Cell proliferation in prostate cancer patients with lymph node metastasis: a marker for progression.

The biological aggressiveness of lymph node-positive prostate cancer is closely linked to cancer volume in nodal metastases. We evaluated MIB-1 (Ki-67) labeling index and bcl-2 expression in primary cancer and matched nodal metastases from 138 node-positive patients treated with radical prostatectomy and bilateral pelvic lymphadenectomy between 1987 and 1992 at the Mayo Clinic. One hundred twenty-eight patients (93%) received androgen deprivation therapy within 90 days after radical prostatectomy. Mean patient age was 66 years (range, 51-78). The median follow-up was 6.7 years (range, 0.03-11). MIB-1 (Ki-67) labeling index was determined by digital image analysis, and nodal cancer volume was determined by the grid method. Systemic progression, defined as the presence of distant metastasis documented by biopsy or radiographic examination, was used as an outcome end point in the Cox proportional hazard models. MIB-1 labeling index in nodal metastases was predictive of systemic progression-free survival (P = 0.001). The 8-year systemic progression-free survival was 100% for those with MIB-1 labeling index <3.5% compared with 78% for those with MIB-1 labeling index > or =7.8%. MIB-1 labeling index correlated with Gleason score, DNA ploidy, and nodal cancer volume (P<0.001, 0.04, and <0.001, respectively). After controlling for nodal cancer volume, MIB-1 labeling index remained significant in predicting systemic progression-free survival (P = 0.047). bcl-2 expression in the primary cancer and lymph node metastasis was associated with systemic progression-free survival in univariate analysis (P = 0.027 and 0.048, respectively) but was not significant after adjusting for nodal cancer volume (P = 0.52 and 0.17, respectively). Our data indicate that assessment of cell proliferation in nodal metastasis is predictive of clinical outcome in prostate cancer patients with regional lymph node metastasis.

Grading and staging of bladder carcinoma in transurethral resection specimens. Correlation with 105 matched cystectomy specimens.

We compared the grading and staging of transurethral resection of the bladder (TURB) and cystectomy specimens for 105 patients who underwent radical cystectomy for urothelial carcinoma between 1980 and 1984. Of 105 patients, 96% underwent cystectomy within 100 days of TURB (median interval, 10 days). Grading was performed according to the 1998 World Health Organization/International Society of Urologic Pathology grading system and staging according to the 1997 TNM classification. Histologic grade was low-grade, 13; high-grade, 92 in TURB specimens; low-grade, 17; high-grade, 88 in cystectomy specimens. Pathologic stage was Ta, 15; T1, 55; and T2, 35 in TURB specimens; Ta, 5; T1, 19; T2, 19; T3, 46; and T4, 16 in cystectomy specimens. Histologic grade at TURB was associated with pathologic stage at cystectomy (P < .001). When all advanced-stage (muscle-invasive) carcinomas (pT2 or more) were considered together, 55 patients were understaged by TURB, 4 had higher stage in TURB than in cystectomy, and 46 were the same stage as by cystectomy. Forty-three of 55 patients with stage T1 carcinoma at TURB had advanced-stage carcinoma at cystectomy, including 34 who had extravesicular extension (pT3 or more). We found pathologic understanding by TURB occurs in a significant number of patients with bladder cancer; the newly proposed grading system predicted final pathologic stage.

Substaging of T1 bladder carcinoma based on the depth of invasion as measured by micrometer: A new proposal.

BACKGROUND: A significant number of T1 bladder carcinoma patients are understaged by transurethral resection of the bladder (TURB), indicating a substantial need for more accurate staging. METHODS: The authors studied 55 patients with T1 bladder carcinoma detected by TURB at the Mayo Clinic between December 1979 and July 1984. The mean age of the patients was 66 years (range, 50-78 years). All patients were treated by cystectomy. The median interval from TURB to cystectomy was 10 days. Grading was performed according to the 1998 World Health Organization/International Society of Urologic Pathology grading system. The 1997 TNM classification was used for pathologic staging. In addition, the depth of invasion was measured from the mucosal basement membrane by micrometer. Receiver operating characteristic (ROC) analysis was used to evaluate the usefulness of depth of invasion as a marker for advanced stage bladder carcinoma (>/= T2). RESULTS: The final pathologic stages were Ta (2 patients), T1 (10 patients), T2a (9 patients), T2b (13 patients), T3 (11 patients), and T4 (10 patients) at cystectomy. There was a significant correlation between the depth of invasion at TURB and the final pathologic stage (Spearman correlation coefficient = 0.63; P < 0.001). The overall accuracy for the prediction of advanced stage (>/= T2) bladder carcinoma as measured by the area under the ROC curve was 0.89 (standard error, 0.05). Using 1.5 mm as a threshold (with >1.5 mm indicating advanced stage disease), the sensitivity, specificity, and positive and negative predictive values were 81%, 83%, 95%, and 56%, respectively. Histologic grade at the time of TURB also was associated significantly with final pathologic stage at cystectomy (P = 0.03) whereas stratification of patients according to invasion above or below the muscularis mucosae at TURB was not a significant predictor of final pathologic stage. CONCLUSIONS: The results of the current study show that substaging of T1 bladder carcinoma according to the depth of invasion (as measured by micrometer) provides significant prognostic information. Therefore the authors recommend that it be reported in specimens obtained by TURB.

