The Prevalence of Clinically Significant Prostate Cancer According to Commonly Used Histological Thresholds in Men Undergoing Template Prostate Mapping Biopsies.

PURPOSE: Transrectal prostate biopsies are inaccurate and, thus, the prevalence of clinically significant prostate cancer in men undergoing biopsy is unknown. We determined the ability of different histological thresholds to denote clinically significant cancer in men undergoing a more accurate biopsy, that of transperineal template prostate mapping. MATERIALS AND METHODS: In this multicenter, cross-sectional cohort of men who underwent template prostate mapping biopsies between May 2006 and January 2012, 4 different thresholds of significance combining tumor grade and burden were used to measure the consequent variation with respect to the prevalence of clinically significant disease. RESULTS: Of 1,203 men 17% (199) had no previous biopsy, 38% (455) had a prior negative transrectal ultrasound biopsy, 24% (289) were on active surveillance and 21% (260) were seeking risk stratification. Mean patient age was 63.5 years (SD 7.6) and median prostate specific antigen was 7.4 ng/ml (IQR 5.3-10.5). Overall 35% of the patients (424) had no cancer detected. The prevalence of clinically significant cancer varied between 14% and 83% according to the histological threshold used, in particular between 30% and 51% among men who had no previous biopsy, between 14% and 27% among men who had a prior negative biopsy, between 36% and 74% among men on active surveillance, and between 47% and 83% among men seeking risk stratification. CONCLUSIONS: According to template prostate mapping biopsy between 1 in 2 and 1 in 3 men have prostate cancer that is histologically defined as clinically significant. This suggests that the commonly used thresholds may be set too low.

MAPPED study design: a 6 month randomised controlled study to evaluate the effect of dutasteride on prostate cancer volume using magnetic resonance imaging.

OBJECTIVE: To evaluate the percentage change in volume of prostate cancer, as assessed by T2-weighted MRI, following exposure to dutasteride (Avodart) 0.5mg daily for six months. PATIENTS AND METHODS: MRI in Primary Prostate cancer after Exposure to Dutasteride (MAPPED) is a double-blind, placebo-controlled trial, supported by GlaxoSmithKline (GSK). Men with prostate cancer suitable for active surveillance (low-intermediate risk prostate cancer on biopsy), and a visible lesion on T2-weighted MRI of at least 0.2 cc, were eligible for consideration. Forty-two men were randomised to 6 months of daily dutasteride 0.5mg or placebo. Multi-parametric MRI (mpMRI) scans were performed at baseline, 3 and 6 months. The percentage changes in cancer volume over time will be compared between the dutasteride and placebo groups. Planned analyses will examine the association between tumour volume and characteristics (perfusion and contrast washout) as seen on mpMRI, HistoScan ultrasound and biopsy histopathology in both groups. DISCUSSION: MAPPED is the first randomised controlled trial to use mpMRI to look at the effect of dutasteride on the volume of prostate cancer. If dutasteride is shown to reduce the volume of prostate cancer, it might be considered as an adjunct for men on active surveillance. Analysis of the placebo arm will allow us to comment on the short-term natural variability of the MR appearance in men who are not receiving any treatment. CONCLUSION: MAPPED will evaluate the short-term effect of dutasteride on prostate cancer volume, as assessed by mpMRI, in men undergoing active surveillance for low or intermediate risk prostate cancer. The study completed recruitment in January 2012.

Allelic imbalance and biochemical outcome after radical prostatectomy.

