Prostate Cancer Diagnosis and Characterization

Filip G. Claus, Hedvig Hricak and Robert R. Hattery
"Pretreatment Evaluation of Prostate Cancer: Role of MR Imaging and 1H MR Spectroscopy"
RadioGraphics 2004;24:S167-S180
additions ([small print] and boxes) by J. Gruber

Deutsche Version

Prostate cancer is a multifocal and histologically heterogeneous disease.

Estimates suggest that with a threshold PSA value of 4.1 ng/mL,
  1. 82% of cancers in men younger than 60 years and
  2. 65% of cancers in men older than 60 years
could be missed (Punglia et al., 2003, in cache).

OW Brawley, DP Ankerst, IM Thompson, "Screening For Prostate Cancer" (in cache)

percentage of significant cancers
Proportion of cancers fulfilling histologic criteria for clinical significance and incurability by prostate-specific antigen (PSA) level at diagnosis. Source: Lucia MS, Darke AK, Goodman PJ et al., "Pathologic characteristics of cancers detected in The Prostate Cencer Prevention Trial, implications for prostate cancer detecton and chemoprevention, Cancer Prev Res [Phila Pa] 2008,1:167-173

  • Biopsy is considered the preferred method for prostate cancer detection and characterization; however, biopsy is limited in defining all cancer sites and grades. When biopsy results were compared with those from radical prostatectomy for sextant tumor localization (Wefer et al. 2000),
    1. the positive predictive value of biopsy PPV = TP/(TP + 1-TN) = 83.3% and
    2. the negative predictive value NPV = TN/(TN + 1-TP) = 36.4%.
      [For localization of prostate cancer MRI and MRSI were more sensitive but less specific than biopsy (Wefer et al. 2000):
      • 67% (sensitivity MRI) and 76% (sensitivity MRSI) versus 50% (sensitivity biopsy), and
      • 69% (specificity MRI) and 68% (specificity MRSI) versus 82% (specificity biopsy).
      The sensitivity of sextant biopsy was significantly less
      • in the prostate apex (38%) than
      • in the mid prostate (52%) or
      • in the prostate base (62%).]

    In other studies,

    [54% of 70 ten-core biopsy negative prostate hemispheres turned out to harbor up to 8 foci of cancer in the biopsy-negative hemisphere, of which 8 (11% of 70) were clinically significant and the remaining 30 clinically minor (Park PC et al. BJU Int. 2006 Nov;98(5):986-8, in cache)].

    [Morphometric analysis on 70 biopsy-negative prostate hemispheres]

    Pca = prostatic adenocarcinoma, AH = anterior horn of the peripheral zone, TZ = transitional zone, NTZ = nontransitional zone, PZ = peripheral zone, sig = clinically significant, nsig = clinically insignificant

    Disregarding their sensitivity and specificity, what do biopsies come up with? (GC Durkan et al. 2002 - in cache, annotations)
    • Where extended-core biopsies were negative for malignancy (493 - 164), the biopsy outcome fell into five main categories, i.e.
      1. BPH, 176 (53%);
      2. prostatitis, 118 (36%);
      3. atypical (suspicious), 21 (6%);
      4. high-grade prostate intraepithelial neoplasia (PIN), 6 (2%); and
      5. low-grade PIN, 8 (3%),

    • Prostate cancer was detected in 164 (33%) of 493 patients;

    • 177 patients (36%) had an abnormal DRE and of these 72 (40%) had positive biopsies [i.e.
      • 28 with T2a,
      • 25 with T2b,
      • 11 with T3,
      • 8 with T4].
    493 patients with elevated PSA

  • One of the most challenging characteristics of prostate cancer is its variability in biologic aggressiveness, Core needle biopsy specimens are not accurate in the prediction of Gleason score. Studies found that biopsy enabled the correct prediction of radical prostatectomy Gleason grade in

    Therefore, the need to improve both tumor detection and assessment of tumor aggressiveness is compelling.

