Targeted Biopsy Validation of Peripheral Zone Prostate Cancer Characterization with MR Fingerprinting and Diffusion Mapping

Abstract

Objective:

Targeted biopsy validation of magnetic resonance fingerprinting (MRF) and diffusion mapping for characterizing peripheral zone (PZ) prostate cancer and non-cancers.

Materials and Methods:

104 PZ lesions in 85 patients who underwent MRI were retrospectively analyzed with apparent diffusion coefficient (ADC) mapping, MRF and targeted biopsy (cognitive or in-gantry). A radiologist blinded to pathology drew regions-of-interest on targeted lesions and visually normal peripheral zone (NPZ) on MRF and ADC maps. Mean T₁, T₂ and ADC were analyzed using linear mixed models. Generalized estimating equations logistic regression analyses were used to evaluate T₁ and T₂ relaxometry combined with ADC in differentiating pathologic groups.

Results:

Targeted biopsy revealed 63 cancers (low-grade cancer/Gleason score 6=10, clinically significant cancer/Gleason score ≥ 7=53), 15 prostatitis and 26 negative biopsies. Prostate cancer T₁, T₂ and ADC (mean±SD, 1660±270 ms, 56±20 ms, 0.70×10⁻³±0.24×10⁻³ mm²/s) were significantly lower than prostatitis (mean±SD, 1730±350 ms 77±36 ms, 1.00×10⁻³±0.30×10⁻³ mm²/s) and negative biopsies (mean±SD, 1810±250 ms, 71±37 ms, 1.00×10⁻³ ±0.33×10⁻³ mm²/s). For cancer versus prostatitis, ADC was sensitive and T₂ specific with comparable area under curve (AUC). (AUC_T2=0.71, AUC_ADC=0.79, difference between AUCs not significant p=0.37). T₁+ADC (AUC_T1+ADC=0.83) provided best separation between cancer and negative biopsies. Low-grade cancer T₂ and ADC (mean±SD, 75±29 ms, 0.96×10⁻³ ±0.34×10⁻³ mm²/s) were significantly higher than clinically significant cancers (mean±SD, 52±16 ms, 0.65± 0.18×10⁻³ mm²/s) and T₂+ADC (AUC_T2+ADC=0.91) provided best separation.

Conclusion:

T₁ and T₂ relaxometry combined with ADC mapping may be useful for quantitative characterization of prostate cancer grades and differentiating cancer from non-cancers for PZ lesions seen on T₂w images.

Introduction

Interpretation of prostate mpMRI sequences as guided by Prostate Imaging, Reporting and Data System version 2 (PIRADS v2) is currently qualitative¹. However, there is increasing interest in quantitative evaluation for more objective lesion assessment^2–4. Prior studies have shown that the histological differences between normal prostate tissue, prostate cancers and inflammation are associated with measurable differences in T₂ and T₂* relaxation times and apparent diffusion coefficient (ADC) ^5–13. In clinical practice, ADC mapping is the only technique used quantitatively in prostate MRI and has been shown to reflect cancer aggressiveness^14–19 and partially separate cancer from prostatitis ^20,21. Magnetic Resonance Fingerprinting (MRF) represents another framework for performing relaxometry and allows simultaneous measurement of T₁ and T₂ relaxation times in a clinically feasible time^22,23. In MRF, user controllable system parameters such as flip angle, time of echo (TE), time of repetition (TR), etc. are allowed to vary in a pseudo-random manner such that unique signal evolutions are produced for each combination of tissue properties (T₁, T₂, etc.) and a dictionary of all possible signal evolutions is computed for that sequence. Obtained signal evolutions are matched against a best entry in the dictionary on a pixel-by-pixel basis, with relaxation properties used to generate the matched entry assigned to that pixel as the measured T₁ and T₂. This yields simultaneous, rapid and co-registered T₁ and T₂ maps that provide combined quantitative information²⁴, with several potential advantages over traditional mapping methods that typically measure either T₁ or T₂ relaxation times per acquisition^7,8,13,25. While relaxation property measurements will necessarily vary slightly based on the system imperfections and confounders that are accounted for in the dictionary^26–29, MRF-based relaxometry has been found to be repeatable and reproducible in both phantom and in-vivo assessment^30,31. Initial application to prostate imaging showed excellent separation between normal peripheral zone, and cancer or prostatitis using a combined quantitative protocol comprising of MRF-relaxometry and echo planar imaging (EPI) based DWI ³². That study also showed moderate accuracy for separating low-grade (Gleason score 6) from intermediate-high grade prostate (Gleason score 7 and above) cancers using quantitative criteria³². However, these results were based on transrectal ultrasound (TRUS) guided biopsy as a pathology reference and a small dataset with cognitive targeting. TRUS-guided biopsy is prone to sampling errors and can either underestimate the grade of cancer or miss cancer altogether ³³ while targeted biopsy methods can produce better correlation with the actual pathology^34,35. The purpose of this study was to provide targeted biopsy validation of combined MRF-based relaxometry and diffusion mapping for characterizing prostate cancer grades and differentiating prostate cancer from prostatitis and negative biopsies in the peripheral zone of prostate.

