Lymph node imaging: basic principles

Lymph nodes are involved in a wide variety of diseases, particularly in cancer. In the latter, precise nodal staging is essential to guide therapeutic options and to determine prognosis. For long, imaging of the lymphatic system has been limited to lymph vessel,especially via the exclusive use of conventional lymphography, at the expense of invasive procedures and patient's discomfort. Three main technical advances, however, have recently completed the clinical armamentarium for lymph node imaging: first, the refinement of cross sectional imaging, i.e. CT and MRI, combined or not with dedicated contrast agents, has progressively replaced conventional lymphography in oncology situations; second, the development of intra-operative sentinel node mapping has profoundly modified the diagnostic and therapeutic procedures in several cancer situations, mostly melanoma and breast cancer; finally, the increased availability of functional imaging, especially through the use of FDG-PET, has greatly contributed to the accuracy improvement of nodal metastases identification. The aim of this review will thus be to briefly review the anatomy and physiology of the lymphatic systems and to overview the basic principles of up-to-date lymph node imaging.     

Elucidation of Percutaneously Accessible Lymph Nodes in Swine: A Large Animal Model for Interventional Lymphatic Research

Purpose

To define percutaneously accessible, anatomically reproducible swine lymph nodes using magnetic resonance imaging, ultrasound, and ethiodized oil (Lipiodol; Guerbet, Bloomington, Indiana) lymphangiography.

MR contrast agents in lymph node imaging

The detection of tumor metastases in lymph nodes is clinically important for tumor staging and therapy planning in cancer patients. However, differentiating between malignant and benign lymph nodes is still a problem because current imaging modalities rely only on the size and shape of the lymph nodes. Thus, small metastases in normal-sized lymph nodes can be missed, and it is difficult to differentiate enlarged nodes (benign hyperplasia versus malignant disease). Therefore, a specific lymphotropic contrast agent is needed to obtain a high contrast between functional and metastatic tissue. Contrast-enhanced MR lymphography is a noninvasive method for the analysis of the lymphatic system after interstitial (intracutaneous or subcutaneous) or intravenous application of contrast media. Interstitial MR lymphography using extracellular, liposomal, polymeric, lipophilic or particulate contrast agents results in high accumulation in regional lymph nodes. The systemic administration of a lymphotropic contrast medium is needed to address each individual lymph node. Ultrasmall superparamagnetic iron oxide particles are in late-stage clinical development for this indication, but they take 24h to show sufficient contrast. Recently, a gadolinium-type contrast agent (Gadofluorine M) was described that detected lymph node metastases within 60 min of intravenous injection.     

Interstitial magnetic resonance lymphography with gadobutrol in rats: evaluation of contrast kinetics

RATIONALE AND OBJECTIVE: To evaluate the contrast kinetics of gadobutrol for interstitial MR lymphography. MATERIALS AND METHODS: In 11 rats, 0.5 mL undiluted gadobutrol was injected subcutaneously into the hind paw. Contrast kinetics were measured in lymph nodes, kidney, liver, muscle, and blood of six animals using a time-resolved 2D GRE sequence. Additionally, high-resolution 3D T1-weighted data sets were obtained in five animals. RESULTS: Immediately after injection, a pronounced signal intensity loss was observed in popliteal, inguinal and aorto-iliac lymph nodes, followed by a continuous signal intensity increase. From the data peak concentrations of up to 78 mmol/L were estimated for selected lymph nodes. A contrast enhancement was also observed in kidneys, liver, muscle, and blood. Regional lymphatic vessels, the thoracic duct, as well as popliteal, inguinal, aorto-iliac, and axillary lymph node groups could be visualized with the high-resolution 3D MRI. CONCLUSION: Gadobutrol is suitable for interstitial MR lymphography, as it rapidly appears in the lymphatic system. Based on estimates of local tissue concentrations future studies have to assess the optimal contrast agent dosage. Furthermore, the investigation of metastatic lymph nodes is required to evaluate the further potential of gadobutrol for interstitial MR lymphography.     

Validation of the Position of Injection Needles with Contrast-Enhanced Ultrasound for Dynamic Contract-Enhanced MR Lymphangiography

Purpose

To assess the feasibility of validating the position of the needle in groin lymph nodes using injection of ultrasound (US) contrast prior to magnetic resonance (MR) lymphangiography.

