Detecting lymph node (LN) metastases (LNMs) in patients with prostate cancer (PCa) is very challenging but crucial for accurate staging with important treatment and prognostic implications. An extended pelvic lymph node dissection (ePLND) is still considered the reference standard for nodal staging, whereas the therapeutic value of this invasive procedure is unclear with similar clinical outcomes in patients in whom ePLND was or was not performed.1,2 Because LNMs in PCa are often small3,4 and can be found outside the surgical resection field in difficult-to-reach anatomical areas,5,6 they can be missed. In addition, small LNMs may not be detected in the assessment of histopathological specimens.7–10 An accurate noninvasive nodal staging technique is therefore warranted.

Prostate-specific membrane antigen (PSMA)–PET/CT is increasingly used in recent years in clinical practice before initial therapy as it outperforms conventional imaging, which depends on morphological and size criteria. It is noninvasive, which is an advantage over ePLND, avoiding potential significant morbidity of ePLND. Initial results of PSMA-PET/CT are promising for detecting LNMs compared with anatomical imaging11 with good specificity (0.67–1.0, pooled 0.95), although there is a large variation in reported sensitivity (0.23–1.0, pooled 0.58).11–13 Sensitivity is hindered by the spatial resolution of PET/CT of 4–5 mm,14 which makes it difficult to detect small LNMs. In concordance, PET-positive LNMs are reported larger (median, 4.0–13.6 mm) than false PET-negative LNMs (median, 2.5–5.0 mm).15 Although the sensitivity of PSMA-PET/CT is not yet sufficient to completely replace ePLND for nodal staging, the negative predictive value seems sufficient to safely omit this procedure in men with a low risk of nodal involvement.13

Ultrasmall superparamagnetic iron oxide (USPIO)–enhanced magnetic resonance imaging (MRI) is another noninvasive functional imaging technique. Because of the high spatial resolution and superior soft tissue contrast of MRI, it offers promising potential for metastatic LN detection. Intravenously administered USPIO nanoparticles accumulate in phagocytic cells of the immune system (ie, macrophages) in healthy LNs, attenuating their signal on T2*-weighted images, whereas LNs that retain MR signal due to the lack of USPIO nanoparticle accumulation are therefore suspicious for harboring metastases. The lower limit of detectable size is therefore not depending on the accumulated contrast agent, but on the attainable spatial resolution of the images.

Initial USPIO-enhanced MRI studies in PCa were performed at 1.5 T.3,16 Magnetic resonance imaging at a higher (3 T) field strength improved the image quality of the technique.17 In addition, 3D acquisition techniques at 3 T enabled imaging at high isotropic image resolutions (0.85 × 0.85 × 0.85 mm), which was used at the time of the reintroduction of USPIO-enhanced MRI.18 In a first direct comparison study between USPIO-enhanced MRI at 3 T and PSMA-PET/CT in the same patients, MRI detected more and smaller suspicious LNs than PSMA-PET/CT did.19

The challenging next step in body MRI is moving to an ultra-high magnetic field strength of 7 T. Exploiting its higher sensitivity by acquiring an even higher spatial resolution than reachable at 3 T, USPIO-enhanced MRI at 7 T could allow improved detection of LNM, which may alter disease management, both in primary PCa and in recurrent disease.20,21 The initial technical challenges of previously seen image inhomogeneity with large field of views in the pelvis at 7 T have been overcome,22,23 and the feasibility of detecting (suspicious) LNs down to 1.5 mm in size on 7 T has already been demonstrated.24–26

To assess the potential of improved detection of suspicious LNs with USPIO-enhanced MRI at 7 T over 3 T, we compared 7 T USPIO-enhanced MRI with 3 T USPIO-enhanced MRI in a cohort of 20 patients with PCa.

