Manit Arya

Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy?

Prostate cancer is generally multifocal and consists of a dominant focus-measured by tumour volume and deemed the index lesion-and one or more separate, secondary tumour foci of smaller volume. Much laboratory and clinical evidence has shown that we need to rethink how we regard low-grade and low-volume prostate lesions. In this Personal View, we discuss why small, low-grade Gleason pattern prostate lesions, which are currently designated as prostate cancer, could be regarded as non-malignant. These lesions either do not meet the criteria of the hallmarks of cancer or robust evidence that they do so is absent, by contrast with large lesions with a high Gleason grade, which seem to cause most metastatic disease.

The accuracy of multiparametric MRI in men with negative biopsy and elevated PSA level--can it rule out clinically significant prostate cancer?

Purpose To assess the performance of multiparametric magnetic resonance imaging (mp-MRI) in patients with previous negative transrectal ultrasound (TRUS) guided prostate biopsy. Materials and methods Fifty-four patients with at least 1 previous negative TRUS prostate biopsy underwent mp-MRI in the form of T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging. This was followed by transperineal template systematic prostate biopsies. Analysis was done based on 2 sectors per prostate, right and left (108 sectors out of 54 prostates). mp-MRI was scored using an ordinal scale 1 to 5 based on the suspicion of the presence of clinically significant disease. We used 6 different definitions for clinically significant disease and tested the performance of mp-MRI at each single definition. Results Median age was 64 (range, 39–75), median PSA level was 10 (range, 2–23), and median number of biopsies was 45 (range, 21–137). Cancer of any volume and any grade was detected in 34 of 54 (63%) patients. mp-MRI accuracy at detection of clinically significant cancer using University College London (UCL) definition 2 (any Gleason score of 4 or maximum cancer core length of ≥4 mm or both) showed sensitivity of 76%, specificity of 42%, positive predictive value of 38%, and negative predictive value of 79%. For a different definition of significant tumor (UCL definition 1; dominant Gleason score 4 or maximum cancer core length ≥6 mm or both), the sensitivity was 90%, specificity 42%, positive predictive value 26%, and negative predictive value 95%. Conclusions mp-MRI showed good performance at both detection and ruling out clinically significant disease, according to the definition used. mp-MRI can then be used as a triage test in the population with persistently elevated or rising PSA levels to select patients that can avoid unnecessary prostate biopsy.

Prostate Cancer Tumour Features on Template Prostate-mapping Biopsies: Implications for Focal Therapy

Background Focal therapy is being offered as a viable alternative for men with localised prostate cancer (PCa), but it is unclear which men may be suitable. Objective To determine the proportion of men with localised PCa who are potentially suitable for focal therapy. Design, setting, and participants Our institutional transperineal template prostate-mapping (TTPM) biopsy registry of 377 men from 2006 to 2010 identified 291 consecutive men with no prior treatment. Intervention TTPM biopsies using a 5-mm sampling frame. Outcome measurements and statistical analysis Suitability for focal therapy required the cancer to be (1) unifocal, (2) unilateral, (3) bilateral/bifocal with at least one neurovascular bundle avoided, or (4) bilateral/multifocal with one dominant index lesion and secondary lesions with Gleason ≤3 + 3 and cancer core involvement ≤3 mm. Binary logistic regression modelling was used to determine variables predictive for focal therapy suitability. Results and limitations The median age was 61 yr, and the median prostate-specific antigen was 6.8 ng/ml. The median total was 29 cores, with a median of 8 positive cores. Of 239 of 291 men with cancer, 29% (70 men), 60% (144 men), and 8% (20 men) had low-, intermediate-, and high-risk PCa, respectively. Ninety-two percent (220 men) were suitable for one form of focal therapy: hemiablation (22%, 53 men), unifocal ablation (31%, 73 men), bilateral/bifocal ablation (14%, 33 men), and index lesion ablation (26%, 61 men). Binary logistic regression modelling incorporating transrectal biopsy parameters showed no statistically significant predictive variable. When incorporating TTPM parameters, only T stage was a significant negative predictor for suitability (p = 0.001) (odds ratio: 0.001 [95% confidence interval, 0.000–0.048]). Limitations of the study include potential selection bias caused by tertiary referral practise and lack of long-term results on focal therapy efficacy. Conclusions Focal therapy requires an accurate tool to localise individual cancer lesions. When such a test, TTPM biopsy, was applied to men with low- and intermediate-risk PCa, most of the men were suitable for a tissue preservation strategy.

