Molecular pathology of prostate cancer.

This chapter includes discussion of the molecular pathology of tissue, blood, urine, and expressed prostatic secretions. Because we are unable to reliably image the disease in vivo, a 12 core method that oversamples the peripheral zone is widely used. This generates large numbers of cores that need to be carefully processed and sampled. In spite of the large number of tissue cores, the amount of tumor available for study is often quite limited. This is a particular challenge for research, as new biomarker assays will need to preserve tissue architecture intact for histopathology. Methods of processing and reporting pathology are discussed. With the exception of ductal variants, recognized subtypes of prostate cancer are largely confined to research applications, and most prostate cancers are acinar. Biomarker discovery in urine and expressed prostatic secretions would be useful since these are readily obtained and are proximate fluids. The well-known challenges of biomarker discovery in blood and urine are referenced and discussed. Mediators of carcinogenesis can serve as biomarkers as exemplified by mutations in PTEN and TMPRSS2:ERG fusion. The use of proteomics in biomarker discovery with an emphasis on imaging mass spectroscopy of tissues is discussed. Small RNAs are of great interest, however, their usefulness as biomarkers in clinical decision making remains the subject of ongoing research. The chapter concludes with an overview of blood biomarkers such as circulating nucleic acids and tumor cells and bound/free isoforms of prostate specific antigen (PSA).

Relationship between obesity and race in predicting adverse pathologic variables in patients undergoing radical prostatectomy.

OBJECTIVES: To determine whether obesity is associated with more advanced prostate cancer (PCa) in radical prostatectomy patients and to explore the ethnic variability in body mass index (BMI) as a potential explanation for racial differences in PCa risk. METHODS: A multi-institutional retrospective analysis of the clinical and pathologic parameters was performed on data from 860 patients with PCa undergoing radical prostatectomy between 1992 and 1998. Patient height and weight was used to calculate the BMI, which categorized patients into obese (BMI 30 kg/m(2) or greater), overweight (BMI 25 to 30 kg/m(2)), and normal (BMI 25 kg/m(2) or less) groups. Age, serum prostate-specific antigen level, pathologic stage, and Gleason score for each group were compared. The distribution of the BMI in each of four ethnic groups was also determined. RESULTS: Of 860 patients, 171 (20%) were obese, 425 (49%) overweight, and 264 (31%) normal. The obese patients presented at a younger mean age (62 years, P = 0.001), had higher mean Gleason scores (6.7, P = 0.002), had a higher likelihood of Gleason score 7 or greater cancer (71%, P = 0.003), and had a lower chance of organ-confined cancer (46%, P = 0.050). The BMI was highest in blacks, followed by whites and Asians, and blacks had significantly higher grade cancers (P = 0.045). In multiple logistic regression analysis of the BMI and race, only BMI remained an independent predictor of Gleason grade. CONCLUSIONS: Obese patients with PCa present for radical prostatectomy at a younger age with higher grade and more pathologically advanced cancers. Blacks have higher grade cancers than other ethnic groups and, at the same time, have significantly higher BMIs. These findings suggest that obesity may in part account for the racial variability in PCa risk.

Radical cystectomy for invasive bladder cancer in the octogenarian.

The incidence of bladder cancer increases with age. As the population lives longer, an increasing number of patients 80 years of age or older will develop invasive bladder cancer. In this study, we reviewed the outcome of 33 patients age 80 years or older treated with radical cystectomy and ileal conduit urinary diversion. Five patients received neoadjuvant chemotherapy, and 2 had salvage cystectomy after failure of external beam radiation therapy. The median age was 82 years, and the median hospital stay was 12 days. There were no perioperative deaths. Twenty-seven complications occurred in 20 patients (60.6%), of which 17 were minor (63%) and 10 were major (37%). There was no difference in the rate of complications in patients receiving neoadjuvant treatment compared to the group treated with cystectomy alone. The median survival was 3.5 years. Our results demonstrate that radical cystectomy and ileal conduit urinary diversion should not be withheld from patients on the basis of age.

Cystectomy in the elderly.

Invasive bladder cancer is a disease of the elderly. With the elderly population rapidly growing and living longer than ever before, a larger number of patients 75 years of age or older will develop invasive bladder cancer. Currently available data indicate that well-selected elderly patients, even those 80 years old or older, do not have a significantly higher risk of morbidity or mortality from cystectomy than do younger patients. Cystectomy in patients of advanced age requires a multidisciplinary team approach and increased vigilance in the perioperative period but can be performed safely. Most elderly patients diagnosed with invasive bladder cancer, if left untreated by cystectomy, will die of the disease and not from competing age-related illness. Therefore, radical cystectomy should not be withheld from elderly patients on the basis of age alone.

A comparison of radical retropubic with perineal prostatectomy for localized prostate cancer within the Uniformed Services Urology Research Group.

OBJECTIVE: To review and compare the outcome of patients undergoing radical retropubic prostatectomy (RRP) or radical perineal prostatectomy (RPP) for clinically localized prostate cancer. PATIENTS AND METHODS: From 1988 to 1997, 1382 men who were treated by RRP and 316 by RPP were identified from databases of the Uniformed Services Urology Research Group. The following variables were assessed; age, race, prostate-specific antigen (PSA) level before surgery, clinical stage, biopsy Gleason sum, estimated blood loss (EBL), margin-positive rate, pathological stage, biochemical recurrence rate, short and long-term complication rates, impotence and incontinence rates. To eliminate selection bias, the analysis was concentrated on pairs of patients matched by race, preoperative PSA level, clinical stage and biopsy Gleason sum. RESULTS: In the 190 matched patients there were no significant differences between the RRP and RPP groups in either organ-confined (57% vs 55%), margin-positive (39% vs 43%), or biochemical recurrence rates (12.9% vs 17.6% at a mean follow-up of 47.1 vs 42.9 months), respectively. The mean EBL was 1575 mL in the RRP group and 802 mL in the RPP group (P < 0.001). The only significant difference in complication rates was a higher incidence of rectal injury in the RPP group (4.9%) than in the RRP group (none, P < 0.05). CONCLUSIONS: In similar populations of patients, RPP offers equivalent organ-confined, margin-positive and biochemical recurrence rates to RRP, while causing significantly less blood loss.

