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MRI-Detectability of Clinically Significant Prostate Cancer Relates to Oncologic Outcomes After Prostatectomy

Published:April 14, 2022DOI:https://doi.org/10.1016/j.clgc.2022.04.001

      Abstract

      Introduction/Background

      Magnetic resonance imaging (MRI) misses a proportion of “clinically significant” prostate cancers (csPC) as defined by histopathology criteria. The aim of this study was to analyze whether long-term oncologic outcomes differ between MRI-detectable and MRI-occult csPC.

      Patients and Methods

      Retrospective analysis of 1449 patients with pre-prostatectomy MRI and csPC on prostatectomy specimens (ie, Grade group ≥2 or extraprostatic spread) between 2001-2006. T2-weighted MRIs were classified according to the Prostate Imaging Reporting and Data System into MRI-occult (categories 1, 2), MRI-equivocal (category 3), and MRI-detectable (categories 4, 5). Cumulative incidence of biochemical recurrence (BCR), metastatic disease, and cancer-specific mortality, estimated with competing risk models. The median follow-up in survivors was 11.0 years (IQR: 8.9-13.1).

      Results

      In 188 (13%) cases, csPC was MRI-occult, 435 (30%) MRIs were equivocal, and 826 (57%) csPC were MRI-detectable. The 15-year cumulative incidence [95% CI] of BCR was 8.3% [2.2, 19.5] for MRI-occult cases, 17.4% [11.1, 24.8] for MRI-equivocal cases, and 43.3% [38.7, 47.8] for MRI-detectable cases (P < .001). The cumulative incidences of metastases were 0.61% [0.06, 3.1], 3.5% [1.5, 6.9], and 19.6% [15.4, 24.2] for MRI-occult, MRI-equivocal, and MRI-detectable cases, respectively (P < .001). There were no deaths from prostate cancer observed in patients with MRI-occult csPC, compared to an estimated 1.9% [0.54, 4.9], and 7.1 % [4.5, 10.6] for patients with MRI-equivocal and MRI-detectable cancer, respectively (P < .001).

      Conclusion

      Oncologic outcomes after prostatectomy for csPC differ between MRI-occult and MRI-detectable lesions. Judging the clinical significance of a negative prostate MRI based on histopathologic surrogates alone might be misleading.

      Microabstract

      Among 1449 patients with pre-prostatectomy MRI and clinically significant prostate cancer on prostatectomy histopathology, MRI-occult cancers (n = 188, 13%) were less likely to recur biochemically (8% vs. 43%, P < .001), metastasize (0.6% vs. 20%, P < .001), or lead to prostate cancer mortality (0% vs. 7%, P < .001) than MRI-detectable cancers (n = 826, 57%). MRI-occult cancers constitute a prognostically distinct subgroup among higher-grade prostate cancers.