梗阻性淋巴水肿淋巴动力学异常的实验观察

目的探讨间质MR淋巴造影对评价淋巴动力学的价值. 材料与方法用改良的Danese手术方法在13只新西兰大白兔后肢一侧形成淋巴水肿模型,另一侧作为对照.在每只大白兔双侧后肢足背部趾蹼处注射0.2 ml欧乃影,按摩注射部位30 s.分别于对比剂注射前后进行三维MR淋巴造影及延迟淋巴造影成像.测量不同延迟时间引流区域淋巴结的信号强度,绘制时间-信号强度曲线. 结果对照侧窝淋巴结、腹股沟淋巴结、髂淋巴结/后腹膜淋巴结分别于注射对比剂10、20、30 min后信号强度达到峰值.实验侧在淋巴水肿的不同时期出现不同程度的引流远端腹股沟及髂窝淋巴结信号强度峰值高度及峰值时间下降和延迟. 结论间质MR淋巴造影可以定量地评价引流区域淋巴动力学的状况.     

Experimental lymph node metastases: enhanced detection with MR lymphography

Magnetic resonance (MR) lymphography with superparamagnetic iron oxide (AMI-25) as a contrast agent was developed in an animal model with tumor-bearing lymph nodes. After interstitial administration of 20 mumol of iron per kilogram of body weight into the footpads of rats, the T2 of popliteal and paraaortic lymph nodes decreased from 67 msec +/- 8.2 to 9.5 msec +/- 0.9 and 9.3 msec +/- 0.9, respectively. T2 relaxation times of lymph nodes containing metastases showed a significantly higher value (61 msec +/- 6.2, P less than .005) after interstitial administration of the contrast agent. Intravenous administration of AMI-25 did not produce enhancement of normal or metastatic lymph node relaxation times. The signal intensity of normal lymph nodes decreased profoundly on spin-echo MR images (repetition time of 500 msec, echo time of 30 msec) after interstitial administration, whereas lymph nodes with metastases showed no significant change in signal intensity. Experimental results indicate that MR lymphography may potentially increase the sensitivity of MR imaging the detection of lymphatic malignancy.     

Sentinel node detection using contrast-enhanced power Doppler ultrasound lymphography

RATIONALE AND OBJECTIVES: To establish the feasibility of using contrast-enhanced interstitial ultrasound (US) lymphography as an alternative to current sentinel node detection methods. METHODS: Aqueous US contrast microbubble suspensions of varying diameter were evaluated in vitro to characterize response to insonation. Contrast media were then injected subcutaneously into the distal extremities of 11 normal dogs to target the cervical and popliteal lymph nodes (nodes, n = 40). First-order (sentinel) lymph nodes and second-order sublumbar nodes were imaged intermittently from 0 to at least 120 minutes following contrast injection using continuous power Doppler mode. Lymphoscintigraphy studies were performed on 4 dogs to verify lymphatic drainage patterns and sentinel lymph nodes. RESULTS: Contrast enhancement occurred in 34/40 (85%) sentinel nodes overall and in 30/32 (94%) nodes when submicron or near-micron diameter bubble formulations were used. In many instances, enhancement persisted throughout the imaging period. Contrast response was most pronounced using a high mechanical index and tissue artifact was reduced or eliminated when using a high pulse repetition frequency. CONCLUSIONS: Contrast-enhanced interstitial US lymphography could serve as an alternative to current sentinel node detection methods. Preliminary findings suggest that submicron or near-micron-diameter bubbles may be suitable for lymphatic imaging applications.     

Interstitial MR lymphography in mice with gadopentetate dimeglumine and gadoxetate disodium

Purpose

To investigate the utility of interstitial MR lymphography with gadopentetate dimeglumine (Gd‐DTPA) or gadoxetate disodium (Gd‐EOB‐DTPA) in mice.

Materials and Methods

We performed MR lymphography after the subcutaneous injection of Gd‐DTPA or Gd‐EOB‐DTPA (0.1, 0.5, or 2.0 μmol per mouse) into the right footpad in six healthy mice, and the time courses of contrast enhancement were assessed. Additionally, the lymphatic pathways from two distinct sites were assessed in tandem by interstitial MR lymphography studies.

