MRI Guided Trans Rectal Ultrasound Biopsy: A Molecular Approach to Diagnosing Prostatic Cancer


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The purpose of this study is to assess the efficacy of second-look Trans- rectal Ultrasound guided biopsy by comparing the histopathological results obtained by Trans Rectal Ultra Sound guided extended sextant core biopsy of the prostate done before and after
localization of lesions using MRI & MRS done prior to the procedure.

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MRI Guided Trans Rectal Ultrasound Biopsy: A Molecular Approach to Diagnosing Prostatic Cancer

  1. 1. MRI Guided Trans Rectal Ultrasound Biopsy: A Molecular Approach to Diagnosing Prostatic Cancer
  2. 2. Page 1 of 18 MRI guided trans rectal ultrasound biopsy: a molecular approach to diagnosing prostatic cancer Poster No.: C-1785 Congress: ECR 2013 Type: Scientific Exhibit Authors: B. Raghavan, A. Wasim, P. Gopalakrishnan, R. BALAJI, J. Govindaraj, M. Logudas; Chennai/IN Keywords: Genital / Reproductive system male, Oncology, MR-Spectroscopy, Ultrasound, Biopsy, Tissue characterisation DOI: 10.1594/ecr2013/C-1785 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to third- party sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations.
  3. 3. Page 2 of 18 Purpose Trans Rectal Ultra Sound gives an idea of the morphology of the prostate gland but it is not a good predictor for malignancy. Though Trans Rectal Ultra Sound is used for obtaining samples for histopathology, the sampling of the prostate gland is a systematic one involving not just the ultrasound detected abnormalities but all areas of the gland even if they appear normal by ultrasound. MRI and MR Spectroscopy is morphological and functional imaging and is a better indicator of malignancy (1). Second-look ultrasound (2) after MRI in breast is done routinely to locate the lesion and biopsy under ultrasound guidance as MRI guided biopsies in the MRI suite are expensive & time consuming as opposed to the more efficient ultrasound guided biopsy. The purpose of this study is to assess the efficacy of second-look Trans- rectal Ultrasound guided biopsy by comparing the histopathological results obtained by Trans Rectal Ultra Sound guided extended sextant core biopsy of the prostate done before and after localization of lesions using MRI & MRS done prior to the procedure. Methods and Materials The study was conducted as a prospective controlled analytical study at Apollo Speciality Hospital, 320 Padma Complex, Anna Salai, Chennai- 600035. Out of a total of 60 patients who were referred by the urologist between September 2011 and February 2012 for prostate biopsy either due to elevated sPSA , abnormal DRE or symptoms suggesting prostate cancer, only 52 patients fulfilled the inclusion criteria and were included. Inclusion criteria: • Patientswith elevated sPSA levels (>4.0 ng/dl) or with sudden increase of sPSA values in two health examinations. • Abnormal digital rectal examination (DRE), • Associated urinary symptoms include dysuria, increased frequency of urination or difficulty initiating urine • Patients with history of prostatic enlargement. Exclusion criteria:
  4. 4. Page 3 of 18 • Patients who were previously diagnosed and treated for prostate cancer, • Patients with known local or distant metastasis on presentation • Patients who have recently undergone TRUS biopsy of the prostate. The final study population consisted of 45 patients. Informed consent was obtained from all the patients prior to the procedure. The patients underwent MRI with MR Spectroscopy followed by extended sextant targeted core tissue prostate biopsies, performed under TRUS guidance with reference to suspicious areas on MRI and MR Spectroscopy in addition to the regular core tissue biopsies. After adequate bowel preparation and informed consent, the patients underwent T2 high resolution MR imaging of the prostate in axial, sagittal and coronal planes. Spectroscopy was planned with reference to the MR images in all three planes and effort was taken to include the entire prostate avoiding the bladder and adjacent structures to reduce signal to noise ratio (SNR) and to confine the voxels within the prostate margins. All images were analyzed for changes in signal intensity in the prostate, and spectroscopy was