Materials and Methods

Patients

This Institutional Review Board approved and Health Insurance Portability and Accountability Act compliant study is a retrospective evaluation of MRF data collected prospectively between September 2014 and April 2018, from patients with suspected prostate cancer who had MRI followed by targeted biopsy (either cognitive or in-gantry biopsy). Written informed consent was obtained from all participants. Exclusion criteria included previous history of prostatectomy, pelvic radiation, chemotherapy or hormonal therapy.

Diagnostic MRI scans and in-gantry biopsies were performed at 3T (Verio or Skyra; Siemens, Erlangen, Germany) using a body array coil and no endorectal coil. The diagnostic MRI protocol is given in Table 1 and in-gantry biopsy protocol in a supplementary table (Supplementary Digital Content 1). MRF acquisitions and b-values for diffusion were kept constant to ensure consistency in quantitative MRI evaluation.

Table 1:

Imaging Parameters for Diagnostic MRI

Sequence	TR (ms) / TE) (ms)	Field of) View) (mm)	Resolution) (mm)	Matrix	Flip) angle) (degrees)	Slice) thickness) (mm)	b Value (s/mm2)	Sequence Duration (minutes)
Localizer- 3 plane	2000/95	305×285	1.2×1.2	320×240	150	5		0.02
Three plane single-shot fast spin echo	2000/92	305×244	1.2×1.2	384×308	150	5		0.32
Transverse turbo spin-echo T2w	8600/103	160×160	0.6×0.6	320×320	150	3		3:30
Diffusion weighted imaging	7900/88	240×240	1.2×1.2	198×198		3	50, 600, 1000, 1400	4:46
MR fingerprinting	13-15	400×400	1×1	400×400	5 –75	5		0.39 per slice
Pre-contrast T1w imaging with DCE perfusion*	3.34/1.02	240×240	1.9×1.9	128× 128	15	3		4:31
Post contrast T1w*	3.63/1.33	240×240	1.0×1.0	128×128	9	2		0.23

Abbreviations: TR: Time of Repetition, TE: Time of Echo, DCE: Dynamic Contrast Enhanced.

^*The patients in cognitive biopsy group underwent a non-contrast MRI protocol

Cognitive biopsies of cancer suspicious lesions were performed in combination with 12-core TRUS biopsies. Targeted lesions were localized based on MRI reads and visualized on TRUS using a prostate sector map and internal landmarks for reference. In-gantry biopsies were performed with a dedicated MR-compatible biopsy device (DynaTRIM, In Vivo, Gainesville, FL) using the assisted planning software (DynaLOC; Invivo) for guiding biopsy needle placement. For in-gantry biopsies, needle placement in the lesion was confirmed with a scan prior to taking biopsy samples. The median interval between MRF and cognitive biopsy was 21 days (range 6–133 days). For in-gantry biopsy, MRF with ADC mapping were performed at the time of biopsy.

141 patients (median 64 years, range 42–81 years) underwent clinical MRI with MRF and targeted biopsy (84 cognitive and 57 in-gantry biopsy). All cognitive biopsy patients were biopsy naïve while 35/57 in-gantry patients had previous TRUS biopsies. The median time interval between prior TRUS and in-gantry biopsy was 16.5 months (2–132 months). Eleven patients were excluded from quantitative analysis due to technical limitations [artifacts on MRF maps, (n=4), lesion not visualized on MRF maps (n=5) and failed reconstruction of MRF maps (n=2)] and if they had only transition zone lesions (n=41). Lesions with histopathologic diagnosis other than cancer, prostatitis or benign prostatic tissue were further excluded from quantitative ROI analysis (Fig.1). None of the targeted lesions had visible post-biopsy hemorrhage to preclude analysis. Part of the dataset (37 patients with 27 prostate cancer lesions) used in this study was also used in a previous publication (reference withheld for blinded review). However, that study did not evaluate lesions with negative biopsies and the results of TRUS biopsy was used as final reference standard for MRF values in cases of discordance.

