Molecular urology最新文献

Androgen deprivation induces substantial changes in the phenotype of prostate cancer that are accompanied by alterations in protein expression. Immunohistochemical studies allow precise cellular localization of such expression, thereby providing an understanding of the biochemical alterations caused by therapy. Expression of proteins may be increased (e.g., multiple growth factors, heat shock protein), decreased (e.g., microvessel density, proliferation markers, certain integrins), or remain unchanged (e.g., prostate specific antigen, prostatic acid phosphatase, prostate-specific membrane antigen, and other secretory proteins). Variations in immunoreactivity may be of prognostic value in some patients. This report summarizes the existing literature regarding changes in tissue expression of proteins, as determined by immunohistochemistry, and the clinical implications of these changes.

Pattern and cellular changes attributable to neoadjuvant hormonal therapy (NHT) might cause the unwary pathologist to overgrade or fail to recognize a treated prostatic cancer. Overdiagnosis and overgrading of surgical resections and biopsies can be avoided if an appropriate history of therapy is conveyed with the surgical specimen and if the pathologist is aware of the altered morphology of prostatic cancer treated by NHT alone or NHT plus radiation. Study of three prostatectomy specimens with post-NHT predominance of neuroendocrine cells showed positive staining for prostate specific antigen (PSA) and prostatic acid phosphatase (PAP), as well as staining for chromogranin and synaptophysin in Paneth-like and small neuroendocrine cells. Difficult-to-interpret needle biopsies and transurethral resection (TUR) biopsies of prostate, where the urologic pathologist's suspicion of a radiation effect was confirmed by additional history, showed absence of the basal cell layer with 34 beta E12 keratin immunostaining in prostatic cancer glands, while basal cells were present in the nonneoplastic glands with radiation-induced atypia. Postradiation salvage prostatectomy specimens showed greater apoptosis after combined NHT and radiation than after radiation without NHT. Changes attributable to radiation and radiation plus NHT are illustrated.

Neoadjuvant hormonal therapy (NHT) induces morphologic changes in prostate adenocarcinoma that result in the assignment of higher Gleason scores on average than in pretreatment biopsy specimens. This outcome has led to the recommendation that the Gleason scoring system not be applied to prostate adenocarcinoma specimens after NHT. We reviewed the radical prostatectomy specimens of 116 patients who had received NHT. Gleason scores were assigned on the post-treatment specimens by applying the usual criteria; in addition, an estimated pretreatment Gleason score was assigned on the basis of knowledge of the morphologic alterations associated with NHT. Finally, an estimate of the degree of therapy effect was assigned: little or no evidence of hormonal effect (grade 1) to marked therapy-related changes (grade 3). Both the post-treatment and the estimated pretreatment Gleason score correlated significantly with biochemical progression (P = 0.03 and P = 0.03, respectively; log-rank test). The degree of therapy effect did not correlate with progression (P = 0.46; log-rank test). This limited analysis suggests that despite the morphologic alterations induced by NHT, post-treatment Gleason score remains a significant prognostic measure. Further studies in more uniformly treated populations are required to confirm this observation.

The incidence of incontinence after radical prostatectomy has ranged from 0 to 57% depending on the series and the type of incontinence considered. When total incontinence (not minimal stress incontinence) is reported, the average incidence is no more than 5%. This figure will increase with age, and in most series, approximately 10% of patients around the age of 70 will have total incontinence postoperatively. Preservation of continence after radical prostatectomy depends largely on the preservation of the distal urethral smooth-muscle sphincteric mechanism, which begins at the pelvic floor and ends at the prostatourethral junction. Newer techniques that attempt to increase postoperative continence include not cutting the puboprostatic ligaments and attempting to preserve as much striated muscle as possible along the length of the remaining urethra. Patients who are incontinent for 6 months after the surgery with no evidence of improvement will probably not become continent on their own. Therefore, some type of therapy should be considered. The options are periurethral injection of a bulking agent, implantation of an artificial sphincter, and, most recently, a bulbourethral sling procedure.

Over the past decade, the sextant biopsy technique has emerged as the standard of care in the detection of prostate cancer. This technique is easy to learn and well tolerated by patients and has a major complication rate of <1%. However, limitations in cancer detection have been appreciated, particularly a false-negative rate approaching 25%. This high failure rate has led investigators to refine biopsy techniques to improve cancer detection. Intuitively, increasing the total number of cores should improve cancer detection. However, the optimal core number has yet to be defined. Confounding factors include variability of prostate size, tumor volume, and tumor location. Currently, a new standard is emerging prescribing a minimum of eight cores, of which at least three are directed at the lateral aspect of the peripheral zone. These additional biopsies appear to enhance cancer detection by about 15%. The improved yield is most pronounced among patients with a serum prostate specific antigen concentration between 4 and 10 ng/mL and larger gland volume (>50 cc). These additional biopsies may decrease the need for repeat biopsies. In the meantime, strategies are being developed for the optimal technique of repeat biopsies among patients with persistent clinical suspicion in the setting of a prior negative biopsy. Currently, recommendations include increasing the biopsy number to a minimum of 10 cores, including sampling of the lateral peripheral and transition zones.

The Canadian Urologic Oncology Group has carried out three studies of neoadjuvant hormonal therapy (NHT) in prostate cancer. The first, a study of 3 months of cyproterone acetate (CPA) 100 mg TID in patients undergoing external-beam radiation therapy, showed a benefit with respect to time to biochemical progression. There are no survival or clinical progression data available from this study. The second study involved 3 months of CPA prior to radical prostatectomy compared with radical prostatectomy alone and enrolled 200 patients. The probability of biochemical progression at 36 months was similar in the two groups (CPA 40%; surgery alone 30%; P = 0.3233). More recently, we have carried out a randomized trial of 3 v 8 months of leuprolide plus flutamide prior to radical prostatectomy in 547 patients. Patients were stratified by clinical stage, Gleason grade, and serum prostate specific antigen (PSA) concentration. In the 3- and 8-month groups, presurgery PSA concentrations were <0.1 ng/mL in 35% v 73%, and >0.3 ng/mL in 37% v 10%, respectively. In the 3- and 8-month groups, the positive margin rates were 17% and 5% and the organ-confined rates 71% and 91% (P < 0.01). One-year follow-up is now available on the entire cohort. Data regarding time to biochemical and clinical progression and overall and disease-specific survival will be required to determine whether this change in the pathologic findings translates into a patient benefit.