Multiparametric MRI for detection of radiorecurrent prostate cancer: added value of apparent diffusion coefficient maps and dynamic contrast-enhanced images.

Background:Multiparametric magnetic resonance imaging (mp-MRI) is increasingly advocated for prostate cancer detection. There are limited reports of its use in the setting of radiorecurrent disease. Our aim was to assess mp-MRI for detection of radiorecurrent prostate cancer and examine the added value of its functional sequences.Methods:Thirty-seven men with mean age of 69.7 (interquartile range, 66–74) with biochemical failure after external beam radiotherapy underwent mp-MRI (T2-weighted, high b-value, multi-b-value apparent diffusion coefficient (ADC) and dynamic contrast-enhanced (DCE) imaging); then transperineal systematic template prostate mapping (TPM) biopsy. Using a locked sequential read paradigm (with the sequence order above), two experienced radiologists independently reported mp-MRI studies using score 1–5. Radiologist scores were matched with TPM histopathology at the hemigland level (n=74). Accuracy statistics were derived for each reader. Interobserver agreement was evaluated using kappa statistics.Results:Receiver–operator characteristic area under curve (AUC) for readers 1 and 2 increased from 0.67 (95% confidence interval (CI), 0.55–0.80) to 0.80 (95% CI, 0.69–0.91) and from 0.67 (95% CI, 0.55–0.80) to 0.84 (95% CI, 0.76–0.93), respectively, between T2-weighted imaging alone and full mp-MRI reads. Addition of ADC maps and DCE imaging to the examination did not significantly improve AUC for either reader (P=0.08 and 0.47 after adding ADC, P=0.90 and 0.27 after adding DCE imaging) compared with T2+high b-value review. Inter-reader agreement increased from k=0.39 to k=0.65 between T2 and full mp-MRI review.Conclusions:mp-MRI can detect radiorecurrent prostate cancer. The optimal examination included T2-weighted imaging and high b-value DWI; adding ADC maps and DCE imaging did not significantly improve the diagnostic accuracy.

Can multiparametric magnetic resonance imaging predict upgrading of transrectal ultrasound biopsy results at more definitive histology

OBJECTIVE To determine whether multiparametric magnetic resonance imaging (mp-MRI) has a role in reducing the uncertainty in risk stratification by transrectal ultrasound (TRUS) biopsy, using histology at transperineal template-guided prostate mapping (TPM) biopsy as the reference test. MATERIALS AND METHODS Overall, 194 patients underwent TRUS biopsy, who were followed up in less than 18 months by means of (a) mp-MRI with pelvic phased array using T2-weighted, diffusion-weighted and dynamic contrast-enhanced sequences and (b) TPM biopsy. Of those patients, low risk on TRUS biopsy was defined in 4 different ways--(a) definition 1: Gleason 3+3 (any cancer core length) (n = 137), (b) definition 2: maximum cancer core length (MCCL)<50% (any Gleason score) (n = 62), (c) definition 3: Gleason 3+3 and MCCL<50% (n = 52), and (d) definition 4: Gleason 3+3, MCCL<50%, prostate-specific antigen level<10 ng/ml, and<50% positive cores (n = 28). Mp-MRI was scored for the likelihood of cancer from 1 (cancer very unlikely) to 5 (cancer very likely). Binary logistic regression analysis was performed to evaluate the association between MRI scores and TPM histology. RESULTS Median prostate-specific antigen level was 7 ng/ml (range: 0.9-29), median time between TRUS biopsy and mp-MRI was 120 days (range: 41-480), and median time between mp-MRI and TPM biopsy was 60 days (range: 1-420). A median of 48 cores (range: 20-118) were taken at TPM biopsy. Gleason score was upgraded in 62 of 137 (45%) patients at TPM biopsy. The negative predictive values of mp-MRI score 1 to 2 for predicting that cancer remained low risk (according to each definition) were 75%, 100%, 83%, and 100% for definitions 1, 2, 3, and 4, respectively. An mp-MRI score of 4 to 5 had positive predictive values for upgrade or upsize of 59%, 67%, 75%, and 69% for definitions 1, 2, 3, and 4, respectively. CONCLUSION The presence of an mp-MRI lesion in men with low-risk prostate cancer on TRUS biopsy confers, in most patients, a high likelihood that higher-risk disease will be present (either Gleason pattern 4 or a significant cancer burden). Conversely, if a lesion is not seen on mp-MRI, the attribution of low-risk grade or cancer burden is much more likely to be correct. Mp-MRI might therefore be used to triage men for resampling biopsies before entering active surveillance.