    [Fine needle aspiration biopsy DNA ploidy status predicts grade shifting in prostate cancer (Ross et al. 1999).
    • The sensitivity of the needle biopsy grade in the detection of high-grade tumors on radical prostatectomy was 30% and the specificity was 86%
    • The sensitivity of ploidy status in the prediction of high-grade tumor at radical prostatectomy was 78% and the specificity was 96%. (more on DNA ploidy)
    • JR Oppenheimer, 1996 "DNA Ploidy Analysis (in chache): Ploidy analysis was more important than Gleason grade (Ross 1994). This last study showed
      • a ten-fold increase in risk for metastasis and
      • a three-fold risk for extracapsular spread
      if the initial needle biopsy demonstrated non-diploidy. These results have not been duplicated.]

      Some background on DNA-ploidy analysis

      • Peter Duesberg, Ruhong Li, David Rasnick
        Department of Molecular and Cell Biology; Donner Laboratory; University of California Berkeley; Berkeley, California USA, Correspondence to: Peter Duesberg; Department of Molecular and Cell Biology; Donner Laboratory; University of California Berkeley; Berkeley, California 94720 USA; Tel.: 510.642.6549; Fax 510.643.6455; Email:,
        Aneuploidy Approaching a Perfect Score in Predicting and Preventing Cancer, Conference Held in Oakland, January 23-26, 2004, Cell Cycle 3:6, 823-828; June 2004. (in cache)
        The meeting, termed the 1st Conference on Aneuploidy and Cancer: Clinical and Experimental Aspects, united about 70 cancer researchers at the Waterfront Plaza Hotel in Oakland. The conference was organized by P. Duesberg and D Rasnick to evaluate the theory that aneuploidy is sufficient to cause cancer. The abstracts or short papers of the participants are recorded in the Scientific Program & Abstractsbooklet of the conference, which is available on request from the conference bureau at An independent meeting report has since also been published in The Scientist [Steinberg D. Appraising aneuploidy as a cancer cause. The Scientist. 2004;18:26-7].
    Comparison of the detection of high-grade tumors
    core needle biopsy histopathological (Gleason) grading and
    fine needle aspiration biopsy DNA ploidy analysis

    The combined use of MR imaging and MR spectroscopy
    1. improves detection of tumors within the peripheral zone (Males et al. 2000, Scheidler et al, 1999, Obek et al. 1999).
    2. It has also been shown to increase the specificity in the localization of prostate cancer in the peripheral zone, although with moderate interreader agreement (Scheidler et al, 1999).
    3. Preliminary reports of MR spectroscopy assessment of tumor aggressiveness have shown promise.
      • The ratio of choline and creatine to citrate in the lesion shows correlation with the Gleason grade, with the elevation of choline and reduction of citrate indicative of increased cancer aggressiveness (Zakian et al. 2005).
      • It has also been shown that metabolic and volumetric data obtained with MR spectroscopy correlate with the Gleason grade at pathologic examination (Zakian et al. 2005). It has been recommended that the maximum ratio of choline and creatine to citrate combined with tumor volume at MR spectroscopy be used as an index to help predict tumor aggressiveness (Zakian et al. 2003).

    MRI versus biopsy: Sensitivities and specificities.

    Comparison of MRI, MRSI model with 2 classic models
    Comparison of the MRI- and the MRI/MRSI models with two models that use a combination of the following test parameters (reference standard for all models: whole mount prostate step section pathology)
    1. the basis model, presented in the form of a clinical nomogram (mathematical form). It considers
      • the total PSA concentration,
      • the clinical cancer stadium (cT = T1 ... T3),
      • the primary and secondary biopsy Gleason grade,
    2. the medium model that considers
      • the total PSA concentration,
      • the clinical cancer stadium (cT = T1 ... T3),
      • the primary and secondary biopsy Gleason grade,
      • the percentage of the biopsy specimen that turn out cancer positive,
      • the prostate volume at the time of the MRI/MRSI.

    The MRI and the MRI/MRSI models take into account 6 test parameters:

    • the total PSA concentration,
    • the clinical cancer stadium (cT = T1 ... T3),
    • the primary and secondary biopsy Gleason grade,
    • the percentage of the biopsy specimen that turn out cancer positive,
    • the prostate volume at the time of the MRI/MRSI,
    • an MRI or MRI/MRSI score.

