Volume 64, Issue 6, Pages 953-960 (December 2013) Combined Ultrasmall Superparamagnetic Particles of Iron Oxide–Enhanced and Diffusion-weighted Magnetic Resonance Imaging Facilitates Detection of Metastases in Normal-sized Pelvic Lymph Nodes of Patients with Bladder and Prostate Cancer  Frédéric D. Birkhäuser, Urs E. Studer, Johannes M. Froehlich, Maria Triantafyllou, Lauren J. Bains, Giuseppe Petralia, Peter Vermathen, Achim Fleischmann, Harriet C. Thoeny  European Urology  Volume 64, Issue 6, Pages 953-960 (December 2013) DOI: 10.1016/j.eururo.2013.07.032 Copyright © 2013 European Association of Urology Terms and Conditions

Fig. 1 Schematic diagram of the functional principle of combined ultrasmall superparamagnetic particles of iron oxide (USPIOs), diffusion-weighted (DW) magnetic resonance imaging (MRI). After intravenous injection, USPIOs are transported through the vascular endothelium into the interstitial space. The USPIOs are taken up by macrophages and subsequently transported into healthy lymph nodes (LNs). The iron oxide crystalline core of the USPIO produces strong susceptibility leading to a signal decrease on T2- or T2*-weighted MRI. This signal decrease can be used to identify healthy LNs, which contain significant amounts of USPIO within the macrophages and appear hypointense. Malignant LNs, in contrast, have few macrophages and are characterised by a total or partial lack of USPIO uptake, depending on the degree of macrophage displacement, and they do not show a change in signal intensity after USPIO injection. The lack of USPIO uptake in metastatic LNs, therefore, acts as a positive contrast agent highlighting and potentially facilitating the identification of metastases in normal-sized LNs, even those the size of a single magnetic resonance voxel. In addition, malignant LNs appear hyperintense on high b-value DW-MRI due to the restriction of extracellular water diffusion in metastatic regions with increased cellular density. Thus metastatic LNs can be characterised by a high signal intensity on DW-MRI and a lack of signal decrease following USPIO injection. European Urology 2013 64, 953-960DOI: (10.1016/j.eururo.2013.07.032) Copyright © 2013 European Association of Urology Terms and Conditions

Fig. 2 Magnetic resonance image of a metastatic lymph node (LN) with histopathologic correlation. These images, from a 48-yr-old man with muscle-invasive bladder cancer stage pT3a pN2 G3, show the typical order of reading: (A) axial diffusion-weighted (DW) magnetic resonance imaging (MRI) at a b-value of 1000 s/mm2 24h after administration of ultrasmall superparamagnetic particles of iron oxide (USPIOs; combined USPIO-DW-MRI) showing a hyperintense, focal, noncontinuous round structure (arrow) in the left internal iliac region that is suspicious due to the lack of USPIO uptake. (B) Axial, reconstructed, T2-weighted image shows the suspicious LN on the left side (arrow) measuring 7×6mm. (C) Parasagittally reconstructed, T1-weighted, fat-saturated image after USPIO administration shows the localisation of the left suspicious LN (arrow) between the internal and external iliac arteries. (D) Histopathologic analysis of the dissected LN (8×5mm) stained with haematoxylin-eosin. #=LN metastases measuring 7×4mm; *=lymphoreticular tissue. European Urology 2013 64, 953-960DOI: (10.1016/j.eururo.2013.07.032) Copyright © 2013 European Association of Urology Terms and Conditions

Fig. 3 Magnetic resonance image of a metastatic and a benign lymph node (LN) with histopathologic correlation. The patient was a 67-yr-old man with prostate cancer stage pT4 (bladder neck) pN1, Gleason score 10, preoperative prostate-specific antigen level of 3.7μg/ml. (A) Axial diffusion-weighted (DW) magnetic resonance imaging (MRI) at a b-value of 1000 s/mm2 24h after administration of ultrasmall superparamagnetic particles of iron oxide (USPIOs; combined USPIO-DW-MRI) shows a suspicious hyperintense structure (arrow) on the left pelvic side posterior to the external iliac vessels. The LN on the right pelvic side is not visible (arrowhead) due to signal loss in normal LNs following USPIO uptake. Note that the posterior bilateral hyperintense structures correspond to sacral nerve roots. (B) Axially reconstructed T2-weighted image shows the suspicious LN on the left side (arrow) measuring 10×7mm and a normal LN on the right side (arrowhead) measuring 5×4mm. (C) Parasagittally reconstructed T2-weighted image shows the suspicious LN located posterior to the left external iliac artery. (D) Histopathologic analysis of the dissected LN (5×4.5mm) stained with haematoxylin-eosin. #=LN metastases measuring 5×4mm; *=lymphoreticular tissue. European Urology 2013 64, 953-960DOI: (10.1016/j.eururo.2013.07.032) Copyright © 2013 European Association of Urology Terms and Conditions