Figure 1: Flow diagram of patient and lesion selection.

PZ = peripheral zone, HGPIN = high-grade intraepithelial neoplasia ASAP = atypical small acinar proliferation, ROI = region of interest.

MRF Acquisition and Post-Processing

MRF with fast imaging with steady-state precession (MRF-FISP)²³ was utilized and the whole prostate was covered. Acquisition time was 39 seconds per slice, and total scan time 5–10 minutes, depending on prostate size. A dictionary containing expected MRF signal evolutions was calculated with T₁ 20–2950ms and T₂ 9–500ms, and MRF maps obtained by template matching the signal timecourse in each pixel, as described previously²³. For patients recruited between September 2014 and September 2017, the raw MRF data were processed offline on Matlab (Matlab 2014a; MathWorks, Natick, Mass) with offline reconstruction time of 190 seconds per slice. For patients recruited after October 2017, a Gadgetron-based framework was used for rapid online reconstruction of MRF data³⁶ and quantitative T₁ and T₂ maps in DICOM format were directly available real-time on the MR scanner. A prior comparison of offline and online reconstruction methods showed that MRF T₁ and T₂ values were similar for both reconstruction methods³⁷.

Clinical Interpretation and Quantitative ROI analysis

Targeted biopsy lesions were evaluated based on PIRADSv2 by a fellowship-trained body radiologist (18 years radiology experience) who also performed all in-gantry targeted biopsies with 1–6 cores obtained per lesion (median 3 cores). Another radiologist (8 years experience) who was blinded to the clinical information and pathology diagnosis but aware of the locations of the targeted lesions retrospectively drew regions-of-interest (ROIs) on suspicious peripheral zone lesions and on the contralateral visually normal peripheral zone (NPZ) on both MRF and ADC maps. As a part of acquisition scheme, both T₂w and ADC slices were anatomically co-registered while MRF T₁ and T₂ maps were anatomically co-registered. The T₂w slice with the largest lesion area and used for biopsy planning, was taken as the reference slice and the T₂ MRF slice anatomically corresponding to this T₂w slice was selected. Lesions and NPZ ROIs were drawn on the selected T₂ MRF slice and, both T₁ and T₂ were obtained simultaneously from these ROIs . Again using T₂w slice and T₂ map as the reference, lesion and NPZ ROIs were replicated independently at the corresponding locations on the ADC maps. Fig. 2 depicts the image analysis workflow. The lesion ROI sizes ranged from 6–442 mm² (median 55 mm²). For each targeted lesion and NPZ, the mean T₁, T₂, and ADC were recorded. Based on targeted-core biopsy reports, final pathologic diagnosis for each targeted lesion was recorded. For cancers, Gleason scores were recorded. For targeted lesions for which more than one Gleason score was given, the highest score was recorded as the final pathological diagnosis.

Figure 2: Regions of Interest (ROI) analysis.

Cancer suspicious lesions (solid arrow) were identified based on axial T₂w slice (A) and ADC map (B). The anatomically corresponding MRF slices (C, D) were aligned with T₂w slice and lesions ROIs were drawn on MRF map (black oval). As MRF maps were co-registered, both T₁ and T₂ values were simultaneously obtained from single MRF ROI. Independent ROIs were drawn on ADC map (red oval) co-registered to the T₂w slice. ROIs were also drawn on the visually normal peripheral zone (NPZ) covering whole contralateral NPZ.

Statistical Analysis

Lesions diagnosed as cancer, prostatitis and negative on biopsy were included for analysis. Mean T₁, T₂, and ADC were compared between individual biopsy groups and with NPZ using linear mixed models. Generalized estimating equations logistic regression analysis was used to assess the utility of MR fingerprinting–derived T₁, T₂, and ADC in the differentiation of 1) All prostate cancers from (a) prostatitis (b) negative biopsies and (c) all non-cancers (prostatitis + negative biopsies) and 2) Clinically significant cancers from (a) low-grade cancers (b) all non-cancers (prostatitis + negative biopsies) and (c) all clinically insignificant lesions (low-grade cancers + prostatitis + negative biopsies).