    Patient characteristics:
    220 patients (cT stage T1c or T2a, prostate-specific antigen level <20 ng/mL, biopsy Gleason score 6, with 41% of the patients having insignificant cancer. Insignificant cancer was defined from surgical pathology as organ-confined cancer of < 0.5 cm3 with no poorly differentiated elements.
    Source: Shukla-Dave A, Hricak H, Kattan MW, Pucar D, Kuroiwa K, Chen HN, Spector J, Koutcher JA, Zakian KL, Scardino PT, The utility of magnetic resonance imaging and spectroscopy for predicting insignificant prostate cancer: an initial analysis., BJU Int. 99(4):786-793 (April 2007)

    For comparison: AUC for pure MRI and MRSI with biopsy as reference standard: 0.70 and 0.63, respectively (Costouros et al, 2007)

    Because Gleason grade is an important predictor of patient outcome, this finding provides a rationale for adding MR imaging and/or MR spectroscopy to the pretreatment evaluation of patients with prostate cancer.

    [Further Literature, mostly on MR(S)I]

  • OW Brawley, DP Ankerst, IM Thompson, Screening for Prostate Cancer, CA A Cancer Journal for Clinicians, 2009 (Abstract, local cache of full article)
  • D Beyersdorff, M Taupitz, B Winkelmann, T Fischer, S Lenk, SA Loening, B Hamm, 2002 "Magnetic resonance (MR), Patients with a History of Elevated Prostate-Specific Antigen Levels and Negative Transrectal USÜguided Quadrant or Sextant Biopsy Results: Value of MR Imaging" (in cache), Radiology. 2002 Sep;224(3):701-6.
  • D Beyersdorff, A Winkel, B Hamm, S Lenk, SA Loening, 2005 "MR Imaging-guided Prostate Biopsy with a Closed MR Unit at 1.5 T: Initial Results" (in cache), Radiology. 2005 Feb;234(2):576-81. Epub 2004 Dec 22.
  • PR Carroll, FV Coakley, and J Kurhanewicz, 2006 "Magnetic Resonance Imaging and Spectroscopy of Prostate Cancer" (in cache), Radiology. 2006 Nov;241(2):546-53.
  • FG Claus, H Hricak, RR Hattery, 2004 "Pretreatment Evaluation of Prostate Cancer: Role of MR Imaging and 1H MR Spectroscopy" (in cache), Radiographics. 2004 Oct;24 Suppl 1:S167-80.
  • FV Coakley, I Chen, A Qayyum, AC Westphalen, PR Carroll, H Hricak, M Chen and J Kurhanewicz, 2006 "Validity of prostate-specific antigen as a tumour marker in men with prostate cancer managed by watchful-waiting: correlation with findings at serial endorectal magnetic resonance imaging and spectroscopic imaging (in cache), BJU Int. 2007 Jan;99(1):41-5.
  • NG Costouros, FV Coakley, AC Westphalen, A Qayyum, BM Yeh, BN Joe, J Kurhanewicz, "Diagnosis of prostate cancer in patients with an elevated prostate-specific antigen level: role of endorectal MRI and MR spectroscopic imaging, AJR Am J Roentgenol. 2007 Mar;188(3):812-6.
  • H Ito, K Kamoi, K Yokoyama, K Yamada, T Nishimura, "Visualization of prostate cancer using dynamic contrast-enhanced MRI: comparison with transrectal power Doppler ultrasound" (in cache), Br J Radiol. 2003 Sep;76(909):617-24.
  • MW Kattan, JA Eastham, TM Wheeler et al., "Counseling men with prostate cancer: a nomogram for predicting the presence of small, moderately differentiated, confined tumors. J Urol 2003Nov;170(5):1792-7 (referred to by Weißbach L and Altwein J, in cache)
  • D Pucar, A Shukla-Dave, H Hricak, CS Moskowitz, K Kuroiwa, S Olgac, LE Ebora, PT Scardino, JA Koutcher, 2005 "Prostate Cancer: Correlation of MR Imaging and MR Spectroscopy with Pathologic Findings after Radiation Therapy: Initial Experience (in cache), Radiology. 2005 Aug;236(2):545-53. Epub 2005 Jun 21
  • A Qayyum, FV Coakley, V Lu1, JD Olpin, L Wu, BM Yeh, PR Carroll and J Kurhanewicz, 2005 "Organ-Confined Prostate Cancer: Effect of Prior Transrectal Biopsy on endorectal MRI and MR Spectroscopic Imaging" (in cache), AJR Am J Roentgenol. 2004 Oct;183(4):1079-83.
  • SF Shariat, PI Karakiewicz, N Suardi, MW Kattan, "Comparison of nomograms with other methodes for predicting outcomes in prostate cancer: a critical analysis of the literature", Clin Cancer Res 2008;14(14):4404-4407, July 15, 2008 (in cache)
  • SF Shariat, PT Scardino, H Lilja, "Screening for prostate cancer: an update", Can J Urol 2008;15(6):4363-4374, December (in cache)
  • A Shukla-Dave, H Hricak, SC Eberhardt, S Olgac, M Muruganandham, PT Scardino, VE Reuter, JA Koutcher, 2004 "Chronic Prostatitis: MR Imaging and 1H MR Spectroscopic Imaging Findings - Initial Observations" (in cache), Radiology. 2004 Jun;231(3):717-24.
  • A Shukla-Dave, H Hricak, MW Kattan, D Pucar, K Kuroiwa, HN Chen, J Spector, JA Koutcher, KL Zakian, PT Scardino. 2007 "The utility of magnetic resonance imaging and spectroscopy for predicting insignificant prostate cancer: an initial analysis." (in cache), BJU Int. 2007 Apr;99(4):786-93. Epub 2007 Jan 12.
  • KL Zakian, S Eberhardt, H Hricak, A Shukla-Dave, S Kleinman, M Muruganandham, K Sircar, MW Kattan, VE Reuter, PT Scardino and JA Koutcher, 2003 "Transition Zone Prostate Cancer: Metabolic Characteristics at 1H MR Spectroscopic Imaging - Initial Results" (in cache), Radiology. 2003 Oct;229(1):241-7. Epub 2003 Aug 14.
  • KL Zakian, K Sircar, H Hricak, HN Chen, A Shukla-Dave, S Eberhardt, M Muruganandham, L Ebora, MW Kattan, VE Reuter, PT Scardino and JA Koutcher, 2005 "Correlation of Proton MR Spectroscopic Imaging with Gleason Score Based on Step-Section Pathologic Analysis after Radical Prostatectomy" (in cache), Radiology. 2005 Mar;234(3):804-14.

