Metastases to Regional Lymph Nodes in Breast Cancer: Current Views of Detection Methods

In Russia, breast cancer is the most prevalent oncological pathology among female patients, accounting for approximately 22.5% of all cancer cases. Approximately 90% of mortalities associated with this condition are attributed to the metastasis of cancer cells. Consequently, the effective detection of metastases within the regional lymphatic system during breast tumor progression is a critical diagnostic component. In recent decades, methodologies for verifying metastatic regional lymph nodes in breast cancer patients have advanced significantly, demonstrating high efficacy. The identification of sentinel lymph nodes became feasible through the use of various dyes, radioisotopes, and superparamagnetic nanoparticles. Detection techniques for metastatically affected formations include radioisotope lymphoscintigraphy, single-photon emission computed tomography (SPECT) often in combination with computed tomography (CT), and positron emission tomography (PET) typically integrated with CT. The accumulated data enabled an assessment of the advantages and limitations of current diagnostic methods. Radioisotope lymphoscintigraphy offers minimal invasiveness, high accuracy, and a low risk of complications; however, it remains insufficiently safe and cost-prohibitive. The application of superparamagnetic nanoparticles exerts negligible adverse effects on the human body and is characterized by straightforward administration. However, this method remains understudied, with its implementation being limited. Although the SPECT in combination with CT offers high sensitivity, thereby facilitating precise sentinel lymph node localization, it is associated with. exposure to ionizing radiation for the patient and the associated high procedural costs. Published data confirm the significance and efficacy of modern techniques for verifying metastatic regional lymph nodes in breast cancer. Therefore, the optimal diagnostic approaches can be selected, while reducing the invasiveness of mastectomy and lymph node dissection, improving survival rates, and decreasing the probability of recurrence or cancer progression.

1. Wilkinson L., Gathani T. Understanding breast cancer as a global health concern. Br J Radiol. 2022;95(1130):20211033. DOI: 10.1259/bjr.20211033

2. Kaprin A.D., Starinsky V.V., Shakhzadova A.O. Malignant neoplasms in Russia in 2023 (morbidity and mortality). М.: P.A Gertsen Moscow Research Oncology Institute — branch of the National Medical Research Center for Radiology; 2024.

3. Yang S.X., Hewitt S.M., Yu J. Locoregional tumor burden and risk of mortality in metastatic breast cancer. NPJ Precis Oncol. 2022;6(1):22. DOI: 10.1038/s41698-022-00265-9

4. Sanvido V.M., Elias S., Facina G., Bromberg S.E., Nazário A.C.P. Survival and recurrence with or without axillary dissection in patients with invasive breast cancer and sentinel node metastasis. Sci Rep. 2021;11(1):19893. DOI: 10.1038/s41598-021-99359-w

5. Zhang-Yin J., Mauel E., Talpe S. Update on sentinel lymph node methods and pathology in breast cancer. Diagnostics (Basel). 2024;14(3):252. DOI: 10.3390/diagnostics14030252

6. Sappey P.C. Anatomie, physiologie, pathologie des vesseaux lymphatiques consideres chez l’homme et les vertebres. Paris A; 1885.

7. Cieśla S., Wichtowski M., Poźniak-Balicka R., Murawa D. The surgical anatomy of the mammary gland. Vascularisation, innervation, lymphatic drainage, the structure of the axillary fossa (Part 2.). NOWOTWORY Journal of Oncology. 2021;71(1):62–9. DOI: 10.5603/NJO.2021.0011

8. Ramakrishnan R. Surgical anatomy. In.: Dev B., Joseph, L.D. (eds) Holistic approach to breast disease. Singapore: Springer; 2023. DOI: 10.1007/978-981-99-0035-0_1

9. Bland K.I. Topographic anatomical relationships of the breast, chest wall, axilla, and related sites of metastases. In: Klimberg V., Kovacs T., Rubio I. (eds) Oncoplastic breast surgery techniques for the general surgeon. Cham: Springer; 2020. DOI: 10.1007/978-3-030-40196-2_2

10. Kantharia S., Gadgil A., Cherian S., Basu P., Lucas E. Atlas of breast cancer early detection. IARC Cancerbase No. 17. Lyon: International Agency for Research on Cancer; 2023.

