Multimodal Optical Coherence Tomography for Intraoperative Evaluation of Tumor Margins and Surgical Margins in Breast-Conserving Surgery

The aim of the study. We compare the effectiveness of multimodal optical coherence tomography (MM OCT) in the traditional structural OCT mode and the OCT elastography (OCE) mode in addressing two clinically important tasks: (1) detecting groups of tumor cells at surgical margins during breast-сonserving surgery (BСS) in breast cancer (BC) and (2) identifying breast tumor margins. The obtained results were correlated with corresponding histological sections.

Materials and Methods. The study was performed on 100 surgical margin samples (top, bottom, medial, and lateral — four samples from each patient in total) obtained from 25 patients with BC who underwent BCS (lumpectomy), and on 25 postoperative tumor samples (to determine tumor margins). With MM OCT method, we visually and numerically assessed the scattering (level and depth of OCT signal penetration) and elastic (stiffness values, or Young’s modulus (kPa)) properties of the tumor and non-tumor breast tissue and the obtained values were compared with the results of postoperative histological examination.

Results. In 4 surgical margin samples (out of 100), with the OCE method we identified groups of histologically confirmed tumor cells (“positive” resection margins) at the distance of about 5 mm from the visible tumor margin. The identified zones were larger than 0.5 mm with stiffness of more than 400 kPa in all these cases. However, the structural OCT could not identify these groups of tumors and they were not distinguishable from the surrounding fibrous tissue.

In the areas of tumor into non-tumor tissue transition, structural OCT images detected tumor margins only if they were adjacent to adipose tissue and did not detect them if there were adjacent to non-tumor fibrous tissue. OCE images with high stiffness values (more than 400 kPa) and high contrast showed a clear tumor margin with both adipose and fibrous tissue.

Conclusion. The study demonstarets the potential of MM OCT, particularly its OCE mode, as a real-time method for intraoperative tumor margin and surgical margin assessment in BCS. OCE images compared to structural OCT images visualize higher contrast between different types of breast tissue (adipose tissue, fibrous stroma, hyalinized stroma, tumor cell clusters), as well as more accurate identification of the tumor border and detection of small groups of tumor cells at surgical margins. An algorithm for intraoperative MM OCT examination of the state of the resection margin is proposed in accordance with standard clinical guidelines for achieving clean surgical margins in breast cancer patients.

1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209–249, https://doi.org/10.3322/caac.21660.
2. Pozhariyskiy K.M., Kuydabergenova A.G., Savelov N.A., Grinevich V.N., Sazonov S.V.; RAOM Expert Council. Klinicheskie rekomendatsii Rossiyskogo obshchestva onkomammologov po patologoanatomicheskomu issledovaniyu raka molochnoy zhelezy [Clinical recommendations of the Russian Association of Oncological Mammology for pathoanatomical examination of breast cancer]. Russian Association of Oncological Mammology; 2016; URL: http://www.breastcancersociety.ru/rek/view/29.
3. Semiglazov V.F., Semiglazov V.V., Nikolaev K.S., Komyakhov A.V., Bryantseva G.V. The control of surgical margins for organ-preserving treatment of breast cancer. Onkohirurgia 2014; 6(1): 58–63.
4. Houssami N., Macaskill P., Marinovich M.L., Dixon J.M., Irwig L., Brennan M.E., Solin L.J. Meta-analysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. Eur J Cancer 2010; 46(18): 3219–3232, https://doi.org/10.1016/j.ejca.2010.07.043.
5. Jorns J.M., Visscher D., Sabel M., Breslin T., Healy P., Daignaut S., Myers J.L., Wu A.J. Intraoperative frozen section analysis of margins in breast conserving surgery significantly decreases reoperative rates: one-year experience at an ambulatory surgical center. Am J Clin Pathol 2012; 138(5): 657–669, https://doi.org/10.1309/ajcp4iemxcj1gdts.
