Sentinel Lymph Node Identification Using Contrast Lymphosonography: A Systematic Review

doi:10.37015/AUDT.2023.230001

Abstract

Abstract:

The sentinel lymph node (SLN) concept hypothesizes that metastatic cancer cells will spread through the lymphatic system to the SLN being the first one in the lymphatic chain to receive the metastatic cells, indicating that if the SLN is free of cancer cells the rest of the lymphatic chain is also without metastatic disease. Diagnostic ultrasound imaging (US) has been used to evaluate lymph nodes (LN) to determine level of suspicion and to guide LN biopsies. However, conventional US cannot be used for lymphatic mapping, which requires administration of a tracer. This has been changed with the use of contrast-enhanced US (CEUS) to detect lymphatic channels and SLNs after subcutaneous injections of microbubble-based US contrast agents (UCAs). The aim of this review is to examine the clinical evidence on the role of subcutaneous injection of UCA, known as lymphosonography, to be used as preoperative identification of SLNs in patients with breast and other cancers.

Key words: Contrast-enhanced ultrasound; Sentinel lymph node; Breast cancer; Lymphatic tracer; Ultrasound contrast agent; Lymphosonography; Lymphatic mapping

Priscilla Machado, MD, Ji-Bin Liu, MD, Flemming Forsberg, PhD. Sentinel Lymph Node Identification Using Contrast Lymphosonography: A Systematic Review. Advanced Ultrasound in Diagnosis and Therapy, 2023, 7(1): 1-7.