      Keywords

      Introduction

      Magnetic resonance imaging (MRI) is the primary modality for the imaging of prostate cancer. Prospective studies have documented that MRI-inclusive diagnostic pathways can detect more “clinically significant” prostate cancer (csPC) compared to using only transrectal ultrasound-guided biopsy.
      • Woo S.
      • Suh C.H.
      • Eastham J.A.
      • Zelefsky M.J.
      • Morris M.J.
      • Abida W.
      Comparison of magnetic resonance imaging-stratified clinical pathways and systematic transrectal ultrasound-guided biopsy pathway for the detection of clinically significant prostate cancer: a systematic review and meta-analysis of randomized controlled trials.
      However, it is also recognized that on a per-lesion basis, MRI will “miss” up to 20% of high-grade tumor foci,
      • Johnson D.C.
      • Raman S.S.
      • Mirak S.A.
      • Kwan L.
      • Bajgiran A.M.
      • Hsu W.
      Detection of individual prostate cancer foci via multiparametric magnetic resonance imaging.
      and that it will deliver false-negative results in approximately 10% to 20% of individuals with csPC.
      • Woo S.
      • Suh C.H.
      • Kim S.Y.
      • Cho J.Y.
      • Kim S.H.
      Diagnostic performance of prostate imaging reporting and data system version 2 for detection of prostate cancer: a systematic review and diagnostic meta-analysis.
      “Clinical significance” in such studies evaluating the diagnostic performance of prostate MRI is usually defined by histopathologic criteria. Most commonly, csPC is defined as the presence of a Grade group of 2 or higher, or histopathology-proven extraprostatic tumor spread (ie, tumor stage pT3).
      • Barkovich E.J.
      • Shankar P.R.
      • Westphalen A.C.
      A Systematic review of the existing prostate imaging reporting and data system version 2 (PI-RADSv2) literature and subset meta-analysis of PI-RADSv2 categories stratified by Gleason scores.
      The variable outcomes reported for so-defined csPC
      • Grimm P.
      • Billiet I.
      • Bostwick D.
      • Dicker A.P.
      • Frank S.
      • Immerzeel J.
      Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the prostate cancer results study group.
      ,
      • Kane C.J.
      • Eggener S.E.
      • Shindel A.W.
      • Andriole G.L.
      Variability in outcomes for patients with intermediate-risk prostate cancer (Gleason score 7, international society of urological pathology Gleason group 2-3) and implications for risk stratification: a systematic review.
      indicate that the natural history of this sub-group of cancers might be more heterogenous than what can be inferred from their histomorphological features.
      In this study of patients with csPC on prostatectomy specimen, we investigated the relationship between the detectability of csPC on MRI and long-term oncologic outcomes including biochemical recurrence (BCR), development of metastases, and prostate cancer-specific mortality (PCSM). Based on prior observations that the MRI appearance of prostate cancer can be associated with oncologic outcomes,
      • Stabile A.
      • Mazzone E.
      • Cirulli G.O.
      • De Cobelli F.
      • Grummet J.
      • Thoeny H.C.
      Association between multiparametric magnetic resonance imaging of the prostate and oncological outcomes after primary treatment for prostate cancer: a systematic review and meta-analysis.
      ,
      • Wibmer A.G.
      • Chaim J.
      • Lakhman Y.
      • Lefkowitz R.A.
      • Nincevic J.
      • Nikolovski I.
      Oncologic outcomes after localized prostate cancer treatment: associations with pretreatment prostate magnetic resonance imaging findings.
      we hypothesized that patients with MRI-occult csPC would experience better oncologic outcomes compared to those with MRI-detectable csPC.

      Patients and Methods

      This was a HIPAA-compliant and IRB-approved retrospective single-center cohort study of patients with clinically significant localized adenocarcinoma of the prostate who underwent prostate MRI within 180 days prior to radical prostatectomy with curative intent between 2001 and 2006 at a tertiary academic cancer center. Patients who received any neoadjuvant systemic therapy before surgery, and those who underwent palliative prostatectomy or cysto-prostatectomy were excluded. Histopathology data from the prostatectomy specimens was used to define csPC as the presence of Grade group ≥2 or pT3 category (ie, presence of extraprostatic extension or seminal vesicle invasion). Patients without csPC (ie, organ-confined Grade group 1 cancers, or no cancer) were excluded from the analyses. In addition, a narrower definition of csPC (ie, Grade group ≥3, or pT3 category) was applied to define a cohort for subgroup analysis. The individuals in this study had been part of previously published cohorts testing different hypothesis: The first study investigated the prognostic value of prostate MRI when benchmarked against pre-therapy biopsy and clinical data
      • Wibmer A.G.
      • Chaim J.
      • Lakhman Y.
      • Lefkowitz R.A.
      • Nincevic J.
      • Nikolovski I.
      Oncologic outcomes after localized prostate cancer treatment: associations with pretreatment prostate magnetic resonance imaging findings.
      while in the current analysis we use prostatectomy specimen histopathology to define csPC. The second previously published study analyzed staging discordances between MRI and prostatectomy histopathology and their associations with oncologic outcomes
      • Wibmer A.G.
      • Nikolovski I.
      • Chaim J.
      • et al.
      Local Extent of Prostate Cancer at MRI versus Prostatectomy Histopathology: Associations with Long-term Oncologic Outcomes.
      , while the present study uses prostatectomy specimens for selecting patients with csPC. Prostate MRIs were performed with an endorectal and body coil and consisted of T1-weighted images of the entire pelvis in the transverse plane, and prostate-focused T2-weighted images in the transverse, and sagittal or coronal planes. MRI scans that were done without an endorectal coil were excluded from the analyses. Prostate MRIs were re-interpreted by one of 7 sub-specialized oncologic uro-radiologists in compliance with the Prostate Imaging and Data System version 2 (PI-RADS), which was described in detail previously.
      • Weinreb J.C.
      • Barentsz J.O.
      • Choyke P.L.
      • Cornud F.
      • Haider M.A.
      • Macura K.J.
      PI-RADS prostate imaging - reporting and data system: 2015, version 2.
      In short, PI-RADS provides consensus diagnostic criteria to categorize T2-weighted images on a 5-tiered scale. PI-RADS scores of 1 and 2 indicate the absence of csPC, equivocal findings are classified as PI-RADS 3, and findings probably or definitely representing csPC are scored as PI-RADS 4 and 5, respectively. Cases were randomly assigned to the study radiologists using the RANDBETWEEN function in Microsoft Excel (Microsoft Corporation) and radiologists were blinded to all clinical, histopathology, and outcome data.