6. Esbona K., Li Z., Wilke L.G. Intraoperative imprint cytology and frozen section pathology for margin assessment in breast conservation surgery: a systematic review. Ann Surg Oncol 2012; 19(10): 3236–3245, https://doi.org/10.1245/s10434-012-2492-2.
7. Decker M.R., Trentham-Dietz A., Loconte N.K., Neuman H.B., Smith M.A., Punglia R.S., Greenberg C.C., Wilke L.G. The role of intraoperative pathologic assessment in the surgical management of ductal carcinoma in situ. Ann Surg Oncol 2016; 23(9): 2788–2794, https://doi.org/10.1245/s10434-016-5192-5.
8. Harness J.K., Giuliano A.E., Pockaj B.A., Downs-Kelly E. Margins: a status report from the Annual Meeting of the American Society of Breast Surgeons. Ann Surg Oncol 2014; 21(10): 3192–3197, https://doi.org/10.1245/s10434-014-3957-2.
9. Ahmed M., Douek M. Intra-operative ultrasound versus wire-guided localization in the surgical management of non-palpable breast cancers: systematic review and meta-analysis. Breast Cancer Res Treat 2013; 140(3): 435–446, https://doi.org/10.1007/s10549-013-2639-2.
10. Olsha O., Shemesh D., Carmon M., Sibirsky O., Abu Dalo R., Rivkin L., Ashkenazi I. Resection margins in ultrasound-guided breast-conserving surgery. Ann Surg Oncol 2011; 18(2): 447–452, https://doi.org/10.1245/s10434-010-1280-0.
11. Keller M.D., Vargis E., de Matos Granja N., Wilson R.H., Mycek M.A., Kelley M.C., Mahadevan-Jansen A. Development of a spatially offset Raman spectroscopy probe for breast tumor surgical margin evaluation. J Biomed Opt 2011; 16(7): 077006, https://doi.org/10.1117/1.3600708.
12. Kothari R., Fong Y., Storrie-Lombardi M.C. Review of laser Raman spectroscopy for surgical breast cancer detection: stochastic backpropagation neural networks. Sensors (Basel) 2020; 20(21): 6260, https://doi.org/10.3390/s20216260.
13. Thomas G., Nguyen T.Q., Pence I.J., Caldwell B., O’Connor M.E., Giltnane J., Sanders M.E., Grau A., Meszoely I., Hooks M., Kelley M.C., Mahadevan-Jansen A. Evaluating feasibility of an automated 3-dimensional scanner using Raman spectroscopy for intraoperative breast margin assessment. Sci Rep 2017; 7(1): 13548, https://doi.org/10.1038/s41598-017-13237-y.
14. Wu X., Chen G., Qiu J., Lu J., Zhu W., Chen J., Zhuo S., Yan J. Visualization of basement membranes in normal breast and breast cancer tissues using multiphoton microscopy. Oncol Lett 2016; 11(6): 3785–3789, https://doi.org/10.3892/ol.2016.4472.
15. Yoshitake T., Giacomelli M.G., Cahill L.C., Schmolze D.B., Vardeh H., Faulkner-Jones B.E., Connolly J.L., Fujimoto J.G. Direct comparison between confocal and multiphoton microscopy for rapid histopathological evaluation of unfixed human breast tissue. J Biomed Opt 2016; 21(12): 126021, https://doi.org/10.1117/1.jbo.21.12.126021.
16. Houssami N., Macaskill P., Marinovich M.L., Morrow M. The association of surgical margins and local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol 2014; 21(3): 717–730, https://doi.org/10.1245/s10434-014-3480-5.
17. Wood W.C. Close/positive margins after breast-conserving therapy: additional resection or no resection? Breast 2013; 22 (Suppl 2): S115–S117, https://doi.org/10.1016/j.breast.2013.07.022.
18. Ha R., Friedlander L.C., Hibshoosh H., Hendon C., Feldman S., Ahn S., Schmidt H., Akens M.K., Fitzmaurice M., Wilson B.C., Mango V.L. Optical coherence tomography: a novel imaging method for post-lumpectomy breast margin assessment-a multi-reader study. Acad Radiol 2018; 25(3): 279–287, https://doi.org/10.1016/j.acra.2017.09.018.