Predicting the survival of bladder carcinoma patients treated with radical cystectomy.

BACKGROUND: Clinical outcomes vary for patients treated with radical cystectomy. The authors sought to identify factors associated with the survival of patients treated with radical cystectomy for urothelial carcinoma of the urinary bladder. METHODS: The authors studied 218 patients treated with radical cystectomy for urothelial carcinoma between 1980 to 1984. Patient ages ranged from 41 to 78 years (mean, 64 years). Using the 1997 TNM system, T classifications were Ta (17 patients), T1 (44), T2 (71), T3a (42), T3b (14), T4a (28), and T4b (2). Thirty-two patients had lymph node metastasis at the time of surgery. Histologic grade was determined according to the newly proposed World Health Organization and International Society of Urological Pathology grading system; tumor was low grade in 43 patients and high grade in 175. The male-to-female ratio was 4.9 to 1. The mean follow-up of patients still alive was 13.1 years (median, 13.8 years; range, 30 days to 18 years). Cox proportional hazards models were used to determine the impact of numerous clinical and pathologic findings on survival. RESULTS: Ten-year local recurrence free, distant metastasis free, cancer specific, and all-cause survival were 71%, 73%, 67%, and 41%, respectively. In univariate analysis, cancer size, T classification, and lymph node status were associated with distant metastasis free, cancer specific, and all-cause survival. Histologic grade and surgical margin status were significantly associated with worse cancer specific and all-cause survival, but not with distant metastasis free survival. In multivariate analysis, cancer size, margin status, T classification, and lymph node status were identified as significantly associated with cancer specific survival after adjustment for age and gender. CONCLUSIONS: Long term survival is achieved in a significant number of patients treated with radical cystectomy. In this study, patients with organ-confined (< or = pT2) and small size (< or = 3 cm) cancer had favorable 10-year distant metastasis free (93%) and cancer specific survival (88%) after cystectomy. Tumor size, margin status, extravesical involvement, and lymph node metastasis are important pathologic factors and should be considered as stratification variables in identifying patients for whom adjuvant chemotherapy should be evaluated in clinical trials.

Tumor size predicts the survival of patients with pathologic stage T2 bladder carcinoma: a critical evaluation of the depth of muscle invasion.

BACKGROUND: Accurate examination of radical cystectomy specimens is critical for stratifying patients into prognostically important groups and determining the need for adjuvant treatment. Evidence has accumulated that cancers invading the superficial muscle wall (T2a) behave similarly to those invading the deep muscle wall (T2b). Quantitative analysis of the depth of invasion in relation to patient outcome is needed. METHODS: The authors systematically evaluated the depth of invasion by micrometer measurement and its relation to the survival of 64 patients with bladder carcinoma pathologic classification as pT2 who had long term follow-up after radical cystectomy. Numerous clinical and pathologic variables were analyzed with univariate and multivariate Cox proportional hazards models. The mean age of patients was 64 years, and their mean follow-up was 8.3 years. RESULTS: There was no significant difference in clinical outcome between patients with T2a carcinoma and those with T2b. Lymph node metastasis and tumor size were each significantly associated with distant metastasis free and cancer specific survival. Ten-year distant metastasis free and cancer specific survival were 100% and 94%, respectively, for patients with tumors <3 cm (P = 0.006) and 68% and 73%, respectively, for patients with tumors > or = 3 cm (P = 0.005). After adjustment for lymph node status, tumor size maintained significance in predicting distant metastasis free survival (risk ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.009) and cancer specific survival (risk ratio, 1.5; 95% confidence interval, 1.1-1.9; P = 0.01). Age was associated with recurrence free survival and all-cause survival. None of the other variables, including gender, vascular invasion, presence of carcinoma in situ, pathologic classification (T2a vs. T2b), depth of invasion, depth of muscle invasion, ratio of depth of invasion to bladder wall thickness, and percentage of muscle wall invasion, were significantly associated with patient outcome. CONCLUSIONS: The findings of this study indicate that the subclassification of T2 bladder carcinoma by depth of muscle invasion is of no prognostic value; conversely, tumor size, an easily measured factor, is predictive of distant metastasis free and cancer specific survival.

p53 alteration in regional lymph node metastases from prostate carcinoma: a marker for progression?