  • Appendix

    TNM stages
    (Source: Prostate Cancer Research Institute)

    T Primary Tumor
    TX: Primary tumor cannot be assessed
    T0: No evidence of primary tumor
    T1: Clinically inapparent tumor not palpable or visible by imaging
    T1a: Tumor incidental histologic finding in > 5% of tissue resected via TURP
    T1b: Tumor incidental histologic finding > 5% of tissue resected via TURP
    T1c: Tumor identified by needle biopsy (e.g., because of elevated PSA)
    T2: Tumor palpable but confined within the prostate
    T2a: Tumor involves half of a lobe or less
    T2b: Tumor involves more than half a lobe, but not both lobes
    T2c: Tumor involves both lobes
    T3: Tumor extends through the prostatic capsule
    T3a: Unilateral extracapsular extension
    T3b: Bilateral extracapsular extension
    T3c: Tumor invades the seminal vesicle(s)
    T4: Tumor is fixed or invades adjacent structures other than the seminal vesicles
    T4a: Tumor invades any of bladder neck, external sphincter or rectum
    T4b: Tumor invades levator muscles and/or is fixed to the pelvic wall
    N Regional Lymph Nodes
    NX: Regional lymph nodes cannot be assessed
    N0: No regional lymph nodes metastasis
    N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension
    N2: Metastasis in a single lymph node, more than 2 cm but not more than 5cm in greatest dimension; or multiple lymph node metastases, none more
    than 5 cm in greatest dimension
    N3: Metastasis in a lymph node more than 5 cm in greatest dimension

    M Distant Metastases
    MX: Presence of distant metastasis cannot be assessed
    M0: No distant metastasis
    M1: Distant metastasis
    M1a: Nonregional lymph node(s)
    M1b: Bone(s)
    M1c: Other site(s)