acquired from the entire prostate including the suspicious areas. Fourier transformation, phase adjustment, frequency adjustment, baseline correction and calculation of the Cho+Cr/Cit (CCr) ratios were automatically performed. The total exam took approximately 20 to 30 minutes. MR image Analysis The T2 weighted images were analyzed for low signal intensity in contrast to the normal high signal intensity especially in the peripheral zone as majority (70%) of the tumors arise from there. The other suspicious nodules with ill defined margins which showed low signal intensity were also taken into account. Capsular breach and seminal vesicle involvement were made note of. 3D MR spectroscopy imaging evaluation T2-weighted images were taken as the reference images, and voxels with suspected tumorous lesions were identified. The CCr ratios from the tumorous lesions and from the rest of the prostate were tabulated . In case of contamination resulting in non-diagnostic spectroscopy spectrum, manual adjustment of the baseline was attempted. Voxels were considered to be sufficient for analysis if there was adequate visual match between the baseline and the obtained spectrum. The classification system described by Kurhanewicz et al was used (3) . In that system voxels are considered suspicious for cancer if the ratio of choline and creatine to citrate is at least 2 standard deviations (SDs) higher than the average ratio for the normal voxels which are calculated from the control population. Voxels are considered very suspicious
  5. 5. Page 4 of 18 for cancer if the ratio of choline and creatine to citrate is higher than 3 SDs above the average ratio. TRUS biopsy The imaging protocol for TRUS included detailed assessment of the prostate and seminal vesicles in both the sagittal and axial planes and estimation of gland volume in grey scale and color (FIG 1). The prostate was analyzed for morphology the presence of any hypo, iso or hyperechoic lesions. Extended sextant core tissue biopsies were performed under TRUS (FIG 2) guidance by two senior consultant radiologists with more than 20 years experience. Extended sextant biopsy is being followed in our institution where two samples from the upper, three from the mid and two from lower gland are taken from either sides, amounting to a total of 14 tissue samples for each case. Any visible nodule was biopsied and separately sent for HPE. Subsequently the T2W MR images were used as reference during TRUS biopsy and suspicious areas which showed low signal on T2WI and/or had an elevated CCr ratio on spectroscopy were also sampled in addition to the regular extended sextant biopsies by visual approximation in reference to the anatomic division of the prostate into sextants , i.e. right and left base, mid-gland, and apex. (FIG 3) The samples obtained were sent for histopathology examination in separately labelled bottles. The histopathology results were taken as gold standard for analysis. Images for this section:
  6. 6. Page 5 of 18 Fig. 1: TRUS of normal prostate
  7. 7. Page 6 of 18 Fig. 2: Endorectal probe fitted with an adapter that accepts the needle of a spring-loaded biopsy gun
  8. 8. Page 7 of 18 Fig. 3: T2W axial and coronal sections of the normal prostate and a normal CCr ratio on MR spectroscopy. Normal TRUS image of the prostate at the mid-gland level with biopsy needle in the right and left lobe
  9. 9. Page 8 of 18 Results Out of the 45 patients who underwent biopsy, 21 patients were diagnosed with prostate cancer from one or more locations and 24 patients were tumor free. The study comprises a total of 242 loci from the base, mid gland and apex of prostate of the 45 patients. All these patients underwent MRI and proton MR spectroscopy followed by TRUS examination and TRUS guided extended sextant biopsy of the prostate. Results of TRUS HPE TUMOR NO TUMOR TOTAL POSITIVE 58 36 94 NEGATIVE 30 118 148 TRUS TOTAL 88 154 242 Estimate 95% CI Sensitivity 0.641 0.555 to 0.74 Specificity 0.742 0.693 to 0.801 PPV 0.617 0.516 to 0.709 NPV 0.781 0.725 to 0.844 P value <0.001 Results of MRI Areas which showed low signal intensity on high resolution T2W images were identified. Based on these, spectroscopy was planned and CCr ratios were obtained from the entire prostate and from the areas which were suspicious for tumor. Out of 242 loci which were studied, hypointense signal suggesting tumor was seen in 115 loci on T2W images. 88 of these loci contained tumor on HPE. Results of Spectroscopy Of the 242 voxels, 49 voxels which were proven on HPE as normal showed CCr ratios in the range of 0.16 and 1.16. The mean CCr ratio from the normal prostate was 0.49 ±0.21 compared to CCr ratio of 0.75±0.16 obtained in the study by Keisuke Saito et al.(4)
