Photoacoustic Imaging Addresses a Long-standing Challenge in Lymphedema

HomeRadiologyVol. 295, No. 2 PreviousNext Reviews and CommentaryFree AccessEditorialPhotoacoustic Imaging Addresses a Long-standing Challenge in LymphedemaAnna P. Lillis , Rajesh KrishnamurthyAnna P. Lillis , Rajesh KrishnamurthyAuthor AffiliationsFrom the Department of Radiology, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205-2664.Address correspondence to A.P.L. (e-mail: [email protected]).Anna P. Lillis Rajesh KrishnamurthyPublished Online:Feb 25 2020https://doi.org/10.1148/radiol.2020192824MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In See also the article by Suzuki et al in this issue.Dr Anna Lillis is a clinical assistant professor of radiology at Ohio State University and a radiologist in the section of interventional radiology at Nationwide Children’s Hospital in Columbus, Ohio, where she primarily focuses on the care of patients with vascular anomalies. Together with members of the multidisciplinary vascular anomalies team, Dr Lillis has worked to expand the interventional techniques available to patients with lymphatic and other vascular disorders, both congenital and acquired.Download as PowerPointOpen in Image Viewer Dr Rajesh Krishnamurthy is a clinical professor of radiology at Ohio State University, as well as radiologist-in-chief and head of cardiovascular imaging at Nationwide Children’s Hospital in Columbus, Ohio. He is part of the multidisciplinary vascular anomalies team, with a specific interest in the role of lymphatic and vascular imaging in the treatment of patients with lymphatic and cardiovascular disorders.Download as PowerPointOpen in Image Viewer Lymphedema is a chronic condition affecting up to 250 million people worldwide. Primary lymphedema results from abnormal development of the lymphatic system. However, the most common cause of lymphedema in the developed world is secondary lymphedema resulting from cancer treatments such as lymph node dissection. Previously, incomplete understanding of the lymphatic system’s anatomy and function limited treatment of lymphedema to supportive care. Recently, breakthroughs in lymphatic imaging and newer supermicrosurgical techniques have led to the increased use of lymphatic-venous bypass (LVB) techniques, whereby surgeons select subdermal lymphatic vessels, less than 0.8 mm in diameter, and anastomose them to venules in an effort to increase drainage of lymph into the local venous circulation.Historically, lymphoscintigraphy with colloid-bound technetium 99m and transpedal fluoroscopic lymphangiography using iodized oil–based contrast material served as the primary means of lymphatic imaging. Although lymphoscintigraphy requires simple intradermal injection and offers high specificity of the colloid-bound tracer for the lymphatic system, low spatial and temporal resolution, as well as exposure to ionizing radiation, are drawbacks. Transpedal fluoroscopic lymphangiography offers high spatial and temporal resolution but requires time-consuming surgical cut-down and cannulation of subcutaneous lymphatic vessels.Direct injection of contrast material into inguinal lymph nodes for fluoroscopic lymphangiography of the central lymphatic vessels (1) significantly decreased the time required to perform fluoroscopic lymphangiography and paved the way for recent advances in imaging of the central conducting lymphatic vessels and the development of percutaneous interventional options to treat congenital or acquired lymphatic leak or obstruction. This has been furthered by the advent of dynamic MR lymphangiography with intranodal gadolinium-based contrast agent injection. Contrast material–enhanced MR lymphangiography demonstrates excellent contrast opacification of the central lymphatic vessels, coupling temporal information with soft-tissue contrast, and three-dimensional depiction of the anatomy of deeper structures (2). Peripheral MR lymphangiography for evaluation of the lymphatic vessels performed with injection of interstitial contrast material enables visualization of both the peripheral and central lymphatic vessels and intervening lymph nodes (3). However, it