Results

Subcutaneous injection of Gd‐DTPA or Gd‐EOB‐DTPA caused lymph node enhancement immediately after injection, followed by a rapid decline. Dose dependency was shown for the lymph node enhancement, and a high‐dose injection caused prominent visualization of the veins. Lymph node enhancement did not differ significantly between Gd‐DTPA and Gd‐EOB‐DTPA or between Gd‐EOB‐DTPA premixed and not premixed with bovine serum albumin. The tandem assessment of two lymphatic pathways was feasible, and image fusion aided detailed comparison.

Conclusion

Interstitial MR lymphography with Gd‐DTPA or Gd‐EOB‐DTPA allowed clear visualization of the lymphatic pathway in healthy mice, and no significant difference was found between the two agents. Their rapid kinetics limits the imaging timing window, however, facilitates repeated assessment in a single imaging session. J. Magn. Reson. Imaging 2011;33:490–497. © 2011 Wiley‐Liss, Inc.     

Visualization of lymphatic basin from the tumor using magnetic resonance lymphography with superparamagnetic iron oxide in patients with thoracic esophageal cancer

OBJECTIVE: To evaluate magnetic resonance (MR) lymphography with submucosal injection of superparamagnetic iron oxide (SPIO) for imaging lymphatic pathways from thoracic esophageal cancer. METHODS: In 24 patients with esophageal cancer, SPIO was injected into the submucosal layer of the peritumoral region endoscopically and MR lymphography was conducted. In study 1, fast spoiled gradient-recalled acquisition using a steady-state (FSPGR) sequence was performed from the neck to the upper abdomen before and at 20, 40, and 60 minutes after injection in 10 patients. In study 2, FSPGR and spin echo T1-weighted images were obtained after injection in 14 patients. Areas scanned were the neck to the upper mediastinum and the upper abdomen. RESULTS: In study 1, at 20 minutes after injection, the signal of each lymph node appeared attenuated when compared with precontrast images. The signal-to-noise ratio in lymph nodes exhibiting influx of SPIO was significantly lower than that found on precontrast images (P < 0.0005). In study 2, influx to the neck lymph nodes was detected in 8 patients (64.3%), whereas influx to the upper abdominal lymph nodes was detected in 13 (92.9%). CONCLUSIONS: Magnetic resonance lymphography with SPIO could visualize the lymphatic pathways draining from the injection site and the location of lymph nodes exhibiting influx of SPIO in patients with thoracic esophageal cancer.     

Interstitial T1-weighted MR lymphography: lipophilic perfluorinated gadolinium chelates in pigs.

PURPOSE: To investigate the enhancement of the regional lymph nodes, lymphatic vessels, and thoracic duct after interstitial administration of lymphotropic perfluorinated gadolinium chelates at magnetic resonance (MR) imaging. MATERIALS AND METHODS: Two perfluorinated gadolinium chelates, gadofluoramide and gadofluorine 8, were injected subcutaneously into the hind legs of 10 pigs, respectively. Both contrast media were studied at doses of 10 and 25 micromol per kilogram of body weight. T1-weighted three-dimensional gradient-echo and maximum intensity projection images were obtained at 1.5 T between 1 and 210 minutes and 24 hours after injection. The contrast agents were qualitatively compared regarding enhancement and depiction of the regional lymph nodes, lymphatic vessels, and thoracic duct. RESULTS: The inguinal and iliac lymph nodes and lymphatic vasculature enhanced substantially within 10 minutes after subcutaneous administration of both lymphotropic contrast agents. Gadofluorine 8 showed a lymphographic effect superior to that of gadofluoramide. The paraaortic lymph nodes and thoracic duct were best visualized 10--50 minutes after injection of 25 micromol/kg of gadofluorine 8. Lymphatic system enhancement diminished after 2 hours, and the liver and bowel tract enhanced within 24 hours. CONCLUSION: Interstitial administration of perfluorinated gadolinium chelates offers great potential for T1-weighted MR lymphography with positive enhancement of the lymph nodes and lymphatic vasculature.     

