Prostate Cancers Invisible on Multiparametric MRI: Pathologic Features in Correlation with Whole-Mount Prostatectomy.

We investigated why some prostate cancers (PCas) are not identified on multiparametric MRI (mpMRI) by using ground truth reference from whole-mount prostatectomy specimens. A total of 61 patients with biopsy-confirmed PCa underwent 3T mpMRI followed by prostatectomy. Lesions visible on MRI prospectively or retrospectively identified after correlating with histology were considered "identified cancers" (ICs). Lesions that could not be identified on mpMRI were considered "unidentified cancers" (UCs). Pathologists marked the Gleason score, stage, size, and density of the cancer glands and performed quantitative histology to calculate the tissue composition. Out of 115 cancers, 19 were unidentified on MRI. The UCs were significantly smaller and had lower Gleason scores and clinical stage lesions compared with the ICs. The UCs had significantly (p < 0.05) higher ADC (1.34 ± 0.38 vs. 1.02 ± 0.30 µm2/ms) and T2 (117.0 ± 31.1 vs. 97.1 ± 25.1 ms) compared with the ICs. The density of the cancer glands was significantly (p = 0.04) lower in the UCs. The percentage of the Gleason 4 component in Gleason 3 + 4 lesions was nominally (p = 0.15) higher in the ICs (20 ± 12%) compared with the UCs (15 ± 8%). The UCs had a significantly lower epithelium (32.9 ± 21.5 vs. 47.6 ± 13.1%, p = 0.034) and higher lumen volume (20.4 ± 10.0 vs. 13.3 ± 4.1%, p = 0.021) compared with the ICs. Independent from size and Gleason score, the tissue composition differences, specifically, the higher lumen and lower epithelium in UCs, can explain why some of the prostate cancers cannot be identified on mpMRI.

Validation of Prostate Tissue Composition by Using Hybrid Multidimensional MRI: Correlation with Histologic Findings.

Background Tissue estimates obtained by using microstructure imaging techniques, such as hybrid multidimensional (HM) MRI, may improve prostate cancer diagnosis but require histologic validation. Purpose To validate prostate tissue composition measured by using HM MRI, with quantitative histologic evaluation from whole-mount prostatectomy as the reference standard. Materials and Methods In this HIPAA-compliant study, from December 2016 to July 2018, prospective participants with biopsy-confirmed prostate cancer underwent 3-T MRI before radical prostatectomy. Axial HM MRI was performed with all combinations of echo times (57, 70, 150, and 200 msec) and b values (0, 150, 750, and 1500 sec/mm2). Data were fitted by using a three-compartment signal model to generate volumes for each tissue component (stroma, epithelium, lumen). Quantitative histologic evaluation was performed to calculate volume fractions for each tissue component for regions of interest corresponding to MRI. Tissue composition measured by using HM MRI and quantitative histologic evaluation were compared (paired t test) and correlated (Pearson correlation coefficient), and agreement (concordance correlation) was assessed. Receiver operating characteristic curve analysis for cancer diagnosis was performed. Results Twenty-five participants (mean age, 60 years ± 7 [standard deviation]; 30 cancers and 45 benign regions of interest) were included. Prostate tissue composition measured with HM MRI and quantitative histologic evaluation did not differ (stroma, 45% ± 11 vs 44% ± 11 [P = .23]; epithelium, 31% ± 15 vs 34% ± 15 [P = .08]; and lumen, 24% ± 13 vs 22% ± 11 [P = .80]). Between HM MRI and histologic evaluation, there was excellent correlation (Pearson r: overall, 0.91; stroma, 0.82; epithelium, 0.93; lumen, 0.90 [all P < .05]) and agreement (concordance correlation coefficient: overall, 0.91; stroma, 0.81; epithelium, 0.90; and lumen, 0.87). High areas under the receiver operating characteristic curve obtained with HM MRI (0.96 for epithelium and 0.94 for lumen, P < .001) and histologic evaluation (0.94 for epithelium and 0.88 for lumen, P < .001) were found for differentiation between benign tissue and prostate cancer. Conclusion Tissue composition measured by using hybrid multidimensional MRI had excellent correlation with quantitative histologic evaluation as the reference standard. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Muglia in this issue.

VERDICT MRI validation in fresh and fixed prostate specimens using patient-specific moulds for histological and MR alignment.

