Original Article
Non-invasive estimation of prostate cancer aggressiveness using diffusion-weighted MRI and 3D proton MR spectroscopy at 3.0 T
Acta Radiologica 2015, Vol. 56(1) 121–128 ! The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0284185113520311 acr.sagepub.com
Gregor Tho¨rmer1, Josephin Otto1, Lars-Christian Horn2, Nikita Garnov1, Minh Do3, Toni Franz3, Jens-Uwe Stolzenburg3, Michael Moche1, Thomas Kahn1 and Harald Busse1
Abstract Background: Clinical management of prostate cancer increasingly aims to distinguish aggressive types that require immediate and radical treatment from indolent tumors that are candidates for watchful waiting. This requires reliable and reproducible parameters to effectively control potential cancer progression. Magnetic resonance imaging (MRI) may provide a non-invasive means for this purpose. Purpose: To assess the value of diffusion-weighted imaging and proton MR spectroscopy for the prediction of prostate cancer (PCa) aggressiveness. Material and Methods: In 39 of 64 consecutive patients who underwent endorectal 3-T MRI prior to radical prostatectomy, prostate specimens were analyzed as whole-mount step sections. Apparent diffusion coefficient (ADC), normalized ADC (nADC: tumor/healthy tissue), choline/citrate (CC), and (choline þ creatine)/citrate (CCC) ratios were correlated with Gleason scores (GS) from histopathological results. The power to discriminate low (GS 6) from higher-risk (GS 7) tumors was assessed with receiver operating characteristics (area under the curve [AUC]). Resulting threshold values were used by a blinded reader to distinguish between aggressive and indolent tumors. Results: Ninety lesions (1 GS ¼ 5, 41 GS ¼ 6, 36 GS ¼ 7, 12 GS ¼ 8) were considered. nADC (AUC ¼ 0.90) showed a higher discriminatory power than ADC (AUC ¼ 0.79). AUC for CC and CCC were 0.73 and 0.82, respectively. Using either nADC < 0.46 or CCC > 1.3, as well as both criteria for aggressive PCa, the reader correctly identified aggressive and indolent tumors in 31 (79%), 28 (72%), and 33 of 39 patients (85%), respectively. Predictions of tumor aggressiveness from TRUS-guided biopsies were correct in 27 of 36 patients (75%). Conclusion: The combination of a highly sensitive normalized ADC with a highly specific CCC was found to be well suited to prospectively estimate PCa aggressiveness with a similar diagnostic accuracy as biopsy results.
Keywords Magnetic resonance imaging (MRI), MR diffusion/perfusion, MR spectroscopy, prostate, staging Date received: 10 October 2013; accepted: 23 December 2013
Introduction Prostate cancer (PCa) is the second most common cause of cancer-related death in Europe (1,2) and in the US (3). Disease progression, however, can be slow and tumors may not become symptomatic or metastatic for many years after initial diagnosis such that the patient may even die with prostate cancer but not from it (4). The adoption of therapeutic strategies like
1 Department of Diagnostic and Interventional Radiology, Leipzig University Hospital, Leipzig, Germany 2 Institute of Pathology, University of Leipzig, Leipzig, Germany 3 Department of Urology, Leipzig University Hospital, Leipzig, Germany
Corresponding author: Harald Busse, Department of Diagnostic and Interventional Radiology, Leipzig University Hospital, Liebigstrasse 20, 04103 Leipzig, Germany. Email: [email protected]
122 watchful waiting or active surveillance (AS) heavily depends on reliable parameters to properly detect and monitor progressing cancer (5). Parameters like the prostate specific antigen (PSA) doubling time or PSA density are easy to assess but rather unspecific (6). To date, the best prognostic factor for the biological malignancy of prostate cancer is the histological grade determined by the Gleason scoring (GS) system (7). Gleason himself has originally reported that prostate cancers show relatively fixed degrees of malignancy and growth rates rather than a steady increase in malignancy with time (7). The large variation in biological cancer aggressiveness seems to be closely linked to histological tumor appearance. Histological grading, however, requires the extraction of tissue, typically sampled by core needle biopsies under transrectal ultrasound (TRUS) guidance. An invasive biopsy, however, may not be the best option for monitoring cancer aggressiveness every 1 to 2 years because of the sideeffects and limited patient compliance. Non-invasive methods before treatment decision, and particularly during follow-up of patients under AS, may therefore be a promising alternative. Recent studies have aimed to determine the value of magnetic resonance imaging (MRI) correlates of cellular density (8,9), metabolite concentration (10), and tumor vascularization (11) for the prediction of tissue reorganization and cancer aggressiveness. While the value of dynamic contrast-enhanced imaging appears to be limited in that respect (11), both diffusion-weighted imaging (DWI) as well as MR spectroscopy (MRS) have shown good correlation with GS (9,10). The aim of this work was therefore to determine to what extent DWI, MRS, and their combination may predict PCa aggressiveness.