Figures/Tables 4

Table 1

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Table 2

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References 67

[1]	Wisner RK, and Bloch SB. Use of ultrasound bubbles in lymph node imaging. Nanoparticles in Biomedical Imaging (Springer) 2008.
[2]	Boughey JC, Suman VJ, Mittendorf EA, Ahrendt GM, Wilke LG, Taback B, et al. Factors affecting sentinel lymph node identification rate after neoadjuvant chemotherapy for breast cancer patients enrolled in ACOSOG Z1071 (Alliance). Annals of Surgery 2015; 261:547. doi: 10.1097/SLA.0000000000000551 pmid: 25664534
[3]	Emerson DK, Limmer KK, Hall DJ, Han SH, Eckelman WC, Kane CJ, et al. A receptor-targeted fluorescent radiopharmaceutical for multireporter sentinel lymph node imaging. Radiology 2012; 265:186-193. pmid: 22753678
[4]	Tokin CA, Cope FO, Metz WL, Blue MS, Potter BM, Abbruzzese BC, et al. The efficacy of Tilmanocept in sentinel lymph mode mapping and identification in breast cancer patients: a comparative review and meta-analysis of the 99mTc-labeled nanocolloid human serum albumin standard of care. Clinical & Experimental Metastasis 2012; 29:681-686.
[5]	Tan VK, Goh BK, Fook-Chong S, Khin LW, Wong WK, Yong WS. The feasibility and accuracy of sentinel lymph node biopsy in clinically node-negative patients after neoadjuvant chemotherapy for breast cancer—a systematic review and meta-analysis. Journal of Surgical Oncology 2011; 104:97-103. doi: 10.1002/jso.21911
[6]	Machado P, Stanczak M, Liu JB, Moore JN, Eisenbrey JR, Needleman L, et al. Subdermal ultrasound contrast agent injection for sentinel lymph node identification: an analysis of safety and contrast agent dose in healthy volunteers. Journal of Ultrasound in Medicine 2018; 37:1611-1620. doi: 10.1002/jum.14502 pmid: 29205451
[7]	Kim T, Giuliano AE, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in early-stage breast carcinoma: a metaanalysis. Cancer 2006; 106:4-16. doi: 10.1002/cncr.21568 pmid: 16329134
[8]	Nielsen Moody A, Bull J, Culpan AM, Munyombwe T, Sharma N, Whitaker M, et al. Preoperative sentinel lymph node identification, biopsy and localisation using contrast enhanced ultrasound (CEUS) in patients with breast cancer: a systematic review and meta-analysis. Clin Radiol 2017; 72:959-971. doi: S0009-9260(17)30356-2 pmid: 28774472
[9]	Shimazu K, Miyake T, Tanei T, Naoi Y, Shimoda M, Kagara N, et al. Real-time visualization of lymphatic flow to sentinel lymph nodes by contrast-enhanced ultrasonography with sonazoid in patients with breast cancer. Ultrasound in Medicine & Biology 2019; 45:2634-2640. doi: 10.1016/j.ultrasmedbio.2019.07.005
[10]	Liu YB, Xia M, Li YJ, Li S, Li H, Li YL. Contrast-enhanced ultrasound in locating axillary sentinel lymph nodes in patients with breast cancer: a prospective study. Ultrasound in Medicine & Biology 2021; 47:1475-1483. doi: 10.1016/j.ultrasmedbio.2021.02.002
[11]	Deng H, Lei J, Jin L, Shi H. Diagnostic efficacy of sentinel lymph node in breast cancer under percutaneous contrast‐enhanced ultrasound: an updated meta-analysis. Thoracic Cancer 2021;1759-1777.
[12]	Lyman GH, Giuliano AE, Somerfield MR, Benson AB 3rd, Bodurka DC, Burstein HJ, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. Journal of Clinical Oncology 2005; 23:7703-7720. doi: 10.1200/JCO.2005.08.001 pmid: 16157938
[13]	Jang S, Lee CU, Hesley GK, Knudsen JM, Brinkman NJ, Tran NV. Lymphatic mapping using us microbubbles before lymphaticovenous anastomosis surgery for lymphedema. Radiology 2022; 304:218-224. doi: 10.1148/radiol.212351
[14]	Wang Z, Cui Y, Zheng M, Ge H, Huang Y, Peng J, et al. Comparison of indocyanine green fluorescence and methylene blue dye in the detection of sentinel lymph nodes in breast cancer. Gland Surgery 2020; 9:1495. doi: 10.21037/gs-20-671 pmid: 33224824
[15]	Zhao J, Zhang J, Zhu QL, Jiang YX, Sun Q, Zhou YD, et al. The value of contrast-enhanced ultrasound for sentinel lymph node identification and characterisation in pre-operative breast cancer patients: a prospective study. European Radiology 2018; 28:1654-1661. doi: 10.1007/s00330-017-5089-0 pmid: 29058028
[16]	Hill ADK, Mann BG, Borgen PI, Cody HS. Sentinel lymphatic mapping in breast cancer. Journal of the American College of Surgeons 1999; 188:545-549. pmid: 10235585
[17]	Eshima D, Fauconnier T, Eshima L, Thornback JR. Radiopharmaceuticals for lymphoscintigraphy: including dusimetry and radiation considerations. Semin Nucl Med 2000; 30:25-32. pmid: 10656241
