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Ultraschall Med 2022; 43(06): 592-598
DOI: 10.1055/a-1917-0016
Original Article

Super-Resolution Ultrasound Localization Microscopy of Microvascular Structure and Flow for Distinguishing Metastatic Lymph Nodes – An Initial Human Study

Lokalisierungsmikroskopie mit Superresolution-Ultraschall der mikrovaskulären Struktur und des Flusses zur Unterscheidung metastatischer Lymphknoten – eine erste Studie am Menschen
Jiaqi Zhu‡
1   Bioengineering, Imperial College London, London, United Kingdom of Great Britain and Northern Ireland
,
Chao Zhang‡
2   Department of Ultrasound, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, People’s Republic of China (Ringgold ID: RIN89681)
,
Kirsten Christensen-Jeffries
3   Imaging Sciences and Biomedical Engineering, King’s College London School of Medical Education, London, United Kingdom of Great Britain and Northern Ireland (Ringgold ID: RIN12196)
,
Ge Zhang
1   Bioengineering, Imperial College London, London, United Kingdom of Great Britain and Northern Ireland
,
Sevan Harput
4   Division of Electrical and Electronic Engineering, London South Bank University, London, United Kingdom of Great Britain and Northern Ireland
,
Christopher Dunsby
5   Physics, Imperial College London, London, United Kingdom of Great Britain and Northern Ireland (Ringgold ID: RIN4615)
,
Pintong Huang
2   Department of Ultrasound, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, People’s Republic of China (Ringgold ID: RIN89681)
,
Meng-Xing Tang 
1   Bioengineering, Imperial College London, London, United Kingdom of Great Britain and Northern Ireland
› InstitutsangabenGefördert durch: Engineering and Physical Sciences Research Council EP/N015487/1
Gefördert durch: NIHR NIHR200972
Gefördert durch: Cancer Research UK C53470/A22353
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Abstract

Purpose Detecting and distinguishing metastatic lymph nodes (LNs) from those with benign lymphadenopathy are crucial for cancer diagnosis and prognosis but remain a clinical challenge. A recent advance in super-resolution ultrasound (SRUS) through localizing individual microbubbles has broken the diffraction limit and tracking enabled in vivo noninvasive imaging of vascular morphology and flow dynamics at a microscopic level. In this study we hypothesize that SRUS enables quantitative markers to distinguish metastatic LNs from benign ones in patients with lymphadenopathy.

Materials and Methods Clinical contrast-enhanced ultrasound image sequences of LNs from 6 patients with lymph node metastasis and 4 with benign lymphadenopathy were acquired and motion-corrected. These were then used to generate super-resolution microvascular images and super-resolved velocity maps. From these SRUS images, morphological and functional measures were obtained including micro-vessel density, fractal dimension, mean flow speed, and Local Flow Direction Irregularity (LFDI) measuring the variance in local flow direction. These measures were compared between pathologically proven reactive and metastasis LNs.

Results Our initial results indicate that the difference in the indicator of flow irregularity (LFDI) derived from the SRUS images is statistically significant between the two groups. The LFDI is 60% higher in metastatic LNs compared with reactive nodes.

Conclusion This pilot study demonstrates the feasibility of super-resolution ultrasound for clinical imaging of lymph nodes and the potential of using the irregularity of local blood flow directions afforded by SRUS for the characterization of LNs.

Zusammenfassung

Ziel Der Nachweis und die Differenzierung metastatischer Lymphknoten (LK) von den LK einer benignen Lymphadenopathie sind entscheidend für die Krebsdiagnose und -prognose, stellen jedoch eine klinische Herausforderung dar. Ein neuer Fortschritt der Superresolution-Ultraschall-Bildgebung (SRUS) durch Lokalisierung einzelner Mikrobläschen hat die Beugungsgrenze durchbrochen und eine nicht invasive In-vivo-Bildgebung der Gefäßmorphologie und Flussdynamik auf mikroskopischer Ebene ermöglicht. In dieser Studie stellen wir die Hypothese auf, dass SRUS quantitativen Markern ermöglicht, metastatische von benignen LK bei Patienten mit Lymphadenopathie zu unterscheiden.

Material und Methoden Klinische kontrastverstärkte Ultraschall-Bildsequenzen der LK von 6 Patienten mit Lymphknoten-Metastasen und von 4 mit gutartiger Lymphadenopathie wurden aufgenommen und bewegungskorrigiert. Diese wurden dann verwendet, um hochaufgelöste mikrovaskuläre Bilder und hochaufgelöste Geschwindigkeitskarten zu erstellen. Aus diesen SRUS-Bildern wurden morphologische und funktionelle Messwerte gewonnen, darunter die Dichte der Mikrogefäße, die fraktale Dimension, die mittlere Flussgeschwindigkeit und die Unregelmäßigkeit der lokalen Flussrichtung („Local Flow Direction Irregularity“, LFDI), die die Abweichung der lokalen Flussrichtung misst. Diese Messungen wurden zwischen pathologisch nachgewiesenen reaktiven und metastatischen LK verglichen.