      Follow-Up and Endpoints

      Follow-up appointments were scheduled as per standard of care, 3 months after prostatectomy, then every 6 months until year 5, and annually thereafter. Endpoints were biochemical recurrence (BCR), development of metastatic disease, and prostate cancer-specific death. BCR was defined as a PSA level of ≥0.1 ng/mL after an interval of undetectable PSA. If salvage therapy was initiated at a lower PSA level, the highest measured PSA level before salvage treatment was defined as the time of BCR. If PSA failed to become undetectable after prostatectomy, the first PSA measurement after the nadir was defined as time of BCR. As recommended by the Intermediate Clinical Endpoints of Cancer of the Prostate working group for studying localized prostate cancer,
      • Pierre V.D.
      • Pinsky P.F.
      • Miller E.
      • Parnes H.
      Other- and all-cause mortality among men diagnosed with prostate cancer in the PLCO trial.
      time to metastatic disease was defined as the time between prostatectomy and the first evidence of distant metastasis confirmed by imaging or histopathology, as documented in the patient's medical record; isolated local tumor recurrence in the prostatectomy bed was not considered a metastasis. The time to prostate cancer specific mortality (PCSM) was measured as the time from prostatectomy to death from prostate cancer; observations from patients with an undetectable PSA, who were free from metastases, and/or alive at the time of last follow-up were censored.

      Statistical Considerations

      MRI results were categorized into “MRI-occult” (ie, T2w PI-RADS categories 1 or 2), “MRI-equivocal” (ie, T2w PI-RADS category 3), and “MRI-detectable” (ie, T2w PI-RADS categories 4 or 5). The cumulative incidences of BCR, metastatic disease, and PCSM were estimated with cumulative incidence functions taking into account non-prostate cancer related death (ie, other-cause mortality [OCM] as competing risk for BCR, metastatic disease, and PCSM, respectively. For estimating the cumulative incidence of OCM, PCSM was considered a competing risk. Cumulative incidence differences between MRI-groups were tested with Gray ‘s test for equality and all test results with a P-value <.05 were regarded statistically significant. Statistical analyses were performed with Statistical Analysis System version 9.3 (SAS Institute Inc., Cary, NC) and GraphPad Prism, version 8.4.2 (GraphPad software LLC, San Diego, CA).

      Results

      Study Cohort

      Of the 2380 patients identified through our initial database query, 220 were excluded because they underwent palliative prostatectomy or cyst-prostatectomy (n = 66), or neoadjuvant systemic therapy (n = 73), due to inappropriate MR imaging (n = 58), or no follow-up data (n = 23). Of the remaining 2160 patients, 711 had organ-confined low-grade disease (non-csPC) on prostatectomy specimens and were also excluded. The final study cohort consisted of 1449 men with csPC with a median age of 60 years (IQR: 55-65) at prostatectomy. The median time from MRI to prostatectomy was 20 days (IQR: 8-48). One-hundred and 88 patients (13%) had MRI-occult disease, 435 (30%) of MRIs were equivocal, and 826 (57%) cases were MRI-detectable. As per inclusion criteria, all patients had csPC on their prostatectomy specimens, detailed frequencies of Grade groups, extraprostatic extension, and seminal vesicle invasion on the prostatectomy specimens are given in Table 1. It shows that of the 188 patients with MRI-occult csPC, the majority had Grade group 1 or 2 cancers on their prostatectomy specimens (n = 158, 84%), and Grade group 3, 4, and 5 cancers were diagnosed in 26 (14%), 3 (1.6%), and 1 (0.53%) prostatectomy specimens. Forty cases (21%) of MRI-occult csPC had extraprostatic extension, and in 7 cases (3.7%) the cancer invaded the seminal vesicles. The median follow-up in survivors was 11.0 years (IQR: 8.9-13.1).
      Table 1Distribution of Histopathologic Findings on Prostatectomy Specimens and Pre-Prostatectomy MRI Categories
      MRI CategoryOverall
      MRI-OccultMRI-EquivocalMRI-Detectable
      Prostatectomy Specimen HistopathologyGrade Group18

