Regional Histopathology and Prostate MRI Positivity: A Secondary Analysis of the PROMIS Trial.

Background The effects of regional histopathologic changes on prostate MRI scans have not been accurately quantified in men with an elevated prostate-specific antigen (PSA) level and no previous biopsy. Purpose To assess how Gleason grade, maximum cancer core length (MCCL), inflammation, prostatic intraepithelial neoplasia (PIN), or atypical small acinar proliferation within a Barzell zone affects the odds of MRI visibility. Materials and Methods In this secondary analysis of the Prostate MRI Imaging Study (PROMIS; May 2012 to November 2015), consecutive participants who underwent multiparametric MRI followed by a combined biopsy, including 5-mm transperineal mapping (TPM), were evaluated. TPM pathologic findings were reported at the whole-prostate level and for each of 20 Barzell zones per prostate. An expert panel blinded to the pathologic findings reviewed MRI scans and declared which Barzell areas spanned Likert score 3-5 lesions. The relationship of Gleason grade and MCCL to zonal MRI outcome (visible vs nonvisible) was assessed using generalized linear mixed-effects models with random intercepts for individual participants. Inflammation, PIN, and atypical small acinar proliferation were similarly assessed in men who had negative TPM results. Results Overall, 161 men (median age, 62 years [IQR, 11 years]) were evaluated and 3179 Barzell zones were assigned MRI status. Compared with benign areas, the odds of MRI visibility were higher when a zone contained cancer with a Gleason score of 3+4 (odds ratio [OR], 3.1; 95% CI: 1.9, 4.9; P < .001) or Gleason score greater than or equal to 4+3 (OR, 8.7; 95% CI: 4.5, 17.0; P < .001). MCCL also determined visibility (OR, 1.24 per millimeter increase; 95% CI: 1.15, 1.33; P < .001), but odds were lower with each prostate volume doubling (OR, 0.7; 95% CI: 0.5, 0.9). In men who were TPM-negative, the presence of PIN increased the odds of zonal visibility (OR, 3.7; 95% CI: 1.5, 9.1; P = .004). Conclusion An incremental relationship between cancer burden and prostate MRI visibility was observed. Prostatic intraepithelial neoplasia contributed to false-positive MRI findings. ClinicalTrials.gov registration no. NCT01292291 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Harmath in this issue.

False Positive Multiparametric Magnetic Resonance Imaging Phenotypes in the Biopsy-naïve Prostate: Are They Distinct from Significant Cancer-associated Lesions? Lessons from PROMIS.

BACKGROUND: False positive multiparametric magnetic resonance imaging (mpMRI) phenotypes prompt unnecessary biopsies. The Prostate MRI Imaging Study (PROMIS) provides a unique opportunity to explore such phenotypes in biopsy-naïve men with raised prostate-specific antigen (PSA) and suspected cancer. OBJECTIVE: To compare mpMRI lesions in men with/without significant cancer on transperineal mapping biopsy (TPM). DESIGN, SETTING, AND PARTICIPANTS: PROMIS participants (n=235) underwent mpMRI followed by a combined biopsy procedure at University College London Hospital, including 5-mm TPM as the reference standard. Patients were divided into four mutually exclusive groups according to TPM findings: (1) no cancer, (2) insignificant cancer, (3) definition 2 significant cancer (Gleason ≥3+4 of any length and/or maximum cancer core length ≥4mm of any grade), and (4) definition 1 significant cancer (Gleason ≥4+3 of any length and/or maximum cancer core length ≥6mm of any grade). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Index and/or additional lesions present in 178 participants were compared between TPM groups in terms of number, conspicuity, volume, location, and radiological characteristics. RESULTS AND LIMITATIONS: Most lesions were located in the peripheral zone. More men with significant cancer had two or more lesions than those without significant disease (67% vs 37%; p< 0.001). In the former group, index lesions were larger (mean volume 0.68 vs 0.50 ml; p< 0.001, Wilcoxon test), more conspicuous (Likert 4-5: 79% vs 22%; p< 0.001), and diffusion restricted (mean apparent diffusion coefficient [ADC]: 0.73 vs 0.86; p< 0.001, Wilcoxon test). In men with Likert 3 index lesions, log2PSA density and index lesion ADC were significant predictors of definition 1/2 disease in a logistic regression model (mean cross-validated area under the receiver-operator characteristic curve: 0.77 [95% confidence interval: 0.67-0.87]). CONCLUSIONS: Significant cancer-associated MRI lesions in biopsy-naïve men have clinical-radiological differences, with lesions seen in prostates without significant disease. MRI-calculated PSA density and ADC could predict significant cancer in those with indeterminate MRI phenotypes. PATIENT SUMMARY: Magnetic resonance imaging (MRI) lesions that mimic prostate cancer but are, in fact, benign prompt unnecessary biopsies in thousands of men with raised prostate-specific antigen. In this study we found that, on closer look, such false positive lesions have different features from cancerous ones. This means that doctors could potentially develop better tools to identify cancer on MRI and spare some patients from unnecessary biopsies.

