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Background: Radical cystectomy (RC) is associated with substantial postoperative mortality. In this study, we analyzed early (30-day; 30 M) and late (30-90-day; 30-90 M) mortality after RC in a Dutch tertiary referral center and determined factors associated with 30 M, 30-90 M and 90-day mortality (90 M)., Patients and Methods: We identified 823 patients who underwent RC for bladder cancer in the Netherlands Cancer Institute between 1997 and 2017. Predictive factors for mortality were analyzed to identify patients with a higher mortality risk. Multivariate logistic regression analysis was performed to examine the influence of patient, surgical and histopathological variables on 30 M, 30-90 M and 90 M., Results: Thirty-day mortality was 1.9% and 90 M was 6.0%. Multivariable analysis showed that age (OR 1.08, 95% CI 1.01-1.1, p = 0.002) and ASA 3-4 (OR 3.57, 95% CI 1.25-10.16, p = 0.002) were significant predictors of 30 M while higher ASA score (OR 2.9, 95% CI 1.31-6.5, p = 0.009) and higher pathological T stage (OR 8.8, 95% CI 1.9-40.4, p = 0.005) were associated with 30-90 M. Risk of 90 M was increased in patients with ASA 3-4 (OR 2.4, 95% CI 1.2-4.9, p = 0.01), pT3-4 (OR 3.1, 95% CI 1.27-7.57, p = 0.01) and positive LNs (OR 2.5, 95% CI 1.25-4.98, p = 0.009)., Conclusions: Patient-related factors predicted 30 M whereas both patient-related and cancer-related factors predicted 30-90 M. This suggests that patient mix, i.e. patient- vs. cancer-related factors for 30 M and 30-90 M, should be taken into account if mortality rates are to be compared between hospitals.

Aims: To evaluate the efficacy of follow-up based on the patterns of recurrence, relapse presentation and survival after cystectomy, and to define a risk adjusted follow-up schedule., Patients and Methods: The records of 343 patients with regular follow-up after cystectomy were reviewed for primary site of recurrence, accompanying symptoms, means of recurrence diagnosis, and clinicopathological factors. Based on Cox proportional hazard models, and the results of imaging studies low and high risk groups are identified and a risk adjusted follow-up protocol is proposed., Results: The risk of a recurrence was related to increasing pT, tumour positive lymph nodes, tumour positive surgical margins, and pre-operative dilatation of the upper urinary tract, and low and high risk groups were defined consequently. 84% of all recurrences occurred within 2 years, with only one recurrence beyond 2 years in the low risk group. Although the minority of all patients (34%) is asymptomatic at time of recurrence, symptomatic recurrences were adversely associated with survival. CT-scans and chest X-rays accounted for 90% of the diagnostic tools to detect a recurrence in patients without symptoms., Conclusions: Asymptomatic patients may benefit from early treatment after disease recurrence. A risk adjusted follow-up strategy based on stage of disease and additional clinicopathological factors can dichotomise patients at high and low risk for recurrence. The small benefit in survival after early detection has to be confirmed in future studies, and weighed against the available treatment options of recurrences and their subsequent costs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To analyse whether the reported differences in nodal yield at pelvic lymph node dissection (PLND) for bladder cancer, between two hospitals, are reflected in the survival rates., Patients and Methods: We assessed follow-up data of all 174 patients (mean age: 62.7, median follow-up: 3 years) who underwent PLND between 1 January 2007 and 31 December 2009 at two different hospitals. PLND was performed according to a standardized template by the same urologists for comparable bladder cancer patients. Mean number of reported lymph nodes was 16 at hospital A versus 28 at hospital B. We compared the overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) between both cohorts and performed a multivariate analysis., Results: The cumulative probability for 2-year OS, DSS and RFS for hospital A are 61, 64 and 54 %, versus 58, 58 and 53 % for hospital B, respectively. Kaplan-Meier survival curves did not reveal statistically significant differences between both groups (OS: p log-rank = 0.75, DSS: p log-rank = 0.56, and RFS: p log-rank = 0.80). Also after adjustment for pT stage and neoadjuvant chemotherapy, survival was not significantly different between hospital A and hospital B., Conclusion: Despite differences in lymph node yield in PLND specimens, this study reveals no significant differences in survival outcomes between both hospitals. Standardized histopathological methods should be agreed upon by pathologists before integrating nodal yield and subsequent lymph node density as indicators of the quality of surgery and as prognostic factors.