Low-grade cancer was defined as Gleason 3+3=6, clinically significant cancer was defined as Gleason score≥7, as Gleason 6 cancers are considered for active surveillance at our institution. Low-grade cancers were grouped with non-cancers and compared them with clinically significant cancers to see if quantitative mapping could be used to differentiate lesions that do not need intervention (low-grade cancers, prostatitis, benign prostatic tissue) versus lesions that are clinically significant.

Receiver operating characteristic curves and areas under the receiver operating characteristic curve (AUC) (C- statistics) were obtained from logistic regressions by using the linear predictors obtained from the generalized estimating equations regressions. For significant univariate models with best AUCs, the cut-off points for maximum sensitivity and specificity were obtained using Youden’s J statistics. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC).

Results

In 89 patients with peripheral zone lesions, 111 lesions were targeted (80 cognitive sampling, 31 in-gantry sampling). 63 lesions were prostate cancer (10 Low Grade (Gleason score 6), 38 Intermediate Grade (Gleason score 7), 15 High Grade (Gleason score ≥ 8)), 15 prostatitis, 26 negative with biopsy showing normal prostatic tissue and 7 had another diagnosis (5 high-grade prostatic intraepithelial neoplasia and 2 atypical small acinar proliferation). These 7 lesions (4 patients) were excluded and the remaining 104 lesions (85 patients) were analyzed (Fig. 1). T₁ and T₂ numbers were available for all 104 targeted lesions included in final analysis, and ADC measurement was not available for one lesion due to distorted ADC map. NPZ ROIs T₁, T₂ measurements were available for 82 patients for comparison with the measurements in the different histologic groups and were not drawn for 3 patients due to lack of visually normal peripheral zone on T₂w images.

Mean T₁, T₂ and ADC for NPZ, histologically proven prostate cancer including low-grade cancer and clinically significant cancers, prostatitis and negative biopsies are summarized in Table 2 and the distributions depicted as box-and-whisker plots in Fig. 3. Table 3 summarizes the AUCs for regression models. The best diagnostic performance cut-off points are summarized in Table 4.

Table 2:

Summary of Means of T₁, T₂ and ADC of normal peripheral zone and different histopathologic groups

Group (Number of samples)	T1 (ms) Mean ± SD	T2 (ms) Mean ± SD	ADC (×10−3 mm2/s) Mean ± SD
Normal Peripheral Zone (n=82)	2240±360	146±61	1.68±0.31
Prostate Cancer (n=63)	1660±270	56±20	0.70±0.24
Prostatitis (n=15)	1760±350	77±36	1.00±0.30
Biopsy-proven Benign Prostatic Tissue (n=26)	1810±250	71±37	1.00±0.33
Low-grade cancer/Gleason score = 6 (n=10)	1690±400	75±29	0.96±0.34
Clinically significant cancers/Gleason score≥7 (n=53)	1650±240	52±16	0.65±0.18
Non-Cancers (Prostatitis + Benign Prostatic tissue) (n=41)	1790±290	73 ±37	1.00±0.32

Figure 3: Box and whisker plots of (A) T₁ (B) T₂ and (C) ADC measurements for normal peripheral zone (NPZ) and different histologic groups.

The boxes represent the interquartile (IQ) range between 25-75^th percentiles, the lines within boxes represent medians and the whiskers represent measurements 1.5 times interquartile range. The circles and crosses represent outliers beyond 1.5 times and beyond 3 times the IQ ranges respectively.

Table 3:

Differentiation of various groups with T₁, T₂ and ADC and their combinations.