19. Schmidt H., Connolly C., Jaffer S., Oza T., Weltz C.R., Port E.R., Corben A. Evaluation of surgically excised breast tissue microstructure using wide-field optical coherence tomography. Breast J 2020; 26(5): 917–923, https://doi.org/10.1111/tbj.13663.
20. Savastru D., Chang E.W., Miclos S., Pitman M.B., Patel A., Iftimia N. Detection of breast surgical margins with optical coherence tomography imaging: a concept evaluation study. J Biomed Opt 2014; 19(5): 056001, https://doi.org/10.1117/1.jbo.19.5.056001.
21. Zysk A.M., Chen K., Gabrielson E., Tafra L., May Gonzalez E.A., Canner J.K., Schneider E.B., Cittadine A.J., Scott Carney P., Boppart S.A., Tsuchiya K., Sawyer K., Jacobs L.K. Intraoperative assessment of final margins with a handheld optical imaging probe during breast-conserving surgery may reduce the reoperation rate: results of a multicenter study. Ann Surg Oncol 2015; 22(10): 3356–3362, https://doi.org/10.1245/s10434-015-4665-2.
22. Gubarkova E.V., Sovetsky A.A., Zaitsev V.Y., Matveyev A.L., Vorontsov D.A., Sirotkina M.A., Matveev L.A., Plekhanov A.A., Pavlova N.P., Kuznetsov S.S., Vorontsov A.Y., Zagaynova E.V., Gladkova N.D. OCT-elastography-based optical biopsy for breast cancer delineation and express assessment of morphological/molecular subtypes. Biomed Opt Express 2019; 10(5): 2244–2263, https://doi.org/10.1364/boe.10.002244.
23. Gubarkova E.V., Kiseleva E.B., Sirotkina M.A., Vorontsov D.A., Achkasova K.A., Kuznetsov S.S., Yashin K.S., Matveyev A.L., Sovetsky A.A., Matveev L.A., Plekhanov A.A., Vorontsov A.Y., Zaitsev V.Y., Gladkova N.D. Diagnostic accuracy of cross-polarization OCT and OCT-elastography for differentiation of breast cancer subtypes: comparative study. Diagnostics (Basel) 2020; 10(12): 994, https://doi.org/10.3390/diagnostics10120994.
24. Allen W.M., Foo K.Y., Zilkens R., Kennedy K.M., Fang Q., Chin L., Dessauvagie B.F., Latham B., Saunders C.M., Kennedy B.F. Clinical feasibility of optical coherence micro-elastography for imaging tumor margins in breast-conserving surgery. Biomed Opt Express 2018; 9(12): 6331–6349, https://doi.org/10.1364/boe.9.006331.
25. Kennedy K.M., Zilkens R., Allen W.M., Foo K.Y., Fang Q., Chin L., Sanderson R.W., Anstie J., Wijesinghe P., Curatolo A., Tan H.E.I., Morin N., Kunjuraman B., Yeomans C., Chin S.L., DeJong H., Giles K., Dessauvagie B.F., Latham B., Saunders C.M., Kennedy B.F. Diagnostic accuracy of quantitative micro-elastography for margin assessment in breast-conserving surgery. Cancer Res 2020; 80(8): 1773–1783, https://doi.org/10.1158/0008-5472.can-19-1240.
26. Allen W.M., Kennedy K.M., Fang Q., Chin L., Curatolo A., Watts L., Zilkens R., Chin S.L., Dessauvagie B.F., Latham B., Saunders C.M., Kennedy B.F. Wide-field quantitative micro-elastography of human breast tissue. Biomed Opt Express 2018; 9(3): 1082–1096, https://doi.org/10.1364/boe.9.001082.
27. Azu M., Abrahamse P., Katz S.J., Jagsi R., Morrow M. What is an adequate margin for breast-conserving surgery? Surgeon attitudes and correlates. Ann Surg Oncol 2010; 17(2): 558–563, https://doi.org/10.1245/s10434-009-0765-1.