Aim: To evaluate the outcome of patients with locally advanced muscle-invasive and/or lymph node positive bladder cancer treated with induction chemotherapy and additional surgery., Methods: All patients who were treated with induction chemotherapy in our institution between 1990 and 2010, were retrospectively evaluated using an institutional database. Induction chemotherapy consisted of methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), or a combination of gemcitabine with either cisplatin or carboplatin (GC)., Results: In total 152 patients were identified, with a mean age of 59 years (range 31-76). One hundred and seven patients (70.4%) received MVAC, 35 patients received GC (23.0%) and 10 patients received GC after initial treatment with MVAC (6.6%). Median follow-up was 68 months (range 4-187 months). Overall 125 patients (82.2%) underwent cystectomy, whereas 12 patients (7.9%) received radiotherapy. Fifteen patients had no local treatment. Median overall survival was 18 months (95%CI 15-23 months). In 37.5% of patients with complete clinical response, residual disease was found at surgery (positive predictive value, PPV 62.5%). Complete pathological response was seen in 26.3% of patients, with a 5 year overall survival (OS) estimate of 54% (39%-74%). For patients with persisting node positive disease after induction chemotherapy and surgery OS was significantly worse (p < 0.0001)., Conclusions: Complete clinical and/or pathological response to induction chemotherapy results in a significant survival benefit. The accuracy of the current clinical response evaluation after induction chemotherapy is limited. Although surgery may be important for staging and prognostic purposes, its role is unclear in node positive disease after induction chemotherapy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: We compared the nodal yield after histopathological examination of extended bilateral pelvic lymph node dissection specimens for bladder cancer at 2 hospitals. Surgery at each hospital was done by the same 4 staff urologists using a standardized extended bilateral pelvic lymph node dissection template., Materials and Methods: All consecutive patients with bladder cancer who underwent extended bilateral pelvic lymph node dissection from January 1, 2007 to December 31, 2009 were included in this study. Specimens were sent for pathological evaluation in a minimum of 2 packages per side. At the 2 pathology departments specimens were processed according to institutional protocols., Results: A total of 174 patients with a mean age of 62.7 years were included in analysis. At hospital 1 a mean of 16 lymph nodes were found after dissection vs a mean of 28 reported at hospital 2 (p <0.001). No significant differences were found in the number of tumor positive lymph nodes (p = 0.65). Mean lymph node density at hospitals 1 and 2 was 9.3% and 3.9%, respectively (p = 0.056)., Conclusions: Despite equal anatomical clearance by the same experienced surgeons we report a statistically significant difference between 2 pathology departments where the number of lymph nodes was evaluated after extended bilateral pelvic lymph node dissection for bladder cancer. Unless standardized methods are agreed on by pathologists, the number of reported lymph nodes as an indicator of surgical quality and lymph node density as a prognostic factor should be used cautiously., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Aim: To compare the outcome of two perioperative protocols with respect to postoperative management of cystectomy patients., Patients and Methods: Between June 2007 and November 2008, 85 consecutive patients with bladder cancer were treated with cystectomy and urinary diversion. Patients were operated in two hospitals by four urologic surgeons. In protocol A, patients were enterally fed via a postpyloric tube while the nasogastric tube (NGT) was removed directly after cystectomy and selective decontamination of the digestive tract was given until normal oral intake. In protocol B, postcystectomy management consisted of total parenteral nutrition by a central venous line and NGT removal after 24 h. Hospital stay and complications were compared between the two hospitals., Results: More than half of all patients (52%) developed one or more complications within 30 days after surgery, 37% in protocol A and 71% in protocol B (p = 0.002). Higher ASA score and protocol type were the only factors significantly associated with early complications in both uni- and multivariate analyses. Length of stay was significantly shorter with protocol A as compared to protocol B, 13 days versus 19 days (p = 0.006)., Conclusions: Cystectomy and urinary diversion is a procedure with considerable risk of complications. Enteral nutrition might be advantageous as compared to parenteral nutrition, showing fewer complications and shorter hospital stay. A high ASA score is associated with more early complications. Selective bowel decontamination may have an additional role in preventing infectious complications after cystectomy., (Copyright © 2012 S. Karger AG, Basel.)