Groups Compared	T1 AUC	T2 AUC	ADC AUC	T1+T2 AUC	T1+ ADC AUC	T2+ ADC AUC	T1+ T2+ ADC AUC	Highest AUC#
All Prostate cancers versus Non-Cancers
Prostate Cancer (n=63) vs. Prostatitis (n=15)	0.60 (0.41-0.78)	0.71* (0.55-0.88)	0.79* (0.65-0.93)	0.71 (0.54-0.88)	0.76 (0.59-0.92)	0.79 (0.64-0.94)	0.79 (0.65-0.95)	ADC (0.79) comparable to T2 (0.71) Difference between two AUCs not significant (p=0.37)
Prostate Cancer (n=63) vs. Negative Biopsies (n=26)	0.67* (0.55-0.79)	0.62 (0.49-0.75)	0.80* (0.69-0.90)	0.67 (0.55-0.79)	0.83* (0.74-0.93)	0.80 (0.70-0.93)	0.83 (0.74-0.93)	T1+ADC (0.83)
Prostate Cancer (n=63) vs. Non-cancers (n=41)	0.64* (0.53-0.75)	0.66* (0.55-0.77)	0.80* (0.71-0.89)	0.68 (0.57-0.78)	0.80* (0.71-0.89)	0.80 (0.71-0.89)	0.80 (0.71-0.89)	T1+ADC (0.80) ADC (0.80)
Clinically-significant (CS) cancers versus other histologic groups
CS Cancer (n=53) vs. Low-grade cancers (n=10)	0.48 (0.25-0.71) [0.553]	0.77* (0.61-0.92) [0.012]	0.84* (0.71-0.97) [0.002]	0.76 (0.61-0.92)	0.85 (0.74-0.96)	0.91* (0.82-0.99)	0.90 (0.79-1.00)	T2+ADC (0.91)
CS Cancer (n=53) vs. Non-cancers (n=41)	0.64* (0.53-0.76) [0.028]	0.70* (0.59-0.81) [0.029]	0.84* (0.76-0.92) [<0.0001]	0.70 (0.60-0.81)	0.85 (0.77-0.93)	0.86* (0.78-0.93)	0.86 (0.74-0.94)	T2+ADC (0.86)
CS Cancer (n=53) vs. Non-cancers + Low-grade cancers (n=51)	0.61 (0.50-0.72) [0.064]	0.71* (0.61-0.81) [0.0002]	0.84* (0.76-0.92) [<0.0001]	0.70 (0.60-0.80)	0.85 (0.77-0.92)	0.86* (0.79-0.93)	0.86 (0.80-0.93)	T2+ADC (0.86)

^*Indicate models with significant variables (p < 0.05) obtained from generalized estimating equation (GEE) logistic regression analysis. The numbers in parenthesis indicate 95% confidence intervals and numbers in brackets indicate P-value for the variables in the univariate models.

^#The highest AUC represents model(s) with significant variables after GEE logistic regression analysis.

Clinically-significant cancers included all cancers with Gleason score ≥ 7 while low-grade cancers was denoted by cancers with Gleason score =6

Negative biopsy =Targeted lesions with biopsy report of benign prostatic tissue

Table 4:

Best-performance cut-off values for T₁, T₂ and ADC based on regression models. For multivariate regression models, the individual cut-off values contributed independently to overall performance. The numbers in parenthesis indicate sensitivity and specificity for respective cut-off values.

Groups Compared	T1 (Sensitivity/ Specificity)	T2 (Sensitivity/ Specificity)	ADC (Sensitivity/ Specificity)
All Prostate cancers versus Non-Cancers
Prostate Cancer (n=63) vs. Prostatitis (n=15)	Regression model not significant	68 ms (79%67%)	1.04×10−3 mm2/s (98%/53%)
Prostate Cancer (n=63) vs. Negative Biopsies (n=26)	1720 ms (68%/62%)	Regression model not significant	0.75×10−3 mm2/s (62%/92%)
Prostate Cancer (n=63) vs. Non-cancers (n=41)	1720 ms (67%/59%)	67 ms (79%/46%)	0.75×10−3 mm2/s (62%/87.5%)
Clinically-significant (CS) cancers versus other histologic groups
CS Cancer (n=53) vs. Low-grade cancers (n=10)	Regression model not significant	52 ms (62%/90%)	0.78×10−3 mm2/s (73.5%/80%)
CS Cancer (n=53) vs. Non-cancers (n=41)	1720 ms (68%/58/5%)	52 ms (62%/71%)	0.75×10−3 mm2/s (70%87.5%)
CS Cancer (n=53) vs. Clinically Insignificant lesions (Non-cancers + Low-grade cancers) (n=51)	1730 ms (68%/55%)	60 ms (62%/74.5%)	0.75×10−3 mm2/s (70%/86%)

All Prostate Cancers versus Non- cancers

Prostate Cancer versus Prostatitis:

Means of T₁, T₂ and ADC differed significantly between prostate cancer and prostatitis (p=0.039 for T₁, p=0.015 for T₂, p<0.0001 for ADC). Both T₂ and ADC were significant predictors in logistic regression models with both having moderate diagnostic performance for separation (Table 3). AUC_T2 was 0.71 while AUC_ADC was 0.79 with no significant difference between the two AUCs (p=0.37).

