Faculty Bibliography

OBJECTIVE: To examine further the relationship between diabetes mellitus (DM), genotype and prostate cancer aggressiveness. Specifically, we sought to evaluate for effect modification between DM, a newly discovered prostate cancer susceptibility locus on chromosome 17q12 (single nucleotide polymorphism rs4430796) and prostate cancer features. PATIENTS AND METHODS: In 593 genotyped men treated with radical prostatectomy (RP), we examined RP features stratified by DM and rs4430796 carrier status. RESULTS: Despite a significantly higher body mass index among patients with DM, individual pathological features were similar between men with and without DM. Using a dominant model, 17q12 carriers were less likely to have DM and more likely to have a RP Gleason score of >or=7. However, the presence or absence of DM did not modify the relationship between 17q12 susceptibility alleles and pathological features. CONCLUSION: Among 17q12 risk allele carriers, there was no significant relationship between DM and adverse tumour features. However, there were relatively few men with DM (7%) in our RP cohort, particularly compared with its 21% prevalence in the USA population aged >60 years. It is unclear whether this reflects selection bias, genetic protection from prostate cancer among patients with DM, or both. Despite these limitations, the present data suggest that DM alone does not appear to modify any association between 17q12 risk alleles with prostate cancer features.

PURPOSE: According to a 1944 publication by Swyer benign prostatic hyperplasia develops in some men after age 45 with further prostatic growth whereas in other men prostate size remains stable or decreases with advancing age. Although there is an abundance of literature describing prostatic enlargement in association with benign prostatic hyperplasia, less is known about the phenomenon of prostate atrophy. MATERIALS AND METHODS: In the Baltimore Longitudinal Study of Aging serial pelvic magnetic resonance imaging was performed in men without prostate cancer beginning in 1993. From this population we retrospectively identified 278 men with 2 or more magnetic resonance imaging determined prostate volume measurements to examine differential growth rates in a cohort of community men over time. RESULTS: Median age was 58 years and median prostate size was 28 cc at study entry. At a median followup of 4.3 years prostate size increased in 61.9% and remained stable or decreased in 38.1% of men. The median rate of volume change was 0.6 cc per year (range -9.9 to 62.1), corresponding to a median growth rate of 2.5% per year (range -29.2 to 176.4%). During followup 64.6% of men with an initial prostate size less than 40 cc had prostate growth compared to only 50.9% of men with an initial prostate size of 40 cc or greater. CONCLUSIONS: These results suggest that changes in prostate size are highly variable among aging men. Although benign prostatic hyperplasia is common, a considerable proportion of aging men have a stable or decreasing prostate size. Further research is needed to identify the underlying mechanism for such differences in prostate growth.

PURPOSE: We investigated the relationship between the tertiary Gleason component in radical prostatectomy specimens and biochemical recurrence in what is to our knowledge the largest single institution cohort to date. MATERIALS AND METHODS: We evaluated data on 3,230 men who underwent radical prostatectomy at our institution from 2000 to 2005. Tertiary Gleason component was defined as Gleason grade pattern 4 or greater for Gleason score 6 and Gleason grade pattern 5 for Gleason score 7 or 8. RESULTS: Biochemical recurrence curves for cancer with tertiary Gleason component were intermediate between those of cancer without a tertiary Gleason component in the same Gleason score category and cancer in the next higher Gleason score category. The only exception was that Gleason score 4 + 3 = 7 with a tertiary Gleason component behaved like Gleason score 8. The tertiary Gleason component independently predicted recurrence when factoring in radical prostatectomy Gleason score, radical prostatectomy stage and prostate specific antigen (HR 1.45, p = 0.029). Furthermore, the magnitude of the tertiary Gleason component effect on recurrence did not differ by Gleason score category (p = 0.593). CONCLUSIONS: Although the tertiary Gleason component is frequently included in pathology reports, it is routinely omitted in other situations, such as predictive nomograms, research studies and patient counseling. The current study adds to a growing body of evidence highlighting the importance of the tertiary Gleason component in radical prostatectomy specimens. Accordingly consideration should be given to a modified radical prostatectomy Gleason scoring system that incorporates tertiary Gleason component in intuitive fashion, including Gleason score 6, 6.5 (Gleason score 6 with tertiary Gleason component), 7 (Gleason score 3 + 4 = 7), 7.25 (Gleason score 3 + 4 = 7 with tertiary Gleason component), 7.5 (Gleason score 4 + 3), 8 (Gleason score 4 + 3 with tertiary Gleason component or Gleason score 8), 8.5 (Gleason score 8 with tertiary Gleason component), 9 (Gleason score 4 + 5 or 5 + 4) and 10.

Approximately one in six men in the United States will develop prostate cancer during their lifetime. Genetic and environmental variables play a role in determining prostate cancer risk. This article highlights the latest evidence regarding the risk factors for prostate cancer. The current screening strategies using prostate-specific antigen and digital rectal examination are also discussed, as well as the limitations of these protocols and potential methods for improving early detection.