Ergebnisse Unsere ersten Ergebnisse deuten darauf hin, dass der Unterschied beim Indikator Fluss-Unregelmäßigkeit (LFDI), der aus den SRUS-Bildern abgeleitet wird, zwischen den beiden Gruppen statistisch signifikant ist. Die LFDI ist bei metastatischen LK um 60% höher als bei reaktiven Knoten.

Schlussfolgerung Diese Pilotstudie zeigt die Durchführbarkeit der klinischen Superresolution-Ultraschall-Bildgebung bei Lymphknoten und das Potenzial der Nutzung der Unregelmäßigkeit lokaler Blutflussrichtungen, wie sie der SRUS für die Charakterisierung von LK bietet.

Keywords

blood flow - localization microscopy - microbubble contrast agents - super-resolution ultrasound - lymph node micro-vessel

Supporting information



Publikationsverlauf

Eingereicht: 08. September 2021

Angenommen nach Revision: 20. Juni 2022

Artikel online veröffentlicht:
07. Oktober 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Liao LJ, Lo WC, Hsu WL. et al. ‘Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck – a meta-analysis comparing different imaging modalities’. BMC Cancer 2012; 12: 236
    CrossrefPubMedGoogle Scholar
  • 2 Krag DN. et al. ‘Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial’. Lancet Oncol 2010; 10 (11) 927-933
    CrossrefPubMedGoogle Scholar
  • 3 Li N, Cui M, Yu P. et al. Correlations of lncRNAs with cervical lymph node metastasis and prognosis of papillary thyroid carcinoma. Onco Targets Ther 2019; 12: 1269-1278 DOI: 10.2147/OTT.S191700. (PMID: 30863094)
    CrossrefPubMedGoogle Scholar
  • 4 Mansel RE. et al. ‘Randomized Multicenter Trial of Sentinel Node Biopsy Versus Standard Axillary Treatment in Operable Breast Cancer: The ALMANAC Trial’, JNCI J. Natl. Cancer Inst 2006; 98 (09) 599-609 DOI: 10.1093/jnci/djj158. (PMID: 16670385)
    CrossrefPubMedGoogle Scholar
  • 5 Carmeliet P, Jain R. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249-257 DOI: 10.1038/35025220. (PMID: 11001068)
    CrossrefPubMedGoogle Scholar
  • 6 Farnsworth R, Lackmann M, Achen M. et al. Vascular remodeling in cancer. Oncogene 2014; 33: 3496-3505 DOI: 10.1038/onc.2013.304. (PMID: 23912450)
    CrossrefPubMedGoogle Scholar
  • 7 Lindner JR. “Microbubbles in medical imaging: current applications and future directions”. Nature Reviews Drug Discovery 2004; 3 (06) 527-532 DOI: 10.1038/nrd1417. (PMID: 15173842)
    CrossrefPubMedGoogle Scholar
  • 8 Sever A, Jones S, Cox K. et al. Preoperative localization of sentinel lymph nodes using intradermal microbubbles and contrast-enhanced ultrasonography in patients with breast cancer. Br J Surg 2009; 96: 1295-1299 DOI: 10.1002/bjs.6725. (PMID: 19847869)
    CrossrefPubMedGoogle Scholar
  • 9 Chen L, Chen L, Liu J. et al. ‘Value of Qualitative and Quantitative Contrast-Enhanced Ultrasound Analysis in Preoperative Diagnosis of Cervical Lymph Node Metastasis From Papillary Thyroid Carcinoma’, J. Ultrasound Med. Off. J. Am. Inst. Ultrasound Med 2020; 39 (01) 73-81 DOI: 10.1002/jum.15074. (PMID: 31222782)
    CrossrefPubMedGoogle Scholar
  • 10 Tang MX. et al. ‘Quantitative contrast-enhanced ultrasound imaging: a review of sources of variability’. Interface Focus 2011; 04 (01) 520-539
    CrossrefPubMedGoogle Scholar
  • 11 Dudau C. et al. ‘Can Contrast-Enhanced Ultrasound Distinguish Malignant from Reactive Lymph Nodes in Patients with Head and Neck Cancers?’, Ultrasound Med. Biol 2014; 40 (04) 747-754 DOI: 10.1016/j.ultrasmedbio.2013.10.015. (PMID: 24462154)
    CrossrefPubMedGoogle Scholar
  • 12 Betzig E, Patterson GH, Sougrat R. et al. Imaging intracellular fluorescent proteins at nanometer resolution. Science 2006; 313: 1642-1645 DOI: 10.1126/science.1127344. (PMID: 16902090)
    CrossrefPubMedGoogle Scholar
  • 13 Christensen-Jeffries K, Couture O, Dayton PA. et al. Super-resolution Ultrasound Imaging. Ultrasound in Medicine & Biology 2020; 46 (04) 865-891 DOI: 10.1016/j.ultrasmedbio.2019.11.013. (PMID: 31973952)
    CrossrefPubMedGoogle Scholar