Material and Methods Patients and MRI This study was approved by the institutional review board and written informed consent was obtained from all patients. Our retrospective analysis included all patients who underwent both 3-T MR examination of the prostate between May 2011 and May 2012 as well as radical prostatectomy with subsequent whole-mount step-section analysis of the prostate specimens. MRI was performed in a 3-T system (Magnetom Trio, Siemens Healthcare, Erlangen, Germany) using the combination of a pelvic phased-array coil with an endorectal coil (eCoil, Medrad, Pittsburg, PA, USA) for signal acquisition. The endorectal coil was filled with 30–40 mL of perfluorocarbon solution
Acta Radiologica 56(1) (Perfluorooctyl bromide, ABCR GmbH, Karlsruhe, Germany). Bowel peristalsis was suppressed by intravenous injection of 1 mg glucagon (Glucagen, NOVO Nordisk Pharma AG, Gentofte, Denmark) before examination. Fast T1-weighted localizer images were used to verify correct placement of the endorectal coil and to adjust the axial slices to be perpendicular to the dorsolateral prostate wall. Morphological images of the gland and seminal vesicles were obtained with a T2-weighted (T2W) fast spin-echo sequence (in-plane resolution [IPR], 0.57 0.57 mm2; repetition and echo time [TR/TE], 4400–4600/126 ms; slice thickness [ST], 3 mm; sections, 19–22; field of view [FOV], 110 110 mm2; flip angle [FA], 120–135 ) in transverse, coronal, and sagittal planes. DWI relied on a transverse, single-shot echo planar imaging sequence (IPR, 1.02 1.02 mm2; TR/TE, 3000/85 ms; ST, 3 mm; sections, 19–22; FOV, 250 250 mm2) with b-values of 50, 500, 800, and 1500 s/mm2. Maps of the ADC parameter were calculated from the raw data of the first three b-values as described elsewhere (12). Three-dimensional 1H chemical shift imaging (CSI) was performed by two spectroscopists (HB and GT, with 7 and 4 years of experience, respectively) according to a previously reported protocol (point-resolved spectroscopy [PRESS], TR/TE, 750/145 ms) (13). CSI data acquisition of the entire prostate (8 slices, nominal voxel size 6 6 6 mm3) took 12 min. Postprocessing included baseline and phase corrections, metabolite peak areas were then determined after automated Gaussian curve fitting (Syngo; Siemens Healthcare, Erlangen, Germany) to the resulting spectra.
Histological work-up Immediately after surgical resection, prostates were submitted to the Pathology Department. Specimens were fixed in 10% neutral-buffered formalin for about 1 week and seminal vesicles were separated. The prostate was cut into transverse, 4–5-mm thick step sections perpendicular to the dorsorectal surface of the gland yielding about 10 slices per specimen. After paraffin embedding and staining, all slices were evaluated by a senior pathologist (L-CH) with 14 years of experience in urogenital pathology who was blinded to the MRI findings. Tumor foci were outlined on the microscope slides and primary through tertiary lesions were labeled with the corresponding Gleason grade. Following the seventh edition of the AJCC cancer staging manual (14), qualitative grade groups G1–G3 were reported indicating low (GS 6), intermediate (GS ¼ 7) and high-risk cancers (GS 8), respectively. All processed slides were also digitized.
Tho¨rmer et al.
123
Fig. 1. Example of a 68-year-old patient with preoperative PSA level of 4.8 ng/mL. (a) The lesion outlined in the whole-mount step section was classified a GS 4 þ 3 tumor. Considering the morphology of central gland, peripheral zone, apex, and base of the prostate as well as landmarks like cysts, calcifications, and urethra, the most similar T2W image was selected (b). If the ADC image showed a corresponding signal loss (c), a freehand circular region of interest (ROI) was drawn within the outline of the respective lesion, avoiding tumor edges, healthy tissue, prostate capsule, and urethra. A mirror ROI was drawn on the contralateral side as healthy tissue reference. Care was taken to avoid any prostate cancer on the corresponding whole-mount step section. The ADC value was normalized by dividing the average ADC of the tumor region by that in the reference tissue. In the next step, both CC and CCC ratios were determined for the CSI voxel that best matched the relative coordinates of the lesion (d).