MATERIALS AND METHODS Participants

This single-center, nonrandomized, prospective trial was approved by the institutional review board (no. 16 7214 BO), and written informed consent was obtained from all participants. The USPIO contrast agent ferumoxtran-10 (Ferrotran; SPL Medical BV, Nijmegen, the Netherlands) was used. This agent is available for clinical studies and in Named Patient Use Programs in the Netherlands and Switzerland. A large phase III international multicenter pivotal trial for EMA approval is ongoing (EudraCT 2018-004310-18). For this study, patients with primary or recurrent PCa, who were referred to our medical center for an investigational USPIO-enhanced 3 T MRI examination due to deemed high risk of LNM (by primary risk classification20 or PSA level after therapy21), were included between March 2014 and February 2015. The patients provided written informed consent to undergo a 7 T USPIO-enhanced MRI on the same day as well.

USPIO-Enhanced MRI at 3 T and 7 T

All participants received an intravenous administration of ferumoxtran-10 (dosage 2.6 mg/kg) 24–36 hours before 3 T and 7 T MRI. High-resolution, 3-dimensional anatomical, and T2*-weighted images were acquired at 3 T (MAGNETOM Prisma-fit; Siemens Healthineers, Erlangen, Germany) and within 5 hours on the same day at 7 T (MAGNETOM 7 T; Siemens Healthineers, Erlangen, Germany). Negligible difference in nodal contrast accumulation was to be expected for these 2 scans within this time frame.27 The scanned area included at least the area from the aortic bifurcation to the bladder neck (see Table 1 for scanning parameters).

TABLE 1 - Overview of Pulse Sequence Parameters for 7 T and 3 T MR Acquisitions 7 T 3 T Water-Selective Imaging 3D mGRE—T2*-Weighted Lipid-Selective Imaging 3D GRE—Anatomical Water-Selective Imaging 3D MEDIC—T2*-Weighted VIBE Dixon 3D GRE—Anatomical Voxel size, mm3 0.66 × 0.66 × 0.66 0.66 × 0.66 × 0.66 0.85 × 0.85 × 0.85 0.85 × 0.85 × 0.85 FOV 210 × 210 × 169 210 × 210 × 169 328 × 328 × 190 328 × 328 × 204 Matrix 320 × 320 × 256 320 × 320 × 256 384 × 384 × 224 384 × 384 × 240 TE, ms 2.1, 4.19, 6.21, 8.3, 10.32 2.0 12 (MEDIC 8, 16) 2.5 TR, ms 14 5.2 21 6.5 Flip angle, degree ≈15* ≈19* 10 10 Bandwidth, Hz 625 625 170 350 Acceleration 2 × 2 2 × 2 3 × 1 3 × 1 Acquisition time, min 8:24 2:50 10:08 6:55 Excitation Water selective Lipid selective Water and slab selective Slab selective Bowel preparation IM dose of 20 mg butylscopolamine just before scan IM dose of 20 mg butylscopolamine just before scan The multiple gradient echoes at 7 T were reconstructed into 1 dataset with a computed echo time of 8 ms.25

*An estimated flip angle over 2 TRs across the pelvic field of view.

MEDIC, multiecho data image combination; VIBE, volumetric interpolated breath-hold examination; mGRE, multiecho gradient echo; FOV, field of view.

Image Evaluation and Annotation

After anonymization, all scans were independently evaluated by 2 experienced abdominal radiologists (A.S.F. with 6.5 years and T.H. with 3 years, R1 and R2, respectively) who were blinded for clinical parameters. First, the 3 T studies were presented to the readers. To avoid recollection, the 7 T scans were assessed in a blinded random order at least 3 months later. R1 is an abdominal radiologist with initial experience for reading USPIO-enhanced imaging; R2 is an expert in assessing clinical USPIO-enhanced MRI.

Both readers were asked to annotate the LNs suspicious for harboring nodal metastases on the basis of both the anatomical and the T2*-weighted 3D datasets with freedom to scroll in 3 dimensions and with optional maximum intensity projection. The water-selective iron-sensitive T2*-weighted images were used to identify suspicious LNs (3 T: multiecho data image combination, 7 T: computed echo time images from multigradient echo); LNs with a homogeneous residual high signal intensity or those with partial high signal components were deemed suspicious for harboring metastases. The reconstructed water and lipid images (3 T: volumetric interpolated breath-hold examination Dixon, 7 T: gradient echo) were used for anatomical correlation. The nodes were annotated on T2*-weighted MRI and scored on a 5-point level of suspicion (LoS) scale (metastases very unlikely [1], unlikely [2], equivocal [3], likely [4], and very likely [5]). The readers had the assignment to find all potentially suspicious LNs (defined as LoS ≥3). Healthy LNs did not have to be scored, although the scores of LoS 1 and 2 could be used to indicate an LN or other small spherical structure retaining signal on T2*-weighted MRI to deem it benign (eg, a slightly gray LN or a ganglion).

