Howard S. Levin

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.

State T1–2 prostate cancer: A multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy

PURPOSE Prostate-specific antigen (PSA) is extensively used in case selection and outcome evaluation after treatment of clinically localized prostate cancer. Careful case selection can have a profound impact on pathologic findings and ultimate outcome. In addition, salvage treatment is frequently initiated at the time of biochemical relapse rather than clinical recurrence. Consequently, patterns of failure can be significantly altered compared to previous times when PSA was not available. To better understand the impact of PSA on pathologic findings, outcome, and salvage treatment, we reviewed our experience in the PSA era with clinical Stage T1-2 prostate cancer treated with radical prostatectomy. METHODS AND MATERIALS Between 1987 and 1993, 423 cases could be identified with clinical Stage T1-2 prostate cancer treated with radical prostatectomy. The distribution of cases by pretreatment PSA levels was as follows: < or = 4 ng/ml (18%), 4-10 ng/ml (42%), 10-20 ng/ml (21%), > 20 ng/ml (14%), and unknown (5%). The median pretreatment PSA level for the entire group was 8.0 ng/ml. Sixteen patients received adjuvant or neoadjuvant androgen suppression and 13 received postoperative radiotherapy. Only 31 patients (7%) had pathologically positive pelvic lymph nodes. The overall margin involvement rate was 46%. Fifty-three percent of patients had surgical Gleason scores > or = 7, and 65% had extracapsular extension. The median follow-up time was 41 months. RESULTS The projected overall survival at 7 years after surgery was 90%. The 5-year clinical relapse-free survival rate was 84%. At 5 years, the local control and distant failure rates were 92% and 91%, respectively. Biochemical relapse was defined as a detectable or rising PSA level after prostatectomy. The 5-year biochemical relapse-free survival (bRFS) rate was 59%. The 5-year RFS was 88% in patients with preoperative PSA levels < or = 4, 62% for 4-10, 48% for 10-20, and 31% for > 20. Combining the two independent preoperative variables, iPSA and biopsy GS (bGS), two risks groups were defined: low risk [initial PSA (iPSA) levels < or = 10.0 and bGS < or = 6] and high risk (iPSA levels > 10.0 ng/ml or bGS > or = 7). The 5-year bRFS rate for the low-risk cases was 81% vs. 40% for high-risk cases (p < 0.001). On multivariate analysis, three factors independently predicted biochemical relapse: iPSA levels (p = 0.005), Gleason score from the surgical specimen (sGS) (p = 0.002), and positive surgical margins (p < or = 0.001). The 5-year bRFS rates for margin positive vs. margin negative patients were 37% vs. 78%, respectively. The 5-year bRFS rates for GS > or = 7 vs. GS > or = 6 were 42% vs. 80%, respectively. All clinical relapses were accompanied by a rise in PSA. In patients who manifested biochemical failure followed by a clinical failure, the median interval between the PSA rise and clinical failure was 19 months (range 7-71). Margin involvement was the only independent predictor of local failure (p = 0.019). The 5-year local failure-free survival for negative margin cases was 96% vs. 87% for positive margin cases (p = 0.012). Lymph node (LN) involvement and high-risk group were the two independent predictors of distant failure. The 5-year distant failure-free survival for negative LN cases was 94% vs. 67% for positive LN cases (p < 0.001). The 5-year distant failure-free survival for low-risk cases was 97% vs. 85% for high-risk cases (p = 0.005). For the 124 patients failing biochemically, 85 were observed and 39 were treated either with radiation or androgen deprivation. With a median follow-up of 32 months, the clinical disease relapse-free survival was 79% for the treated patients vs. only 32% for the patients observed (p < 0.001). CONCLUSION Pretreatment PSA is the most potent clinical factor independently predicting biochemical relapse, thereby allowing markedly better case selection. Achieving negative margins, even in relatively advanced disease, provides excellent lon

Adenocarcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer

The prostate glands of 84 men undergoing cystoprostatectomy for bladder cancer were examined by whole‐mount sections at 4‐mm to 5‐mm intervals to identify unsuspected prostate adenocarcinoma (PCa). Of 72 white patients with entirely normal digital rectal examinations (DRE), 33 (46%) were found to have PCa, including 12 (17%) who had a Gleason score of 6 or greater and seven (10%) who had penetration through the prostatic capsule. These observations are consistent with previous studies in autopsy populations but allow a more appropriate comparison with morphologic data generated from radical prostatectomy specimens. If these data can be extended to the age‐matched general population, treatment at a 1% mortality rate for all white men 60 to 74 years of age with a PCa with a Gleason score of 6 or greater could cause between 6190 and 30,951 deaths, in contrast to 7335 deaths expected from the cancer. These data stress the need for a control group in a study designed to evaluate the benefit of early diagnosis and treatment of PCa.

Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer.

OBJECTIVES To better identify factors affecting prostate-specific antigen (PSA) level elevation after radical prostatectomy alone in men with clinical Stage T1-2 prostate cancer, we have reviewed our experience in the PSA era with 337 cases. The identification of these factors permits better understanding of the impact of case selection on treatment outcome in prostate cancer. METHODS The charts of all patients treated with radical prostatectomy alone between 1987 and 1993 were reviewed. Patients with clinical Stage T3 disease, without preoperative Gleason scores or PSA levels, with synchronous bladder cancer, and who received adjuvant or neoadjuvant therapy were excluded. The distribution of cases by pretreatment PSA levels was as follows: 4 ng/mL or less (16%); greater than 4 to 10 ng/mL (48%); greater than 10 to 20 ng/mL (22%); and greater than 20 ng/mL (14%). The median pretreatment PSA level for the entire group was 8 ng/mL. Only 26 patients (8%) had pathologically positive pelvic lymph nodes. The overall margin involvement rate was 43%. Margin involvement rates increased with increasing preoperative PSA levels. One hundred eighty-two patients (54%) had surgical Gleason scores of 7 or higher and 208 (62%) had extracapsular extension. The median follow-up time was 36 months. RESULTS The 3- and 5-year relapse-free survival (RFS) rates were 74% and 61%, respectively, with relapse being defined as either a clinically detectable recurrence or detectable/rising PSA levels. Among preoperative factors, PSA level was the only independent factor predicting relapse (P = 0.006); the 5-year RFS was 89% in patients with preoperative PSA levels of 4 ng/mL or less; 62% for PSA level of 4 to 10 ng/mL; 56% for PSA level to 10 to 20 ng/mL; and 26% for a PSA level greater than 20 ng/mL. Among pathologic parameters, margin involvement was the most potent independent factor predicting relapse (P < 0.001), followed by Gleason score (P = 0.002) and capsular penetration (P = 0.006). The 5-year RFS rates for margin-positive versus margin-negative patients were 37% versus 80%, respectively (P < 0.001). With pretreatment PSA levels of 10 ng/mL or less, lymph node involvement was seen in 3%, and margin involvement in 36%; the 5-year RFS rate was 71%. With pretreatment PSA levels of greater than 10 ng/mL, lymph node involvement was seen in 16%, and margin involvement in 57%; the 5-year RFS rate was 42%. However, patients with an initial PSA level greater than 10 ng/mL and positive margins had a 5-year RFS rate of 22% versus 73% in patients with a PSA level of 10 ng/mL or less or negative margins (P < 0.001). All clinical relapses were accompanied by a rise in PSA. In patients manifesting a clinical recurrence, PSA elevations preceded clinical recurrences by an average of 15 months (range 0 to 71). Only 34 cases (10%) had clinical failures within 5 years. CONCLUSIONS Pretreatment PSA is the most potent clinical factor independently predicting biochemical relapse. The great range in the relapse-free survival rates predicted by preoperative PSA levels demonstrates the importance of pretreatment PSA levels in case selection. Gleason score, extracapsular extension, and surgical margin involvement are also independent predictors of biochemical relapse. Achieving negative margins, even in relatively advanced disease, provides excellent long-term local control.