间质磁共振淋巴造影的技术方法及其实验研究

目的探讨间质磁共振淋巴造影对评价正常淋巴系统结构与功能的价值及技术方法。方法选取纯种新西兰大白兔24只,在每只大白兔双侧后肢足背部趾蹼处注射0.2 m l欧乃影,按摩注射部位30 s。分别于造影剂注射之前及注射按摩后5、10、20、30、60、90、120 m in进行三维增强磁共振淋巴造影成像(3D CE-MRL)。测量不同延迟时间引流区域淋巴结的信号强度,绘制时间-信号强度曲线。结果引流区域各组淋巴结、淋巴管及胸导管显示清晰。腘窝淋巴结、腹股沟淋巴结、髂淋巴结/后腹膜淋巴结分别于注射造影剂10 m in、20 m in和30 m in后信号强度达到峰值。双足注射部位未见炎症反应。结论间质磁共振淋巴造影可以有效可靠地显示引流区域淋巴管、淋巴结的解剖形态和功能。     

MR淋巴管造影显示VX2兔乳腺癌前哨淋巴结

目的:探讨钆剂增强的MR淋巴管造影(MR- LG)用于VX2兔乳腺癌前哨淋巴结(SLN)显像的可行性.方法:采用VX2肿瘤软组织块悬液注射法建立30只兔原位乳腺癌动物模型.实验兔在肿瘤接种前后共行2次MR- LG检查(包括对比剂注射前的STIR序列扫描).图像3D重建后,淋巴管引流通路上距离原发肿瘤最近的淋巴结定义为SLN,且成像效果根据3D图像上有无淋巴结和淋巴管显像分成良好和较差两个等级;记录STIR序列扫描和MR- LG显示的所有淋巴结,并与前哨淋巴结病理对照.结果:80％ (24/30)的荷瘤兔完成第二次MR- LG检查,良好3D图像为79.2％ (19/24).在MR - LG图像上,淋巴结信噪比(SNR)均高于其引流淋巴管和同层肌肉(P值均＜ 0.05),SLN与n-SLN、引流淋巴管与同层肌肉之间的SNR无统计学差异.MR- LG图像上可清晰显示SLN和n-SLN(共26枚)的17只荷瘤兔,其STIR图像上共有28枚淋巴结,且两者淋巴结的大小无明显差异(t=0.124,P=0.902);其SLNB检查获得32枚淋巴结(SLN18枚,n- SLN 14枚),且淋巴结大小与MR- LG图像上和STIR序列扫描所显示的淋巴结无统计学差异.结论:钆剂增强MR-LG可较好地显像VX2兔乳腺癌SLN.     

Interstitial MR lymphography with MS-325: characterization of normal and tumor-invaded lymph nodes in a rabbit model

OBJECTIVE: The aim of our study was to evaluate the performance of a new blood-pool contrast agent, MS-325, in depicting regional lymph nodes when injected interstitially and in allowing the subsequent classification of the lymph nodes as normal or tumor-bearing (VX2 tumor). MATERIALS AND METHODS: Six New Zealand white rabbits underwent adapted fast three-dimensional (3D) MR imaging before implantation of VX2 tumor cells in the flank and again 3 weeks after the implantation. For each imaging session, 0.5 mL of undiluted MS-325 was injected subcutaneously into both dorsal foot pads. For more than 120 min, the rabbits underwent repeated 3D MR imaging. The size of the individual lymph nodes and the amount of contrast agent uptake in the nodes were measured 5, 10, 15, 30, 60, and 120 min after the injection. After the rabbits had been sacrificed, their lymph nodes were removed and histopathologically analyzed. RESULTS. In normal as well as tumor-bearing hindlegs, the subcutaneous administration of MS-325 resulted in rapid delineation of popliteal, inguinal, iliac, and paraaortal lymph nodes. Tumor invasion into lymph nodes presented as circumscribed signal voids in the areas infiltrated by tumor, whereas the surrounding residual lymphatic tissue showed enhancement identical to that of normal nodes. CONCLUSION: In addition to providing a safe means of displaying the normal lymphatic system, MS-325-enhanced 3D MR lymphography depicts direct tumor invasion in lymph nodes.     