Prostate Cancer versus Negative Biopsies:

Means of T₁, T₂ and ADC differed significantly between prostate cancer and negative biopsies (p=0.0029 for T₁, p=0.0058 for T₂, p<0.0001 for ADC) Best separation was provided by T₁+ADC (AUC_T1+ADC=0.83) and was significantly higher than AUC_ADC (p=0.028) (Table 3).

Prostate Cancer versus Non-Cancers (Prostatitis and Negative Biopsies):

Means of T₁, T₂ and ADC differed significantly between prostate cancer and all non-cancers (p=0.0009 for T₁, p=0.0004 for T₂, p<0.0001 for ADC). Both ADC and T₁+ADC had comparable diagnostic performances for separation (AUC_ADC=0.797, AUC_ADC+T1= 0.801) (Table 3) (Figure 4b).

Figure 4: Quantitative characterization with combined MRF-relaxometry and ADC mapping.

(a) Scatterplot of T₂ versus ADC for prostatitis (n = 15), low-grade cancers (n =10) and clinically significant cancers (n = 53). ADC value of 1.04 × 10⁻³ mm²/s is sensitive but not specific for differentiating all cancers from prostatitis (right vertical line). ADC value of 0.78 × 10⁻³ mm²/s (left vertical line) is the best cut-off for differentiating clinically significant cancers from low-grade cancers and prostatitis. In the ADC overlap zone (between two vertical lines), a T₂ ≤ 68 ms is additionally helpful in differentiating cancers from prostatitis (horizontal line).

(b) Scatterplot of T₁ versus ADC for non-cancers including prostatitis (n = 15), negative biopsies (n = 26), low-grade cancers (n =10) and clinically significant cancers (n = 53). ADC values of 0.75 × 10⁻³ mm²/s followed by T₁ of 1720 ms are the best cut-offs for differentiating cancers from non-cancers (horizontal line). In the ADC overlap zone (between vertical lines), while five clinically significant cancers had T₁ > 1720 ms, they also had T₂ ≤ 68 ms.

Clinically Significant Prostate Cancers versus Low-grade cancers and Non-Cancers

Clinically significant cancer versus low-grade cancers:

Means of T₂ and ADC differed between low-grade and high/intermediate grade cancer (p< 0.0031 for T₂ and p<0.0001 for ADC) and both were significant univariable predictors with similar diagnostic performances for differentiating cancer grades (AUC_T2=0.77, AUC_ADC=0.84, difference between two AUCs not significant, p=0.48). The best separation was obtained with T₂+ADC (AUC_T2+ADC=0.91) (Table 3).

Clinically significant cancer versus all Non-cancers (Prostatitis and Negative Biopsies)

Means of T₁, T₂ and ADC differed between clinically significant prostate cancer and all non-cancers (p=0.0003 for T₁, p=0.0004 for T₂, p<0.0001 for ADC). Best separation was provided by T₂+ADC (AUC_T2+ADC=0.86) and was significantly higher than AUC_ADC (p=0.04) (Table 3).

Clinically significant cancer versus Clinically insignificant lesions (Low-grade cancers and non-cancers)

Mean T₁, T₂ and ADC differed between clinically significant prostate cancer and low-grade cancers + non-cancers (p=0.0027 for T₁, p=0.0003 for T₂, p0.0001 for ADC). Best separation was provided by T₂+ADC (AUC_T2+ADC=0.86), and was significantly higher than AUC_ADC (p=0.005) (Table 3).

Figure 5 shows representative cases from our dataset.

Figure 5: Comparison of ADC, T₁ and T₂ values for targeted biopsy-proven prostate cancer (A-D), prostatitis (E-H) and benign prostatic tissue (I-L).

Prostate cancer: T₂w image (A) shows focal dark lesion against diffuse dark background signal in right peripheral zone with ADC of 0.87 × 10⁻³ mm²/s (B). T₁ and T₂ values were 1560 ms and 42 ms respectively.