11. Varghese S. A. Secondary lymphedema: pathogenesis. J Skin Sex Transm Dis. 2021;3(1):7–15. DOI: 10.25259/JSSTD_3_2021

12. Welch D.R., Hurst DR. Defining the hallmarks of metastasis. Cancer Res. 2019;79(12):3011–27. DOI: 10.1158/0008-5472.CAN-19-0458

13. Nathanson S., Nelson L. Interstitial fluid pressure in breast cancer, benign breast conditions and breast parenchyma. Ann Surg Oncol. 1994;1(4):333–8. DOI: 10.1007/BF03187139

14. Zhou H., Lei P.J., Padera T.P. Progression of metastasis through lymphatic system. Cells. 2021;10(3):627. DOI: 10.3390/cells10030627

15. Jana S., Muscarella R.A. Jr, Jones D. The multifaceted effects of breast cancer on tumor-draining lymph nodes. Am J Pathol. 2021;191(8):1353–63. DOI: 10.1016/j.ajpath.2021.05.006

16. Zikiryakhodzhaev A.D., Grushina T.I., Starkova M.V., Kazaryan L.P., Volkova Yu.I., Bagdasarova D.V., Ablitsova N.V., Skreptsova N.S., Usov F.N. Methods for sentinel lymph node detection in patients with breast cancer. Siberian journal of oncology. 2020;19(5):88–96 (In Russ.). DOI: 10.21294/1814-4861-2020-19-5-88-96

17. Riis M. Modern surgical treatment of breast cancer. Ann Med Surg (Lond). 2020;56:95–107. DOI: 10.1016/j.amsu.2020.06.016

18. Kett K., Varga G., Lukacs L. Direct lymphography of the breast. Lymphology. 1970;3(1):2–12. PMID: 4317224

19. White K.P., Sinagra D., Dip F., Rosenthal R.J., Mueller E.A., Lo Menzo E., et al. Indocyanine green fluorescence versus blue dye, technetium-99M, and the dual-marker combination of technetium-99M + blue dye for sentinel lymph node detection in early breast cancer-metaanalysis including consistency analysis. Surgery. 2024;175(4):963–73. DOI: 10.1016/j.surg.2023.10.021

20. Olivier F., Courtois A., Jossa V., Bruck G., Aouachria S., Coibion M., et al. Sentinel lymph node mapping with patent blue dye in patients with breast cancer: a retrospective single institution study. Gland Surg. 2021;10(9):2600–7. DOI: 10.21037/gs-21-415

21. Morton D.L., Wen D.R., Wong J.H., Economou J.S., Cagle L.A., Storm F.K., et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127(4):392–9. DOI: 10.1001/archsurg.1992.01420040034005

22. Simmons R., Thevarajah S., Brennan M.B., Christos P., Osborne M. Methylene blue dye as an alternative to isosulfan blue dye for sentinel lymph node localization. Ann Surg Oncol. 2003;10(3):242–7. DOI: 10.1245/aso.2003.04.021

23. Perenyei M., Barber Z.E., Gibson J., Hemington-Gorse S., Dobbs T.D. Anaphylactic reaction rates to blue dyes used for sentinel lymph node mapping: systematic review and meta-analysis. Ann Surg. 2021;273(6):1087–93. DOI: 10.1097/SLA.0000000000004061

24. Alex J.C., Krag D.N. Gamma-probe guided localization of lymph nodes. Surg Oncol. 1993;2(3):137–43. DOI: 10.1016/0960-7404(93)90001-f

25. D’Eredita G., Ferrarese F., Cecere V., Massa S.T., de Carne F., Fabiano G. Subareolar injection may be more accurate than other techniques for sentinel lymph node biopsy in breast cancer. Ann Surg Oncol. 2003;10(8):942–7. DOI: 10.1245/aso.2003.01.022

26. Shimazu K., Tamaki Y., Taguchi T., Takamura Y., Noguchi S. Comparison between periareolar and peritumoral injection of radiotracer for sentinel lymph node biopsy in patients with breast cancer. Surgery. 2002;131(3):277–86. DOI: 10.1067/msy.2002.121378

27. Cody H.S., Fey J., Akhurst T., Fazzari M., Mazumdar M., Yeung H., et al. Complementarity of blue dye and isotope in sentinel node localization for breast cancer: univariate and multivariate analysis of 966 procedures. Ann Surg Oncol. 2001;8(1):13–9. DOI: 10.1007/s10434-001-0013-9

