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USPIO-enhanced MRI for pre-operative lymph node staging after neoadjuvant chemoradiotherapy: feasibility and validation framework
Didi de Gouw1, Bastiaan Klarenbeek1, Marnix Maas2, Rutger Stijns2, Maroeska Rovers3, Cor Slagt4, Jörg Mühling4, John Hermans2, Tom Scheenen2, and Camiel Rosman1

1Surgery, Radboudumc, Nijmegen, Netherlands, 2radiology and nuclear medicine, Radboudumc, Nijmegen, Netherlands, 3health evidence and operating rooms, Radboudumc, Nijmegen, Netherlands, 4anesthesiology, pain and palliative medicine, Radboudumc, Nijmegen, Netherlands

Synopsis

Extensive lymph node dissections during esophagectomy may be omitted in patients with esophageal cancer without lymph node metastases, reducing associated morbidity. A promising technique to detect lymph node metastases is MRI with ultrasmall superparamagnetic iron oxide nanoparticles (USPIO, ferumoxtran-10). To validate USPIO-enhanced MRI in patients with esophageal cancer, a framework is designed to compare lymph nodes of the MRI scans with histopathology data on a node-to-node level.

Background

In 69% of patients suffering from operable esophageal cancer, no metastatic lymph nodes are found after neoadjuvant chemoradiotherapy (nCRT)1. Ideally, extensive lymph node dissections during esophagectomy should be omitted or minimized in these patients to reduce associated morbidity. MRI with ultrasmall superparamagnetic iron oxide nanoparticles (USPIO, ferumoxtran-10) has been proven to be a valuable contrast agent to detect lymph node metastases in prostatic cancer2. Contrary to other diagnostic modalities, USPIO-enhanced MRI has an excellent spatial resolution to detect small lymph nodes, e.g. reaching short axis diameters < 3 mm in prostate cancer3. For esophageal cancer, USPIO-enhanced MRI is more challenging due to the location of the lymph nodes close to the heart and lungs. The aim of this study is to assess the feasibility of USPIO-enhanced MRI in the detection of locoregional lymph node metastases in patients with esophageal cancer and to design a framework enabling validation of this method by node-to-node comparison between MRI and histopathology.

Method

The study is a prospective, single centre, feasibility study in patients undergoing minimally invasive esophagectomy with suspected lymph node metastases. USPIO-nanoparticles (Ferumoxtran-10, 2.6 mg Fe/kg body weight) are intravenously infused 24 to 36 hours before MRI. All patients undergo MRI examination before nCRT (3T Magnetom PrismaFit, Siemens Healthcare, Erlangen, Germany). MR sequences are described in table 1. After nCRT (~3 months), USPIO-enhanced MRI is repeated on the day of the surgical procedure (nanoparticle administration one day before surgery). This MRI examination is performed under anaesthesia in a 3T MR system (Magnetom Skyra, Siemens Healthcare) in a hybrid operation room. Breathhold MRI scans are performed under controlled mechanical ventilation, as well as a four-minute iron-sensitive MRI acquisition during controlled prolonged apnea. This scan is used to visualize suspicious esophageal lymph nodes without breathing motion artefacts (figure 1). After the MRI, the esophagus including locoregional lymph nodes is removed en bloc, enabling histopathological analysis. Suspicious nodes on the surgical specimen are marked with stitches. After resection, but before pathological examination, an ex-vivo USPIO-enhanced MRI of the dissected formalin-fixed esophagus is made on a 7T preclinical MRI system (Bruker Clinscan). Water-selective iron-sensitive scans enable the visualization of the presence or absence of nanoparticles in the lymph nodes in the specimen. Lymph nodes without nanoparticles retain MR signal intensity, an indication for abnormal nodal status and thus suspicious for malignancy. All nodes are labeled, excised and worked up histopathologically to provide the gold standard of the presence or absence of metastases in these nodes.

Results

Currently, five patients have completed the full study protocol. Two patients underwent the first UPSIO-enhanced MRI but did not undergo surgery due to progressive disease. First results show that MRI under anesthesia prior to surgery with controlled mechanical ventilation was possible resulting in a clinically relevant spatial resolution to visualize possibly malignant lymph nodes. In these five patients, the radiologist found 58 lymph nodes with a mean diameter of 8.4 mm before nCRT and 40 lymph nodes with a mean diameter of 7.4 mm after nCRT. In total, 126 lymph nodes were analyzed by histopathology. Suspicious nodes were identified and could be matched using corresponding anatomical landmarks to the ex-vivo MRI, which showed good visual agreement with esophageal specimen after resection (figure 2).

Discussion

The preliminary data of this ongoing study show that is feasible to perform USPIO-MRI in patients with esophageal cancer. A radiological assessment of the presence of in-vivo suspicious lymph nodes was performed at nodal stage level. Ex-vivo detected nodes on preclinical MRI were matched node-to-node to histopathology, providing the ground truth for the presence of metastases. Nodal matching from in-vivo to ex-vivo is still challenging. The additional 7T USPIO-enhanced ex-vivo MRI of the surgical specimen is essential to match nodes without nanoparticles uptake with MR-guided histopathology. Information of the ex-vivo MRI is used to guide the pathologist in order to detect the smallest lymph nodes.

Conclusion

We performed USPIO-enhanced MRI in patients with esophageal cancer and proposed a method to validate USPIO-enhanced MRI to detect suspicious lymph nodes in these patients. Matching ex-vivo USPIO-MRI images with histopathology results, provides direct information for validation of in-vivo USPIO-MRI and characteristics of locoregional lymph nodes. Results on the feasibility of USPIO-enhanced MRI to detect lymph node metastases after nCRT are still awaited.

Acknowledgements

The authors have no conflicts of interest to declare.

References

1. van Hagen P, Hulshof MC, van Lanschot JJ, et al: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074-84, 2012

2. Fortuin AS, Bruggemann R, van der Linden J, et al: Ultra-small superparamagnetic iron oxides for metastatic lymph node detection: back on the block. Wiley Interdiscip Rev Nanomed Nanobiotechnol 10, 2018

3. Birkhauser FD, Studer UE, Froehlich JM, et al: 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. Eur Urol 64:953-60, 2013


Figures

Figure 1. Example of USPIO-MRI scans before nCRT and after nCRT in the axial (left) and coronal plane (right) of a patient with esophageal cancer one day after the administration of Ferumoxtran-10. The anatomical images (a+c) are used to identify lymph nodes. In the water-selective iron sensitive T2* weighted MRI (b+d, computed TE12 ms GRE image) the signal of healthy lymph nodes disappears, whereas metastatic lymph nodes, in which the USPIO-particles do not accumulate, retain MRI signal. The blue circle points out one suspicious lymph node.

Figure 2.Example of the workflow. Suspicious nodes were identified on in-vivo MRI(a) and could be matched using corresponding anatomical landmarks to the resected esophageal specimen (b) and ex-vivo MRI (c). The ex-vivo MRI guided the pathologist towards suspicious nodes (d) for histopathological analysis of each node with H&E staining (e).

Table 1. Imaging parameters for the MR protocols

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)
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