What Type of Prostate Cancer Is Systematically Overlooked by Multiparametric Magnetic Resonance Imaging? An Analysis from the PROMIS Cohort.

BACKGROUND: All risk stratification strategies in cancer overlook a spectrum of disease. The Prostate MR Imaging Study (PROMIS) provides a unique opportunity to explore cancers that are overlooked by multiparametric magnetic resonance imaging (mpMRI). OBJECTIVE: To summarise attributes of cancers that are systematically overlooked by mpMRI. DESIGN, SETTING, AND PARTICIPANTS: PROMIS tested performance of mpMRI and transrectal ultrasonography (TRUS)-guided biopsy, using 5 mm template mapping (TPM) biopsy as the reference standard. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were overall and maximum Gleason scores, maximum cancer core length (MCCL), and prostate-specific antigen density (PSAD). Cancer attributes were compared between cancers that were overlooked and those that were detected. RESULTS AND LIMITATIONS: Of men with cancer, 7% (17/230; 95% confidence interval [CI] 4.4-12%) had significant disease overlooked by mpMRI according to definition 1 (Gleason ≥ 4 + 3 of any length or MCCL ≥ 6 mm of any grade) and 13% (44/331; 95% CI 9.8-17%) according to definition 2 (Gleason ≥ 3 + 4 of any length or MCCL ≥ 4 mm). In comparison, TRUS-guided biopsy overlooked 52% (119/230; 95% CI 45-58%) of significant disease by definition 1 and 40% (132/331; 95% CI 35-45%) by definition 2. Prostate cancers undetected by mpMRI had significantly lower overall and maximum Gleason scores (p = 0.0007; p < 0.0001) and shorter MCCL (median difference: 3 mm [5 vs 8 mm], p < 0.0001; 95% CI 1-3) than cancers that were detected. No tumours with overall Gleason score > 3 + 4 (Gleason Grade Groups 3-5; 95% CI 0-6.4%) or maximum Gleason score > 4 + 3 (Gleason Grade Groups 4-5; 95% CI 0-8.0%) on TPM biopsy were undetected by mpMRI. Application of a PSAD threshold of 0.15 reduced the proportion of men with undetected cancer to 5% (12/230; 95% CI 2.7-8.9%) for definition 1 and 9% (30/331; 95% CI 6.2-13%) for definition 2. Application of a PSAD threshold of 0.10 reduced the proportion of men with undetected disease to 3% (6/230; 95% CI 1.0-5.6%) for definition 1 cancer and to 3% (11/331; 95% CI 1.7-5.9%) for definition 2 cancer. Limitations were post hoc analysis and uncertain significance of undetected lesions. CONCLUSIONS: Overall, a small proportion of cancers are overlooked by mpMRI, with estimates ranging from 4.4% (lower boundary of 95% CI for definition 1) to 17% (upper boundary of 95% CI for definition 2). Prostate cancers undetected by mpMRI are of lower grade and shorter length than cancers that are detected. PATIENT SUMMARY: Prostate cancers that are undetected by magnetic resonance imaging (MRI) are smaller and less aggressive than those that are detected, and none of the most aggressive cancers are overlooked by MRI.