28. Anan K., Mitsuyama S., Kuga H., Saimura M., Tanabe Y., Suehara N., et al. Double mapping with subareolar blue dye and peritumoral green dye injections decreases the false-negative rate of dye-only sentinel node biopsy for early breast cancer: 2-site injection is more accurate than 1-site injection. Surgery. 2006;139(5):624–9. DOI: 10.1016/j.surg.2005.11.007

29. Aron A., Zavaleta C. Current and developing lymphatic imaging approaches for elucidation of functional mechanisms and disease progression. Mol Imaging Biol. 2024;26(1):1–16. DOI: 10.1007/s11307-023-01827-4

30. Kamata A., Miyamae T., Koizumi M., Kohei H., Sarukawa H., Nemoto H., et al. Using computed tomography lymphography for mapping of sentinel lymph nodes in patients with breast cancer. J Clin Imaging Sci. 2021;11:43. DOI: 10.25259/JCIS_33_2021

31. Vidal-Sicart S., Rioja M.E., Prieto A., Goñi E., Gómez I., Albala M.D., et al. Sentinel lymph node biopsy in breast cancer with 99mTc-Tilmanocept: a multicenter study on real-life use of a novel tracer. J Nucl Med. 2021;62(5):620–7. DOI: 10.2967/jnumed.120.252064

32. Aragon-Sanchez S., Oliver-Perez M.R., Madariaga A., Tabuenca M.J., Martinez M., Galindo A., et al. Accuracy and limitations of sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer patients with positive nodes. Breast J. 2022;2022:1507881. DOI: 10.1155/2022/1507881

33. Lazar A.M., Mutuleanu M.D., Spiridon P.M., Bordea C.I., Suta T.L., Blidaru A., et al. Feasibility of sentinel lymph node biopsy in breast cancer patients with axillary conversion after neoadjuvant chemotherapy. A single-tertiary centre experience and review of the literature. Diagnostics (Basel). 2023;13(18):3000. DOI: 10.3390/diagnostics13183000

34. Cuccurullo V., Rapa M., Catalfamo B., Cascini G.L. Role of nuclear sentinel lymph node mapping compared to new alternative imaging methods. J Pers Med. 2023;13(8):1219. DOI: 10.3390/jpm13081219

35. Chahid Y., Qiu X., van de Garde E.M.W., Verberne H.J., Booij J. Risk factors for nonvisualization of the sentinel lymph node on lymphoscintigraphy in breast cancer patients. EJNMMI Res. 2021;11(1):54. DOI: 10.1186/s13550-021-00793-8

36. Mushtaq S., Bibi A., Park J.E., Jeon J. Recent progress in technetium-99m-labeled nanoparticles for molecular imaging and cancer therapy. Nanomaterials (Basel). 2021;11(11):3022. DOI: 10.3390/nano11113022

37. Blidaru A., Bordea C.I., Radu M., Noditi A., Iordache I. Sentinel lymph node biopsy techniques. In: Breast cancer essentials: perspectives for surgeons. Cham: Springer; 2021. P. 487–98. DOI: 10.1007/978-3-030-73147-2_43

38. Britton T.B., Solanki C.K., Pinder S.E., Mortimer P.S., Peters A.M., Purushotham A.D. Lymphatic drainage pathways of the breast and the upper limb. Nucl Med Commun. 2009;30(6):427–30. DOI: 10.1097/MNM.0b013e328315a6c6

39. Noguchi M., Yokoi M., Nakano Y. Axillary reverse mapping with indocyanine fluorescence imaging in patients with breast cancer. J Surg Oncol. 2010;101(3):217–21. DOI: 10.1002/jso.21473

40. Israel O., Pellet O., Biassoni L., De Palma D., Estrada-Lobato E., Gnanasegaran G. et al. Two decades of SPECT/CT — the coming of age of a technology: An updated review of literature evidence. Eur J Nucl Med Mol Imaging. 2019;46(10):1990–2012. DOI: 10.1007/s00259-019-04404-6