      (12, 4.3)
      24

      (36, 5.5)
      35

      (52, 4.2)
      67

      (4.6)
      2150

      (17, 80)
      316

      (35, 73)
      441

      (49, 53)
      907

      (63)
      326

      (8.2, 14)
      77

      (24, 18)
      216

      (68, 26)
      319

      (22)
      43

      (4.1, 1.6)
      12

      (16, 2.8)
      58

      (79, 7.0)
      73

      (5.0)
      51

      (1.2, 0.5)
      6

      (7.2, 1.4)
      76

      (92, 9.2)
      83

      (5.7)
      Extraprostatic ExtensionPresent40

      (6.2, 21)
      131

      (20, 30)
      479

      (74, 58)
      650

      (45)
      Absent148

      (19, 79)
      304

      (38, 70)
      347

      (43, 42)
      799

      (55)
      Seminal Vesicle InvasionPresent7

      (5.3, 3.7)
      22

      (17, 5.1)
      102

      (79, 12)
      131

      (9.0)
      Absent181

      (14, 96)
      413

      (31, 95)
      724

      (55, 88)
      1,318

      (91)
      Lymph Node StatusN+2

      (1.8, 1.1)
      12

      (11, 2.8)
      99

      (88, 12)
      113

      (7.8)
      N0169

      (14, 90)
      387

      (31, 89)
      677

      (55, 82)
      1,233

      (85)
      NX17

      (17, 9.0)
      36

      (35, 8.3)
      50

      (49, 6.1)
      103

      (7.1)
      Overall188

      (13)
      435

      (30)
      826

      (57)
      1,449

      (100)
      Numbers are presented as absolute counts and percentages (Row %, Column %).

      Oncologic Outcome Analyses

      In patients with MRI-occult csPC, 8 cases of BCR were observed and the estimated 15-year cumulative incidence was 8.3% [95% CI: 2.2, 19.5]. Prostatectomy histopathology details and clinical baseline and outcome data for these 8 patients are listed in Table 2. In comparison, the 15-year BCR cumulative incidence among MRI-equivocal cases was 17.4% [95% CI: 11.1, 24.8], and 43.3% [95% CI: 38.7, 47.8] for MRI-detectable cases (P < .001) (Table 3) and (Figure 1).
      Table 2Clinical, Pathological, and Outcome Data of 8 Patients With Clinically Significant Prostate Cancer on Prostatectomy Specimens and no Detectable Lesion on T2-Weighted Pre-Prostatectomy MRI (ie, MRI-Occult Cancer) Who Developed Biochemical Recurrence After Radical Prostatectomy
      Patient
      ABCDEFGH
      Age at Prostatectomy (years)63.455.651.462.250.162.549.355.4
      Clinical Cancer Stage (cT)1C1C2A2C2C1C1C1C
      PSA at Diagnosis (ng/ml)4.44.32.08.85.020.15.27.3
      Biopsy Grade Group31111123
      Prostatectomy HistopathologyGrade Group32222222
      Extraprostatic

      Extension
      AbsentAbsentAbsentAbsentAbsentAbsentAbsentAbsent
      Seminal Vesicle InvasionAbsentAbsentAbsentAbsentAbsentAbsentAbsentAbsent
      Surgical MarginsNegativePositivePositiveNegativeNegativeNegativeNegativeNegative
      Nodal StatuspN0pN0pN0pN0pN0pN0pN0pN0
      Time to Biochemical Recurrence (Years)PSA never undetectable13.04.75.73.2PSA never undetectable7.16.1
      Salvage TreatmentEBRTNoneEBRTNoneEBRTEBRTEBRTEBRT
      Time To Metastases (Years)5.9 y-------
      Post-Prostatectomy Follow-Up (Years)14.013.816.415.314.214.411.712.7
      Status At Last