Prostate cancer detection using quantitative T2 and T2 -weighted imaging: The effects of 5-alpha-reductase inhibitors in men on active surveillance.

BACKGROUND: T2 -weighted imaging (T2 -WI) information has been used in a qualitative manner in the assessment of prostate cancer. Quantitative derivatives (T2 relaxation time) can be generated from T2 -WI. These outputs may be useful in helping to discriminate clinically significant prostate cancer from background signal. PURPOSE/HYPOTHESIS: To investigate changes in quantitative T2 parameters in lesions and noncancerous tissue of men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo daily for 6 months. STUDY TYPE: Retrospective. POPULATION/SUBJECTS: Forty men randomized to 6 months of daily dutasteride (n = 20) or placebo (n = 20). FIELD STRENGTH/SEQUENCE: Multiparametric 3T MRI at baseline and 6 months. This included a multiecho MR sequence for quantification of the T2 relaxation times, in three regions of interest (index lesion, noncancerous peripheral [PZ] and transitional [TZ] zones). A synthetic signal contrast (T2 Q contrast) between lesion and noncancerous tissue was assessed using quantitative T2 values. Signal contrast was calculated using the T2 -weighted sequence (T2 W contrast). ASSESSMENT: Two radiologists reviewed the scans in consensus according to Prostate Imaging Reporting and Data System (PI-RADS v. 2) guidelines. STATISTICAL TESTS: Wilcoxon and Mann-Whitney U-tests, Spearman's correlation. RESULTS: When compared to noncancerous tissue, shorter T2 values were observed within lesions at baseline (83.5 and 80.5 msec) and 6 months (81.5 and 81.9 msec) in the placebo and dutasteride arm, respectively. No significant differences for T2 W contrast at baseline and after 6 months were observed, both in the placebo (0.40 [0.29-0.49] vs. 0.43 [0.25-0.49]; P = 0.881) and dutasteride arm (0.35 [0.24-0.47] vs. 0.37 [0.22-0.44]; P = 0.668). There was a significant, positive correlation between the T2 Q contrast and the T2 W contrast values (r = 0.786; P < 0.001). DATA CONCLUSION: The exposure to antiandrogen therapy did not significantly influence the T2 contrast or the T2 relaxation values in men on active surveillance for prostate cancer. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1646-1653.

MRI findings in men on active surveillance for prostate cancer: does dutasteride make MRI visible lesions less conspicuous? Results from a placebo-controlled, randomised clinical trial.

OBJECTIVES: To investigate changes in the Apparent Diffusion Coefficient (ADC) using diffusion-weighted imaging (DWI) in men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo. METHODS: We analysed 37 men, randomised to 6 months of daily dutasteride (n = 18) or placebo (n = 19), undergoing 3T multi-parametric Magnetic Resonance Imaging (mpMRI) scans at baseline and 6 months. Images were reviewed blind to treatment allocation and clinical information. Mean ADC of peripheral (PZ) and transition (TZ) zones, and MR-suspicious lesions were compared between groups over 6 months. Conspicuity was defined as the PZ divided by tumour ADC, and its change over 6 months was assessed. RESULTS: A decrease in mean conspicuity in the dutasteride group (but not the controls) was seen over 6 months (1.54 vs 1.38; p = 0.025). Absolute changes in ADC and conspicuity were significantly different between placebo and dutasteride groups at 6 months: (-0.03 vs 0.08, p = 0.033) and (0.11 vs -0.16, p = 0.012), as were percentage changes in the same parameters: (-2.27% vs 8.56% p = 0.048) and (9.25% vs -9.89% p = 0.013). CONCLUSIONS: Dutasteride was associated with increased tumour ADC and reduced conspicuity. A lower threshold for triggering biopsy might be considered in men on dutasteride undergoing mpMRI for prostate cancer. KEY POINTS: • Dutasteride increases ADC and reduces conspicuity in small mpMRI-visible prostate cancers. • Knowledge of dutasteride exposure is important in the interpretation of prostate mpMRI. • A lower threshold for triggering biopsy may be appropriate on dutasteride.

