David G. Bostwick

The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder

In October 1997, Dr. F.K. Mostofi assembled a group of individuals interested in bladder neoplasia at a meeting in Washington DC. The participants included urologic pathologists, urologists, urologic oncologists, and basic scientists with an interest in bladder neoplasia. The purpose of this meeting was to discuss bladder terminology and make recommendations to the World Health Organization (WHO) Committee on urothelial tumors. Following this meeting, a group of the urologic pathologists who attended the Washington meeting decided to broaden the representation of the group and arranged a meeting primarily of the members of the International Society of Urologic Pathologists (ISUP) at the 1998 United States and Canadian Academy of Pathology Meeting held in Boston. Massachusetts. At this meeting. issues regarding terminology of bladder lesions, primarily neoplastic and putative preneoplastic lesions, were discussed, resulting in a consensus statement. The WHO/ ISUP consensus classification arises from this consensus conference committees recommendations to the WHO planning committee and their agreement with virtually all of the proposals presented herein. 29 The effort involved in reaching such a consensus was often considerable. Many of those involved in this process have compromised to arrive at a consensus. The aim was to develop a universally acceptable classification system for bladder neoplasia that could be used effectively by pathologists, urologists, and oncologists.

Effect of dutasteride on the risk of prostate cancer

BACKGROUND We conducted a study to determine whether dutasteride reduces the risk of incident prostate cancer, as detected on biopsy, among men who are at increased risk for the disease. METHODS In this 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, we compared dutasteride, at a dose of 0.5 mg daily, with placebo. Men were eligible for inclusion in the study if they were 50 to 75 years of age, had a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng per milliliter, and had had one negative prostate biopsy (6 to 12 cores) within 6 months before enrollment. Subjects underwent a 10-core transrectal ultrasound-guided biopsy at 2 and 4 years. RESULTS Among 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P<0.001). Overall, in years 1 through 4, among the 6706 men who underwent a needle biopsy, there were 220 tumors with a Gleason score of 7 to 10 among 3299 men in the dutasteride group and 233 among 3407 men in the placebo group (P=0.81). During years 3 and 4, there were 12 tumors with a Gleason score of 8 to 10 in the dutasteride group, as compared with only 1 in the placebo group (P=0.003). Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in our study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P=0.03). CONCLUSIONS Over the course of the 4-year study period, dutasteride reduced the risk of incident prostate cancer detected on biopsy and improved the outcomes related to benign prostatic hyperplasia. (ClinicalTrials.gov number, NCT00056407.)

Intraductal dysplasia: A premalignant lesion of the prostate

Foci of cytologic atypia with some of the histologic features of malignancy were identified in ductal and acinar lining epithelia from 100 serially blocked prostates with adenocarcinoma and 100 benign prostates obtained at autopsy. Criteria for diagnosis and grading of severity were established for this lesion, which is referred to as intraductal dysplasia. The histologic features, extent, and severity of intraductal dysplasia were compared between the two groups. Eighty-two prostates with carcinoma and 43 benign prostates contained foci of dysplasia. The severity (grade) and extent of dysplasia were greater in the prostates with carcinoma. Grade 3 dysplasia was found in 33 per cent of the prostates with cancer but in only 4 per cent of the benign prostates. The frequency of multiple, independent invasive carcinomas was high among prostates with multiple foci of dyplasia. It was concluded that dysplasia is probably a direct biologic precursor of prostatic carcinoma and may be the antecedent lesion in the majority of prostatic cancers.

PATTERNS OF PROGRESSION IN PROSTATE CANCER

Tumour volume was related to metastasis, seminal vesicle invasion, capsule invasion, and histological differentiation in a series of 100 unselected prostates with carcinoma removed at necropsy and 38 removed at radical prostatectomy. All these variables were highly inter-related. In both series, metastases were associated only with tumours larger than 4 ml, a volume attained by only 13% of the necropsy tumours. Loss of differentiation was strongly correlated with tumour volume, and only tumours of Gleason grade 4 or 5 had metastasised. It was concluded that the natural history of prostate cancer is highly predictable. The capacity to metastasise probably develops only in tumours which have grown much larger than 1 ml and acquired poorly differentiated areas as a manifestation of the phenomenon of tumour progression. The unusually low proportion of metastatic prostate cancer is readily explained by the large proportion of small-volume tumours in this organ.