Purpose: We evaluated the delivery and oncolytic potential of targeted replication competent adenoviruses in bladder cancer lines., Materials and Methods: Seven established human bladder cancer tumor lines (5637, SW800, TCCsup, J82, Scaber, T24 and 253J) were studied for the expression of integrins alpha(v)beta3, alpha(v)beta5, Coxsackievirus and adenovirus receptor, epidermal growth factor receptor (EGF-R) and epithelial cell adhesion molecule antigens using flow cytometry analysis. Bispecific single chain Fv fragments were used to target replication deficient luciferase reporter adenovirus to EGF-R (425-s11) or to epithelial cell adhesion molecule (C28-s11) antigens. Moreover, a fiber modified adenovirus targeting alpha(v)-integrins was studied. Replication competent serotype-5 adenoviruses attenuated to replicate specifically in retinoblastoma pRb (Ad5-d24) or p53 deficient (Ad5-d55K) cells were tested in vitro for oncolytic properties., Results: Low to absent Coxsackievirus and adenovirus receptor expression was found in 5 of the 7 tumor lines (SW800, J82, T24, 5637 and Scaber). EGF-R expression was found in all cell lines, whereas elevated epithelial cell adhesion molecule expression was seen in 3 (5637, Scaber and TCCsup), alpha(v)beta3-integrin was found in 1 (Scaber) and alpha(v)beta5-integrin was found in 3 (TCCsup, 253J and T24). EGF-R targeting using 425-s11 improved transgene expression in all cell lines from 2.1 to 12.5 times over nontargeted viruses. Epithelial cell adhesion molecule and integrin targeting was inferior to EGF-R targeting with a maximal increase in transgene expression of 2 times for epithelial cell adhesion molecule in 5637cells and 1.6 times for integrin targeting in T24 cells. Comparison of the wild-type replication competent virus with conditionally replicating adenoviruses (Ad5-d55K and Ad5-d24) showed superior oncolytic activity for the latter 2 in all lines. Furthermore, improved cytotoxicity (29% to 33%) was obtained in 4 of the 7 lines after pre-incubation of Ad5-d24 with 425-s11., Conclusions: EGF-R directed bispecific single chain antibodies enhance adenovirus mediated transgene expression and oncolysis in bladder cancer lines.

Cystoscopy is currently considered the gold standard for the detection of bladder tumors. The role of urine cytology in the initial detection and follow-up of patients is under discussion. New elaborative and rapid assays are available that may circumvent the low sensitivity and poor reproducibility of urine cytology. The methods that have been tested extensively are the nuclear matrix protein (NMP22) assay, the BTA stat assay, and the BTA TRAK enzyme-linked immunosorbent assay. Both outperform cytology in the detection of low-grade lesions. The specificity of both assays, however, lags behind that of cytology. The data from retrospective analyses are insufficient to justify clinical integration, and the need to replace cystoscopy with these novel assays remains to be proven.