[18]	Veronesi U, Paganelli G, Viale G, Luini A, Zurrida S, Galimberti V, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. New England Journal of Medicine 2003; 349:546-553. doi: 10.1056/NEJMoa012782
[19]	Goldfarb LR, Alazraki NP, Eshima D, Eshima LA, Herda SC, Halkar RK. Lymphoscintigraphic identification of sentinel lymph nodes: clinical evaluation of 0.22-micron filtration of Tc-99m sulfur colloid. Radiology 1998; 208:505-509. doi: 10.1148/radiology.208.2.9680583 pmid: 9680583
[20]	Goldberg BB, Merton DA, Liu JB, Murphy G, Forsberg F. Contrast‐enhanced sonographic imaging of lymphatic channels and sentinel lymph nodes. Journal of Ultrasound in Medicine 2005; 24:953-965. doi: 10.7863/jum.2005.24.7.953 pmid: 15972710
[21]	Goldberg BB, Merton DA, Liu JB, Forsberg F, Zhang K, Thakur M, et al. Contrast-enhanced ultrasound imaging of sentinel lymph nodes after peritumoral administration of Sonazoid in a melanoma tumor animal model. Journal of Ultrasound in Medicine 2011; 30:441-453. pmid: 21460143
[22]	Goonawardena J, Yong C, Law M. Use of indocyanine green fluorescence compared to radioisotope for sentinel lymph node biopsy in early-stage breast cancer: systematic review and meta-analysis. The American Journal of Surgery 2020; 220:665-676. doi: 10.1016/j.amjsurg.2020.02.001
[23]	Mazouni C, Koual M, De Leeuw F, Conversano A, Leymarie N, Rimareix F, et al. Prospective evaluation of the limitations of near‐infrared imaging in detecting axillary sentinel lymph nodes in primary breast cancer. The breast Journal 2018; 24:1006-1009. doi: 10.1111/tbj.2018.24.issue-6
[24]	Ma X, Wen S, Liu B, Li D, Wang X, Kong X, et al. Relationship between upper extremity lymphatic drainage and sentinel lymph nodes in patients with breast cancer. Journal of Oncology 2019: 8637895.
[25]	Giuliano AE, Ballman KV, McCall L, Beitsch PD, Brennan MB, Kelemen PR, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA 2017; 318:918-926. doi: 10.1001/jama.2017.11470 pmid: 28898379
[26]	Evans KD, Boyd A. Sonographic and vascular assessment of axillary lymph nodes: a review. Journal of Diagnostic Medical Sonography 2007; 23:63-72. doi: 10.1177/8756479306296949
[27]	Cho N, Moon WM, Han W, Park IA, Cho J, Noh DY. Preoperative sonographic classification of axillary lymph nodes in patients with breast cancer: node-to-node correlation with surgical histology and sentinel node biopsy results. American Journal of Roentgenology 2009; 193:1731-1737. doi: 10.2214/AJR.09.3122 pmid: 19933672
[28]	Voit CA, van Akkooi AC, Schäfer-Hesterberg G, Schoengen A, Schmitz PI, Sterry W, et al. Rotterdam criteria for sentinel node (SN) tumor burden and the accuracy of ultrasound (US)-guided fine-needle aspiration cytology (FNAC): can US-guided FNAC replace SN staging in patients with melanoma? Journal of Clinical Oncology 2009; 27:4994-5000.
[29]	Romeo V, Accardo G, Perillo T, Basso L, Garbino N, Nicolai E, et al. Assessment and prediction of response to neoadjuvant chemotherapy in breast cancer: a comparison of imaging modalities and future perspectives. Cancers 2021; 13:3521. doi: 10.3390/cancers13143521
[30]	Liu JB, Merton DA, Berger AC, Forsberg F, Witkiewicz A, Zhao H, et al. Contrast‐enhanced sonography for detection of secondary lymph nodes in a melanoma tumor animal model. Journal of Ultrasound in Medicine 2014; 33:939-947. doi: 10.7863/ultra.33.6.939
[31]	Mattrey RF, Kono Y, Baker K, Peterson T. Sentinel lymph node imaging with microbubble ultrasound contrast material. Academic Radiology 2002; 9:231-235.
[32]	Omoto K, Matsunaga H, Take N, Hozumi Y, Takehara M, Omoto Y, et al. Sentinel node detection method using contrast-enhanced ultrasonography with sonazoid in breast cancer: preliminary clinical study. Ultrasound in Medicine & Biology 2009; 35:1249-1256. doi: 10.1016/j.ultrasmedbio.2009.02.004
[33]	Sever AR, Mills P, Jones SE, Cox K, Weeks J, Fish D, et al. Preoperative sentinel node identification with ultrasound using microbubbles in patients with breast cancer. American Journal of Roentgenology 2011; 196:251-256. doi: 10.2214/AJR.10.4865 pmid: 21257873
[34]	Sever AR, Mills P, Weeks J, Jones SE, Fish D, Jones PA, et al. Preoperative needle biopsy of sentinel lymph nodes using intradermal microbubbles and contrast-enhanced ultrasound in patients with breast cancer. American Journal of Roentgenology 2012; 199:465-470. doi: 10.2214/AJR.11.7702 pmid: 22826414