  10. 10. Page 9 of 18 On the basis of this data the threshold value for the diagnosis of prostate cancer by H- MRS was determined to be #0.91, which is equivalent to the mean +2 SD of the CCr ratio for a normal prostate in our study. The corresponding threshold value for cancer in the study by Keisuke Saito et al was # 1.07 (4). In 21 patients with prostate cancer, tumor was found in 96 loci on HPE. Of these, 8 loci could not be evaluated due to non-diagnostic spectrum on MR spectroscopy. The mean CCr ratio (+3SD) for a very high suspicion for prostate cancer was calculated to be 1.41 ±0.75 compared to 1.40±0.20 seen in the study by Keisuke Saito et al (4). Sensitivity, specificity, positive predictive value, negative predictive value and ROC curves were calculated from 242 voxels of 45 patients based on the threshold value of #0.91. MRI and MRS combined HPE TUMOR NO TUMOR TOTAL POSITIVE 86 27 113 NEGATIVE 2 127 129 Combined MRI and MRS TOTAL 88 154 242 Estimate 95% CI Sensitivity 0.977 [0.921 to 0.994] Specificity 0.825 [0.757 to 0.877] PPV 0.761 [0.675 to 0.83] NPV 0.984 [0.945 to 0.996] P value <0.001 Combining MRI and MRS, the sensitivity, specificity, positive predictive and negative predictive values in our study were 97.7%, 82.5%, 76.1% and 98.4% which is comparable to Axel Wetter et al, who obtained a combined MRI and MRS statistical data of 75%,93%,75% and 93% respectively.(5) Similarly, the study by E. Squillaci et al combining MRI and MRS too showed a greater specificity of 90 %. The sensitivity, positive and negative predictive values were 71, 89 and 74 % respectively (6). MRI & MRS COMBINED
  11. 11. Page 10 of 18 Sensitivity Specificity Positive predictive value Negative predictive value Our study 97% 83% 76% 98% Axel wetter et al 75% 93% 75% 93% E. Squillaci et al 71% 90% 89% 74% Senstivity & Specificity of TRUS ,MRI, MRS Furthermore, overall TRUS features of the prostate were evaluated and compared with the HPE results obtained after biopsy and statistical analysis was done (Fig 4). We obtained a statistically significant sensitivity of 64%, specificity of 74%, positive predictive value of 61 % and negative predictive value of 78% which is higher compared to other studies which have shown sensitivity and specificity of TRUS guided biopsy to be around 40 - 50 % (7). This increase in sensitivity and specificity compared to earlier studies is mainly due to the role of MRI and MRS in localizing the areas suspicious for malignancy on TRUS. Since MRI and MRS combined had a higher statistical significance, this reflected in better sample yield on TRUS guided prostate biopsy thereby improving the overall detection of prostate cancer. Evaluation of TRUS detected nodules : 19 hypo and hyperechoic suspicious nodules were identified on TRUS during the extended sextant biopsy procedure. These nodules were evaluated for echogenicity and vascularity. They were subsequently biopsied separately and sent for HPE (Fig 5). On HPE, 6 nodules showed the presence of tumor (FIG 6), 9 nodules showed hyperplasia (FIG 7), 2 were normal prostatic tissue , 1 was indeterminate and 1 showed acute inflammation. Retrospectively, on spectroscopy analysis of the nodules which were identified on TRUS, 5 out of the 6 nodules which showed the presence of tumor had a CCr > 0.91 (i.e +3 SDs from normal) . 11 nodules showed a CCr within +1 standard deviation from the normal threshold value of 0.49 and 3 nodules had a CCr +2 standard deviations from 0.49 (Fig 8). Images for this section:
  12. 12. Page 11 of 18 Fig. 4 Fig. 5: HPE of 19 nodules identified in TRUS.
  13. 13. Page 12 of 18 Fig. 6: TRUE POSITIVE MRI shows hypointense peripheral zones with capsular breach on the left. MRS shows elevated CCr ratios from in all voxels including nodules in the peripheral zones, suspicious for carcinoma. TRUS shows ill defined hypoechoic nodules in both lobes. Adenocarcinoma was seen on HPE in all samples.