28. Gatek J., Vrana D., Lukesova L., Pospiskova M., Vazan P., Melichar B. Significance of resection margin as a risk factor for local control of early stage breast cancer. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2013; 157(3): 209–213, https://doi.org/10.5507/bp.2013.067.
29. Gelikonov V.M., Romashov V.N., Shabanov D.V., Ksenofontov S.Yu., Terpelov D.A., Shilyagin P.A., Gelikonov G.V., Vitkin I.A. Cross-polarization optical coherence tomography with active maintenance of the circular polarization of a sounding wave in a common path system. Radiophys Quantum Electron 2018; 60: 897–911, https://doi.org/10.1007/s11141-018-9856-9.
30. Moiseev A., Ksenofontov S., Sirotkina M., Kiseleva E., Gorozhantseva M., Shakhova N., Matveev L., Zaitsev V., Matveyev A., Zagaynova E., Gelikonov V., Gladkova N., Vitkin A., Gelikonov G. Optical coherence tomography-based angiography device with real-time angiography B-scans visualization and hand-held probe for everyday clinical use. J Biophotonics 2018; 11(10): e201700292, https://doi.org/10.1002/jbio.201700292.
31. Zaitsev V.Y., Matveyev A.L., Matveev L.A., Sovetsky A.A., Hepburn M.S., Mowla A., Kennedy B.F. Strain and elasticity imaging in compression optical coherence elastography: the two-decade perspective and recent advances. J Biophotonics 2021; 14(2): e202000257, https://doi.org/10.1002/jbio.202000257.
32. Zaitsev V.Y., Matveyev A.L., Matveev L.A., Gelikonov G.V., Sovetsky A.A., Vitkin A. Optimized phase gradient measurements and phase-amplitude interplay in optical coherence elastography. J Biomed Opt 2016; 21(11): 116005, https://doi.org/10.1117/1.jbo.21.11.116005.
33. Zaitsev V.Y., Matveyev A.L., Matveev L.A., Gelikonov G.V., Gubarkova E.V., Gladkova N.D., Vitkin A. Hybrid method of strain estimation in optical coherence elastography using combined sub-wavelength phase measurements and supra-pixel displacement tracking. J Biophotonics 2016; 9(5): 499–509, https://doi.org/10.1002/jbio.201500203.
34. Matveyev A.L., Matveev L.A., Sovetsky A.A., Gelikonov G.V., Moiseev A.A., Zaitsev V.Y. Vector method for strain estimation in phase-sensitive optical coherence elastography. Laser Phys Lett 2018; 15(6): 065603, https://doi.org/10.1088/1612-202x/aab5e9.
35. Zaitsev V.Y., Matveyev A.L., Matveev L.A., Gubarkova E.V., Sovetsky A.A., Sirotkina M.A., Gelikonov G.V., Zagaynova E.V., Gladkova N.D., Vitkin A. Practical obstacles and their mitigation strategies in compressional optical coherence elastography of biological tissues. J Innov Opt Health Sci 2017; 10(06): 1742006, https://doi.org/10.1142/s1793545817420068.
36. Sovetsky A.A., Matveyev A.L., Matveev L.A., Shabanov D.V., Zaitsev V.Y. Manually-operated compressional optical coherence elastography with effective aperiodic averaging: demonstrations for corneal and cartilaginous tissues. Laser Phys Lett 2018; 15(8): 085602, https://doi.org/10.1088/1612-202x/aac879.
37. Sovetsky A.A., Matveyev A.L., Matveev L.A., Gubarkova E.V., Plekhanov A.A., Sirotkina M.A., Gladkova N.D., Zaitsev V.Y. Full-optical method of local stress standardization to exclude nonlinearity-related ambiguity of elasticity estimation in compressional optical coherence elastography. Laser Phys Lett 2020; 17(6): 065601, https://doi.org/10.1088/1612-202x/ab8794.