      Follow-Up
      Castration-sensitive osseous metastasesRising PSA non-castrateRising PSA non-castrateRising PSA non-castrateUndetectable PSARising PSA non-castrateRising PSA non-castrateUndetectable PSA
      EBRT, external beam radiation therapy; PSA, prostate specific antigen.
      Table 3. Estimated Cumulative Incidences of Biochemical Recurrence (BCR), Metastatic Disease, and Prostate Cancer-Specific Mortality (PCSM) in Patients With Clinically Significant Prostate Cancer 15 y After Prostatectomy, Stratified by MRI Category, With Other-Cause Mortality (OCM) as Competing Risk
      WIDE Histopathologic Definition of csPC on Prostatectomy Specimens(Grade Group ≥2, or Extra-Prostatic Spread; n = 1,449)
      MRI-Occult

      (n = 188)
      MRI-Equivocal (n = 435)MRI-Detectable

      (n = 826)
      P-value
      Biochemical Recurrence

      (Observed Events: 370)
      8.3

      [2.2, 19.5]
      17.4

      [11.1, 24.8]
      43.3

      [38.7, 47.8]
      <.001
      Metastatic Disease

      (Observed Events: 116)
      0.61

      [0.06, 3.1]
      3.5

      [1.5, 6.9]
      19.6

      [15.4, 24.2]
      <.001
      Prostate Cancer-Specific Mortality

      (Observed Events: 39)
      No events1.9

      [0.54, 4.9]
      7.1

      [4.5, 10.6]
      <.001
      Other-Cause Mortality

      (Observed Events: 105)
      4.0

      [1.2, 9.5]
      19.2

      [11.5, 28.3]
      16.1

      [12.1, 20.7]
      .062
      NARROW Histopathologic Definition of csPC on Prostatectomy Specimens

      (Grade Group ≥3, or Extra-Prostatic Spread; n = 826)
      MRI-occult (n = 63)MRI-equivocal (n = 188)MRI-detectable

      (n = 575)
      P-value
      Biochemical Recurrence

      (Observed Events: 310)
      1.6

      [0.13, 7.6]
      21.2

      [15.2, 28.0]
      53.6

      [47.6, 59.2]
      <.001
      Metastatic Disease

      (Observed Events: 109)
      1.9

      [0.15, 8.9]
      8.2

      [3.4, 15.8]
      24.3

      [19.2, 29.7]
      <.001
      Prostate Cancer-Specific Mortality

      (Observed Events: 39)
      No events4.4

      [1.2, 11.0]
      9.7

      [6.2, 14.1]
      .043
      Other-Cause Mortality

      (Observed Events: 74)
      5.8

      [0.96, 17.3]
      31.7

      [14.2, 50.8]
      17.4

      [12.7, 22.7]
      .5
      Cumulative incidences of OCM with PCSM as competing risk. Data are presented as percentages and [95% confidence intervals], P-values derived from Gray's tests for equality.
      Figure 1
      Figure 1Estimated cumulative incidences of post-prostatectomy biochemical recurrence (BCR, left upper graph), metastatic disease (right upper graph), and prostate cancer-specific mortality (PCSM, left lower graph) in patients with clinically significant prostate cancer (ie, Grade group ≥2 or pT3 disease on prostatectomy specimens), stratified by T2-weighted MRI category (ie, “MRI-occult”, "MRI-equivocal", and “MRI-detectable”), taking into account other-cause mortality (OCM) as competing risk. Cumulative incidence of OCM (right lower graph) with PCSM as competing risk.
      The estimated 15-year cumulative incidence of metastatic disease in patients with MRI-occult csPC was 0.61% [95%CI: 0.06, 3.1]. We observed one case of osseous metastases in this group and at the time of this patient's last follow-up, which was 14 years after prostatectomy and 8 years after the diagnosis of metastatic disease, he was alive with castration-sensitive osseous metastases. In comparison, the estimated 15-year cumulative incidences of metastases for patients with MRI-equivocal and MRI-detectable csPC were 3.5% [95%CI: 1.5, 6.9] and 19.6% [95%CI: 15.4, 24.2], respectively (P < .001) (Table 3) and (Figure 1).
      We did not observe death from prostate cancer in patients with MRI-occult csPC, compared to an estimated 1.9% [95%CI: 0.54, 4.9] and 7.1% [95%CI: 4.5, 10.6] cumulative incidence of PCSM in patients with MRI-equivocal and MRI-detectable csPC, respectively (P < .001) (Table 3) and (Figure 1).