Outcomes of varicocele ligation done for pain.

PURPOSE: Surgical ligation is an option in the management of patients with painful varicocele. Little objective data exist addressing the effectiveness of this treatment. We reviewed records from 58 patients who underwent varicocele ligation at our institution from January 1985 to May 1996 to establish success of surgical ligation of the painful varicocele. MATERIALS AND METHODS: ICD-9 billing codes were used to identify all patients who had undergone varicocele ligation for pain since 1985. We documented patient age, grade and location of varicocele, duration and quality of pain, response to conservative therapy and surgical approach to ligation. Telephone interviews and chart reviews were conducted to determine resolution of pain, complications of the procedure and if the patient would choose surgery again. RESULTS: We obtained followup on 35 of the 58 painful varicocele patients (60%). Average patient age was 25.7 years (range 15 to 65). The varicocele was on the left side in 30 men and bilateral in 5. Of the patients 31 described the pain as a dull throbbing ache, 2 as sharp and 2 as a pulling sensation. Initial conservative therapy failed in all 35 men. Varicocele was grade III in 18 cases, grade II in 16 and grade I in 1. The inguinal or subinguinal approach was used in 24 patients, high ligation in 10 and laparoscopic repair in 1. In 30 patients there was (86%) complete resolution of pain postoperatively and 1 had partial resolution. Only 4 patients (11%) had persistent or worse symptoms. CONCLUSIONS: This retrospective review supports the conclusion that varicocele ligation is an effective treatment for painful varicocele in properly selected patients.

Telomerase activity in solid transitional cell carcinoma, bladder washings, and voided urine.

Telomerase activity has been detected in a wide variety of human malignancies. It appears to be one of the fundamental ingredients necessary for cellular immortality. We sought to determine the incidence of telomerase activity in solid transitional cell carcinoma (TCC) specimens, benign urothelium, bladder washings, and voided urine from patients with TCC identified cystoscopically compared with controls. Telomerase activity was measured in 26 solid bladder cancers and 13 benign urothelial specimens using the telomere repeat amplification protocol (TRAP), a polymerase chain reaction (PCR) based assay. Telomerase activity was further measured in the centrifuged cellular material obtained from the bladder washings of 26 patients with TCC and 40 with benign urologic disease found to have a normal cystoscopy. All patients with hematuria were additionally evaluated with an upper tract radiographic examination and found to be free of malignancy. Voided urine was likewise evaluated in 11 patients with TCC, 12 with benign urologic diseases, and 56 asymptomatic control subjects. Telomerase activity was detected in 25 of 26 (96%) solid specimens, 21 of 26 (81%) bladder washings, and 6 of 11 (54%) voided urine specimens from patients with histologically confirmed TCC. In the control group, 2 of 13 (15%) benign urothelial specimens and 2 of 56 (4%) voided urine specimens from the asymptomatic volunteer group demonstrated telomerase activity. Of those with benign urologic disease, 16 of 40 (40%) bladder barbotage specimens and 6 of 12 (50%) voided urine specimens demonstrated telomerase activity. Sensitivity and specificity of telomerase as a marker for TCC were 81% and 60%, respectively, in the bladder washings group and 54% and 50%, respectively, in voided urine. These data indicate that activation of telomerase is frequent in solid TCC and appears to be a sensitive marker in bladder washings of patients with TCC. We noted an unexpectedly high false positive detection rate in patients with benign urologic diseases, especially those with symptomatic benign prostatic hyperplasia. An additional study of a larger number of both bladder cancer patients and those at risk is necessary to determine if telomerase activity could play a role as a diagnostic and/or surveillance marker of TCC. Published by Elsevier Science Inc.

Infrequent RAS oncogene mutations in human prostate cancer.

The RAS gene family includes three functional genes, H-RAS, K-RAS, and N-RAS, which have been most widely studied in human tumors. Point mutations most commonly occurring at codons 12, 13, or 61 of these genes allow the RAS protooncogene to be converted to a RAS oncogene. A variety of human tumors have been studied for RAS mutations to date, however, conflicting data has been reported regarding prostate cancer. Cell line studies and two American studies of clinical material have found a low incidence of RAS mutation in prostate cancer. The few mutations found were predominantly in the H-RAS gene. Conversely, a recent study of Japanese occult autopsy specimens found an approximate 25% incidence of K-RAS mutations. In this current study, DNA was extracted from 24 archival paraffin-embedded, formalin-fixed radical prostatectomy specimens. Twenty-one of the 24 cases had pathologic stage C disease, and paraffin blocks were selected having the most concentrated area of neoplasm. Twelve, seven, and five cases demonstrated moderate, well and poorly differentiated histologic grade respectively. Polymerase chain reaction (PCR) was used to amplify the K-RAS, N-RAS, and H-RAS 12, 13, 61 codons of these specimens and mutations were detected with mutation-specific oligonucleotide probe hybridization of southern and slot blots. No definite point mutations were detected. PCR's and hybridizations were performed three separate times by three investigators to confirm these results. PCR-generated mutation-specific positive controls and known negative controls were used and found to be important to interpret oligonucleotide hybridization assays. RAS gene mutations appear to be infrequent in clinical prostate carcinomas in American males.