  14. 14. Page 13 of 18 Fig. 7: Benign prostatic hypertrophy on MRI and TRUS with normal CCr ratios on MRS. HPE confirmed BPH
  15. 15. Page 14 of 18 Fig. 8
  16. 16. Page 15 of 18 Conclusion MRI and MR Spectroscopy is a non-invasive procedure which does not require special hardware and there is no radiation involved. The total time taken for MR imaging of the prostate including MR spectroscopy analysis is around 25 minutes. The addition of MR spectroscopy to the protocol contributes to only 6 minutes of the total scanning time. MR Spectroscopy as a technique has to be standardized for each individual MR unit and the patient population. This study is one of the early studies where an attempt has been made to establish the normal CCr ratios in our population. A CCr ratio threshold value of 0.91 can objectively differentiate between benign and malignant lesions as inferred from this study.We have found the results of MR spectroscopy to correlate well with histopathology with a high degree of specificity (83%) and few false positives (3%) (FIG 6) and false negatives (5%) (FIG 7) which are comparable to other studies byAxel Wetter et al andE. Squillaci et al. However MR Spectroscopy cannot be done in isolation as a stand-alone procedure as anatomical and morphological analysis in identifying the abnormal areas is required. The zonal anatomy, capsular breach, invasion of the seminal vesicles and bladder base form an important part in local staging. These are analyzed by T2W high resolution MR imaging. TRUS guidance for prostate biopsy is primarily used as a convenient real time method to perform a meticulous and methodical biopsy avoiding the urethra, seminal vesicles and bladder base. There has been a progressive trend to increase the number of cores taken from the prostate in an attempt to increase the sensitivity of cancer detection. Therefore MR imaging of the prostate combined with MR spectroscopy can be effectively used as a modality for detection of prostate cancer and create a more accurate localizing method for targeted TRUS guided biopsies. Multi-modality fusion techniques using MRI and MR spectroscopy can increase the accuracy and efficiency of targeted TRUS guided biopsies in diagnoses of prostate cancer. Images for this section:
  17. 17. Page 16 of 18 Fig. 9: MRI showes diffuse hypointensity in both peripheral zones. Cystic areas appearing hyperintense on T2W sequences are seen in the right lobe. MRS shows elevated CCr ratios from both peripheral zones, suspicious of carcinoma. TRUS shows heteroechoic areas in both lobes of prostate with no definite cystic areas. HPE showed inflammation with abscess.
  18. 18. Page 17 of 18 Fig. 10: Normal MRS from entire gland including hypointense foci in left peripheral zone and right central zone of mid-gland seen on MRI. TRUS showing ill defined nodular hypoechoic areas in both lobes with subsequent biopsy from the nodule in the right lobe. HPE showed adenocarcinoma.
  19. 19. Page 18 of 18 References 1. Filip G. Claus, Hedvig Hricak, Robert R. Hattery :Pretreatment Evaluation of Prostate Cancer: Role of MR Imaging and 1H MR Spectroscopy ; RadioGraphics 2004;24:S170 2. MR-Directed ("Second-Look") Ultrasound Examination for Breast Lesions Detected Initially on MRI: MR and Sonographic Findings Hiroyuki Abe, Robert A. Schmidt, Rajshri N. Shah, et al; AJR February 2010 vol. 194 no. 2 370-377 3. Kurhanewicz J, Vigneron DB, Hricak H, Narayan P, Carroll P, Nelson SJ. Three-dimensional 1H spectroscopic imaging of the in situ human prostate with high spatial (0.24 to 0.7 cm3) spatial resolution. Radiology 1996; 198:795- 805. 4. Keisuke saito et al :Clinical efficacy of proton magnetic resonance spectroscopy (1H-MRS) in the diagnosis of localized prostate cancer ; ANTICANCER RESEARCH 28: 1900 (2008) 5. Axel Wetter, Tobias A. Eng Darius, Nadjmabadi Klaus Fliessbach, Thomas Lehnert, Jessen Gurung, Wolf-Dietrich Beecken, Thomas J. Vog:Combined MRI and MR Spectroscopy of the Prostate Before Radical ProstatectomyAJR 2006; 187:726 6. E. Squillaci, G. Manenti, S. Mancino, M. Carlani, M. Di Roma, V. Colangelo, G. Simonetti.MR Spectroscopy of Prostate Cancer. Initial Clinical Experience.J. Exp. Clin. Cancer Res., 2005; 527 7. Beerlage HP, Aarnink RG, Ruijter ET, et al. Correlation of transrectal ultrasound, computer analysis of transrectal ultrasound and histopathology of radical prostatectomy specimen. Prostate Cancer Prostatic Dis 2001; 4:56-62 Personal Information Dr.Bagyam Raghavan Consultant Radiologist Apollo Speciality Hospitals Chennai.INDIA e-mail:
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