Potential of magnetic resonance lymphography with intrapulmonary injection of gadopentetate dimeglumine for visualization of the pulmonary lymphatic basin in dogs: preliminary results

PURPOSE: To evaluate a new approach of magnetic resonance (MR) lymphography with intraalveolar injection of a conventional extracellular contrast agent (gadopentetate dimeglumine) for imaging lymphatic basin draining from specific portions of the lung. METHODS: Three-dimensional T1-weighted spoiled gradient-recalled echo MR sequence images were acquired serially before and for 40 minutes after intraalveolar injection of gadopentetate dimeglumine in a total of 14 anesthetized beagle dogs. Six of these dogs received 1 mL undiluted and low-concentration (75%) contrast agent into the same portion of the right caudal lobe during a 7-day interval. In all dogs, including these 6 dogs, MR lymphography was repeated with injection of the low-concentration contrast agent into different lung regions at 7-day intervals to evaluate the differences of the visualized draining lymphatic station. Lymphatic enhancement was quantified by percent increases of signal intensity against precontrast. Postmortem examination of the lymphatic anatomy was performed in 7 of these animals. RESULTS: In all dogs, the lymphatic station draining from the injection sites was visualized within 5 minutes after contrast injection. The maximum percent increase of signal intensity of the same middle tracheobronchial lymph nodes was significantly greater with a low-concentration (75%) contrast agent than with an undiluted one in the same 6 dogs (n = 6, 247.6 +/- 30.5% vs. 204.2 +/- 33.8%; P < 0.01). Different lymphatic stations draining from the different injection sites were visualized in all dogs. In a total of 12 MR studies that showed extended nodal enhancement after injection of the low-concentration contrast agent, the enhancement peak of the most proximal nodes (n = 12) from the injection sites appeared earlier than that of their distant nodes (n = 12), with a maximum percent increase of signal intensity of 249.8 +/- 42.4%. The visualized lymph nodes were found in the appropriate locations postmortem, with significant correlation for nodal sizes (r = 0.965; P < 0.0001). CONCLUSION: MR lymphography with low-concentration gadopentetate dimeglumine can quickly and sufficiently visualize the drainage lymphatic station from specific lung portions, and may have the potential of sentinel node mapping in lung cancer.     

肢体淋巴水肿MR淋巴造影与病理对照的实验研究

目的研究肢体水肿演变过程中不同时期的MR淋巴造影影像特征及其病理基础,探讨MR淋巴造影在肢体淋巴水肿方面的诊断价值。方法用改良的Danese手术方法在13只新西兰大白兔后肢一侧形成淋巴水肿模型,另一侧作为对照。在每只大白兔双侧后肢足背部趾蹼处注射0.2ml欧乃影,于淋巴水肿演变过程的不同时期进行三维MR淋巴造影。取肢体标本进行病理检查。结果MR淋巴造影能准确地确定淋巴管阻塞的部位,反映淋巴管形态、功能的状况。肢体淋巴水肿的不同时期,由于其病理基础不同,产生不同的MR淋巴造影表现。结论间质MR淋巴造影可以在解剖背景下敏感而又可靠地显示各期肢体淋巴水肿。     

Contrast-Enhanced MR Imaging of Lymph Nodes in Cancer Patients

The accurate identification and characterization of lymph nodes by modern imaging modalities has important therapeutic and prognostic significance for patients with newly diagnosed cancers. The presence of nodal metastases limits the therapeutic options, and it generally indicates a worse prognosis for the patients with nodal metastases. Yet anatomic imaging (CT and MR imaging) is of limited value for depicting small metastatic deposits in normal-sized nodes, and nodal size is a poor criterion when there is no extracapsular extension or focal nodal necrosis to rely on for diagnosing nodal metastases. Thus, there is a need for functional methods that can be reliably used to identify small metastases. Contrast-enhanced MR imaging of lymph nodes is a non-invasive method for the analysis of the lymphatic system after the interstitial or intravenous administration of contrast media. Moreover, some lymphotrophic contrast media have been developed and used for detecting lymph node metastases, and this detection is independent of the nodal size. This article will review the basic principles, the imaging protocols, the interpretation and the accuracies of contrast-enhanced MR imaging of lymph nodes in patients with malignancies, and we also focus on the recent issues cited in the literature. In addition, we discuss the results of several pre-clinical studies and animal studies that were conducted in our institution.     