38. Plekhanov A.A., Sirotkina M.A., Sovetsky A.A., Gubarkova E.V., Kuznetsov S.S., Matveyev A.L., Matveev L.A., Zagaynova E.V., Gladkova N.D., Zaitsev V.Y. Histological validation of in vivo assessment of cancer tissue inhomogeneity and automated morphological segmentation enabled by optical coherence elastography. Sci Rep 2020; 10(1): 11781, https://doi.org/10.1038/s41598-020-68631-w.
39. Zikiryakhodzhaev A.D., Ermoshchenkova M.V., Sukhot’ko A.S., Fetisova E.Yu., Tyshchenko E.V. Indications and technology for determining resection margins in organ-preserving operations for breast cancer. Onkologia i hirurgia 2015; 1: 14–24.
40. Blair S.L., Thompson K., Rococco J., Malcarne V., Beitsch P.D., Ollila D.W. Attaining negative margins in breast-conservation operations: is there a consensus among breast surgeons? J Am Coll Surg 2009; 209(5): 608–613, https://doi.org/10.1016/j.jamcollsurg.2009.07.026.
41. Erickson-Bhatt S.J., Nolan R.M., Shemonski N.D., Adie S.G., Putney J., Darga D., McCormick D.T., Cittadine A.J., Zysk A.M., Marjanovic M., Chaney E.J., Monroy G.L., South F.A., Cradock K.A., Liu Z.G., Sundaram M., Ray P.S., Boppart S.A. Real-time imaging of the resection bed using a handheld probe to reduce incidence of microscopic positive margins in cancer surgery. Cancer Res 2015; 75(18): 3706–3712, https://doi.org/10.1158/0008-5472.can-15-0464.
42. Nguyen F.T., Zysk A.M., Chaney E.J., Kotynek J.G., Oliphant U.J., Bellafiore F.J., Rowland K.M., Johnson P.A., Boppart S.A. Intraoperative evaluation of breast tumor margins with optical coherence tomography. Cancer Res 2009; 69(22): 8790–8796, https://doi.org/10.1158/0008-5472.can-08-4340.
43. Lowery A.J., Kell M.R., Glynn R.W., Kerin M.J., Sweeney K.J. Locoregional recurrence after breast cancer surgery: a systematic review by receptor phenotype. Breast Cancer Res Treat 2012; 133(3): 831–841, https://doi.org/10.1007/s10549-011-1891-6.
44. Huang D., Swanson E.A., Lin C.P., Schuman J.S., Stinson W.G., Chang W., Hee M.R., Flotte T., Gregory K., Puliafito C.A., Fujimoto J.G. Optical coherence tomography. Science 1991; 254(5035): 1178–1181, https://doi.org/10.1126/science.1957169.
45. Wijesinghe P., Kennedy B.F., Sampson D.D. Optical elastography on the microscale. In: Tissue elasticity imaging. Alam S.K., Garra B.S. (editors). Amsterdam: Elsevier; 2020; p.  185–229, https://doi.org/10.1016/b978-0-12-809661-1.00009-1.
46. Iftimia N., Park J., Maguluri G., Krishnamurthy S., McWatters A., Sabir S.H. Investigation of tissue cellularity at the tip of the core biopsy needle with optical coherence tomography. Biomed Opt Express 2018; 9(2): 694–704, https://doi.org/10.1364/boe.9.000694.

Vorontsov D.A., Gubarkova E.V., Sirotkina M.A., Sovetsky A.A., Plekhanov A.A., Kuznetsov S.S., Davydova D.A., Bogomolova A.Yu., Zaitsev V.Y., Gamayunov S.V., Vorontsov A.Y., Sobolevskiy V.A., Gladkova N.D. Multimodal Optical Coherence Tomography for Intraoperative Evaluation of Tumor Margins and Surgical Margins in Breast-Conserving Surgery. Sovremennye tehnologii v medicine 2022; 14(2): 26, https://doi.org/10.17691/stm2022.14.2.03