON K M, et al. Real-time visualization of breast carcinoma in pathology specimens from patients receiving fluorescent tumor-marking agent tozuleristide[J]. Arch Pathol Lab Med, 2019, 143(9):1076-1083. doi: 10.5858/arpa.2018-0197-OA pmid: 30550350
[35]	SMITH B L, GADD M A, LANAHAN C R, et al. Real-time, intraoperative detection of residual breast cancer in lumpectomy cavity walls using a novel cathepsin-activated fluorescent imaging system[J]. Breast Cancer Res Treat, 2018, 171(2):413-420.
[36]	MIAMPAMBA M, LIU J, HAROOTUNIAN A, et al. Sensitive in vivo visualization of breast cancer using ratiometric protease-activatable fluorescent imaging agent, AVB-620[J]. Theranostics, 2017, 7(13):3369-3386.
[37]	MONDAL S B, GAO S, ZHU N, et al. Binocular goggle augmented imaging and navigation system provides real-time fluorescence image guidance for tumor resection and sentinel lymph node mapping[J]. Sci Rep, 2015, 5:12117. doi: 10.1038/srep12117 pmid: 26179014
[38]	KELLER M D, MAJUMDER S K, KELLEY M C, et al. Autofluorescence and diffuse reflectance spectroscopy and spectral imaging for breast surgical margin analysis[J]. Lasers Surg Med, 2010, 42(1):15-23. doi: 10.1002/lsm.20865 pmid: 20077490
[39]	PHIPPS J E, GORPAS D, UNGER J, et al. Automated detection of breast cancer in resected specimens with fluorescence lifetime imaging[J]. Phys Med Biol, 2017, 63(1):015003.
[40]	ZÚÑIGA W C, JONES V, ANDERSON S M, et al. Raman spectroscopy for rapid evaluation of surgical margins during breast cancer lumpectomy[J]. Sci Rep, 2019, 9(1):14639. doi: 10.1038/s41598-019-51112-0 pmid: 31601985
[41]	YIN H, JIN Z, DUAN W, et al. Emergence of responsive surface-enhanced raman scattering probes for imaging tumor-associated metabolites[J]. Adv Healthc Mater, 2022, 11(12):e2200030.
[42]	WANG Y, KANG S, KHAN A, et al. Quantitative molecular phenotyping with topically applied SERS nanoparticles for intraoperative guidance of breast cancer lumpectomy[J]. Sci Rep,2016, 6:21242 doi: 10.1038/srep21242 pmid: 26878888
[43]	WANG Y W, REDER N P, KANG S, et al. Raman-encoded molecular imaging with topically applied SERS nanoparticles for intraoperative guidance of lumpectomy[J]. Cancer Res, 2017, 77(16):4506-4516. doi: 10.1158/0008-5472.CAN-17-0709 pmid: 28615226
[44]	JIN Z, YUE Q, DUAN W, et al. Intelligent SERS navigation system guiding brain tumor surgery by intraoperatively delineating the metabolic acidosis[J]. Adv Sci (Weinh), 2022, 9(7):e2104935.
[45]	THOMAS G, NGUYEN T Q, PENCE I J, et al. Evaluating feasibility of an automated 3-dimensional scanner using Raman spectroscopy for intraoperative breast margin assessment[J]. Sci Rep, 2017, 7(1):13548. doi: 10.1038/s41598-017-13237-y pmid: 29051521
[46]	BROWN J Q, BYDLON T M, KENNEDY S A, et al. Optical spectral surveillance of breast tissue landscapes for detection of residual disease in breast tumor margins[J]. PLoS One, 2013, 8(7):e69906.
[47]	DE BOER L L, MOLENKAMP B G, BYDLON T M, et al. Fat/water ratios measured with diffuse reflectance spectroscopy to detect breast tumor boundaries[J]. Breast Cancer Res Treat, 2015, 152(3):509-518.
[48]	BALOG J, SASI-SZABó L, KINROSS J, et al. Intraoperative tissue identification using rapid evaporative ionization mass spectrometry[J]. Sci Transl Med, 2013, 5(194):194ra93.
[49]	CALLIGARIS D, CARAGACIANU D, LIU X, et al. Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis[J]. Proc Natl Acad Sci USA, 2014, 111(42):15184-15189. doi: 10.1073/pnas.1408129111 pmid: 25246570
[50]	SCHARTNER E P, HENDERSON M R, PURDEY M, et al. Cancer detection in human tissue samples using a fiber-tip pH probe[J]. Cancer Res, 2016, 76(23):6795-6801. pmid: 27903493
[51]	THILL M, DITTMER C, BAUMANN K, et al. MarginProbe^®-final results of the German post-market study in breast conserving surgery of ductal carcinoma in situ[J]. Breast, 2014, 23(1):94-96.
[52]	DIXON J M, RENSHAW L, YOUNG O, et al. Intra-operative assessment of excised breast tumour margins using ClearEdge imaging device[J]. Eur J Surg Oncol, 2016, 42(12):1834-1840. doi: S0748-7983(16)30836-8 pmid: 27591938
[53]	VARTHOLOMATOS G, HARISSIS H, ANDREOU M, et al. Rapid assessment of resection margins during breast conserving surgery using intraoperative flow cytometry[J]. Clin Breast Cancer, 2021, 21(5):e602-e610.
[54]	DICORPO D, TIWARI A, TANG R, et al. The role of Micro-CT in imaging breast cancer specimens[J]. Breast Cancer Res Treat, 2020, 180(2):343-357.

Techniques		in vivo applicability	Surface condition tolerance	Pathological typing capability	Non-destructive sample handling
Frozen section analysis			√	√
Advanced microscopy	Nonlinear microscopy			√	√，enabled by pretreatment
Advanced microscopy	Confocal laser microscopy	√		√	√，enabled by pretreatment
Advancements in conventional imaging technologies	Micro-computed tomography		√		√
	Mobile magnetic resonance imaging system		√		√
	Breast positron emission tomography using novel scintillator		√		√
	Cerenkov luminescence imaging		√		√
Optical imaging techniques exploiting surface and structural properties	Optical coherence tomography	√			√
	Hyperspectral imaging	√			√
	Terahertz pulsed imaging				√
	Photoacoustic imaging	√			√
Fluorescence imaging		√			√，enabled by pretreatment
Techniques based on biochemical property contrast of tissues	Raman spectroscopy	√			√
	Diffuse reflectance spectroscopy	√			√
	Rapid evaporative ionization mass spectrometry	√	√		√
	Desorption electrospray ionization mass spectrometry	√			√
	Optical fiber sensing	√			√
Techniques based on electrical property contrast of tissues	Radiofrequency spectroscopy	√			√
Techniques based on electrical property contrast of tissues	Bioimpedance spectroscopy	√			√
Flow cytometry			√