间质磁共振淋巴管造影在检测乳腺癌患者前哨淋巴结转移情况中的应用价值

目的探讨间质磁共振(MR)淋巴管造影与弥散加权成像(DWI)序列相结合检测乳腺癌患者前哨淋巴结转移情况的应用价值。方法选取河南大学第一附属医院2018年6月至2019年6月30例前哨淋巴结阳性乳腺癌患者,并招募30名健康志愿者作为阴性组,给予MR间质淋巴造影检查,观察乳腺癌患者淋巴管及前哨淋巴结情况,对比分析2组淋巴管走行、管径情况和前哨淋巴结数目、大小、边缘、形态及弥散系数(ADC)值的指标。结果阳性组淋巴管走行、管径与阴性组对比差异有统计学意义(P<0.05);阳性组及阴性组前哨淋巴结平均数目差异无统计学意义(P>0.05);阳性组前哨淋巴结大小、边缘、形态及ADC值的指标均有明显差异(P<0.05)。结论 MR间质淋巴管造影与DWI序列相结合可以高分辨率的显示淋巴管和淋巴结的形态和功能,提高了乳腺癌患者前哨淋巴结转移的检出率。     

Interstitial magnetic resonance lymphography using a polymeric t1 contrast agent: initial experience with Gadomer-17

RATIONALE AND OBJECTIVES: The detection of lymph node metastases is an important step in tumor staging and is significant for therapy planning. Lymph node-specific contrast agents can raise the sensitivity and specificity of modern diagnostic methods. This study investigated the suitability of the dendritic contrast agent Gadomer-17 in magnetic resonance (MR) lymph node imaging and compared three different dosages in such an application. METHODS: Doses of 1.0, 2.5, and 10.0 micromol Gd/kg body weight were interstitially injected into the hind legs of dogs; the signal intensities of two successive lymph node groups (inguinal and iliacal) were then recorded up to 120 minutes after injection. RESULTS: Gadomer-17 induced a strong increase in signal intensity of the examined lymph node groups. At 15 minutes postinjection, the enhancement increased by 120% to 680%, depending on the dose. The maximum enhancement was 450% to 960% at 60 to 90 minutes postinjection. Doses of 2.5 and 10.0 micromol Gd/kg showed comparable results; even the lowest dose (1.0 micromol Gd/kg) enhanced the contrast of the inguinal lymph nodes in 4 of 5 animals and the iliacal lymph nodes in three of five animals. Therefore, the minimum effective dose of Gadomer-17 in this study was approximately 2.5 micromol Gd/kg. CONCLUSION: This study revealed the excellent suitability of the dendritic contrast agent Gadomer-17 for MR imaging of the lymphatic system (lymph nodes and lymph vessels).     

Interstitial magnetic resonance lymphography using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid in rabbits with lymph node metastasis

RATIONALE AND OBJECTIVES: To investigate the dose dependency of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) for interstitial magnetic resonance (MR) lymphography and the detection of lymph node metastasis in rabbits. METHODS: Eighteen VX2 tumor-bearing rabbits were subjected to MR lymphography using clinical MRI equipment. The enhancement of popliteal lymph nodes was studied in these rabbits before and at 2.5 to 10 minutes after the subcutaneous administration of 4, 8, or 17 micromol Gd/kg of Gd-EOB-DTPA in TSE and 3D-FLASH (n = 6). Signal-to-noise ratio and contrast-to-noise ratio were statistically compared between each group by the Tukey test. After MR imaging, the popliteal lymph nodes were removed, and sections were prepared for microscopic examination. RESULTS: In the histologic findings, all metastases (3-12 mm) in the popliteal lymph nodes were detected by 3D-FLASH images. Gd-EOB-DTPA-enhanced T1WI showed a hypointense region for metastasis and a hyperintense region for nontumor regions, although the lymph nodes containing metastasis were detected as a hyperintense region by conventional PDWI and T2WI. Signal enhancement of the nontumor regions and contrast between the nontumor regions and metastasis showed dose dependency and reached a plateau at 8 micromol Gd/kg on T1WI (signal-to-noise ratio: 13.9 +/- 1.6; contrast-to-noise ratio: -12.7 +/- 1.7). CONCLUSIONS: This study showed that interstitial MR lymphography with Gd-EOB-DTPA can detect metastasis and that the optimal dose in rabbits is 8 micromol Gd/kg as a subcutaneous application.