Over-expression of cyclooxygenase-2 in human prostate adenocarcinoma.

Aberrant or increased expression of cyclooxygenase (COX)‐2 has been implicated in the pathogenesis of many diseases including carcinogenesis. COX‐2 has been shown to be over‐expressed in some human cancers.

Prostatic Intra-Epithelial Neoplasia and Early Invasion in Prostate Cancer

Prostatic intra‐epithelial neoplasia (PIN, or intraductal dysplasia) is considered a precursor of invasive carcinoma, characterized by proliferation and anaplasia of cells lining prostatic ducts and acini. The highest grade of PIN, Grade 3, is thought to represent carcinoma in situ. To quantitate the degree of disruption of the basal cell layer in human prostatic ducts and acini as a potential marker of early invasion in PIN, a monoclonal antibody to keratin proteins of 49, 51, 57, and 66 kd which selectively labels the prostatic basal cell layer was used. A total of 1093 acini with PIN were identified in 14 cases with invasive carcinoma. Tumor cells consistently failed to be decorated with this antibody. The frequency of disruption of the basal cell layer increased with increasing grades of PIN, with disruption present in 0.7% of cases of PIN 1, 15% of cases of PIN 2, and 56% of cases of PIN 3. The amount of disruption of the basal cell layer also increased with increasing grades of PIN, with loss of more than one third of the basal layer in 52% of foci of PIN 3 compared with less than 2% in lower grades of PIN. Disruption of the basal layer was more common in acini adjacent to invasive carcinoma than in distant acini. These findings suggest that early invasion in prostate cancer is characterized by disruption of the basal layer, and that invasion occurs commonly in association with foci of high‐grade prostatic intra‐epithelial neoplasia. Cancer 59:788‐794, 1987.

Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases

OBJECTIVES Prostate-specific membrane antigen (PSMA) is an integral membrane protein highly specific for the prostate. PSMA may be clinically useful for predicting outcome in patients with prostate cancer. We compared the expression of PSMA in prostate adenocarcinoma and lymph node metastases in a large series of patients with node-positive cancer. METHODS We studied 232 patients with node-positive adenocarcinoma who underwent bilateral pelvic lymphadenectomy and radical retropubic prostatectomy at the Mayo Clinic between 1987 and 1992. Immunohistochemistry was performed using monoclonal antibody 7E11-5.3 directed against PSMA. For each case, the percentage of immunoreactive cells in benign prostate tissue, adenocarcinoma, and lymph node metastases was estimated in 10% increments. Intensity was recorded using a scale of 0 to 3 (0 = no staining, 3 = highest). RESULTS Cytoplasmic immunoreactivity for PSMA was observed in all cases in benign epithelium and cancer, and most lymph node metastases. The number of cells stained was lowest in benign epithelium; cancer and lymph node metastases were similar (46.2% +/- 27.5% versus 79.3% +/- 18.5% versus 76.4% +/- 26.1%, respectively; all pairs P < 0.05). Intensity of staining was greatest in primary cancer and lowest in lymph node metastases. CONCLUSIONS PSMA is expressed in benign prostatic epithelium and primary cancer in all cases and in 98% of cases with lymph node metastases. Expression of PSMA was greatest in primary cancer for both percentage and intensity of immunoreactive cells. PSMA expression allows the identification of benign and malignant prostatic epithelium and may be a potentially valuable marker in the treatment of patients with prostate cancer.

High-grade prostatic intraepithelial neoplasia

High-grade prostatic intraepithelial neoplasia (PIN) is now accepted as the most likely preinvasive stage of adenocarcinoma, almost two decades after its first formal description. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma. The only method of detection is biopsy; PIN does not significantly elevate serum prostate-specific antigen (PSA) concentration or its derivatives and cannot be detected by current imaging techniques, including ultrasound. Most patients with PIN will develop carcinoma within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype, which are similar to cancer rather than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.