      Subgroup analysis

      When applying a narrower definition of csPC (ie, Grade group ≥3, or pT3 disease on prostatectomy specimens), 826 individuals had csPC. Of these, 63 (7.6%) had MRI-occult disease, 188 (23%) had an equivocal MRI, and 575 (70%) had MRI-detectable cancer. Among the 63 patients with MRI-occult csPC, one patient (ie, individual “A” in Table 2) developed BCR and metastatic disease, but no prostate-cancer specific death was observed. These incidences were significantly higher in patients with MRI-equivocal and MRI-detectable csPC, as detailed in Table 3.

      Discussion

      In this retrospective analysis we corroborated previous observations that prostate MRI delivers false negative results in a considerable proportion of patients with csPC, ie, 13% in our cohort compared to 10% to 20% in prior studies.
      • Johnson D.C.
      • Raman S.S.
      • Mirak S.A.
      • Kwan L.
      • Bajgiran A.M.
      • Hsu W.
      Detection of individual prostate cancer foci via multiparametric magnetic resonance imaging.
      ,
      • Woo S.
      • Suh C.H.
      • Kim S.Y.
      • Cho J.Y.
      • Kim S.H.
      Diagnostic performance of prostate imaging reporting and data system version 2 for detection of prostate cancer: a systematic review and diagnostic meta-analysis.
      We then compared the oncologic outcomes of patients with MRI-detectable lesions to individuals in whom MRI “missed” the cancer. We found that the cumulative incidences of BCR and metastatic disease after prostatectomy were substantially lower for patients with MRI-occult cancer and we did not observe death from prostate cancer in this group. The variability in oncologic outcomes among patients with histopathologically-defined csPC is in line with previous studies
      • Kane C.J.
      • Eggener S.E.
      • Shindel A.W.
      • Andriole G.L.
      Variability in outcomes for patients with intermediate-risk prostate cancer (Gleason score 7, international society of urological pathology Gleason group 2-3) and implications for risk stratification: a systematic review.
      ,
      • Stabile A.
      • Mazzone E.
      • Cirulli G.O.
      • De Cobelli F.
      • Grummet J.
      • Thoeny H.C.
      Association between multiparametric magnetic resonance imaging of the prostate and oncological outcomes after primary treatment for prostate cancer: a systematic review and meta-analysis.
      and underscores the biologic heterogeneity of these cancers. We infer from these results that judging the clinical significance and possible implications of a negative prostate MRI based on histopathologic surrogates alone might be misleading. Our results resemble observations from previous smaller cohort studies that MRI-occult prostate cancers are less likely to recur after definite treatment. Jambor and colleagues, for example, reported post-prostatectomy outcomes in 91 patients (median follow-up: 3.6 years) and observed BCR in 1 of 6 patients with a PI-RADS score ≤2.
      • Jambor I.
      • Falagario U.
      • Ratnani P.
      • Perez I.M.
      • Demir K.
      • Merisaari H.
      Prediction of biochemical recurrence in prostate cancer patients who underwent prostatectomy using routine clinical prostate multiparametric MRI and decipher genomic score.
      Similarly, Capogrosso et al reported 1 case of post-prostatectomy BCR in 24 patients with MRI-occult cancers during a median follow-up of 1.4 years.
      • Capogrosso P.
      • Vertosick E.A.
      • Benfante N.E.
      • Sjoberg D.D.
      • Vickers A.J.
      • Eastham J.A.
      Can we improve the preoperative prediction of prostate cancer recurrence with multiparametric MRI?.
      Concordant numbers have been reported in patients treated with radiotherapy, for example by Turchan et. al who did not observe biochemical failure in 9 patients with intermediate- or high-risk prostate cancer and a PIRADS-score ≤3 on MRI (median follow-up: 5.6 years).
      • Turchan W.T.
      • Kauffmann G.
      • Patel P.
      • Oto A.
      • Liauw S.L.
      PI-RADS score is associated with biochemical control and distant metastasis in men with intermediate-risk and high-risk prostate cancer treated with radiation therapy.
      In addition to the larger sample size and longer follow-up period, our study differs from these previous reports as it focuses on patients with csPC on prostatectomy specimens. This sub-population is on-average at a higher risk for treatment failure and cancer progression, and false negative MRI results are thought to be of higher clinical relevance. The failure to detect a proportion of these “clinically significant” cancers is often considered the most impactful shortcoming of prostate MRI and a major reason why MRI is regarded not reliable enough for clinical decision making by some.
      • Carlsson S.V.
      • Eastham J.A.
      Re: use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study.
      The herein presented oncologic outcome data adds to this ongoing discussion that among histopathologically-defined csPC, MRI-occult cancers constitute a distinct sub-population with more favorable oncologic outcomes. The true clinical significance of a false-negative MRI seems to be less than suggested by histopathology surrogates.
      In addition to more favorable prostate cancer-related outcomes we also observed lower non-prostate cancer related mortality (ie, OCM) for patients with MRI-occult disease. This appears analogous to observations from prior studies that reported lower OCM rates in patients with low-risk prostate cancer compared to individuals with intermediate- or high-risk disease.
      • Rider J.
      • Sandin F.
      • Andren O.
      • Wiklund P.
      • Hugosson J.
      • Stattin P.
      Long-term outcomes among noncuratively treated men according to prostate cancer risk category in a nationwide, population-based study.
      • Rasul R.
      • Golden A.
      • Feuerstein M.A.