41. Nikolaeva E.A., Krylov A.S., Ryzhkov A.D., Batyrov Kh.Kh., Parokonnaya A.A., Bilik M.E., et al. Diagnostic value of nuclear medicine modaities for the detection of sentinel lymph nodes in patients with breast cancer. Siberian journal of oncology. 2022;21(2):12–23 (In Russ.). DOI: 10.21294/1814-4861-2022-21-2-12-23

42. Luan T., Li Y., Wu Q., Wang Y., Huo Z., Wang X., et al. Value of quantitative SPECT/CT lymphoscintigraphy in improving sentinel lymph node biopsy in breast cancer. Breast J. 2022;2022:6483318. DOI: 10.1155/2022/6483318

43. Li P., Sun D. Advanced diagnostic imaging of sentinel lymph node in early stage breast cancer. J Clin Ultrasound. 2022;50(3):415–21. DOI: 10.1002/jcu.23151

44. Ou X., Zhu J., Qu Y., Wang C., Wang B., Xu X., et al. Imaging features of sentinel lymph node mapped by multidetector-row computed tomography lymphography in predicting axillary lymph node metastasis. BMC Med Imaging. 2021;21(1):193. DOI: 10.1186/s12880-021-00722-0

45. Wen S., Liang Y., Kong X., Liu B., Ma T., Zhou Y., et al. Application of preoperative computed tomographic lymphography for precise sentinel lymph node biopsy in breast cancer patients. BMC Surg. 2021;21(1):187. DOI: 10.1186/s12893-021-01190-7

46. Li P., Sun D. Advanced diagnostic imaging of sentinel lymph node in early stage breast cancer. J Clin Ultrasound. 2022;50(3):415–421. DOI: 10.1002/jcu.23151

47. Benjamin J., O’Leary C., Hur S., Gurevich A., Klein W.M., Itkin M. Imaging and interventions for lymphatic and lymphatic-related disorders. Radiology. 2023;307(3):e220231. DOI: 10.1148/radiol.220231

48. Engels S., Michalik B., Meyer L.M., Nemitz L., Wawroschek F., Winter A. Magnetometer-guided sentinel lymph node dissection in prostate cancer: rate of lymph node involvement compared with radioisotope marking. Cancers (Basel). 2021;13(22):5821. DOI: 10.3390/cancers13225821

49. Scally N., Armstrong L., Mathers H. A single centre experience in the use of superparamagnetic iron oxide as an alternative tracer in sentinel node biopsy in early breast cancer. Ann Breast Surg 2022;6:2. DOI: 10.21037/abs-21-24

50. Pantiora E., Eriksson S., Wärnberg F., Karakatsanis A. Magnetically guided surgery after primary systemic therapy for breast cancer: implications for enhanced axillary mapping. Br J Surg. 2024;111(2):znae008. DOI: 10.1093/bjs/znae008

51. Lorek A., Steinhof-Radwanska K., Zarębski W., Lorek J., Stojcev Z., Zych J., et al. Comparative analysis of postoperative complications of sentinel node identification using the sentimag® method and the use of a radiotracer in patients with breast cancer. Curr Oncol. 2022;29(5):2887–94. DOI: 10.3390/curroncol29050235

52. Aribal E., Çelik L., Yilmaz C., Demirkiran C., Guner D.C. Effects of iron oxide particles on MRI and mammography in breast cancer patients after a sentinel lymph node biopsy with paramagnetic tracers. Clin Imaging. 2021;75:22–6. DOI: 10.1016/j.clinimag.2020.12.011

53. Abidi H., Bold R.J. Assessing the Sentimag system for guiding sentinel node biopsies in patients with breast cancer. Expert Rev Med Devices. 2023;21(1–2):1–9. DOI: 10.1080/17434440.2023.2284790

54. Makita M., Manabe E., Kurita T., Takei H., Nakamura S., Kuwahata A., et al. Moving a neodymium magnet promotes the migration of a magnetic tracer and increases the monitoring counts on the skin surface of sentinel lymph nodes in breast cancer. BMC Med Imaging. 2020;20(1):58. DOI: 10.1186/s12880-020-00459-2

55. Samiei S., Smidt M.L., Vanwetswinkel S., Engelen S.M.E., Schipper R.J., Lobbes M.B.I., et al. Diagnostic performance of standard breast MRI compared to dedicated axillary MRI for assessment of node-negative and node-positive breast cancer. Eur Radiol. 2020;30(8):4212–22. DOI: 10.1007/s00330-020-06760-6