Lymph node annotations from both readers were imported independently into an adapted dedicated viewer (Mevislab; Mevis Medical Solutions, Bremen, Germany). The annotations of both readers could be turned on and off and projected over the patient's images, enabling precise matching between the annotations of both readers. When both readers independently annotated an LN and scored it with LoS 3–5, it was considered “suspicious.” When both readers independently detected an LN with a score of LoS 4–5, it was considered “highly suspicious.” An independent reader (A.V.) performed matching of annotations and nodal size measurements in 3 orthogonal directions (noted as short axis diameter and ellipsoid volume). R1 assessed the image quality of all 3 T and 7 T images (see Supplementary Material, https://links.lww.com/RLI/A888).

Statistical Analysis

To compare the detection of suspicious LNs on 3 T and 7 T MRI, the number of suspicious LNs was analyzed per participant by Wilcoxon matched pairs signed rank tests. Mann-Whitney U tests were performed to compare the size of annotated LNs. The LN size is compared between the LoS score groups by Dunn multiple comparison tests after Kruskal-Wallis nonparametric analysis of variance. A subgroup of LNs that were scored on both field strengths by both readers was analyzed on LoS scores with Wilcoxon matched pairs signed rank tests. A P value <0.05 indicated a statistically significant difference.

RESULTS Participants

Twenty patients were included with a mean age of 63 years (range, 50–74 years). Participants with primary PCa (n = 7) and patients with recurrent disease (n = 13) had mean serum prostate-specific antigen levels of 33.1 ng/mL and 2.8 ng/mL, respectively (Table 2). In all 20 participants, the infusion of the contrast agent was without any adverse events, and they underwent both MRI examinations successfully. The overall image quality and the delineation of anatomical structures on the T2*-weighted images were scored significantly higher on 7 T, with a median score for overall image quality of 4 and 5 for 3 T and 7 T, respectively (P < 0.001) (Fig. 1). For more extensive elaboration of analysis of image quality and a movie comparing 3 T with 7 T data, see the Supplementary Materials, https://links.lww.com/RLI/A889.

TABLE 2 - Demographic Data of Participants Primary PCa Recurrent PCa No. participants 7 13 Age, y 61 (50–74) 64 (52–71) PSA, ng/mL 33.1 (8.2–88) 2.8 (0.2–17.5) No. suspicious LNs  7 T 5 (2–34) 4 (0–11)  3 T 3 (0–14) 3 (0–11)

Data for age and PSA are noted as means (range); number of nodes are noted as median per participant with (range).

PCa, prostate cancer; PSA, prostate-specific antigen; LN, lymph nodes.

FIGURE 1:

Example of USPIO-enhanced MRI of a patient with advanced prostate cancer at 7 T and 3 T in transversal planes. A big LN (short axis 7.5 mm, arrows) was scored by both readers with an LoS of 5 on both 7 T and 3 T. The smaller LN (short axis 3.0 mm, arrowheads) was scored suspicious with LoS 5 by both readers on 7 T. On 3 T, possibly due to its size or appearance, this node was not annotated by either of the readers.

Number of LNs

The total number of annotated LNs by either of the 2 readers was 599 at 7 T and 408 at 3 T (Table 3). The total number of LNs observed per patient (across all levels of suspicion) was higher at 7 T than at 3 T, with a median number (and range) of LNs annotated by at least 1 reader of 23.5 (2–88) versus 17.5 (2–45), P < 0.001 (Fig. 2A). Subgroup analysis showed significant differences in median number of LNs per patient for both primary (7 T: 20 vs 3 T: 17, P = 0.03) and recurrent disease (7 T: 28 vs 3 T: 18, P = 0.009), respectively.