has been hampered by venous contamination, as the interstitial contrast material can be absorbed by venules as well as lymphatic vessels. When opacification of solely the peripheral lymphatic vessels is desired, the problem of venous contamination has been overcome through the introduction of dual-agent relaxation contrast (4). In this method, venous signal suppression is achieved with the intravenous administration of ferumoxytol, which nulls all signal from the veins (including any inadvertent gadolinium-based contrast agent uptake) at longer echo times, enabling improved visualization of the gadolinium-based contrast agent–enhanced signal in lymphatic vessels.As remarkable as the innovations in central and peripheral lymphatic imaging have been over the past decade, none of these modalities have provided a solution to the visualization of both peripheral lymphatic vessels and adjacent venules as targets for LVB.Indocyanine green (ICG) near-infrared fluorescence (NIRF) lymphangiography relies on intradermal or subcutaneous injection of ICG fluorescent dye, which binds proteins in tissues and then is taken up by subcutaneous lymphatic vessels. Illuminating the anatomic region of interest with a light source emitting at 760–780 nm, while simultaneously imaging at 830 nm (near-infrared spectrum), allows for the acquisition of real-time information on the presence and function of lymphatic vessels and the presence of lymphatic dermal backflow. Use of ICG NIRF lymphangiography has allowed for presurgical staging (5) and intraoperative identification and selection of functional lymphatic vessels for LVB, increasing surgical efficiency and number of bypasses performed per limb and leading to a greater reduction in lymphedema severity after LVB in patients with early-stage lymphedema (6). However, ICG NIRF lymphangiography cannot demonstrate vessels deeper than 1.5–2 cm and, as such, is limited in its capability to image lymphatic vessels in the thigh or in obese patients. Further, it provides no soft-tissue anatomic information and does not demonstrate adjacent venules as possible LVB targets. US mapping in conjunction with ICG NIRF lymphangiography can be used to help identify lymphatic vessels, classifying those likely to be most successful (ectasis type), and proximate veins for LVB (7). However, differentiating lymphatic from venous channels with US can be challenging and is dependent on the skillset of the operator (7).Recently, the introduction of a new imaging modality called photoacoustic imaging (PAI) has shown promise in offering such a comprehensive solution. Kajita and Kishi (8) demonstrated the feasibility of PAI for visualization of both peripheral lymphatic vessels and veins in a patient with secondary lymphedema. PAI relies on the photoacoustic effect that occurs when a laser illuminates the tissues. The absorption of photons causes the local temperature to increase, resulting in transient thermal expansion and generation of localized pressure waves that can be detected with ultrasound. PAI can produce images relying on intrinsic tissue contrast, such as that found in hemoglobin to create images of blood vessels, or by using an optical absorption contrast agent, in this case ICG taken up by lymphatic vessels.In this issue of Radiology, Suzuki and colleagues extend this work by using a method for visualizing peripheral lymphatic vessels and adjacent venules in three dimensions using PAI and comparing the results to those of ICG NIRF lymphangiography in 15 healthy participants and one patient with secondary lymphedema (9). After injecting ICG into the web spaces of the toes and below the lateral malleolus, the authors irradiated the tissue with lasers at alternating wavelengths of 797 and 835 nm. ICG fluorescent dye in the lymphatic channels yielded strong enhancement at 797 nm but not at 835 nm, while venous blood enhanced similarly at both wavelengths. A large difference in molar extinction of ICG between these two wavelengths, compared with a small difference for hemoglobin, allowed the authors to differentiate lymphatic from blood vessels, something not previously done with ICG NIRF