OBJECTIVE: To compare the outcomes between patients with stage T1a/b with those of patients with T1c cancer of the prostate treated with radical retropubic prostatectomy (RRP), as the appropriate management of clinical stage T1a/b prostate cancer is subject to debate; although many patients are managed expectantly, some have adverse pathological features suggesting that more active treatment might be beneficial. PATIENTS AND METHODS: From 1983 to 2003, 3478 men had RRP by one surgeon. From this group, we retrospectively identified 29 men with clinical stage T1a and 83 with clinical stage T1b disease. Using statistical analysis we compared the treatment outcomes of these patients with those of 1774 men with clinical stage T1c disease. RESULTS: Men with T1a/b disease had a significantly lower preoperative prostate-specific antigen (PSA) level, a greater proportion with organ-confined disease, and a lower mean/median prostatectomy Gleason score than those with T1c disease. Also, men with T1a/b disease were less likely to be potent before surgery, although the frequency of recovery of potency was similar among all groups. On multivariate analysis with age, year of surgery, PSA level and Gleason score, there was no statistical difference in the rates of biochemical recurrence and the 10-year overall survival rates. However, patients with T1b disease had a significantly lower cancer-specific survival. CONCLUSIONS: T1a and T1b prostate cancer can be associated with aggressive pathological features and have a similar rate of progression as clinical stage T1c disease. That notwithstanding, most patients in the study were cured with RRP and had favourable long-term functional outcomes.

PURPOSE: Prostate specific antigen is used for prostate cancer screening but its specificity is limited. Specificity might be increased by considering genotype associated prostate specific antigen levels. MATERIALS AND METHODS: We examined associations between single nucleotide polymorphisms on chromosomes 10 and 19 (previously shown to be associated with prostate specific antigen) with prostate specific antigen and prostate cancer in 505 men from the Baltimore Longitudinal Study of Aging. RESULTS: In a model with age and date the risk ratio for prostate cancer was 1.18 (95% CI 1.13-1.23) per unit increase in prostate specific antigen. Including the interaction between alleles and prostate specific antigen significantly altered the risk ratio for prostate cancer (Cox proportional hazards p <0.001). Specifically prostate cancer risk per unit increase in prostate specific antigen was significantly different in carriers than in noncarriers of a minor allele (1.28 vs 1.10, respectively, Cox proportional hazards p <0.001), whereas men with a minor allele had a significantly higher risk of prostate cancer at prostate specific antigen levels greater than 6 ng/ml. CONCLUSIONS: Our data suggest that genotype influences the risk of prostate cancer per unit increase in prostate specific antigen. Prostate cancer risk stratification using prostate specific antigen and genotype could improve prostate specific antigen test performance.

PURPOSE: Recent studies have identified 2 distinct genetic variants along chromosome 17, including allele T of single nucleotide polymorphism rs4430796 on 17q12 and allele G of single nucleotide polymorphism rs1859962 on 17q24, that have been linked to prostate cancer risk. Less is known about tumor pathological features in carriers of these variants. MATERIALS AND METHODS: Genotypes for regions 17q12 and 17q24 were determined in 759 white men with prostate cancer and compared to those in 790 healthy control volunteers using logistic regression. In patients with prostate cancer the Fisher exact or Kruskal-Wallis test was used as appropriate to assess the relationship(s) between clinical and pathological characteristics with 17q carrier status. RESULTS: The frequency of the 17q12 and 17q24 genetic variants was significantly higher in patients with prostate cancer compared to that in controls (OR 1.32, 1.15, respectively). Of patients with prostate cancer 83% and 77% were carriers of the 17q12 and 17q24 variants as well as 75% and 75% of controls, respectively. Carriers of 17q12 risk variants were significantly more likely to have high grade disease using an additive best fit genetic model. In addition, there were trends toward adverse pathological features associated with 17q12 independent of the best fit genetic model. CONCLUSIONS: Sequence variants along 17q12 and 17q24 were present in a significantly higher proportion of our prostate cancer cases than in our controls. Adverse pathological features, including higher Gleason grade and pathological stage, were more frequent in 17q12 carriers. Since these alleles may act in conjunction with variants on other chromosomes to influence prostate cancer risk, additional research is required to determine the cumulative associations of genetic risk variants with prognosis.

PURPOSE: The Prostate Cancer Prevention Trial reported that 15% of men with a prostate specific antigen less than 4 ng/ml and a normal digital rectal examination have biopsy detectable prostate cancer. However, limited published data describe the tumor features of prostate cancer detected at low prostate specific antigen levels (less than 2.5 ng/ml). MATERIALS AND METHODS: A total of 1,278 men underwent radical retropubic prostatectomy by 1 surgeon between 2003 and 2008. We describe the clinicopathological features of 77 patients with a preoperative prostate specific antigen of less than 2.5 ng/ml. RESULTS: Of the men with a low prostate specific antigen (less than 2.5 ng/ml) tumor 51 (66%) had findings suspicious for prostate cancer on digital rectal examination. Indications for prostate biopsy in the remainder of men included an increased prostate specific antigen velocity, hematospermia and abnormal transrectal ultrasound findings. Prostate cancer was detected at transurethral resection of the prostate in the remaining 8% of men. Despite having a low prostate specific antigen at diagnosis 8 (10.4%) and 20 (26%) men, respectively, had biopsy and radical retropubic prostatectomy Gleason grade 7 disease or greater, while 7 (9%) and 6 (7.8%), respectively, had extracapsular tumor extension or positive surgical margins. Compared to men with a normal digital rectal examination mean tumor volume was significantly higher in those with a suspicious digital rectal examination (3.3 vs 1.7 cc, p = 0.018). CONCLUSIONS: Despite having a prostate specific antigen of less than 2.5 ng/ml at diagnosis, a considerable proportion of men had aggressive pathological features at radical retropubic prostatectomy. Digital rectal examination remains an important component of early prostate cancer detection.