TABLE 3 - Number of Annotated LNs on Both Field Strengths, Given for Each Reader Separately and Divided Further on Level of Suspicion 7 T 3 T R1 R2 R1 and R2 Total R1 R2 R1 and R2 Total All nodes 474 284 159 599 344 162 98 408  LoS 1 + 2 73 15% 92 32% 64 19% 32 20%  LoS 3 201 42% 54 19% 145 42% 62 38%  LoS 4 146 31% 73 26% 116 477 98 28% 46 28% 79 331  LoS 5 54 11% 65 23% 37 11% 22 14%

The subset R1 and R2 contains the LNs that were annotated by both readers; the total number encompasses all LNs annotated by either of the 2 readers.

LoS, level of suspicion.

FIGURE 2:

A, All annotated LNs per patient for 7 T and 3 T, with all patients (n = 20) and divided into primary (n = 7) and recurrent PCa (n = 13). B, Suspicious LNs (both readers LoS ≥3), for 7 T and 3 T. p indicates primary prostate cancer; r, recurrent disease.

Suspicious LNs (ie, LoS 3 or higher indicated by both readers) were found in 17/20 patients at both field strengths (Fig. 2B), with 116 suspicious LNs annotated on 7 T and 79 on 3 T (Table 3). The number of suspicious LNs annotated per patient was higher at 7 T than at 3 T, but the difference was not statistically significant (median [range], 4 [0–34] vs 3 [0–14]; P = 0.10). However, the number of highly suspicious LNs per patient (LoS ≥ 4 indicated by both readers) was significantly higher at 7 T (P = 0.02). The number of suspicious LNs per patient did not differ significantly between patients with primary and recurrent disease, neither at 7 T (5 [2–34] vs 4 [0–11], P = 0.30) nor at 3 T (3 [0–14] vs 3 [0–11], P = 0.60) (Table 2). Fifteen percent of suspicious LNs, for both field strengths, were located outside of the standard resection area of ePLND (see Supplemental Materials, https://links.lww.com/RLI/A888).

LN Size

Lymph nodes annotated by at least 1 reader (across all levels of suspicion) had a median short axis at 7 T and 3 T of 2.5 and 2.6 mm (Fig. 3), respectively (not significantly different, P = 0.78). Subgroup analysis showed no significant differences in median short axis of LNs for primary (7 T: 2.5 vs 3 T: 2.7 mm, P = 0.24) or recurrent disease (7 T: 2.5 vs 3 T: 2.5 mm, P = 0.61), respectively.

FIGURE 3:

Size distribution of annotated LNs per field strength (all levels of suspicion). Bars are cumulative, showing the LNs with their short axis, split by reader.

For suspicious LNs (7 T: n = 116, 3 T: n = 79), the median short axis diameters were 2.6 mm (range, 1.3–9.5 mm) and 2.8 mm (range, 1.7–10.4 mm) for 7 T and 3 T, respectively (Fig. 4, not significantly different, P = 0.05). The volume of suspicious LNs annotated at 7 T was overall significantly smaller compared with 3 T (median, 13.0 vs 19.1 mm3; P = 0.008). Also at 7 T, more (44%) suspicious LNs than at 3 T (27%) had a short axis <2.5 mm.

FIGURE 4:

Size distributions of suspicious LNs at 7 T and 3 T, noted as percentage of the total number (116 at 7 T and 79 at 3 T), ordered by short axis (A) and volume (B). 3 T data (semitransparent) is in front of 7 T data, with overlapping bars in purple.

Figure 5 illustrates the size and LoS of all annotated LNs. The short axis diameter shows great overlap between the LoS groups. At 7 T, the median value for LoS 5 shows a significant difference to both LoS 4 (P = 0.002) and LoS 3 (P = 0.02). At 3 T, the median value for LoS 5 shows a significant difference to LoS 3 (P < 0.001).

FIGURE 5:

Annotated LNs and their size ordered by LoS, with median value per LoS score group indicated. Scores of 1 and 2 were only given to mark a notable but unsuspicious LN, not incorporating any nodes without signal intensity on T2*-weighted imaging. *P < 0.05, **P < 0.005, ***P < 0.001.