OBJECTIVE: To compare the incidence of allelic imbalance (AI) in men with rapid disease progression with those who remained disease free after radical prostatectomy, with the aim of identifying genetic markers to predict prognosis and guide further treatment. PATIENTS AND METHODS: Tumour and normal DNA were extracted from two matched groups of 31 men with extracapsular node-negative (pT3N0) prostate cancer who had undergone radical prostatectomy. One group comprised men who developed biochemical recurrence within 2 years of surgery and one group were prostate-specific antigen (PSA) free for at least 3 years. Men were matched for Gleason grade, preoperative PSA and pathological stage. Analysis was performed by genotyping. RESULTS: Allelic imbalance was analysed using 30 markers, and was seen in at least one marker in 57 (92%) of the cases. Deletion at marker D10S211 (10p12.1) was significantly more common in the relapse group than the non-relapse group (35 vs 5%, P=0.03). CONCLUSIONS: This study demonstrates significant association between AI on chromosome 10 and biochemical progression after radical prostatectomy.

p21WAF1/CIP1 gene is inactivated in metastatic prostatic cancer cell lines by promoter methylation.

INTRODUCTION: p21WAF1/CIP1 may act as a tumour suppressor gene (TSG) and loss of the p21WAF1/CIP1 gene has been reported in several solid tumours. The aim of this study was to see whether p21WAF1/CIP1 was expressed in metastatic prostate cancer cell lines and to determine if there was methylation of the p21WAF1/CIP1 promoter. METHOD: PC3, LNCaP and DU145 metastatic prostate cancer cell lines, 1542NP normal prostate, and RD rhabdomyosarcoma cell lines were cultured in the demethylating agent 5-Aza-2 deoxycytidine (5-Aza-CdR). p21WAF1/CIP1 mRNA expression was analysed by RT-PCR. DNA from untreated cell lines was modified with sodium bisulphite and promoter sequencing was performed. RESULTS: p21WAF1/CIP1 was expressed at low or undetectable levels in metastatic prostate cancer cell lines but expression was reactivated by treatment with 5-Aza-CdR. Sequence analysis of the promoter region revealed several sites of methylation at the 5' end of a CpG island in the PC3, LNCaP and DU145 cell line DNA but not in the normal prostate control DNA. Most notably the Sis-inducible element (SEI)-1-a STAT1-binding site, was methylated. CONCLUSIONS: In this study, we show that p21WAF1/CIP1 expression in metastatic prostate cancer cell lines is enhanced as a result of demethylation of the DNA. Furthermore, several cytosine residues in the promoter region are methylated, including critical binding sites. The inhibition of the STAT1-signalling pathway by methylation of the promoter may inactivate the p21WAF1/CIP1 TSG in prostate cancer.

Subcutaneous leiomyosarcoma of the frenulum.

Leiomyosarcomas of the penis are rare, with only 29 reported cases to date. We record the case of a patient who presented with a 2-year history of a seemingly indolent penile skin lesion. On histopathology of the local resection, a diagnosis of subcutaneous leiomyosarcoma was made. Specifically, leiomyosarcoma of the penile frenulum has not been clearly reported previously. The patient underwent a further excision to ensure an adequate resection margin and has had no disease recurrence at subsequent follow-up. Our case was of a lesion that, although clinically benign, was malignant and this possibility should be borne in mind when assessing patients.

Molecular changes in prostatic cancer.

Prostate cancer is one of the most commonly diagnosed and potentially devastating cancers in men, throughout the world. However, the clinical manifestation of this disease varies greatly, from indolent tumours, requiring little or no treatment, to those aggressive cancers which require radical therapies. Prostate cancer, like all other cancers, develops and progresses as a consequence of an accumulation of genetic changes. While several putative genes have been isolated for the development of breast, ovarian and colon cancer, the aetiology and pathogenesis of prostate cancer remains poorly understood. In this review, we discuss important genetic markers in early, metastatic and hormone refractory prostate cancer which may, in the future, be used as markers for diagnosis and prognosis, as well as targets for therapeutic intervention.

Management of recurrent disease after radical prostatectomy.

Prostate cancer has undergone a stage migration since the advent of widespread PSA testing, yet still a significant number of men develop PSA recurrence following radical prostatectomy. This causes anxiety to the patient and the urologist. This review examines the clinical significance of biochemical relapse and the role of imaging modalities and anastomotic biopsies. The importance of the radical prostatectomy pathological features and the PSA kinetics in determining the site of recurrence and the best treatment modality is emphasised. The optimal timing and dose of salvage radiotherapy and the role of hormonal therapy is discussed.