The Effect of Dutasteride on Magnetic Resonance Imaging Defined Prostate Cancer: MAPPED-A Randomized, Placebo Controlled, Double-Blind Clinical Trial.

PURPOSE: Dutasteride, which is licensed for symptomatic benign prostatic hyperplasia, has been associated with a lower progression rate of low risk prostate cancer. We evaluated the effect of dutasteride on prostate cancer volume as assessed by T2-weighted magnetic resonance imaging. MATERIALS AND METHODS: In this randomized, double-blind, placebo controlled trial, men with biopsy proven, low-intermediate risk prostate cancer (up to Gleason 3 + 4 and PSA up to 15 ng/ml) who had visible lesion of 0.2 ml or greater on T2-weighted magnetic resonance imaging sequences were randomized to daily dutasteride 0.5 mg or placebo for 6 months. Lesion volume was assessed at baseline, and 3 and 6 months with image guided biopsy to the lesion at study exit. The primary end point was the percent reduction in lesion volume over 6 months. This trial was registered with the European Clinical Trials register (EudraCT 2009-102405-18). RESULTS: A total of 42 men were recruited between June 2010 and January 2012. In the dutasteride group, the average volumes at baseline and 6 months were 0.55 and 0.38 ml, respectively and the average reduction was 36%. In the placebo group, the average volumes at baseline and 6 months were 0.65 and 0.76 ml, respectively, and the average reduction was -12%. The difference in percent reductions between the groups was 48% (95% CI 27.4-68.3, p <0.0001). The most common adverse event was deterioration in erectile function, which was 25% in men randomized to dutasteride and 16% in men randomized to placebo. CONCLUSIONS: Dutasteride was associated with a significant reduction in prostate cancer volume on T2-weighted magnetic resonance imaging compared to placebo.

The role of transperineal template prostate biopsies in restaging men with prostate cancer managed by active surveillance.

OBJECTIVE: To evaluate the role of transperineal template prostate biopsies in men on active surveillance. PATIENTS AND METHODS: In all, 101 men on active surveillance for prostate cancer underwent restaging transperineal template prostate biopsies at a single centre. Criteria for active surveillance were ≤75 years, Gleason ≤3+3, prostate-specific antigen (PSA) ≤15 ng/mL, clinical stage T1-2a and ≤50% ultrasound-guided transrectal biopsy cores positive for cancer with ≤10 mm of disease in a single core. The number of men with an increase in disease volume or Gleason grade on transperineal template biopsy and the number of men who later underwent radical treatment were assessed. The role of PSA and PSA kinetics were studied. RESULTS: In all, 34% of men had more significant prostate cancer on restaging transperineal template biopsies compared with their transrectal biopsies. Of these men, 44% had disease predominantly in the anterior part of the gland, an area often under-sampled by transrectal biopsies. In the group of men who had their restaging transperineal template biopsies within 6 months of commencing active surveillance 38% had more significant disease. There was no correlation with PSA velocity or PSA doubling time. In total, 33% of men stopped active surveillance and had radical treatment. CONCLUSIONS: Around one-third of men had more significant prostate cancer on transperineal template biopsies. This probably reflects under-sampling by initial transrectal biopsies rather than disease progression.

The index lesion and focal therapy: an analysis of the pathological characteristics of prostate cancer.