  • 14 Siepmann M, Schmitz G, Bzyl J. et al. Imaging tumor vascularity by tracing single microbubbles. IEEE IUS 2011; 1906-1909
    PubMedGoogle Scholar
  • 15 Christensen-Jeffries K, Browning RJ, Tang MX. et al. In vivo acoustic super-resolution and super-resolved velocity mapping using microbubbles. IEEE TMI 2015; 34: 433-440
    PubMedGoogle Scholar
  • 16 Errico C, Pierre J, Pezet S. et al. Ultrafast ultrasound localization microscopy for deep super-resolution vascular imaging. Nature 2015; 527: 499 DOI: 10.1038/nature16066. (PMID: 26607546)
    CrossrefPubMedGoogle Scholar
  • 17 Lin F, Shelton SE, Espíndola D. et al. 3-D ultrasound localization microscopy for identifying microvascular morphology features of tumor angiogenesis at a resolution beyond the diffraction limit of conventional ultrasound. Theranostics 2017; 7: 196
    CrossrefPubMedGoogle Scholar
  • 18 Song P, Trzasko JD, Manduca A. et al. Improved super-resolution ultrasound microvessel imaging with spatiotemporal nonlocal means filtering and bipartite graph-based microbubble tracking. IEEE T UFFC 2017; 65: 149-167
    CrossrefPubMedGoogle Scholar
  • 19 Zhu J, Rowland EM, Harput S. et al. 3D Super-Resolution US Imaging of Rabbit Lymph Node Vasculature in Vivo by Using Microbubbles. Radiology 2019; 291: 642-650 DOI: 10.1148/radiol.2019182593. (PMID: 30990382)
    CrossrefPubMedGoogle Scholar
  • 20 Kanoulas E, Butler M, Rowley C. et al. Super-Resolution Contrast-Enhanced Ultrasound Methodology for the Identification of In Vivo Vascular Dynamics in 2D. Investigative Radiology 2019; 54 (08) 500-516 DOI: 10.1097/RLI.0000000000000565. (PMID: 31058661)
    CrossrefPubMedGoogle Scholar
  • 21 Opacic T, Dencks S, Theek B. et al. Motion model ultrasound localization microscopy for preclinical and clinical multiparametric tumor characterization. Nature communications 2018; 9: 1527 DOI: 10.1038/s41467-018-03973-8. (PMID: 29670096)
    CrossrefPubMedGoogle Scholar
  • 22 Zhang W, Lowerison MR, Dong Z. et al. Super-Resolution Ultrasound Localization Microscopy on a Rabbit Liver VX2 Tumor Model: An Initial Feasibility Study. Ultrasound Med Biol 2021; 47 (08) 2416-2429 DOI: 10.1016/j.ultrasmedbio.2021.04.012. (PMID: 34045095)
    CrossrefPubMedGoogle Scholar
  • 23 Harput S, Christensen-Jeffries K, Brown J. et al. Two-Stage Motion Correction for Super-Resolution Ultrasound Imaging in Human Lower Limb. IEEE T UFFC 2018; 65: 803-814 DOI: 10.1109/TUFFC.2018.2824846. (PMID: 29733283)
    CrossrefPubMedGoogle Scholar
  • 24 Zhang G, Harput S, Hu H. et al. « Fast Acoustic Wave Sparsely Activated Localization Microscopy: Ultrasound Super-Resolution Using Plane-Wave Activation of Nanodroplets ». IEEE T UFFC 2019; 66 (06) 1039-46
    CrossrefPubMedGoogle Scholar
  • 25 Russell DA, Hanson JD, Ott E. ‘Dimension of Strange Attractors’. Phys Rev Lett 1980; 45 (14) 1175-1178
    CrossrefPubMedGoogle Scholar
  • 26 Suad I, Jayaweera Ananda R, Camarano G. et al. ‘Relation Between Air-Filled Albumin Microbubble and Red Blood Cell Rheology in the Human Myocardium’. Circulation 1996; 94 (03) 445-451
    CrossrefPubMedGoogle Scholar
  • 27 Leunig M. et al. ‘Angiogenesis, Microvascular Architecture, Microhemodynamics, and Interstitial Fluid Pressure during Early Growth of Human Adenocarcinoma LS174T in SCID Mice’. Cancer Res 1992; 52 (23) 6553-6560
    PubMedGoogle Scholar
  • 28 Saad R, Kordunsky L, Liu Y. et al. Lymphatic microvessel density as prognostic marker in colorectal cancer. Mod Pathol 2006; 19: 1317-1323 DOI: 10.1038/modpathol.3800651. (PMID: 16799477)
    CrossrefPubMedGoogle Scholar
  • 29 Ahuja AT, Ying M. ‘Sonographic Evaluation of Cervical Lymph Nodes’. Am J Roentgenol 2005; 184 (05) 1691-1699
    CrossrefPubMedGoogle Scholar
  • 30 Nagy JA, Chang SH, Dvorak AM. et al. ‘Why are tumour blood vessels abnormal and why is it important to know?’. Br J Cancer 2009; 100 (06) 865-869 DOI: 10.1038/sj.bjc.6604929. (PMID: 19240721)
    CrossrefPubMedGoogle Scholar