    (Source: Weißbach L, Altwein J, "Active Surveillance or Active Treatment in Localized Prostate Cancer?", Dtsch Arztebl Int 2009; 106(22): 371-6, in cache)

    Although randomized controlled studies are lacking, current data of active surveillance permit the conclusion that doctors have an obligation to alert patients to this option [of active surveillance]. Current guidelines on the treatment of PCa [prostate cancer] also confirm that the treatment of localized prostate cancer has undergone a rethink. However, this is barely reflected in clinical practice, at least not in Germany. In spite of the shift in tumor stage to earlier diagnosis as described earlier, the number of radical prostatectomies is rising steadily, particularly in the group of patients for whom active surveillance as laid out in the latest guidelines would be a suitable option. According to 2006 DRG statistics, almost 69% of men younger than 70 undergo RP. The numbers of operations have risen in recent years. The Brandenburg cancer registry shows that the following therapies were applied in men younger than 70 with tumor categories pT1 to pT3, for 2003 - 2005:
    • Radical prostatectomy in 70% of patients
    • Exclusively radiotherapy in 15% of patients
    • Defensive strategies such as hormone therapy, WW [Watchful Waiting], or active surveillance were used in only 15% of patients.

    Almost two thirds of PCa found were at stage T1 or T2 and would have been suitable for active surveillance [Bandemer-Greulich U, Wulff V, Marquaß S, Kindt B, "7.16 Prostatakarzinome (C61)" in Qualitätsbericht Onkologie 2009, Tumorzentrum Land Brandenburg e.V. und Qualitätskonferenz Onkologie (QKO), 2009 (in cache)].

    There are no more precise data from Germany that show how many patients have a low risk PCa and would therefore be suitable to undergo active surveillance. Currently the best data source on PCa is the longitudinal data collection of CaPSURE. Of more than 10 000 patients included between 1989 and 2003,

    • 29.7% had low risk tumors, for which NICE recommends active surveillance as the first therapeutic option.
    • In 1989/90, 31% were in this risk group, but the proportion rose to 47% in 2001/2002.
    • Over the same time period, the proportion of high risk tumors fell from 41% to 15%.

    These data give rise to the assumption that in Germany, the 69% of prostatectomies in men younger than 70 include many cases with an excellent prognosis.

    PCa treatment should aim to provide each patient with the treatment that is appropriate for his personal needs, individual medical history, and tumor biology. Radical, risk prone interventions should be considered if they are unavoidable and the patient's survival gain justifies the risks associated with the intervention.

    In the range of options, active surveillance is the strategy that enables risk assessment and making considered, unhurried therapeutic decisions: a retrospective controlled study with 188 participants (level of evidence 2b) showed that radical prostatectomy delayed by 26 months does not impair the chances of curative treatment in small and well differentiated tumors if they

    1. are category T1c,
    2. have a PSA density <0.15 ng/mL/cm,sup>3,
    3. have a Gleason score <7, and
    4. are detectable in no more than two positive biopsy cores with less than 50% of tumor mass in each core.

    Knowledge of the tumor biology and giving appropriate consideration to all available treatment strategies can enable primary care physicians to become important decision-makers jointly with their patients. Some food for thought: an editorial, suitably entitled "Prostate Cancer: are we over-diagnosing - or under-thinking?", concludes with the following advice: "Think more!".

    The use of Power Doppler Ultrasound
    (Source: Ito H et al., "Visualization of prostate cancer using dynamic contrast-enhanced MRI: comparison with transrectal power Doppler ultrasound", British Journal of Radiology (2003) 76:617-624, im Cache)

    1. transrectal power Doppler ultrasound (PDUS, ultrasound machine: SSD-5500, Aloka, Tokyo, Japan, endorectal biplanar probe: convex 5 MHz and linear 7.5 MHz) and
    2. dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI, 1.5 T superconducting MR system: Gyroscan Intera, Philips Medical Systems, Best, The Netherlands)
    can be used to demonstrate hypervascularity in many prostate cancers. DCE-MRI was significantly more sensitive than PDUS for visualizing of prostate cancers without loss of specificity in the peripheral zone.

    Comparison between Dynamic MRI and PDUS

    Version: 17. August 2012
    Address of this page
    Joachim Gruber