Magnetic resonance imaging targeted transperineal prostate biopsy: a local anaesthetic approach

Background:Despite high rates of disease misclassification and sepsis, the use of transrectal biopsy remains commonplace. Transperineal mapping biopsies mitigate these problems but carry increased cost and patient burden. Local anaesthetic, multiparametric magnetic resonance imaging (MRI)-targeted transperineal biopsy may offer an alternative. Here, we aim to determine the feasibility, tolerability and detection rates of clinically significant prostate cancer using a local anaesthetic, transperineal, MRI-targeted biopsy technique.Methods:Tertiary referral centre in which 181 consecutive men underwent local anaesthetic, transperineal MRI-targeted prostate biopsy (September 2014 to January 2016). A standardized local anaesthetic technique was used to obtain targeted biopsies using visual estimation with the number of targeted cores determined by each of a number of users. We assessed adverse events, patient visual analogue pain scores and detection rates of clinically significant cancer (defined by University College London (UCL) definitions one and two and separately by the presence of dominant and non-dominant Gleason pattern 4). We secondarily assessed detection of any cancer, rates of detection by MRI (Likert) score and by presenting PSA. Differences were assessed using Chi-squared tests (P<0.05).Results:One hundred eighty-one men with 243 lesions were included. There were no episodes of sepsis or re-admissions and one procedure was abandoned owing to patient discomfort. Twenty-three out of 25 (92%) men would recommend the procedure to another. Median visual analogue pain score was 1.0 (interquartile range: 0.0–2.4). A total 104/181 (57%) had UCL definition 1 disease (Gleason ⩾4+3 and/or maximum cancer length ⩾6 mm) and 129/181 (71%) had UCL definition 2 cancer (Gleason ⩾3+4 and/or maximum cancer length ⩾4 mm). Fifty-four out of 181 (30%) and 124/181 (69%) had dominant and non-dominant pattern 4 disease or greater (irrespective of cancer length). Any cancer was detected in 142/181 (78%). Significant disease was more likely in higher MRI-scoring lesions and in men with PSAs ⩾10 ng ml−1.Conclusions:This approach to prostate biopsy is feasible, tolerable and can be performed in ambulatory settings.

Targets of Wnt/ß-catenin transcription in penile carcinoma.

Penile squamous cell carcinoma (PeCa) is a rare malignancy and little is known regarding the molecular mechanisms involved in carcinogenesis of PeCa. The Wnt signaling pathway, with the transcription activator ß-catenin as a major transducer, is a key cellular pathway during development and in disease, particularly cancer. We have used PeCa tissue arrays and multi-fluorophore labelled, quantitative, immunohistochemistry to interrogate the expression of WNT4, a Wnt ligand, and three targets of Wnt-ß-catenin transcription activation, namely, MMP7, cyclinD1 (CD1) and c-MYC in 141 penile tissue cores from 101 unique samples. The expression of all Wnt signaling proteins tested was increased by 1.6 to 3 fold in PeCa samples compared to control tissue (normal or cancer adjacent) samples (p<0.01). Expression of all proteins, except CD1, showed a significant decrease in grade II compared to grade I tumors. High magnification, deconvolved confocal images were used to measure differences in co-localization between the four proteins. Significant (p<0.04-0.0001) differences were observed for various permutations of the combinations of proteins and state of the tissue (control, tumor grades I and II). Wnt signaling may play an important role in PeCa and proteins of the Wnt signaling network could be useful targets for diagnosis and prognostic stratification of disease.

Novel Therapies for Localized Prostate Cancer

© 2014 by John Wiley & Sons, Ltd. All rights reserved. The use of minimally invasive energy sources in organ-confined prostate cancer offers potential for a middle ground between expectant management and conventional invasive treatments. The recent increased interest and employment of organ-preserving approaches, namely, focal therapy, may represent the ideal option for most patients affected by localized prostate cancer aiming to minimize harms while not compromising life expectancy. This chapter reviews the evidence to date for cryotherapy, high-intensity focused ultrasound, photodynamic therapy, irreversible electroporation, and photothermal therapy.