Interreader Agreement

R1 and R2 both annotated more LNs on 7 T MRI (474 and 284) compared with 3 T MRI (344 and 162, respectively), see Table 3. Both readers had 98 matching LNs of a total of 408 nodes at 3 T and 159 matching LNs of 599 at 7 T. The individual LoS scores for LNs for both readers can be found in Table 4. R1 gave higher LoS scores for both field strengths (P < 0.001 for 7 T and 3 T).

TABLE 4 - Confusion Matrices of Interreader Agreement on 159 From 599 Annotated Nodes at 7 T and on 98 From 408 Annotated Nodes at 3 T Confusion Matrix 7 T Confusion Matrix 3 T R2 R2 R1 LoS 1 LoS 2 LoS 3 LoS 4 LoS 5 R1 LoS 1 LoS 2 LoS 3 LoS 4 LoS 5 LoS 1 1 0 1 0 0 LoS 1 0 1 0 0 0 LoS 2 0 2 0 0 0 LoS 2 0 1 1 0 0 LoS 3 0 22 9 9 1 LoS 3 0 3 6 10 1 LoS 4 0 15 13 22 25 LoS 4 0 13 18 10 4 LoS 5 0 2 2 10 25 LoS 5 0 0 6 11 13

Scores of 1 and 2 were only given to mark a notable but unsuspicious LN. LNs with scores ≥ Los3, in bold, were considered suspicious.

Matched LNs Between Field Strengths

Lymph nodes that were annotated by both readers were matched between field strengths (example in Fig. 1). From the 79 suspicious LNs found on 3 T images, almost all were also annotated on the 7 T images: either by both readers (51) or one of them (21). Of 116 suspicious LNs on 7 T images, 33 were not scored on 3 T images by either of the 2 readers (median short axis of 2.2 mm; range, 1.5–3.0 mm).

Fifty-eight LNs were scored by both readers on both field strengths and therefore further analyzed. There was no difference in size for the matched LNs on both field strengths (short axis mean: 3.64 [7 T], 3.40 [3 T]; P = 0.11). The interpretation of one reader did differ between field strengths in these matched LNs, as R2 gave significantly higher LoS scores for the same LNs on 7 T images compared with 3 T (P < 0.001, R1: P = 0.60).

DISCUSSION

This is the first study in which 7 T USPIO-enhanced MRI is compared with 3 T USPIO-enhanced MRI to detect LNs suspicious of metastases in the same patients with PCa. At 7 T, high-quality images allow the detection of more and especially more small (<2.5 mm) suspicious LNs. More highly suspicious LNs (LoS 4/5) were found per patient on 7 T compared with 3 T (P = 0.02). We showed that suspicious nodes in PCa are generally very small, with 44% of the suspicious LNs found on 7 T measuring <2.5 mm in short axis.

With different radiofrequency coils and pulse sequence possibilities at both field strengths, pulse sequences and sequence parameters were not the same for this comparison between 7 T and 3 T, but optimized to imaging on either 7 T or 3 T to exploit the advantages of that specific field strength. Examinations at 7 T with its substantially higher spatial resolution (voxel size being a factor 2.14 higher than 3 T: 0.29 mm3 vs 0.61 mm3) enabled us to detect more LNs with a short axis diameter below 2 mm. Although the short axis diameters of suspicious nodes did not differ significantly between 7 and 3 T, incorporating 3 spatial dimensions by measuring nodal volumes did reveal a significant difference in size between suspicious nodes detected at 7 T versus 3 T. Matching annotated LNs between field strengths showed that many of these very small LNs were not annotated on 3 T, possibly just due to their small size or due to being closely adjacent to and thereby indistinguishable from neighboring structures. As matched LNs did not show a difference in measured short axis diameter between field strengths, this indicates that there is no consistent measurement error due to the image quality or resolution.