lymphangiography. PAI avoids a common problem encountered with NIRF, which is difficulty in distinguishing lymphatic vessels from blood vessels when ICG strays into blood vessels.The medial aspect of the lower limb was imaged in each case, taking approximately 15 minutes to acquire images. Suzuki et al observed a significantly greater number of lymphatic vessels with PAI than with NIRF in both distal and proximal segments and obtained more detailed images with PAI. They were also able to distinguish lymphatic from blood vessels and overlay images that demonstrated their relationship.Given the limitations of light penetration, both PAI and NIRF techniques are likely to produce poorer images in patients with thicker subcutaneous tissues, as can be seen in obesity and lymphedema. However, Suzuki et al demonstrated successful photoacoustic lymphatic imaging in one obese participant and found it to be superior to NIRF. There was minimal lymphatic signal detectable with NIRF in this participant, yet PAI demonstrated lymphatic vessels and subcutaneous veins. In a patient with secondary lymphedema, NIRF images showed dermal backflow only, whereas a linear pattern of ICG in lymphatic vessels as well as dermal backflow alongside veins was demonstrated on PAI images. Further technologic development will be required to overcome challenges inherent to imaging patients with extremely thick subcutaneous tissue. However, even in its current state, PAI appears to be superior to NIRF in patients with obesity or lymphedema.Although Suzuki et al clearly note that PAI in this context is currently limited in its imaging range and depth to superficial lymphatic vessels and veins above the fascia, different imaging agents, including methylene blue, have been shown to reach imaging depths as great as 52 mm in a phantom using a combined handheld photoacoustic and US probe (10). Other agents may facilitate even greater depth of imaging in the future. The potential for integrated real-time photoacoustic and conventional B-mode US imaging, while not used by the authors, could provide a convenient platform for intraoperative imaging to localize and classify lymphatic vessels and their adjacent venules as potential LVB targets.In summary, Suzuki et al have obtained photoacoustic lymphangiographic images detailing superficial peripheral lymphatic and venous vessels and their interrelationship, overcoming one of the main drawbacks of ICG NIRF lymphangiography, the current clinical standard. Further studies are anticipated demonstrating the utility of PAI lymphangiography as a diagnostic tool in patients with lymphedema. The lymphedema severity staging system developed with ICG NIRF lymphangiography (5) uses dermal backflow patterns. It will remain to be seen if this correlates with PAI over a larger cohort, but examples in this article and in the article by Kajita and Kishi (8) suggest that it might. Proof of this capability may well lead to accelerated development of portable handheld PAI devices. Further, if a combined photoacoustic and US device becomes commercially available, we believe that PAI is uniquely positioned to play a dominant role in both the preoperative assessment and intraoperative planning of LVB in patients with lymphedema. As this technology improves and new contrast agents are developed, the current tissue depth limitations may be overcome, paving the way for the use of PAI in other applications. Lymphatic uses such as in the diagnosis of central lymphatic disorders, intraprocedural guidance during percutaneous lymphatic intervention (eg, embolization of leaking or refluxing lymphatic channels), and sentinel lymph node detection in the setting of malignancy (10) may represent only a few among a broader sampling of future clinical applications.Disclosures of Conflicts of Interest: A.P.L. disclosed no relevant relationships. R.K. disclosed no relevant relationships.References1. Rajebi MR, Chaudry G, Padua HM, et al. Intranodal lymphangiography: feasibility and preliminary experience in children. J Vasc Interv Radiol 2011;22(9):1300–1305. Crossref, Medline, Google Scholar2. Krishnamurthy R, Hernandez A, Kavuk S, Annam A, Pimpalwar S. Imaging the central conducting lymphatics: initial experience with dynamic MR lymphangiography. Radiology 2015;274(3):871–878. Link, Google Scholar3. Ruehm SG, Schroeder T, Debatin JF. Interstitial MR lymphography with gadoterate meglumine: initial experience in humans. Radiology 2001;220(3):816–821. Link, Google Scholar4. Ripley B, Wilson GJ, Lalwani N, Briller N, Neligan PC, Maki JH. Initial Clinical Experience with Dual-Agent Relaxation Contrast for Isolated Lymphatic Channel Mapping. Radiology 2018;286(2):705–714. Link, Google Scholar5. Yamamoto T, Narushima M, Doi K, et al. Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns. Plast Reconstr Surg 2011;127(5):1979–1986. Crossref, Medline, Google Scholar6. Chang DW, Suami H, Skoracki R. A prospective analysis of 100 consecutive lymphovenous bypass cases for treatment of extremity lymphedema. Plast Reconstr Surg 2013;132(5):1305–1314. Crossref, Medline, Google Scholar7. Mihara M, Hara H, Kawakami Y. Ultrasonography for classifying lymphatic sclerosis types and deciding optimal sites for lymphatic-venous anastomosis in patients with lymphoedema. J Plast Reconstr Aesthet Surg 2018;71(9):1274–1281. Crossref, Medline, Google Scholar8. Kajita H, Kishi K. High-resolution imaging of lymphatic vessels with photoacoustic lymphangiography. Radiology 2019;292(1):35. Link, Google Scholar9. Suzuki Y, Kajita H, Konishi N, et al. Subcutaneous lymphatic vessels in the lower extremities: comparison between photoacoustic lymphangiography and near-infrared fluorescence lymphangiography. Radiology 2020;295:469–474. Link, Google Scholar10. Zackrisson S, van de Ven SMWY, Gambhir SS. Light in and sound out: emerging translational strategies for photoacoustic imaging. Cancer Res 2014;74(4):979–1004. Crossref, Medline, Google ScholarArticle HistoryReceived: Dec 26 2019Revision requested: Jan 7 2020Revision received: Jan 8 2020Accepted: Jan 10 2020Published online: Feb 25 2020Published in print: May 2020 FiguresReferencesRelatedDetailsCited ByLED-based photoacoustic imaging for preoperative visualization of lymphatic vessels in patients with secondary limb lymphedemaSaskiaVan Heumen, Jonas J.M.Riksen, Mithun Kuniyil AjithSingh, GijsVan Soest, DaliborVasilic2023 | Photoacoustics, Vol. 29Visualization of Lymphatic Vessels Using Photoacoustic ImagingHirokiKajita, YushiSuzuki, HisashiSakuma, NobuakiImanishi, TetsuyaTsuji, MasahiroJinzaki, SadakazuAiso, KazuoKishi2020 | The Keio Journal of Medicine, Vol. 70, No. 4The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and SurvivorsMelissa B.Aldrich, John C.Rasmussen, Caroline E.Fife, Simona F.Shaitelman, Eva M.Sevick-Muraca2020 | Cancers, Vol. 12, No. 8Accompanying This ArticleSubcutaneous Lymphatic Vessels in the Lower Extremities: Comparison between Photoacoustic Lymphangiography and Near-Infrared Fluorescence LymphangiographyFeb 25 2020RadiologyRecommended Articles Subcutaneous Lymphatic Vessels in the Lower Extremities: Comparison between Photoacoustic Lymphangiography and Near-Infrared Fluorescence LymphangiographyRadiology2020Volume: 295Issue: 2pp. 469-474Lower-Limb Lymphatic Drainage Pathways and Lymph Nodes: A CT Lymphangiography Cadaver StudyRadiology2019Volume: 294Issue: 1pp. 223-229Lymphatic Mapping Using US Microbubbles before Lymphaticovenous Anastomosis Surgery for LymphedemaRadiology2022Volume: 304Issue: 1pp. 218-224Bringing Lymphangiography into the 21st CenturyRadiology2019Volume: 294Issue: 1pp. 230-231High-Resolution Imaging of Lymphatic Vessels with Photoacoustic LymphangiographyRadiology2019Volume: 292Issue: 1pp. 35See More RSNA Education Exhibits Imaging of the Lymphatic System: Current Perspective with Multi-Modality Imaging and New HorizonDigital Posters2019The Forgotten System: Lymphatics of Abdomen and PelvisDigital Posters2022Secondary Lymphedema in Oncologic Patients: What Can Non-Contrast Magnetic Resonance Lymphangiography (NCMRL) Tell Us?Digital Posters2019 RSNA Case Collection "Cold" Sentinel Lymph Node in Cutaneous Melanoma RSNA Case Collection2020Diffuse pulmonary lymphangiomatosisRSNA Case Collection2020 Portal Vein AneurysmRSNA Case Collection2022 Vol. 295, No. 2 Metrics Altmetric Score PDF download