Prostatitis: T₂w (E) shows a wedge-shaped mildly dark lesion in left peripheral zone with ADC of 0.87 × 10⁻³ mm²/s (F). T₁ and T₂ values were higher than cancer at 1770 ms and 83 ms respectively.

Benign prostatic tissue: T₂w (I) shows a focal lesion in right apical peripheral zone with ADC of 0.82 × 10⁻³ mm²/s. Based on suspicious morphology on clinical MRI, biopsy was performed which revealed benign prostatic tissue. T₁ and T₂ values were higher than cancer at 2310 ms and 73 ms respectively.

Discussion

This study provides targeted biopsy validation of MRF-based relaxometry and ADC mapping for prostate imaging and adds to previous work on the demonstration of a combined quantitative exam using MRF and ADC mapping. Using targeted biopsy as a pathology reference allowed better exploration of the differences in relaxation times and ADC between grades of prostate cancer, prostatitis and negative biopsies and quantitative comparison of these histologic groups with visually NPZ. As reported previously ³² and expected due to the choice of ROIs, mean T₁, T₂ and ADC in visually NPZ were higher than prostate cancer and prostatitis (Table 2). Histologically, the long T₂ and high ADC in NPZ have been attributed to the larger volume of glandular lumen which has “water-like” T₂ relaxation times and shows increased diffusivity within the lumen^38,39. The longer T₁ in NPZ may relate to the proteinaceous contents of the glandular sections within the lumen¹². The destruction of glandular architecture in cancers is also associated with decreased secretory function⁴⁰, which may potentially account for the difference in T₁ relaxation times between NPZ and cancer. More interestingly, targeted lesions diagnosed as normal prostatic tissue on biopsy, despite confirmed intra-lesional needle positions, had T₁, T₂ and ADC lower than visually NPZ, but higher than prostate cancer (Table 2). While the exact histological basis for these changes in negative biopsies is not known, these may represent non-specific changes in peripheral zone as prior ischemic/biopsy/inflammatory sequelae or may be attributed to the proposed existence of two populations of water protons in normal prostate tissue, one with characteristic long T₂ and ADC within the glandular lumen and the other with shorter T₂ and ADC due to increased stromal content^12,38,39.

There were significant differences in T₁ and T₂ between prostate cancer and non-cancers (prostatitis and negative biopsies), which have not been reported previously ³². T₁ and T₂ were found to be complementary to ADC for differentiating prostate cancers from negative biopsies and prostatitis, respectively (Table 3). Previous studies have shown an overlap in ADC values between prostatitis, negative biopsies and prostate cancer. ADC values are dependent on the b-values used and the MR system gradient performance; thus no absolute ADC cut-off value can be recommended for diagnosis^20,21,41. In practice, ADC values between 0.75–0.95×10⁻³ mm²/s, are the usual recommended thresholds for diagnosing malignancy ¹. In this study too, an ADC value of less than 0.75×10⁻³ mm²/s was specific for differentiating a) prostate cancers from non-cancers and b) clinically significant cancers from both non-cancers and low-grade cancers, but missed cancers with higher ADC values (Table 4, Fig. 4). Vice-versa, a higher ADC cutoff of 1.04×10⁻³ mm²/s was sensitive for separating prostate cancer from prostatitis but had lower specificity due to a considerable overlap in ADC values between low-grade cancers, clinically significant cancers and prostatitis (Table 4, Fig. 4). However using T₂ values below 68 ms may be additionally useful in differentiating prostatitis from prostate cancers for lesions with overlapping ADC values between 0.75–1.0×10⁻³ mm²/s (as shown in Fig. 4a). Similarly, T₁ values below 1720 ms may be useful in separating cancers from non-cancers in the ADC overlap zone (Fig. 4b). Such additional measures of quantification may potentially improve pre-biopsy characterization of indeterminate or equivocal lesions seen on mpMRI, subject to future prospective validation.

For separation of cancers and non-cancers, AUC_T2 and AUC_ADC were higher than the previously reported AUC_T2 of 0.52–0.74 and AUC_ADC of 0.66–0.69^7,32 which may be due to better pathologic correlation provided by targeted biopsy while the T₁ differences between prostate cancers and non-cancers is an additional finding in this study. The MRF-T₂ values for different histopathologic groups are lower compared to values previously reported elsewhere ^{5,7,10,25,42–44} and may relate to differences from multiple spin-echo mapping^7,43,45, such as noise floor effects at long echo times.