[35]	Goldberg BB, Merton DA, Liu JB, Thakur M, Murphy GF, Needleman L, et al. Sentinel lymph nodes in a swine model with melanoma: contrast-enhanced lymphatic US. Radiology 2004; 230:727-734.
[36]	Cox K, Sever A, Jones S, Weeks J, Mills P, Devalia H, et al. Validation of a technique using microbubbles and contrast enhanced ultrasound (CEUS) to biopsy sentinel lymph nodes (SLN) in pre-operative breast cancer patients with a normal grey-scale axillary ultrasound. European Journal of Surgical Oncology 2013; 39:760-765. doi: 10.1016/j.ejso.2013.03.026 pmid: 23632319
[37]	Cox K, Taylor-Phillips S, Sharma N, Weeks J, Mills P, Sever A, et al. Enhanced pre-operative axillary staging using intradermal microbubbles and contrast-enhanced ultrasound to detect and biopsy sentinel lymph nodes in breast cancer: a potential replacement for axillary surgery. The British Journal of Radiology 2018; 91:626.
[38]	Cox K, Weeks J, Mills P, Chalmers R, Devalia H, Fish D, et al. Contrast-enhanced ultrasound biopsy of sentinel lymph nodes in patients with breast cancer: implications for axillary metastases and conservation. Annals of Surgical Oncology 2016; 23:58-64. doi: 10.1245/s10434-015-4606-0 pmid: 25990967
[39]	Moody AN, Cox K, Haigh I, Chen Y, Sharma N. Does contrast enhanced ultrasound (CEUS) of normal/benign axillary lymph nodes in patients with breast cancer identify significant axillary nodal burden? European Journal of Radiology 2020; 132:109-111.
[40]	Esfehani MH, Yazdankhah-Kenari A, Omranipour R, Mahmoudzadeh HA, Shahriaran S, Zafarghandi MR, et al. Validation of contrast enhanced ultrasound technique to wire localization of sentinel lymph node in patients with early breast cancer. Indian Journal of Surgical Oncology 2015; 6:370-373. doi: 10.1007/s13193-015-0446-4 pmid: 27065663
[41]	Hao Y, Sun Y, Lei Y, Zhao H, Cui L. Percutaneous Sonazoid-enhanced ultrasonography combined with in vitro verification for detection and characterization of sentinel lymph nodes in early breast cancer. European Radiology 2021; 31:5894-5901. doi: 10.1007/s00330-020-07639-2 pmid: 33502555
[42]	Jin L, Wang R, Zhuang L, Jin Y, Sun X, Jia C, et al. Evaluation of whole axillary status with lymphatic contrast-enhanced ultrasound in patients with breast cancer. European Radiology 2022; 32:630-638. doi: 10.1007/s00330-021-08100-8
[43]	Li J, Lu M, Cheng X, Hu Z, Li H, Wang H, et al. How pre-operative sentinel lymph node contrast-enhanced ultrasound helps intra-operative sentinel lymph node biopsy in breast cancer: initial experience. Ultrasound in Medicine & Biology 2019; 45:1865-1873. doi: 10.1016/j.ultrasmedbio.2019.04.006
[44]	Liu YB, Xia M, Li YJ, Li S, Li H, Li YL. Contrast-enhanced ultrasound in locating axillary sentinel lymph nodes in patients with breast cancer: a prospective study. Ultrasound in Medicine & Biology 2021; 47:1475-1483. doi: 10.1016/j.ultrasmedbio.2021.02.002
[45]	Liu J, Liu X, He J, Gou B, Luo Y, Deng S, et al. Percutaneous contrast-enhanced ultrasound for localization and diagnosis of sentinel lymph node in early breast cancer. Scientific Reports 2019; 9:1-6. doi: 10.1038/s41598-018-37186-2
[46]	Ma S, Xu Y, Ling F. Preoperative evaluation and influencing factors of sentinel lymph node detection for early breast cancer with contrast-enhanced ultrasonography: What matters. Medicine 2021:100:e25183.
[47]	Qiao J, Li J, Wang L, Guo X, Bian X, Lu Z. Predictive risk factors for sentinel lymph node metastasis using preoperative contrast-enhanced ultrasound in early-stage breast cancer patients. Gland Surgery 2021; 10:761-769. doi: 10.21037/gs-20-867 pmid: 33708558
[48]	Saidha NK, Aggarwal R, Sen A. Identification of sentinel lymph nodes using contrast-enhanced ultrasound in breast Cancer. Indian Journal of Surgical Oncology 2018; 9:355-361. doi: 10.1007/s13193-017-0646-1 pmid: 30287998
[49]	Rautiainen S, Sudah M, Joukainen S, Sironen R, Vanninen R, Sutela A. Contrast-enhanced ultrasound-guided axillary lymph node core biopsy: diagnostic accuracy in preoperative staging of invasive breast cancer. European Journal of Radiology 2015; 84:2130-2136. doi: 10.1016/j.ejrad.2015.08.006 pmid: 26343047
[50]	Xu YL, Liu XJ, Zhu Y, Lu H. Preoperative localization of sentinel lymph nodes using percutaneous contrast-enhanced ultrasonography in patients with breast cancer. Gland Surgery 2022; 11:369-377. doi: 10.21037/gs
[51]	Wu X, Tang L, Huang W, Huang S, Peng W, Hu D. Contrast-enhanced ultrasonography and blue dye methods in detection of sentinel lymph nodes following neoadjuvant chemotherapy in initially node positive breast cancer. Archives of Gynecology and Obstetrics 2020; 302:685-692. doi: 10.1007/s00404-020-05646-8 pmid: 32602000