Gleason grading of prostatic needle biopsies. Correlation with grade in 316 matched prostatectomies.

The automated spring-loaded 18-gauge gun recently introduced for prostatic needle biopsy provides less than half the tissue of the traditional 14-gauge biopsy, possibly influencing the accuracy and predictive ability of biopsy tumor grade. In order to determine the value of tumor grade in contemporary needle biopsy specimens, we compared grade in 316 biopsies with matched whole-mounted radical retropubic prostatectomy specimens according to Gleason primary pattern, Gleason secondary pattern, Gleason score, percent of Gleason patterns 4 and 5, and nuclear grade. Biopsy grading accuracy was correlated with rates of capsular perforation, seminal vesicle invasion, pelvic lymph node metastasis, serum prostate specific antigen level, prostatic volume, prostatic weight, cancer volume, perineural invasion, DNA ploidy, and pathologic stage. The greatest grading error was encountered with low-grade tumors; there was no correlation of grading error with clinical staging error or other pathologic factors. Significant differences were noted between biopsy and prostatectomy for Gleason primary pattern, secondary pattern, and score. The percent of poorly differentiated carcinoma (Gleason patterns 4 and 5) in biopsies and prostatectomies showed a moderate positive correlation. The results indicate that the accuracy of 18-gauge needle biopsy in predicting tumor grade in the prostatectomy is similar to that reported with 14-gauge biopsies. Based on these findings, we recommend that the Gleason score (sum of primary and secondary patterns) be employed in all needle biopsies, recognizing that the accuracy of grade is decreased in cases with low-grade cancer and small amounts of cancer.

Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on outcome after radical prostatectomy

OBJECTIVES The impact of a positive surgical margin in otherwise confined prostate cancer after radical prostatectomy remains unclear. We analyzed the outcome of a large number of patients with organ-confined prostate cancer according to the presence and anatomic site of margin positivity. METHODS We evaluated 2712 prostatectomy patients with Stage pT2N0 cancer (ie, no evidence of extra-prostatic disease, seminal vesicle or regional node involvement) and no prior therapy who were treated by radical prostatectomy between 1987 and 1995 at Mayo Clinic. A total of 697 patients (26%) had positive margins. To assess the effect of margin status in the absence of treatment, 378 patients with postoperative adjuvant therapy were not considered for the study group: the final group consisted of 2334 patients. RESULTS Overall, 253 (58%) tumors were positive at the apex and/or urethra, 85 (19%) at the prostate base, 11 (2.5%) at the anterior prostate, and 174 (40%) at the posterior prostate; 89 (20%) had at least two margins involved and 21 (8.3%) had more than two involved. The apex/urethra was the only positive anatomic site in 183 (42%). Five-year survival free of clinical recurrence or prostate-specific antigen (PSA) biochemical failure (postoperative serum PSA of 0.2 ng/mL or more) for patients with a single positive margin was 79% for apex or urethra, 78% for anterior/posterior, and 56% for prostate base. Five-year survival free of clinical recurrence or PSA (biochemical) failure was slightly higher for those with one versus two margin-positive regions (77% versus 68%, respectively). Multivariate analysis revealed that positive surgical margins were a significant predictor of clinical recurrence and PSA (biochemical) failure (relative risk [95% confidence interval]: 1.65 [1.24, 2.18]) after controlling for Gleason grade, preoperative PSA, and deoxyribonucleic acid (DNA) ploidy. The effect of margin positivity on recurrence at a specific anatomic site (versus negative margins or positive at a different anatomic site) revealed the prostate base to be the only significant anatomic site when adjusted for grade, PSA, and ploidy. Five-year survival free of the combined clinical or PSA failure end point for those with versus those without positive margins at the prostate base was 56% versus 85%, respectively (P < 0.0001). CONCLUSIONS Positive surgical margins are a significant predictor of recurrence in Stage pT2N0 cancer, which is independent of grade, PSA, and DNA ploidy. The impact of positive margin status on recurrence-free survival appears to be anatomic and site-specific, with prostate base positivity significantly associated with poor outcome. The benefit of adjuvant therapy based on anatomic site-specific margin positivity remains to be tested in order to optimize recurrence-free survival.