BACKGROUND: Alterations of the p53 tumor suppressor gene are associated with advanced stage prostate carcinoma. The biologic significance of p53 nuclear accumulation in prostate cancer patients with regional lymph node metastases is uncertain. METHODS: The authors investigated p53 alterations by immunohistochemistry in 220 lymph node positive patients who were treated with radical prostatectomy, bilateral pelvic lymphadenectomy, and androgen deprivation therapy between 1987-1992 at the Mayo Clinic. The mean follow-up was 6.3 years. Tumor volume of lymph node metastases was measured using the grid method. RESULTS: p53 immunoreactivity was detected in 109 of 211 primary tumors (52%) and 83 of 144 matched regional lymph node metastases (58%); this expression was strongly concordant (correlation coefficient 0.53; P = 0.0001). Overexpression of p53 protein in lymph node metastases was associated with distant metastasis free survival by univariate analysis (P = 0.03), but did not reach statistical significance by multivariate analysis (P = 0.07). Regional lymph node cancer volume was the single most important predictor of distant metastases after adjusting for Gleason score, DNA ploidy, and p53 expression. CONCLUSIONS: The findings of the current study suggest that assessment of biologic changes (including p53 alterations in regional lymph node metastases) could be of value in the assessment of the biologic aggressiveness of prostate carcinoma, whereas p53 expression in the primary tumor does not appear to influence patient outcome.

Predictors of cancer progression in T1a prostate adenocarcinoma.

BACKGROUND: The biologic behavior of T1a prostate adenocarcinoma is variable. A critical issue in the management of patients with T1a prostate adenocarcinoma is to distinguish those who will develop cancer progression from those who will not. Predictive factors that identify those at high risk of cancer progression are needed to stratify patients for treatment. In the current study the authors attempted to identify such predictors of cancer progression in a large series of untreated patients with lengthy follow-up. METHODS: The authors studied 102 patients who were diagnosed with T1a prostate adenocarcinoma (incidental tumor involving < or = 5% of the resected prostatic tissue) at the time they underwent transurethral resection of the prostate (TURP) at the Mayo Clinic between 1960-1970. None of these patients were treated. Patient ages ranged from 48-91 years (mean +/- standard deviation, 69 +/- 7 years). The average weight of the resected prostate tissue was 24 +/- 18 g (range, 3-115 g; median, 18 g). Tumor volume was measured by the grid method. Cox proportional hazards models were used to identify factors associated with cancer progression. Survival curves were estimated using the Kaplan-Meier method. RESULTS: Five-year and 10-year progression free survival rates were 93% and 87%, respectively. During the mean follow-up of 9.5 +/- 6.8 years (range, 0.3-31 years; median, 9.0 years), 14 patients developed clinical cancer progression, including 5 patients with systemic progression (1 with distant metastases and 4 who died of prostate adenocarcinoma). The interval from diagnosis to clinical cancer progression ranged from 1-23 years (mean, 7.3 years). The amount of resected prostate tissue (TURP weight) was associated with progression (P = 0.04). Patients with a TURP weight > or = 30 g had 100% progression free survival at 10 years compared with a progression free survival rate of 73% in patients with a TURP weight < 12 g. Gleason score, tumor volume, number of chips involved by tumor, number of tumor foci, and the presence of high grade prostatic intraepithelial neoplasia were not significant in predicting cancer progression. There was a trend toward a worse prognosis with the increasing number of chips involved by cancer (P = 0.16). Patients with < 3 chips involved by cancer had a 88% 10-year progression free survival rate compared with 73% in patients with > or = 3 chips involved by cancer. CONCLUSIONS: The clinical course of T1a prostate adenocarcinoma is variable. If left untreated, a small but significant proportion of patients are at risk for disease progression and death. However, the current study found that patients with a TURP weight > or = 30 g have an excellent prognosis and can be managed conservatively.