The VERDICT framework for modelling diffusion MRI data aims to relate parameters from a biophysical model to histological features used for tumour grading in prostate cancer. Validation of the VERDICT model is necessary for clinical use. This study compared VERDICT parameters obtained ex vivo with histology in five specimens from radical prostatectomy. A patient-specific 3D-printed mould was used to investigate the effects of fixation on VERDICT parameters and to aid registration to histology. A rich diffusion data set was acquired in each ex vivo prostate before and after fixation. At both time points, data were best described by a two-compartment model: the model assumes that an anisotropic tensor compartment represents the extracellular space and a restricted sphere compartment models the intracellular space. The effect of fixation on model parameters associated with tissue microstructure was small. The patient-specific mould minimized tissue deformations and co-localized slices, so that rigid registration of MRI to histology images allowed region-based comparison with histology. The VERDICT estimate of the intracellular volume fraction corresponded to histological indicators of cellular fraction, including high values in tumour regions. The average sphere radius from VERDICT, representing the average cell size, was relatively uniform across samples. The primary diffusion direction from the extracellular compartment of the VERDICT model aligned with collagen fibre patterns in the stroma obtained by structure tensor analysis. This confirmed the biophysical relationship between ex vivo VERDICT parameters and tissue microstructure from histology.

Diagnosis of Prostate Cancer with Noninvasive Estimation of Prostate Tissue Composition by Using Hybrid Multidimensional MR Imaging: A Feasibility Study.

Purpose To evaluate whether compartmental analysis by using hybrid multidimensional magnetic resonance (MR) imaging can be used to diagnose prostate cancer and determine its aggressiveness. Materials and Methods Twenty-two patients with prostate cancer underwent preoperative 3.0-T MR imaging. Axial images were obtained with hybrid multidimensional MR imaging by using all combinations of echo times (47, 75, 100 msec) and b values of 0, 750, 1500 sec/mm2, resulting in a 3 × 3 array of data associated with each voxel. Volumes of the tissue components stroma, epithelium, and lumen were calculated by fitting the hybrid data to a three-compartment signal model, with distinct, paired apparent diffusion coefficient (ADC) and T2 values associated with each compartment. Volume fractions and conventional ADC and T2 were measured for regions of interest in sites of prostatectomy-verified malignancy (n = 28) and normal tissue (n = 71). Receiver operating characteristic (ROC) analysis was used to evaluate the performance of various parameters in differentiating prostate cancer from benign tissue. Results Compared with normal tissue, prostate cancer showed significantly increased fractional volumes of epithelium (23.2% ± 7.1 vs 48.8% ± 9.2, respectively) and reduced fractional volumes of lumen (26.4% ± 14.1 vs 14.0% ± 5.2) and stroma (50.5% ± 15.7 vs 37.2% ± 9.1) by using hybrid multidimensional MR imaging. The fractional volumes of tissue components show a significantly higher Spearman correlation coefficient with Gleason score (epithelium: ρ = 0.652, P = .0001; stroma: ρ = -0.439, P = .020; lumen: ρ = -0.390, P = .040) compared with traditional T2 values (ρ = -0.292, P = .132) and ADCs (ρ = -0.315, P = .102). The area under the ROC curve for differentiation of cancer from normal prostate was highest for fractional volume of epithelium (0.991), followed by fractional volumes of lumen (0.800) and stroma (0.789). Conclusion Fractional volumes of prostatic lumen, stroma, and epithelium change significantly when cancer is present. These parameters can be measured noninvasively by using hybrid multidimensional MR imaging and have the potential to improve the diagnosis of prostate cancer and determine its aggressiveness. © RSNA, 2018 Online supplemental material is available for this article.

Apparatus for Histological Validation of In Vivo and Ex Vivo Magnetic Resonance Imaging of the Human Prostate.

This article describes apparatus to aid histological validation of magnetic resonance imaging studies of the human prostate. The apparatus includes a 3D-printed patient-specific mold that facilitates aligned in vivo and ex vivo imaging, in situ tissue fixation, and tissue sectioning with minimal organ deformation. The mold and a dedicated container include MRI-visible landmarks to enable consistent tissue positioning and minimize image registration complexity. The inclusion of high spatial resolution ex vivo imaging aids in registration of in vivo MRI and histopathology data.