56. Chen S.T., Lai H.W., Chang J.H., Liao C.Y., Wen T.C., Wu W.P., et al. Diagnostic accuracy of pre-operative breast magnetic resonance imaging (MRI) in predicting axillary lymph node metastasis: variations in intrinsic subtypes, and strategy to improve negative predictive value-an analysis of 2473 invasive breast cancer patients. Breast Cancer. 2023;30(6):976–85. DOI: 10.1007/s12282-023-01488-9

57. Song S.E., Cho K.R., Cho Y., Jung S.P., Park K.H., Woo O.H., et al. Value of breast MRI and nomogram after negative axillary ultrasound for predicting axillary lymph node metastasis in patients with clinically T1-2 N0 breast cancer. J Korean Med Sci. 2023;38(34):e251. DOI: 10.3346/jkms.2023.38.e251

58. Atallah D., Moubarak M., Arab W., El Kassis N., Chahine G., Salem C. MRI-based predictive factors of axillary lymph node status in breast cancer. Breast J. 2020;26(11):2177–82. DOI: 10.1111/tbj.14089

59. Kim J.A., Wales D.J., Yang G-Z. Optical spectroscopy for in vivo medical diagnosis—a review of the state of the art and future perspectives. Prog Biomed Eng. 2020;2:042001. DOI: 10.1088/2516-1091/abaaa3

60. Hanna K., Krzoska E. Shaaban A.M, Muirhead D., Abu-Eid R., Speirs V. Raman spectroscopy: current applications in breast cancer diagnosis, challenges and future prospects. Br J Cancer. 2022;126(8):1125–39. DOI: 10.1038/s41416-021-01659-5

61. Barkur S., Boitor R.A., Mihai R., Gopal N.S.R., Leeney S., Koloydenko A.A., et al. Intraoperative spectroscopic evaluation of sentinel lymph nodes in breast cancer surgery. Breast Cancer Res Treat. 2024;207(1):223–32. DOI: 10.1007/s10549-024-07349-z

62. Buzatto I.P.C., Dos Reis F.J.C., de Andrade J.M., Rodrigues T.C.G.F., Borba J.M.C., Netto A.H. Axillary ultrasound and fine-needle aspiration cytology to predict clinically relevant nodal burden in breast cancer patients. World J Surg Oncol. 2021;19(1):292. DOI: 10.1186/s12957-021-02391-3

63. Zhu Y., Fan X., Yang D., Dong T., Jia Y., Nie F. Contrast-enhanced ultrasound for precise sentinel lymph node biopsy in women with early breast cancer: a preliminary study. Diagnostics (Basel). 2021;11(11):2104. DOI: 10.3390/diagnostics11112104

64. Cui Q., Dai L., Li J., Shen Y., Tao H., Zhou X., et al. Contrast-enhanced ultrasound-guided sentinel lymph node biopsy in early-stage breast cancer: a prospective cohort study. World J Surg Oncol. 2023;21(1):143. DOI: 10.1186/s12957-023-03024-7

65. Fan Y., Luo J., Lu Y., Huang C., Li M., Zhang Y., et al. The application of contrast-enhanced ultrasound for sentinel lymph node evaluation and mapping in breast cancer patients. Quant Imaging Med Surg. 2023;13(7):4392–404. DOI: 10.21037/qims-22-901

66. Marino M.A., Avendano D., Zapata P., Riedl C.C., Pinker K. Lymph node imaging in patients with primary breast cancer: concurrent diagnostic tools. Oncologist. 2020;25(2):e231–42. DOI: 10.1634/theoncologist.2019-0427

67. Tan H., Wu Y., Bao F., Zhou J., Wan J., Tian J., et al. Mammographybased radiomics nomogram: a potential biomarker to predict axillary lymph node metastasis in breast cancer. Br J Radiol. 2020;93(1111):20191019. DOI: 10.1259/bjr.20191019

68. Zheng M., Huang Y., Peng J., Xia Y., Cui Y., Han X., et al. Optimal selection of imaging examination for lymph node detection of breast cancer with different molecular subtypes. Front Oncol. 2022;12:762906. DOI: 10.3389/fonc.2022.762906