      Prostate cancer risk group is associated with other-cause mortality in men with localized prostate cancer.
      • Pierre V.D.
      • Pinsky P.F.
      • Miller E.
      • Parnes H.
      Other- and all-cause mortality among men diagnosed with prostate cancer in the PLCO trial.
      From an analysis of 76,437 individuals treated with noncurative intent in the National Prostate Cancer Register of Sweden, for example, it was reported that OCM among men with higher-risk disease was higher than for patients with low-risk cancer.
      • Rider J.
      • Sandin F.
      • Andren O.
      • Wiklund P.
      • Hugosson J.
      • Stattin P.
      Long-term outcomes among noncuratively treated men according to prostate cancer risk category in a nationwide, population-based study.
      This was recently corroborated in an analysis of over 400,000 prostate cancer patients in the Surveillance, Epidemiology, and End Results database showing that intermediate- and high-risk patients had a higher risk of OCM after radical treatment independently of age, race, and poverty level.
      • Rasul R.
      • Golden A.
      • Feuerstein M.A.
      Prostate cancer risk group is associated with other-cause mortality in men with localized prostate cancer.
      Similarly, a report from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort demonstrated that OCM was lower in low-risk compared to intermediate- and high- risk disease, even after controlling for comorbidities and lifestyle factors.
      • Pierre V.D.
      • Pinsky P.F.
      • Miller E.
      • Parnes H.
      Other- and all-cause mortality among men diagnosed with prostate cancer in the PLCO trial.
      We acknowledge several important limitations of our study. Due to its retrospective design, bias might be present resulting from selection of patients for pre-prostatectomy MRI and from the fact that surgeons were not blinded to pre-prostatectomy MRI findings. Also, the post-prostatectomy follow-up was probably imperfect as indicated by a lower incidence of metastases and prostate cancer-specific death compared to previous prospectively followed cohorts.
      • Holmberg L.
      • Bill Axelson A.
      • Steineck G.
      • Garmo H.
      • Palmgren J.
      • Johansson E.
      Results from the scandinavian prostate cancer group trial number 4: a randomized controlled trial of radical prostatectomy versus watchful waiting.
      ,
      • Wilt T.J.
      • Brawer M.K.
      • Jones K.M.
      • Barry M.J.
      • Aronson W.J.
      • Fox S.
      Radical prostatectomy versus observation for localized prostate cancer.
      Second, our data stems from the early 2000′s when prostate MRI was limited to “anatomical” sequences (ie, T1- and T2-weighted sequences) whereas modern prostate MRI protocols include one or more “functional” sequences (eg, diffusion-weighted or dynamic contrast-enhanced imaging). These modern MRI protocols substantially increase the diagnostic precision of MRI
      • Tan C.H.
      • Hobbs B.P.
      • Wei W.
      • Kundra V.
      Dynamic contrast-enhanced MRI for the detection of prostate cancer: meta-analysis.
      and we do not know how the availability of functional MRI sequences would have affected the results of our study. Technical innovation and improvement of MRI, however, is an ongoing and probably infinite process. Thus, this issue will always be present in a study correlating MRI-derived data and long-term clinical outcomes. The fact that all study radiologist were sub-specialized limits the generalizability of our findings. Given the strong effect of dedicated training
      • Akin O.
      • Riedl C.C.
      • Ishill N.M.
      • Moskowitz C.S.
      • Zhang J.
      • Hricak H.
      Interactive dedicated training curriculum improves accuracy in the interpretation of MR imaging of prostate cancer.
      and sub-specialization
      • Wibmer A.
      • Vargas H.A.
      • Donahue T.F.
      • Zheng J.
      • Moskowitz C.
      • Eastham J.
      Diagnosis of extracapsular extension of prostate cancer on prostate MRI: impact of second-opinion readings by subspecialized genitourinary oncologic radiologists.
      on a radiologist's precision in interpreting prostate MRIs, it is uncertain whether non-specialized general radiologist would be able to reproduce our results. The benefits of sub-specialization, however, are not limited to prostate radiology but also observed in pathologist interpreting prostate samples.
      • Brimo F.
      • Schultz L.
      • Epstein J.I.
      The value of mandatory second opinion pathology review of prostate needle biopsy interpretation before radical prostatectomy.
      ,
      • Barqawi A.B.
      • Turcanu R.
      • Gamito E.J.
      • Lucia S.M.
      • O'Donnell C.I.
      • Crawford E.D.
      The value of second-opinion pathology diagnoses on prostate biopsies from patients referred for management of prostate cancer.
      The main strength of our study is its large cohort size and long follow-up duration which allowed for robust statistical analyses of late – however important – clinical endpoints, namely metastases and cancer-specific death. The definition of csPC based on prostatectomy specimens rather than biopsy samples is another strength as it is known that prostate biopsy may under- or overestimate of Gleason scores/Grade groups.
      • Cohen M.S.
      • Hanley R.S.
      • Kurteva T.
      • Ruthazer R.
      • Silverman M.L.
      • Sorcini A.
      Comparing the Gleason prostate biopsy and Gleason prostatectomy grading system: the Lahey clinic medical center experience and an international meta-analysis.
      In summary, patients with MRI-occult “clinically significant” prostate cancer experience substantially more favorable long-term oncologic outcomes after radical prostatectomy than patients with MRI-detectable cancer. The significance of a “false-negative” MRIs appears less severe when judged in relation to oncologic endpoints rather than histopathology surrogates.