Diffusion anisotropy in fresh and fixed prostate tissue ex vivo.

PURPOSE: To investigate diffusion anisotropy in whole human prostate specimens METHODS: Seven whole radical prostatectomy specimens were obtained with informed patient consent and institutional ethics approval. Diffusion tensor imaging was performed at 9.4 Tesla. Diffusion tensors were calculated from the native acquired data and after progressive downsampling RESULTS: Fractional anisotropy (FA) decreased as voxel volume increased, and differed widely between prostates. Fixation decreased mean FA by ∼0.05-0.08 at all voxel volumes but did not alter principle eigenvector orientation. In unfixed tissue high FA (> 0.6) was found only in voxels of volume <0.5 mm(3) , and then only in a small fraction of all voxels. At typical clinical voxel volumes (4-16 mm(3) ) less than 50% of voxels had FA > 0.25. FA decreased at longer diffusion times (Δ = 60 or 80 ms compared with 20 ms), but only by ∼0.02 at typical clinical voxel volume. Peripheral zone FA was significantly lower than transition zone FA in five of the seven prostates CONCLUSION: FA varies widely between prostates. The very small proportion of clinical size voxels with high FA suggests that in clinical DWI studies ADC based on three-direction measurements will be minimally affected by anisotropy. Magn Reson Med 76:626-634, 2016. © 2015 Wiley Periodicals, Inc.

Assessment of non-Gaussian diffusion with singly and doubly stretched biexponential models of diffusion-weighted MRI (DWI) signal attenuation in prostate tissue.

Non-Gaussian diffusion dynamics was investigated in the two distinct water populations identified by a biexponential model of diffusion in prostate tissue. Diffusion-weighted MRI (DWI) signal attenuation was measured ex vivo in two formalin-fixed prostates at 9.4 T with diffusion times Δ = 10, 20 and 40 ms, and b values in the range 0.017-8.2 ms/µm(2) . A conventional biexponential model was compared with models in which either the lower diffusivity component or both of the components of the biexponential were stretched. Models were compared using Akaike's Information Criterion (AIC) and a leave-one-out (LOO) test of model prediction accuracy. The doubly stretched (SS) model had the highest LOO prediction accuracy and lowest AIC (highest information content) in the majority of voxels at Δ = 10 and 20 ms. The lower diffusivity stretching factor (α2 ) of the SS model was consistently lower (range ~0.3-0.9) than the higher diffusivity stretching factor (α1 , range ~0.7-1.1), indicating a high degree of diffusion heterogeneity in the lower diffusivity environment, and nearly Gaussian diffusion in the higher diffusivity environment. Stretched biexponential models demonstrate that, in prostate tissue, the two distinct water populations identified by the simple biexponential model individually exhibit non-Gaussian diffusion dynamics.

Microscopic diffusion properties of fixed breast tissue: Preliminary findings.

PURPOSE: To investigate the microscopic diffusion properties of formalin-fixed breast tissue. METHODS: Diffusion microimaging was performed at 16.4T with 40-µm isotropic voxels on two normal and two cancer tissue samples from four patients. Results were correlated with histology of the samples. RESULTS: Diffusion-weighted images and mean diffusivity maps demonstrated distinct diffusivity differences between breast tissue components. Mean diffusivity (MD) in normal tissue was 0.59 ± 0.24 µm(2) /ms for gland lobule (voxels containing epithelium and intralobular stroma) and 1.23 ± 0.34 µm(2) /ms for interlobular fibrous stroma. In the cancer samples, MD = 0.45 ± 0.23 µm(2) /ms for invasive ductal carcinoma (voxels contain epithelium and intralobular stroma) and 0.61 ± 0.35 µm(2) /ms for ductal carcinoma in situ. There were significant MD differences between all tissue components (P < 0.005), except between gland lobule and ductal carcinoma in situ (P = 0.71). The low diffusivity of epithelium-rich cancer tissue and of normal epithelium relative to its supporting fibrous stroma was similar to that reported for prostate tissue and the esophageal wall. CONCLUSION: Diffusion microimaging demonstrates distinct diffusivity differences between breast tissue glandular structures. Low diffusivity may be a distinctive feature of mammalian epithelia.