Declining Rates of Extracapsular Extension After Radical Prostatectomy: Evidence for Continued Stage Migration

PURPOSE Prostate-specific antigen (PSA)-based screening is responsible for a profound clinical stage migration in newly detected prostate cancers. Extracapsular extension (ECE) is an important predictor of outcome after radical prostatectomy (RP). We examined trends in the rate of ECE for cancers detected by PSA screening in 731 RP specimens between 1987 and 1997, when screening became routine urologic practice in the United States. METHODS The rates of ECE were examined in 311 prostates with nonpalpable (stage T1c) disease and 420 with palpable but clinically localized (stage T2) disease. Specimens were step-sectioned and examined by a senior pathologist. Rates of ECE were compared with respect to time, and logistic regression was used to identify predictors of ECE. RESULTS The rate of ECE decreased from 81% to 36% during the 10-year observation period. Multivariateanalysis involving clinical tumor stage, preoperative serum PSA level, and Gleason score demonstrated that year of treatment was an independent predictor of ECE, with a two-fold reduction of risk occurring during the study period (P <. 001; odds ratio, 1.96; 95% confidence interval, 1.37 to 2.78). CONCLUSION PSA screening has resulted in a downward trend in pathologic stage in clinically localized prostate cancer, independent of preoperative PSA level, tumor stage, and Gleason score. This time-dependent downward stage migration suggests the need for continuous updating of predictive nomograms and caution in interpreting differences in contemporarily treated patients compared with historical controls. Further study is needed to determine whether this trend will translate into improved disease-free survival.

Prospective Evaluation of Fine Needle Aspiration of Small, Solid Renal Masses: Accuracy and Morbidity

OBJECTIVES To determine the accuracy and clinical utility of fine needle aspiration (FNA) of small, solid renal masses. METHODS A total of 25 patients with small (less than 5.0 cm), solid, clinically localized renal masses were prospectively identified and evaluated with computed tomography guided FNA with analysis for presence of malignant cells and determination of nuclear grade. The final pathologic findings were used for comparison in each case. All patients had renal cell carcinoma and were managed with radical or partial nephrectomy; 3 had low-grade lesions (Fuhrmans grade 1/4), 2 had high-grade lesions (Fuhrmans grade 4/4), and all other patients had intermediate-grade lesions (Fuhrmans grade 2/4 or 3/4) on final histopathologic assessment. RESULTS Overall, 10 aspirations yielded diagnostic malignant cells, and 9 were read as rare as rare atypical cells suspicious for malignancy. The remainder were negative (n = 6). Correlation with final nuclear grade was observed in eight instances and discordance in two instances. Subcapsular hematomas were observed at the time of surgery in 10 patients, but in no instance was the operation adversely affected. CONCLUSIONS The diagnostic yield of FNA of small, solid renal masses appears to be too low to justify the potential morbidity of the procedure.

Impact of bladder neck preservationduring radical prostatectomy on continence and cancer control

OBJECTIVES To assess the effect of preservation of the bladder neck and other factors on the rate of postoperative urinary continence and cancer control after radical prostatectomy. METHODS Prospective analysis of clinical and pathologic findings in 206 consecutive patients undergoing radical prostatectomy with a surgical technique that emphasizes preservation of periurethral supporting tissue, urethral length, incorporation of the posterior periurethral fascia into the vesicourethral anastomosis, and preservation of the bladder neck. RESULTS Uni- and multivariate statistical analysis demonstrated that patient age (p = 0.033) and vesical neck contracture (p = 0.047) were predictive of incomplete return of urinary control. Preservation of the vesical neck had no impact on return of continence, but was associated with a trend to a lower incidence of vesical neck contractures. A positive bladder neck margin occurred in 6.8% of surgical specimens and was associated with a higher grade, more advanced local stage, and other positive margins in all cases. The rate of local recurrence or prostate-specific antigen (PSA)-only failure was similarly independent of whether the vesical neck was preserved or resected and reconstructed. CONCLUSIONS Age greater than 65 and occurrence of a vesical neck contracture are adverse predictors for return of urinary continence after radical prostatectomy. Preservation of the bladder neck does not have an impact on return of urinary control but may be associated with a lower risk of vesical neck contracture. Preservation of the bladder neck does not compromise cancer control as assessed by local or PSA-only failure rates.

Testicular biopsy in the study of male infertility: Its current usefulness, histologic techniques, and prospects for the future

Testicular biopsy has been widely used for the diagnosis of male infertility for more than three decades. During that time, with advances in cytogenetics, radioimmunoassay, and endocrinology, the role of testicular biopsy has changed. Testicular biopsy is still useful in the diagnosis of azoospermic and oligospermic males without stigmata of gonadotropic insufficiency or Klinefelters syndrome. A classification and description is presented of pathologic changes in the testis as seen on testicular biopsy by light microscopy. The present rationale for testicular biopsy in infertility, the processing and staining of histologic material, and the role of testicular biopsy in infertility and infertility related situations, including cryptorchidism, malignant disease, and chemotherapy related changes, are discussed. Further understanding of testicular function and disease will depend upon the correlation of histologic and ultramicroscopic changes, immunohistologic localization of hormones, and epidemiologic and endocrinologic data.

Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer

Specimens from 84 radical cystectomies for bladder carcinoma performed between January 1984 and July 1986 were reviewed to characterize the involvement of the prostate with transitional cell carcinoma. Whole-mount sectioning of the prostate was performed at 4 mm. intervals and processed in the same manner as radical prostatectomy specimens. A total of 36 patients (43 per cent) had transitional cell carcinoma of the prostate: 94 per cent of these had prostatic urethra involvement and 6 per cent had a normal prostatic urethra but transitional cell carcinoma was present in the periurethral structures. In situ prostatic duct or acini, ejaculatory duct and seminal vesicle involvement occurred, respectively, in 67, 8 and 17 per cent of the patients with prostatic involvement. Of the patients with prostatic involvement 39 per cent had stromal invasion (22 per cent focal and 17 per cent diffuse invasion). The incidence of carcinoma in situ of the bladder neck or trigone (59 per cent), previous intravesical chemotherapy (59 per cent) and ureteral carcinoma (79 per cent) was significantly increased in patients with prostatic involvement. In patients with carcinoma in situ of the trigone or bladder neck, or in whom previous intravesical chemotherapy treatments have failed prostatic involvement should be suspected so that this disease can be detected before stromal invasion occurs.

Phase II trial of neoadjuvant estramustine and etoposide plus radical prostatectomy for locally advanced prostate cancer

OBJECTIVES To report the results of a Phase II trial of neoadjuvant estramustine and etoposide before radical prostatectomy in patients with locally advanced disease. METHODS Treatment consisted of three cycles of estramustine (10 mg/kg/day) and etoposide (50 mg/m(2)/day) orally on days 1 through 21, repeated every 28 days, followed by radical prostatectomy. The eligibility criteria included locally advanced prostate cancer (clinical Stage T2b/c or T3, prostate-specific antigen [PSA] level of 15 ng/mL or greater, or Gleason score of 8 or higher) without evidence of metastatic disease. The median PSA level was 14 ng/mL (range 5.3 to 50), the median Gleason score was 7 (range 6 to 9), and 44% had Stage T2b/c or T3 disease. The primary endpoint was feasibility of neoadjuvant therapy and radical prostatectomy, including drug and surgery-related toxicities. Secondary endpoints included the pre-prostatectomy PSA level, local response, pathologic outcomes, and time to PSA failure. RESULTS Eighteen patients were entered and completed all three cycles of therapy, and 16 (89%) underwent radical prostatectomy. A local response occurred in 15 (94%) of 16 patients with palpable tumors, and the serum PSA reached undetectable levels after therapy and before radical prostatectomy in 9 patients (50%). Five patients (28%) experienced grade 3 toxicity (two with deep venous thrombosis, two with neutropenia, and one with diarrhea) and one (6%) experienced grade 4 toxicity (pulmonary embolus) before surgery. The median operative time was 125 minutes, the mean blood loss was 665 mL, and the mean length of stay was 2.5 nights. Five minor surgical complications occurred in 4 patients. The pathologic analysis demonstrated residual carcinoma with squamous metaplasia and androgen deprivation effect in all patients. Five patients (31%) had organ-confined disease and 9 patients (56%) had specimen-confined disease. All patients achieved an undetectable PSA level postoperatively and at a median follow-up of 14 months (range 5 to 20) and without additional therapy, all 14 patients with negative lymph nodes were disease free. CONCLUSIONS This trial confirms the feasibility of radical prostatectomy with acceptable surgical morbidity after neoadjuvant therapy with estramustine and etoposide in patients with locally advanced prostate cancer. However, this regimen is associated with estramustine-induced thromboembolic toxicity. The results of the pathologic analysis suggest a higher than expected rate of organ-confined and specimen-confined disease, but little histologic evidence of antitumor effect beyond that associated with androgen deprivation. Additional study of this paradigm with other drug regimens is warranted.