OBJECTIVE: To determine the pathological characteristics of radical prostatectomy specimens with respect to index and secondary lesions. METHODS: A total of 100 consecutive radical prostatectomy specimens examined at a single hospital were assessed. Patients undergoing salvage prostatectomy or those who had received neoadjuvant hormonal manipulation were excluded. Preoperative data and the number, volume and Gleason grade of each tumour focus were recorded. Criteria used to define a clinically significant lesion were tumour volume ≥0.5 mL and/or Gleason pattern 4 or 5 and/or extra-capsular disease. RESULTS: Overall, 374 foci were examined. The median number of tumours per patient was 3.5 (range 1-15). The overall median tumour volume was 1.4 mL (range 0.1-18.2), the median volume of the largest (index) tumour was 0.95 mL (range 0.1-18.2) and the median volume of the largest secondary tumour was 0.2 mL (range 0.05-1.7). There were no patients in whom the index lesion was insignificant and secondary tumours were significant (by grade or extra-capsular disease). Seventy-seven fulfilled the clinical parameters of low-to-intermediate-risk disease. If focal therapy can be delivered with the aim of ablating all clinically significant disease, with untreated areas harbouring no cancer or clinically insignificant disease, between 58.5 and 67.5% might have been suitable for such a strategy. CONCLUSIONS: The proportion of men with low-to-intermediate-risk prostate cancer who may potentially be suitable for a focal therapy approach is unknown. The key question is whether the volume of individual lesions points to clinically significant cancer and whether ablation of these lesions alone would lead to cancer control. This research question is currently undergoing evaluation within a prospective clinical trial.

Plexin-B1 mutations in prostate cancer.

Semaphorins are a large class of secreted or membrane-associated proteins that act as chemotactic cues for cell movement via their transmembrane receptors, plexins. We hypothesized that the function of the semaphorin signaling pathway in the control of cell migration could be harnessed by cancer cells during invasion and metastasis. We now report 13 somatic missense mutations in the cytoplasmic domain of the Plexin-B1 gene. Mutations were found in 89% (8 of 9) of prostate cancer bone metastases, in 41% (7 of 17) of lymph node metastases, and in 46% (41 of 89) of primary cancers. Forty percent of prostate cancers contained the same mutation. Overexpression of the Plexin-B1 protein was found in the majority of primary tumors. The mutations hinder Rac and R-Ras binding and R-RasGAP activity, resulting in an increase in cell motility, invasion, adhesion, and lamellipodia extension. These results identify a key role for Plexin-B1 and the semaphorin signaling pathway it mediates in prostate cancer.

Are prostatic biopsies necessary in men aged > or =80 years?

OBJECTIVE: To examine whether prostatic biopsies are necessary in all men aged > or =80 years, as men found to have prostate cancer are frequently treated with a 'watch and wait' policy or with hormonal withdrawal alone, and biopsies are associated with a small but significant complication rate. PATIENTS AND METHODS: The findings on a digital rectal examination (DRE), the prostate-specific antigen (PSA) level, the biopsy and staging bone scan results for all men aged > or = 80 years who had prostatic biopsies over a 3-year period were reviewed, together with those in a group of men aged <80 years for comparison. All biopsy samples had been examined in one of three histopathology units, and 33 consultant urological surgeons contributed. RESULTS: In all, 210 biopsies from 205 men aged > or = 80 years were identified, of whom 163 (79%) had biopsy-confirmed prostate cancer. All 29 men with a PSA level of > or = 100 ng/mL, 98% of 47 with > or = 50 ng/mL, 97% of 76 with > or = 30 ng/mL and 92% of 101 with > or = 20 ng/mL had biopsy cores containing cancer; 63% of men with a PSA level of <20 ng/mL had cancer on biopsy. In men with cancer and a PSA level of > or = 30 ng/mL, 92% had Gleason grade > or = 7 and 93% were treated with hormonal withdrawal alone. In all men with cancer the DRE was abnormal in 91%, the mean number of positive cores was 59% and the bone scan was positive in 18%. The DRE was abnormal in 77% of men with benign biopsies. CONCLUSIONS: In men aged > or = 80 years with a PSA level of > or = 30 ng/mL, at least 97% had prostate cancer, >90% of whom had high-grade disease, and nearly all with cancer received active pharmacological treatment. In the vast majority of these men prostate biopsies did not alter their cancer management. The value of prostatic biopsy in this age group, with a PSA level of > or = 30 ng/mL, is questionable.

Extensive transperineal template biopsies of prostate: modified technique and results.