Both T₂ and ADC had comparable performance for differentiating low-grade from clinically significant cancers, with the combination of T₂ and ADC being additive (Table 3). Again, the AUC_T2 from targeted biopsy validation is higher than the AUC_T2 of 0.67–0.77 reported previously using TRUS biopsy^7,32 while the AUC_ADC for differentiating grades of cancers is comparable to the AUC_ADC of 0.70–0.82 reported previously ^{4,16,17,46–49}. At the microstructural level, higher Gleason grades are correlated with increased nuclear count and area, increased epithelial and decreased luminal and stromal volume fractions⁵⁰. While ADC was previously shown to correlate better with tissue composition changes and increased cellularity metrics as compared to T₂^6,50,51, both tissue properties had similar performance for predicting cancer aggressiveness in this study. Due to the FISP acquisition scheme utilized^22,23, MRF as implemented is less adversely affected by rectal gas than echo planar imaging based diffusion acquisitions (Fig. 6). Subject to future validation, relaxation time mapping obtained in this manner could potentially have quantitative utility as an alternative to ADC mapping in situations when DWI is distorted due to susceptibility artifacts. Mean T₂ and ADC for low-grade cancers were similar to those of prostatitis and benign biopsies (Table 2). This is concordant with previous results⁷ and the knowledge that low-grade cancers often have a have a low fraction of tumor cells intermixed with normal prostatic tissue⁵¹ and have lower epithelial and higher luminal fraction compared to higher grade cancers¹².

Figure 6: MRF with susceptibility artifacts on ADC mapping in a biopsy-proven case of 4 + 3 = 7 cancer.

T₂w image (A) shows ill-defined dark lesion in right apical peripheral zone (arrow) with low ADC value of 0.60 × 10⁻³ mm²/s (B). However due to gas in rectum (*), there is susceptibility artifact on ADC map with anteroposterior deformation of the gland. MRF T₁ (A) and T₂ (B) color maps are relatively unaffected by rectal gas and corresponding lesion T₁ and T₂ values were 1600 ms and 52 ms respectively.

This study had several limitations. First, only peripheral zone lesions were analyzed in this study. This is because both peripheral and transition zones have different histological characteristics and are evaluated differently on conventional MRI, with ADC being the primary sequence for peripheral zone lesions and T₂w imaging being the primary sequence for transition zone lesions. Separate analysis evaluating transition zone lesions will add further insight on the utility of this approach in prostate imaging. Second, the utilities of relaxometry and ADC mapping were utilized for lesion characterization and not for detection. Third, since the resolution of the technique is not comparable yet to T₂w imaging, volumetric analysis was not performed and this remains a limitation of the work at this time. Efforts are underway at multiple institutions to develop and implement MRF examinations with higher spatial resolutions that would be better suited for detection and volumetric analysis in the future. Fourth as targeted biopsy correlation was used instead of whole-mount prostatectomy specimens for a more practical and clinically feasible histologic validation, our dataset contained of a larger number clinically significant cancers versus low-grade cancers and prostatitis. This introduces a potential selection bias because targeted biopsy is known to detect a higher number of clinically significant cancers as compared to TRUS biopsy or prostatectomy³³. In the future, a prospective analysis accompanied by prostatectomy correlations may also allow analysis of larger subject/lesion populations. Fifth, cognitive biopsy was the predominant biopsy method in our study because in our institution, in-gantry biopsy was performed more often for anterior transition zone lesions and in patients with prior negative biopsies and this may have introduced an element of sampling bias. Finally, this was a single-center retrospective study with a single-reader analysis. Thus, the findings described need future prospective validation with larger datasets obtained from multi-institutional studies.

Conclusions

This work shows that the combination of T₁ and T₂ relaxometry can be complementary to ADC in predicting prostate cancer aggressiveness and may help in additional separation of cancers from prostatitis and negative biopsies for lesions on T₂w images in the peripheral zone.

Abbreviations:

mpMRI

Multiparametric Magnetic Resonance Imaging

DWI

Diffusion weighted Imaging

MRF

Magnetic Resonance Fingerprinting

NPZ

Normal Peripheral Zone

ADC

Apparent Diffusion Coefficient

TRUS

Transrectal Ultrasound