Prostate cancer management: 2. An update on locally advanced and metastatic disease.

Just under half of men with prostate cancer present with locally advanced or metastatic disease. A multidisciplinary approach is required to improve survival, minimise complications, and provide adequate palliation. Radiotherapy remains the mainstay of treatment for pelvic disease control and encouraging results have been reported with androgen ablation as adjuvant therapy. In metastatic disease androgen ablation is usually first line, although ultimately most tumours become hormone refractory, requiring second or third line treatments. Localised or systemic radiotherapy may be used for palliation in metastatic disease. With the advent of more potent bisphosphonates the common bony complications associated with metastases may be reduced. This, the second review of prostate cancer, explores the various treatments available to the multidisciplinary team.

Prostate cancer management: (1) an update on localised disease.

Prostate cancer is receiving ever more publicity with the result that more men are having their prostate specific antigen checked and a greater proportion of men are diagnosed with potentially curable localised disease. Advances in the therapeutic modalities including radical surgery, external beam radiotherapy, and brachytherapy have reduced the incidence of side effects and now offer patients a choice of treatments depending on their tumour characteristics, age, and co-morbidity. A significant proportion of men do not need intervention and may be safely kept under a "watch and wait" policy. The use of genetic markers may in the future distinguish between patients most likely to benefit from radical therapy and those in who either palliation or observation is more appropriate. This review examines the potentially curative options, as well as expectant management, outlining the pros and cons of each. The use of adjuvant and neoadjuvant therapy is also discussed.

A large prostate at radical retropubic prostatectomy does not adversely affect cancer control, continence or potency rates.

OBJECTIVES: To determine the effect of a large prostate at radical retropubic prostatectomy (RRP) on the pathological outcome, biochemical recurrence rates, potency and continence. PATIENTS AND METHODS: From a database of 440 patients treated with RRP, retrospective information was obtained on prostate weights, patient and tumour characteristics, and follow-up. Potency and continence after RRP was obtained using a self-reported validated questionnaire. Patients with prostates of > 75 or < or = 75 g were compared. RESULTS: The median (range) prostate size was 87 (76-182) and 42 (4.1-75) g in the two groups. The response rate to the questionnaire was 78% (344 men). Patients with prostates of > 75 g were older, with a median (range) age of 65 (51-74) years, than the other group, at 61 (40-76) years (P = 0.01), and had higher initial prostate-specific antigen (PSA) levels, at 9.6 (3.4-37.8) and 7.6 (0.1-30.0) ng/mL, respectively (P = 0.001). Tumours within larger prostates were of a lower stage (P = 0.035), lower Gleason grade (median 6 and 7, P = 0.015), of smaller volume (median 1.0, 0.1-12.4; and 1.5, 0.1-21.1 mL; P = 0.04) and more often 'clinically insignificant' (23% and 6%, P = 0.001). There was no difference in the number or distribution of positive surgical margins. For a limited median follow-up of 20-25 months, patients with prostates of > 75 g were less likely to have biochemical recurrence (5% vs 24%, P < 0.001). Potency and continence rates were similar between the groups. CONCLUSIONS: Prostate size at RRP does not affect the risk of impotence or incontinence afterward. A prostate of > 75 g is associated with a lower likelihood of PSA-relapse, potentially as a result of lead-time bias. While an enlarged prostate may contraindicate other potentially curative cancer treatments, the outcomes of RRP appear to be unaffected.

Testicular torsion unravelled.

Testicular torsion is a true vascular emergency-prompt diagnosis and surgical management is critical. If treatment is not instigated within 4-6 hours of the onset of pain, irreversible testicular infarction may result, necessitating orchidectomy. This review presents the key features, management principles and medicolegal considerations of this serious condition.

Incidental findings in pelvic lymph nodes at radical prostatectomy.