Responsiveness of quantitative cartilage measures over one year in knee osteoarthritis: comparison of radiography and MRI assessments.

PURPOSE: To directly compare the responsiveness of quantitative imaging measures of disease progression in knee osteoarthritis (OA). In the medial compartment of the knee comparison was made between: 1) radiographic joint space narrowing (JSN); 2) global quantitative magnetic resonance imaging (qMRI) of cartilage volume; 3) regional qMRI of cartilage thickness; and 4) regional analysis using an ordered value (OV) methodology. MATERIALS AND METHODS: 3T MRI and weight-bearing radiography of the knees were performed at baseline and 1-year timepoints in 23 subjects (mean age 63 years) with symptomatic knee OA. Standardized response means (SRM) were calculated for each measure. Statistical analysis to determine significance of change between timepoints was performed with a two-tailed Student's t-test (JSN, global, regional analysis) and nonparametric Mann-Whitney test (ordered values). RESULTS: At 1 year, global cartilage volume losses of 2.3% (SRM -0.44) in the medial tibia and 6.9% in the medial femur (SRM -0.74) were recorded. SRM for JSN was -0.46. Regional analysis revealed largest reductions in cartilage thickness in the external (SRM -0.84) weight-bearing subregion of the medial femur and in the posterior subregion of the medial tibia (SRM -0.79). OV analysis in the medial compartment revealed areas of cartilage thinning (four ranked OV) and cartilage thickening (two ranked OV). CONCLUSION: The MRI OV approach proved to be a superior analysis tool for detecting changes in cartilage morphology over a 1-year period. Radiographically defined JSN was found to be the least responsive measurement method of knee OA disease progression.

Information theoretic ranking of four models of diffusion attenuation in fresh and fixed prostate tissue ex vivo.

PURPOSE: To compare the theoretical information content of four popular models of diffusion-weighted signal attenuation. METHOD: Four whole prostates were imaged fresh unfixed and fixed at 9.4T. Biexponential, kurtosis, stretched exponential, and monoexponential models were ranked using Akaike's Information Criterion (AIC) with validation by a leave-one-out test of model prediction error. RESULTS: For unfixed tissue measurements (b-value range: 17-2104 s/mm(2)) the biexponential and kurtosis models had similar information content to each other and this was distinctly higher than for the stretched and monoexponential models. In fixed-tissue measurements (b-value range: 17-8252 s/mm(2)), the biexponential model had much higher information content than the three other models. CONCLUSION: AIC-based model ranking is consistent with an independent prediction accuracy test. Biexponential and kurtosis models consistently perform better than stretched and monoexponential models. The biexponential model has increasing superiority over all three other models as maximum b-value increases above ∼2000 s/mm(2).

Markers of good performance in mammography depend on number of annual readings.

PURPOSE: To explore relationships between reader performance and reader characteristics in mammography for specific radiologist groupings on the basis of annual number of readings. MATERIALS AND METHODS: The institutional review board approved the study and waived the need for patient consent to use all images. Readers gave informed consent. One hundred sixteen radiologists independently reviewed 60 mammographic cases: 20 cases with cancer and 40 cases with normal findings. Readers located any visualized cancer, and levels of confidence were scored from 1 to 5. A jackknifing free response operating characteristic (JAFROC) method was used, and figures of merit along with sensitivity and specificity were correlated with reader characteristics by using Spearman techniques and standard multiple regressions. RESULTS: Reader performance was positively correlated with number of years since qualification as a radiologist (P ≤ .01), number of years reading mammograms (P ≤ .03), and number of readings per year (P ≤ .0001). The number of years since qualification as a radiologist (P ≤ .004) and number of years of reading mammograms (P ≤ .002) were negatively related to JAFROC values for radiologists with annual volumes of less than 1000 mammographic readings. For individuals with more than 5000 mammographic readings per year, JAFROC values were positively related to the number of years that the reader was qualified as a radiologist (P ≤ .01), number of years of reading mammograms (P ≤ .002), and number of hours per week of reading mammograms (P ≤ .003). Number of mammographic readings per year was positively related with JAFROC scores for readers with an annual volume between 1000 and 5000 readings (P ≤ .03). Differences in JAFROC scores appear to be more related to specificity than location sensitivity, with the former demonstrating significant relationships with four of the five characteristics analyzed, whereas no relationships were shown for the latter. CONCLUSION: Radiologists' determinants of performance are associated with annual reading volumes. Ability to recognize normal images is a discriminating factor in individuals with a high volume of mammographic readings.