Correlation with MRI and data analysis
Prospective estimation of tumor aggressiveness
Histological step sections were visually matched to an optimum T2W image for correlation between pathological and multiparametric MRI findings (Fig. 1). Apparent diffusion coefficient (ADC), normalized ADC (nADC: tumor ADC/ADC in mirror region of healthy tissue), choline/citrate (CC), and (choline þ creatine)/citrate (CCC) ratios were determined for all lesions suspicious on DWI. Lesions with diameters
Non-invasive estimation of prostate cancer aggressiveness using diffusion-weighted MRI and 3D proton MR spectroscopy at 3.0 T
Acta Radiologica 2015, Vol. 56(1) 121–128 ! The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0284185113520311 acr.sagepub.com
Gregor Tho¨rmer1, Josephin Otto1, Lars-Christian Horn2, Nikita Garnov1, Minh Do3, Toni Franz3, Jens-Uwe Stolzenburg3, Michael Moche1, Thomas Kahn1 and Harald Busse1
Abstract Background: Clinical management of prostate cancer increasingly aims to distinguish aggressive types that require immediate and radical treatment from indolent tumors that are candidates for watchful waiting. This requires reliable and reproducible parameters to effectively control potential cancer progression. Magnetic resonance imaging (MRI) may provide a non-invasive means for this purpose. Purpose: To assess the value of diffusion-weighted imaging and proton MR spectroscopy for the prediction of prostate cancer (PCa) aggressiveness. Material and Methods: In 39 of 64 consecutive patients who underwent endorectal 3-T MRI prior to radical prostatectomy, prostate specimens were analyzed as whole-mount step sections. Apparent diffusion coefficient (ADC), normalized ADC (nADC: tumor/healthy tissue), choline/citrate (CC), and (choline þ creatine)/citrate (CCC) ratios were correlated with Gleason scores (GS) from histopathological results. The power to discriminate low (GS 6) from higher-risk (GS 7) tumors was assessed with receiver operating characteristics (area under the curve [AUC]). Resulting threshold values were used by a blinded reader to distinguish between aggressive and indolent tumors. Results: Ninety lesions (1 GS ¼ 5, 41 GS ¼ 6, 36 GS ¼ 7, 12 GS ¼ 8) were considered. nADC (AUC ¼ 0.90) showed a higher discriminatory power than ADC (AUC ¼ 0.79). AUC for CC and CCC were 0.73 and 0.82, respectively. Using either nADC < 0.46 or CCC > 1.3, as well as both criteria for aggressive PCa, the reader correctly identified aggressive and indolent tumors in 31 (79%), 28 (72%), and 33 of 39 patients (85%), respectively. Predictions of tumor aggressiveness from TRUS-guided biopsies were correct in 27 of 36 patients (75%). Conclusion: The combination of a highly sensitive normalized ADC with a highly specific CCC was found to be well suited to prospectively estimate PCa aggressiveness with a similar diagnostic accuracy as biopsy results.
Keywords Magnetic resonance imaging (MRI), MR diffusion/perfusion, MR spectroscopy, prostate, staging Date received: 10 October 2013; accepted: 23 December 2013
Introduction Prostate cancer (PCa) is the second most common cause of cancer-related death in Europe (1,2) and in the US (3). Disease progression, however, can be slow and tumors may not become symptomatic or metastatic for many years after initial diagnosis such that the patient may even die with prostate cancer but not from it (4). The adoption of therapeutic strategies like
1 Department of Diagnostic and Interventional Radiology, Leipzig University Hospital, Leipzig, Germany 2 Institute of Pathology, University of Leipzig, Leipzig, Germany 3 Department of Urology, Leipzig University Hospital, Leipzig, Germany
Corresponding author: Harald Busse, Department of Diagnostic and Interventional Radiology, Leipzig University Hospital, Liebigstrasse 20, 04103 Leipzig, Germany. Email: [email protected]
122 watchful waiting or active surveillance (AS) heavily depends on reliable parameters to properly detect and monitor progressing cancer (5). Parameters like the prostate specific antigen (PSA) doubling time or PSA density are easy to assess but rather unspecific (6). To date, the best prognostic factor for the biological malignancy of prostate cancer is the histological grade determined by the Gleason scoring (GS) system (7). Gleason himself has originally reported that prostate cancers show relatively fixed degrees of malignancy and growth rates rather than a steady increase in malignancy with time (7). The large variation in biological cancer aggressiveness seems to be closely linked to histological tumor appearance. Histological grading, however, requires the extraction of tissue, typically sampled by core needle biopsies under transrectal ultrasound (TRUS) guidance. An invasive biopsy, however, may not be the best option for monitoring cancer aggressiveness every 1 to 2 years because of the sideeffects and limited patient compliance. Non-invasive methods before treatment decision, and particularly during follow-up of patients under AS, may therefore be a promising alternative. Recent studies have aimed to determine the value of magnetic resonance imaging (MRI) correlates of cellular density (8,9), metabolite concentration (10), and tumor vascularization (11) for the prediction of tissue reorganization and cancer aggressiveness. While the value of dynamic contrast-enhanced imaging appears to be limited in that respect (11), both diffusion-weighted imaging (DWI) as well as MR spectroscopy (MRS) have shown good correlation with GS (9,10). The aim of this work was therefore to determine to what extent DWI, MRS, and their combination may predict PCa aggressiveness.