      Clinical Practice Points

      • Prostate MRI misses a proportion of “clinically significant” prostate cancers as defined by histopathology criteria.
      • We found that patients with a negative pre-prostatectomy MRI but “clinically significant” cancer on final surgical pathology were less likely to develop recurrent metastatic malignancy or die from prostate cancer than those with MRI-detectable disease.
      • The true clinical significance of a negative MRI might be misjudged when referenced only against histopathology surrogates.

      Disclosure

      Dr Hedvig Hricak has served on the Board of Directors of Ion Beam Applications (IBA), a publicly traded company, since May 2017 and she receives annual compensation for her service. Furthermore, Dr Hricak is a member of the External Advisory Board of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (SKCCC), the International Advisory Board of the University of Vienna, Austria, the Scientific Committee of the DKFZ (German Cancer Research Center), Germany, the Board of Trustees the DKFZ (German Cancer Research Center), Germany and a member of the Scientific Advisory Board (SAB) of Euro-BioImaging ERIC; she does not receive financial compensation for any of these roles. The other authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

      Key Take-Home Messages

      • Prostate MRI misses a proportion of higher-grade/stage “clinically significant” prostate cancers.
      • Patients with MRI-occult “clinically significant” cancer are less likely to develop cancer recurrence or die from prostate cancer after prostatectomy compared to those with MRI-detectable disease.
      • By referencing prostate MRI solely against histopathology results, one might misjudge the true clinical significance of a negative prostate MRI.

      Acknowledgments

      This work was supported in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 , NIH/NCI Research Project (R01) CA076423-01A2 , the Peter Michael Foundation, and the Strawbridge Foundation.

      Appendix. Supplementary materials

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