Quantitative measures confirm the inverse relationship between lesion spiculation and detection of breast masses.

OBJECTIVE: To identify specific mammographic appearances that reduce the mammographic detection of breast cancer. MATERIALS AND METHODS: This study received institutional board review approval and all readers gave informed consent. A set of 60 mammograms each consisting of craniocaudal and mediolateral oblique projections were presented to 129 mammogram Breastscreen readers. The images consisted of 20 positive cases with single and multicentric masses in 16 and 4 cases, respectively (resulting in a total of 24 cancers), and readers were asked to identify and locate the lesions. Each lesion was then ranked according to a detectability rating (ie, the number of observers who correctly located the lesion divided by the total number of observers), and this was correlated with breast density, lesion size, and various descriptors of lesion shape and texture. RESULTS: Negative and positive correlations between lesion detection and density (r = -0.64, P = .007) and size (r = 0.65, P = .005), respectively, were demonstrated. In terms of lesion size and shape, there were significant correlations between the probability of detection and area (r = 0.43, P = .04), perimeter (r = 0.66, P = .0004), lesion elongation (r = 0.49, P = .02), and lesion nonspiculation (r = 0.78, P < .0001). CONCLUSIONS: The results of this study have identified specific lesion characteristics associated with shape that may contribute to reduced cancer detection. Mammographic sensitivity may be adversely affected without appropriate attention to spiculation.

Use of 3T MRI and an unspoiled 3D fast gradient echo sequence for porcine knee cartilage volumetry: preliminary findings.

PURPOSE: To assess the utility of knee cartilage volumetry using an unspoiled fat-suppressed 3D fast gradient echo (FGRE) sequence at 3T. MATERIALS AND METHODS: Sagittal magnetic resonance (MR) images were obtained with an unspoiled fat-suppressed 3D FGRE sequence in eight porcine knees. Manual segmentation was used to derive the cartilage volume. This volume was compared to a volume measurement of cartilage scraping specimens obtained by water displacement. Imaging was repeated five times in four of the knees to assess interscan volume measurement reproducibility and calculate precision error. A single 3D dataset was manually segmented five times at weekly intervals to assess intraobserver volume measurement reproducibility. RESULTS: Total cartilage volume obtained from MRI and water displacement correlated well (r = 0.75). The interscan reproducibility of total volume measurements, expressed as the coefficient of variation (CV), was 4.2%, and the precision error (root mean square [RMS] CV) was 4.1%. The CV of intraobserver estimates of total cartilage volume by MRI was 3.6%. CONCLUSION: Interscan reproducibility of quantification of total cartilage volume and reproducibility of the manual segmentation technique were both high (>95%). Accurate and reproducible cartilage volumetry can be obtained by using a clinical unspoiled fat-suppressed 3D FGRE acquired at 3T MRI.

Microscopic diffusivity compartmentation in formalin-fixed prostate tissue.

MR microimaging at 16.4 T with 40-µm isotropic voxels was used to investigate compartmentation of water diffusion in formalin-fixed prostate tissue. Ten tissue samples (~ 28 mm(3) each) from five organs were imaged. The mean diffusivity of epithelial, stromal, and ductal/acinar compartments was estimated by two methods: (1) manual region of interest selection and (2) Gaussian fitting of voxel diffusivity histograms. For the region of interest-method, the means of the tissue sample compartment diffusivities were significantly different (P < 0.001): 0.54 ± 0.05 µm(2)/ms for epithelium-containing voxels, 0.91 ± 0.17 µm(2)/ms for stroma, and 2.20 ± 0.04 µm(2)/ms for saline-filled ducts. The means from the histogram method were also significantly different (P < 0.001): 0.45 ± 0.08 µm(2)/ms for epithelium-containing voxels, 0.83 ± 0.16 µm(2)/ms for stroma, 2.21 ± 0.02 µm(2)/ms for duct. Estimated partial volumes of epithelial, stromal, and ductal/acinar compartments in a "tissue only" subvolume of each sample were significantly different (P < 0.02) between cancer and normal tissue for all three compartments. It is concluded that the negative correlation between apparent diffusion coefficient and cancer Gleason grade observed in vivo results from an increase of partial volume of epithelial tissue and concomitant decrease of stromal tissue and ductal space.