[52]	Xie F, Zhang D, Cheng L, Yu L, Yang L, Tong F, et al. Intradermal microbubbles and contrast-enhanced ultrasound (CEUS) is a feasible approach for sentinel lymph node identification in early-stage breast cancer. World Journal of Surgical Oncology 2015; 13:319. doi: 10.1186/s12957-015-0736-x pmid: 26585236
[53]	Zhong J, Sun DS, Wei W, Liu X, Liu J, Wu X, et al. Contrast-enhanced ultrasound-guided fine-needle aspiration for sentinel lymph node biopsy in early-stage breast cancer. Ultrasound in Medicine & Biology 2018; 44:1371-1378. doi: 10.1016/j.ultrasmedbio.2018.03.005
[54]	Zhou P, Zheng W, Liu Y, Wang Y. Preoperative contrast-enhanced ultrasound (CEUS) combined with 125I seeds localization in sentinel lymph node biopsy for breast cancer. Cancer Management and Research 2021; 13:1853-1860. doi: 10.2147/CMAR.S296142
[55]	Zhou Y, Li Y, Mao F, Zhang J, Zhu Q, Shen S, et al. Preliminary study of contrast-enhanced ultrasound in combination with blue dye vs. indocyanine green fluorescence, in combination with blue dye for sentinel lymph node biopsy in breast cancer. BMC Cancer 2019; 19:939. doi: 10.1186/s12885-019-6165-4 pmid: 31604469
[56]	Machado P, Liu JB, Needleman L, Lazar M, Willis AI, Brill K, et al. Sentinel lymph node identification in patients with breast cancer using lymphosonography. Ultrasound in Medicine & Biology 2023; 49:616-625. doi: 10.1016/j.ultrasmedbio.2022.10.020
[57]	Albertini JJ, Lyman GH, Cox C, Yeatman T, Balducci L, Ku N, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 1996; 276:1818-1822. doi: 10.1001/jama.1996.03540220042028
[58]	Shimazu K, Ito T, Uji K, Miyake T, Aono T, Motomura K, et al. Identification of sentinel lymph nodes by contrast‐enhanced ultrasonography with Sonazoid in patients with breast cancer: a feasibility study in three hospitals. Cancer Medicine 2017; 6:1915-1922. doi: 10.1002/cam4.1142 pmid: 28766883
[59]	Wong SL, Edwards MJ, Chao C, Tuttle TM, Noyes RD, Carlson DJ, et al. Sentinel lymph node biopsy for breast cancer: impact of the number of sentinel nodes removed on the false-negative rate. Journal of the American College of Surgeons 2001; 192:684-689. doi: 10.1016/s1072-7515(01)00858-4 pmid: 11400961
[60]	Hu Z, Cheng X, Li J, Jiang J, Jiang Z, Li H, et al. Preliminary study of real-time three-dimensional contrast-enhanced ultrasound of sentinel lymph nodes in breast cancer. European Radiology 2020; 30:1426-1435. doi: 10.1007/s00330-019-06494-0 pmid: 31776739
[61]	Li J, Chen X, Qi M, Li Y. Sentinel lymph node biopsy mapped with methylene blue dye alone in patients with breast cancer: a systematic review and meta-analysis. PloS one 2018; 13:e0204364.
[62]	Pesek S, Ashikaga T, Krag LE, Krag D. The false-negative rate of sentinel node biopsy in patients with breast cancer: a meta-analysis. World Journal of Surgery 2021; 36:2239-2251. doi: 10.1007/s00268-012-1623-z
[63]	Wakisaka N, Endo K, Kitazawa T, Shimode Y, Kato K, Moriyama-Kita M, et al. Detection of sentinel lymph node using contrast-enhanced agent, Sonazoid™, and evaluation of its metastasis with superb microvascular imaging in oral and oropharyngeal cancers: a preliminary clinical study. Acta Oto-laryngologica 2019; 139:94-99. doi: 10.1080/00016489.2018.1535193 pmid: 30676845
[64]	Wei Y, Yu MA, Niu Y, Hao Y, Di JX, Zhao ZL, et al. Combination of lymphatic and intravenous contrast-enhanced ultrasound for evaluation of cervical lymph node metastasis from papillary thyroid carcinoma: a preliminary study. Ultrasound in Medicine & Biology 2021; 47:252-260. doi: 10.1016/j.ultrasmedbio.2020.10.003
[65]	Gvetadze SR, Xiong P, Lv M, Li J, Hu J, Ilkaev KD, et al. Contrast-enhanced ultrasound mapping of sentinel lymph nodes in oral tongue cancer—a pilot study. Dentomaxillofacial Radiology 2017; 46:345-350.
[66]	Lahtinen O, Eloranta M, Anttila M, Kärkkäinen H, Sironen R, Vanninen R, et al. Preoperative sentinel lymph node localization in vulvar cancer: preliminary experience with inguinal intradermal contrast-enhanced ultrasound. European Radiology 2018; 28:2089-2095. doi: 10.1007/s00330-017-5155-7 pmid: 29189931
[67]	Liu JB, Machado P, Eisenbrey JR, et al. Identification of sentinel lymph nodes in esophageal cancer patients using contrast-enhanced endoscopic ultrasound with peritumoral injections. Endoscopic Ultrasound (2023; in press)