Material and Methods Patients and MRI This study was approved by the institutional review board and written informed consent was obtained from all patients. Our retrospective analysis included all patients who underwent both 3-T MR examination of the prostate between May 2011 and May 2012 as well as radical prostatectomy with subsequent whole-mount step-section analysis of the prostate specimens. MRI was performed in a 3-T system (Magnetom Trio, Siemens Healthcare, Erlangen, Germany) using the combination of a pelvic phased-array coil with an endorectal coil (eCoil, Medrad, Pittsburg, PA, USA) for signal acquisition. The endorectal coil was filled with 30–40 mL of perfluorocarbon solution
Acta Radiologica 56(1) (Perfluorooctyl bromide, ABCR GmbH, Karlsruhe, Germany). Bowel peristalsis was suppressed by intravenous injection of 1 mg glucagon (Glucagen, NOVO Nordisk Pharma AG, Gentofte, Denmark) before examination. Fast T1-weighted localizer images were used to verify correct placement of the endorectal coil and to adjust the axial slices to be perpendicular to the dorsolateral prostate wall. Morphological images of the gland and seminal vesicles were obtained with a T2-weighted (T2W) fast spin-echo sequence (in-plane resolution [IPR], 0.57 0.57 mm2; repetition and echo time [TR/TE], 4400–4600/126 ms; slice thickness [ST], 3 mm; sections, 19–22; field of view [FOV], 110 110 mm2; flip angle [FA], 120–135 ) in transverse, coronal, and sagittal planes. DWI relied on a transverse, single-shot echo planar imaging sequence (IPR, 1.02 1.02 mm2; TR/TE, 3000/85 ms; ST, 3 mm; sections, 19–22; FOV, 250 250 mm2) with b-values of 50, 500, 800, and 1500 s/mm2. Maps of the ADC parameter were calculated from the raw data of the first three b-values as described elsewhere (12). Three-dimensional 1H chemical shift imaging (CSI) was performed by two spectroscopists (HB and GT, with 7 and 4 years of experience, respectively) according to a previously reported protocol (point-resolved spectroscopy [PRESS], TR/TE, 750/145 ms) (13). CSI data acquisition of the entire prostate (8 slices, nominal voxel size 6 6 6 mm3) took 12 min. Postprocessing included baseline and phase corrections, metabolite peak areas were then determined after automated Gaussian curve fitting (Syngo; Siemens Healthcare, Erlangen, Germany) to the resulting spectra.
Histological work-up Immediately after surgical resection, prostates were submitted to the Pathology Department. Specimens were fixed in 10% neutral-buffered formalin for about 1 week and seminal vesicles were separated. The prostate was cut into transverse, 4–5-mm thick step sections perpendicular to the dorsorectal surface of the gland yielding about 10 slices per specimen. After paraffin embedding and staining, all slices were evaluated by a senior pathologist (L-CH) with 14 years of experience in urogenital pathology who was blinded to the MRI findings. Tumor foci were outlined on the microscope slides and primary through tertiary lesions were labeled with the corresponding Gleason grade. Following the seventh edition of the AJCC cancer staging manual (14), qualitative grade groups G1–G3 were reported indicating low (GS 6), intermediate (GS ¼ 7) and high-risk cancers (GS 8), respectively. All processed slides were also digitized.
Tho¨rmer et al.
123
Fig. 1. Example of a 68-year-old patient with preoperative PSA level of 4.8 ng/mL. (a) The lesion outlined in the whole-mount step section was classified a GS 4 þ 3 tumor. Considering the morphology of central gland, peripheral zone, apex, and base of the prostate as well as landmarks like cysts, calcifications, and urethra, the most similar T2W image was selected (b). If the ADC image showed a corresponding signal loss (c), a freehand circular region of interest (ROI) was drawn within the outline of the respective lesion, avoiding tumor edges, healthy tissue, prostate capsule, and urethra. A mirror ROI was drawn on the contralateral side as healthy tissue reference. Care was taken to avoid any prostate cancer on the corresponding whole-mount step section. The ADC value was normalized by dividing the average ADC of the tumor region by that in the reference tissue. In the next step, both CC and CCC ratios were determined for the CSI voxel that best matched the relative coordinates of the lesion (d).
Correlation with MRI and data analysis
Prospective estimation of tumor aggressiveness
Histological step sections were visually matched to an optimum T2W image for correlation between pathological and multiparametric MRI findings (Fig. 1). Apparent diffusion coefficient (ADC), normalized ADC (nADC: tumor ADC/ADC in mirror region of healthy tissue), choline/citrate (CC), and (choline þ creatine)/citrate (CCC) ratios were determined for all lesions suspicious on DWI. Lesions with diameters