AIMS: To assess the frequency and cause of incidental (non-metastatic) lymph node pathology discovered before or at radical prostatectomy. METHODS: Eight hundred and fifty four consecutive lymphadenectomies received between 1988 and 2001 were reviewed. All had been processed and stained routinely. Additional techniques, indicated by morphology, were then performed. RESULTS: Incidental pathology was found in 15 cases: florid sinus histiocytosis following prosthetic joint replacement (eight), non-caseating granulomas (three), small lymphocytic cell lymphoma (two), follicular lymphoma (one), and foreign body reaction (one). Incidental pathology was present in 1.8% of 854 patients who underwent pelvic lymphadenectomy during radical prostatectomy. CONCLUSION: Awareness of possible non-metastatic lymph node pathology aids histological diagnosis and may be clinically relevant.

Screening for prostatic cancer and its evolution within Britain.

The arguments for and against screening for prostatic cancer are frequently discussed (Albertsen PC. Screening for prostate cancer is neither appropriate nor cost-effective. Urol Clin North Am 1996; 23: 521-530; Schroder FH, Alexander FE, Bangma CH, Hugosson J, Smith DS. Screening and early detection of prostate cancer. Prostate 2000; 44: 255-263). In contrast, this paper outlines how screening became possible, why the decision was made not to initiate a national screening programme in Britain, the other pathways being pursued, and the current problems, in particular the issue of histopathology workload.

Anterior prostate cancer: is it more difficult to diagnose?

UNLABELLED: OBJECTIVE; To determine whether anterior prostatic tumours are adequately sampled using the Stamey sextant protocol, as a fifth of prostate cancers are anterior in distribution at radical prostatectomy. MATERIALS AND METHODS: All tumours (62) with an anterior distribution (>or=75% of the tumour anterior to the urethra) on radical prostatectomy whole-mounts, and in which the number and results of the sextant biopsies were available, were extracted from a prostate cancer database. Sixty-one posterior tumours (>or=75% of the malignant tissue posterior to the urethra) and their corresponding sextant biopsies were also retrieved for comparison. The number of biopsy sessions, the number of cores involved and the summated tumour length were recorded, together with the prostate gland weight, the tumour volume and the site of >or=75% of tumour in the superior-inferior axis. RESULTS: Anterior tumours required significantly more biopsy sessions to diagnose prostate cancer than posterior neoplasms (anterior, one set 47; > one set 15; posterior, one set 57; > one set, four, P=0.007). Anterior tumours had fewer cores with tumour involvement and less summated tumour length than had posterior cancers. The mean (sd) number of positive cores was; anterior 1.8 (1.01), posterior 2.50 (1.30) (P=0.001); the summated tumour length was; anterior 5.05 (4.10) mm, posterior 9.25 (7.80) mm (P<0.001). There was no significant difference in gland weight (mean anterior 43.8 g; posterior 48.3 g, P=0.3) or tumour volume (mean anterior 1.85 mL; posterior 1.49 mL, P=0.11) between the groups. There was no significant difference between the incidence of anterior and posterior neoplasms with respect to their position in the superior-inferior axis (P=0.96). CONCLUSIONS: Anterior prostate tumours account for 21% of all prostate cancers. They more often require multiple sets of sextant biopsies for diagnosis, and yield smaller areas of cancer on core biopsies than do posterior tumours in glands of similar weight and tumour volume. If prostate cancer is suspected clinically but biopsies are negative, targeting the anterior gland at subsequent prostatic biopsy should be considered.

Avoidance and management of positive surgical margins before, during and after radical prostatectomy.

Positive surgical margins after radical prostatectomy lead to an increased risk of progression and reduced disease free survival. Earlier detection of prostate cancer, appropriate patient selection and improved operative techniques can reduce the incidence of positive margins, though the risk can not be eliminated as pre-operative staging techniques are not sufficiently sensitive. Nerve sparing and bladder neck sparing do not adversely affect margin status in appropriately selected men. Once positive margins have been diagnosed the optimal management and the timing of treatment remains controversial. Adjuvant radiotherapy or salvage radiotherapy in men with a low PSA may improve local control and PSA free survival in some individuals, a survival benefit has not yet been established.