Author Year Country	Patient (N) Cancer type	UCA/Dose Injection site	Comparison	Results
Liu, et al. 2022 USA	N = 30 Esophageal Adenocarcinoma and squamous cell carcinoma	Sonazoid/1.0 ml Peritumoral	FNA cytology	CE-EUS showed enhancement in 19 of the 22 malignant LNs. The rate of metastatic node identification from EUS was 45% (10/22) and it was 86% (19/22; P = 0.008) for CE-EUS.
Wakisaka et al. 2019 Japan	N = 10 Oral Squamous cell and mucinous epidermoid carcinomas	Sonazoid/2.0 ml Peritumoral	Surgical pathology	SLNs were successfully detected in 8 out of 10 cases.
Wei et al. 2021 China	N = 24 Thyroid Papillary carcinoma	Sonazoid/0.1 ml At front of the tumor	FNA cytology	To evaluated lymphatic-CEUS (LCEUS) and intravenous-CEUS (IVCEUS) to identify cervical node metastasis (CLNM). LCEUS had more value (AUC = 0.850) in diagnosing CLNM than IVCEUS (AUC = 0.692) and routine US (AUC = 0.581).
Gvetadze et al. 2017 China	N = 12 Tongue Squamous cell carcinoma	Sonovue/0.3 ml Peritumoral	Surgical pathology	The identification rate of the sentinel nodes was 91.7%. 15 SLN were found in 11 cases (1.4 SLN/patient).
Lahtinen et al. 2018 Finland	N = 12 Vulva Squamous cell carcinoma	Sonovue/0.4 ml Upper lateral of mons pubis	Surgical pathology	To compare to routing SLN biopsy, overall sensitivity was 81.2% (13/16). CEUS detected enhancing SLN in 2 cases not seen by traditional method. All metastatic SLNs (n = 5) were correctly identified by CEUS procedure.