OBJECTIVES: To describe the modified technique and results of extensive transperineal template prostate biopsies in men with a high risk of prostate cancer in whom repeated transrectal biopsies are not diagnostic. METHODS: Men who had a rising prostate-specific antigen (PSA) level and had at least two sets of benign octant biopsies or two or more prior biopsies containing high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation were included. A biplanar transrectal ultrasound probe was attached to a brachytherapy stepping unit and a standard 0.5-cm brachytherapy template was positioned over the perineum. In the transverse image, the prostate was divided into right and left and anterior, middle, and posterior regions, and three to five transperineal biopsy cores were taken in each of the six regions through the template. RESULTS: Sixty men underwent extensive transperineal template biopsies. Their mean age was 64 years (SD 6.4), the median PSA level was 12.9 ng/mL (range 4.6 to 35.7), and the median prostate volume was 54 cm3 (range 34 to 199). Cancer was detected in 23 men (38%), of whom 17 (74%) had Gleason grade 6, 5 (21%) Gleason grade 7, and 1 (4%) Gleason grade 9 disease. Cancer was identified in the anterior region of the prostate alone in 12 men (60%). One man required overnight admission for hematuria and two developed urinary retention; no cases of sepsis developed. CONCLUSIONS: In men with a clinical suspicion of prostate cancer, but benign or equivocal prostate biopsies, extensive transperineal template biopsy of the prostate is a useful diagnostic tool. It allows sampling of the whole prostate in a systematic and safe fashion.

Radical prostatectomy: pathology findings in 1001 cases compared with other major series and over time.

OBJECTIVE: To examine the preoperative features and pathological outcomes of clinical significance of 1001 consecutive essentially unscreened men who had a radical prostatectomy (RP) in the UK between 1988 and 2002, and their changes over time. PATIENTS AND METHODS: The details of men whose RP specimen was submitted for analysis were entered into the RP database held at the University College Hospital, London; the National Health Service and private patients of 17 surgeons were included. The age, mode of diagnosis, preoperative prostate specific antigen (PSA) level, biopsy and RP findings were compared over time. RESULTS: The mean (range) age of the men was 62 (40-76) years, the median PSA 8 (0.1-146) ng/mL and the median biopsy Gleason sum score 6; these preoperative features did not change over the study period. The diagnosis of prostate cancer was made by transurethral resection of the prostate alone in 48 men (5%). The maximum number of patients receiving neoadjuvant androgen ablation was 21 (33%) in 1996, and subsequently declined. The median (range) RP Gleason sum score was 7 (4-9). The biopsy Gleason score correlated with the prostatectomy Gleason score in 252 (47%) of 536 men, being lower in 170 (32%) and higher in 113 (21%). The median tumour volume was 2 mL (focus of invasive acini - 31 mL) and the incidence of positive intra- and extraprostatic margins was 52%. Both tumour volume and extraprostatic margin positivity declined with time. CONCLUSIONS: The preoperative features and pathological findings from this UK series are similar to those of other reported cohorts from unscreened populations. The incidence of positive extraprostatic surgical margins, tumour volume and stage decreased with time.

An update on the use of 5alpha-reductase inhibitors.

Twelve years ago, finasteride, the first 5alpha-reductase inhibitor, was introduced as drug therapy for benign prostatic hyperplasia, and more recently dutasteride has emerged as an alternative. The efficacy, safety and ability of these 5alpha-reductase inhibitors to reverse the natural progression of benign prostatic hyperplasia have been convincingly demonstrated and both drugs are now well established in the medical armamentarium against the disease. Given the multifactorial etiology of benign hyperplasia, the usefulness of 5alpha-reductase inhibitors in combination with alpha adrenergic blockers has also been investigated and justified in select patients. Wider applications of 5alpha-reductase inhibitors are also emerging, though their perhaps most important new role as chemopreventive agents remains unclear.

Benign prostatic hyperplasia: solutions to an ageing problem.

As the population ages, the demand for treatment of the symptoms of benign prostatic hyperplasia has never been higher. Equally the choice of treatments has never been greater. This review considers the medical and surgical options.