Microscopic diffusion anisotropy in formalin fixed prostate tissue: preliminary findings.

Diffusion tensor microimaging at 16.4 T with 40 µm isotropic voxels was used to investigate anisotropic water diffusion in prostate tissue at spatial resolution approaching the cellular scale. Nine normal glandular tissue samples were collected from the peripheral zone of six formalin fixed radical prostatectomy specimens. Fibromuscular stromal tissue exhibited microscopic diffusion anisotropy (mean fractional anisotropy range 0.47-0.66) significantly higher (P < 0.01, Student's t-test) than in epithelium-containing voxels (mean fractional anisotropy range 0.31-0.54) in six of the seven normal tissue samples in which both compartments could be measured. Fiber tracking demonstrated principle stromal fiber directions consistent with myocyte orientation seen on light microscopy of the same sample. Diffusion tensor microimaging may be valuable for investigation of variable results from attempts to measure diffusion anisotropy in the prostate in vivo.

Biexponential diffusion decay in formalin-fixed prostate tissue: preliminary findings.

Magnetic resonance microimaging was used to measure diffusion decay over an extended b-factor range in a formalin-fixed normal prostate sample and a Gleason pattern 3+4 cancer tissue sample. The coefficients of biexponential fits to diffusion decay data from 1600 voxels of dimension 160 × 160 × 160 µm(3) in each sample were correlated with underlying epithelial and stromal compartment partial volumes estimated from high-resolution apparent diffusion coefficient (ADC) data (40 × 40 × 40 µm(3) voxels) from the same tissue. In the normal tissue sample, the signal fractions of the low and high ADC components of the biexponential fits correlated linearly with partial volumes of epithelial tissue (R(2) = 0.6) and stromal tissue (R(2) = 0.5), respectively. Similar but weaker correlations were observed in the cancer sample. Epithelium-containing high spatial resolution voxels appeared to be composed of ∼60% low ADC and ∼40% high ADC component. Stromal voxels appeared to be composed of ∼20% low ADC and ∼80% high ADC component. This preliminary report suggests that distinctly different diffusion properties in microscopically adjacent cell types contribute to the multiexponential diffusion decay phenomenon in prostate tissue.

In vivo and ex vivo proton MR spectroscopy of primary and secondary melanoma.

In vivo magnetic resonance (MR) spectroscopy at 1.5T was performed on a large polypoid cutaneous melanoma, and two enlarged lymph nodes containing metastatic melanoma, from three patients. Spectra were acquired in vivo from voxels wholly within the primary tumour or secondary lymph node and were thus uncontaminated by signals from adjacent tissue. Tissue biopsies taken after resection of primary tumours and secondary lymph nodes were examined by 8.5T magnetic resonance spectroscopy (MRS) and the results compared with the in vivo spectra, and with spectra from normal skin and a benign skin lesion. There was good agreement between the dominant features of 1.5T spectra acquired in vivo and 8.5T spectra acquired from resected tissue. However, less intense resonances observed at 8.5T in malignant biopsy tissue were not consistently observed at 1.5T in vivo. In vivo spectra from primary and metastatic melanoma showed high levels of choline metabolites. An intense lactate resonance was also present in the in vivo spectrum of primary melanoma. All 8.5T spectra of biopsies from primary and secondary melanoma showed high levels of choline metabolites and lactate, and additional resonances consistent with elevated levels of taurine, alanine, lysine, and glutamate/glutamine relative to normal and benign tissue. Elevated levels of choline, lactate, taurine, and amino acids appear to be clinically useful markers for identifying the pathology of primary and metastatic melanoma.

Device for aeration and mixing of cell and organelle suspensions during NMR experiments.

A device for aeration and mixing of cell or organelle suspensions in a vertical bore NMR magnet is described. Multiple external sensors (e.g., ion-selective electrodes) may be immersed in the suspension within the bore of the magnet. The sensors are positioned to avoid noise due to contact with gas bubbles and proximity to the probe head. The required sample volume is minimised. The modular design of components permits the use of the device in magnets of various internal dimensions, or with probe heads of different sample tube diameter, by modification of the simpler components of the assembly.