The high number of suspicious LNs per patient is not unexpected, as the pelvis is known to hold many LNs (range, 19–91 LNs per healthy volunteer on 7 T MRI).24 The large variability in the number of annotated LNs per patient in this work represents the actual differences in patients at high risk for metastatic disease: 3 participants had more than 10 suspicious LNs, 3 patients had none, and in the remaining participants, the number of suspicious LNs ranged from 1 to 7. The number of annotated LNs located (partly) outside the standard ePLND resection field is in line with previous work19 and underlines the diagnostic and therapeutic challenges of ePLND.

As a large proportion of suspicious LNs in PCa were very small, the ability to identify these LNs could have important clinical implications. As a comparison, in breast cancer, direct ultrasound-guided fine-needle aspiration or core biopsy is recommended in axillary LNs with a cutoff point of maximum cortex thickness as small as 2.3 mm to achieve a high sensitivity of 95% and accepting a limited specificity of 44%.28 A positive result directly changes further diagnostics.29 In our study, there was a large overlap in short axis of annotated LNs between LoS groups. The idea that large LNs are suspicious and small LNs are not suspicious might no longer be valid in PCa, as most suspicious LNs were very small. The benefit for the patient in detecting more and more small suspicious LNs will most probably not be found in extending pelvic LN dissections, as its current impact on overall survival is already under debate,1,2 and removal of all small suspicious nodes will be very challenging. The combination of high-resolution MRI and functional USPIO contrast could introduce a new approach to personalized image-guided LNM-targeted therapy by enabling primary radiotherapy of these small LNMs.30–32 Although PSMA-PET/CT is of increasing clinical benefit for image-guided therapy and has the advantage of simultaneous assessment of distant (bone) metastases, its spatial resolution for LN detection is limited compared with the spatial resolution of 7 T USPIO-enhanced MRI.

R1 annotated many more LNs on both 7 T and 3 T examinations compared with R2, possibly because of the difference in experience with USPIO-enhanced MRI in combination with a continuous scale of nodal signal intensity. Annotating and scoring LNs based on the presence or absence of USPIO contrast–loaded macrophages enable a functional assessment that is no longer based on size and morphological characteristics. This requires, however, a different approach to “reading” images. The interpretation of USPIO accumulation with its different shades of gray without quantifying signal intensity requires a learning process. Of note is the increased confidence of the experienced USPIO-MRI reader R2 in scoring field strength-matched suspicious nodes, presumably because of the improved image quality at 7 T. Recently, Driessen et al33,34 have described a new paradigm for evaluating USPIO-enhanced MRI of the head and neck region, incorporating differences in retained signal intensity of nodes. Aided by an extensive workflow for node-to-node matching of in vivo detected LNs with histopathology of resected nodes,34 a new reading algorithm was designed incorporating the signal intensity of LNs compared with the surrounding fat, improving discrimination between metastatic and nonmetastatic LNs.33,34 This algorithm potentially also improves the agreement between readers in future studies if lipid tissue is not fully suppressed (not excited) in the multiecho gradient echo pulse sequence.

An important limitation of this study is that there is no histopathological reference standard for the suspicious LNs. Four of the 20 participants underwent ePLND after USPIO-enhanced imaging, but without a dedicated workflow for node-to-node matching of surgical specimens to pathological review of nodes.34,26 On a patient level, the USPIO-enhanced MRI results corresponded to the histopathological outcome: 3 patients with suspicious LNs on 3 T and 7 T MRI had LNMs on histopathology; the other patient who had no suspicious LNs on 7 T imaging and 1 suspicious LN on 3 T had no LNMs on histopathology. In absence of matched histopathology, we have chosen to deem LNs suspicious in case both readers annotated the LN with a high LoS. The sensitivity and specificity of 7 T USPIO-enhanced MRI to detect especially small LNMs in PCa remain to be investigated, this study however gives an indication of what to expect of high field strength MRI.

In conclusion, this first comparison of 7 T USPIO-enhanced MRI with 3 T USPIO-enhanced MRI in the same cohort of PCa patients reveals an increased detection of small LNs suspicious for harboring metastases on 7 T MRI. The high resolution of USPIO-enhanced 7 T MRI potentially expands the in vivo detection limits of pelvic LNM in PCa patients and can offer insight in pelvic LNM distributions. This may provide a new gateway to personalized image-guided therapy.

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