Objectives: Quantitative cytology (Quanticyt) provides an objective reproducible alternative for routine cytology. To increase the sensitivity of cytology, we studied the application of consecutive cytology in patients in follow-up for superficial bladder cancer., Methods: Between 1991 and 1998, a set of five or more bladder wash samples was obtained from 614 patients. These patients were retrospectively studied for follow-up data. Each sample was scored according to the Quanticyt risk score., Results: In 614 patients (508 men, 106 women), 5832 bladder wash samples were taken. The mean interval between the first and fifth sample per patient was 21.5 months (SD 13.8 months). The mean number of tumor recurrences per patient was 2.17 (SD 1.82). The risk score of the first sample was not predictive of recurrence. Invasive disease was found in 0%, 0%, and 0.8% of patients with one low, intermediate, and high-risk sample, respectively. After five samples, the corresponding rate was 0%, 0%, and 10%. A comparison of visual cytology and quantitative cytology revealed that the false-negative rate was significantly different (17% versus 3.8%). The positive predictive value was highest for visual cytology (17% versus 9.2%)., Conclusions: Adding consecutive quantitative cytology to urine cytopathologic evaluation improves the detection rate of high-grade lesions. Combining quantitative cytology and visual cytology provided a more accurate prediction of tumor stage.

In this pilot study, we tested whether it is possible to apply neural network-based diagnostics on bladder washings to detect urothelial cell carcinoma of the bladder. Eighty-five bladder wash (BW) samples were chosen at random from our own database. Cystoscopy, histology, and follow-up data concerning tumor recurrence were available. Each slide was scanned by the neural network-based digitized cell image system. The neural network-based diagnosis (NNBD) was based on 128 digitized cell images provided by the system. The light microscopic diagnosis (LMD) was rendered by an experienced cytopathologist using the same terminology, i.e., negative, low-grade tumor, and high-grade tumor. Finally, an automatic QUANTICYT analysis was performed on the same material, with as classification low, intermediate, and high risk. The sensitivity for diagnosing a histologically confirmed tumor was for NNBD 92%, for LMD 50%, and for QUANTICYT 69%. For the three methods, receiver operating characteristic (ROC) curves were made for the thresholds low grade/intermediate risk and high grade/high risk. For the prediction of a positive cystoscopy, the highest area under the curve (AUC) was found for NNBD, being 0.71. The AUC for LMD was 0.58. QUANTICYT analysis had the highest AUC value (0.62) for predicting tumor recurrence after a negative cystoscopy, with a lower value for NNBD (0.50). These findings indicate that neural network-based diagnosis of bladder washing samples is highly promising., (Copyright 2000 Wiley-Liss, Inc.)

Objectives: To compare stage distribution between men and women with bladder cancer at first presentation., Methods: The population-based Netherlands Cancer Registry was used to investigate stage differences of newly diagnosed bladder cancer, including upper urinary tract tumors in female and male patients., Results: The stage distribution at first presentation for both bladder cancer and upper urinary tract tumors was slightly worse in female patients with transitional cell carcinoma than in male patients. The stage differences were more clear in non-transitional cell carcinoma (squamous cell carcinoma, adenocarcinoma, and sarcoma) of the bladder, with female patients presenting with higher stages. Because of the large numbers, these gender differences in stage distribution were statistically significant in both TCC (P <0.0001) and non-TCC (P <0.0001)., Conclusions: Treating physicians should be aware that female patients are more frequently diagnosed with higher stages at the first presentation for bladder cancer and upper urinary tract tumors.

Objectives: Karyometric analysis (Quanticyt) has proved of value as a cytologic marker for bladder cancer. This study was conducted to identify diagnostic and prognostic factors in a high-risk Quanticyt population to predict the prognosis of transitional cell carcinoma (TCC) of the bladder., Methods: Quanticyt is a karyometric system for quantitative bladder wash cytologic findings based on two nuclear features: the 2c-deviation index (2cDI) and the mean of nuclear shape. Samples are scored as low, intermediate, or high risk. Before 1995, 109 patients with high-risk quantitative bladder wash cytologic findings were identified at our clinic. Four patients with previous invasive tumors were excluded., Results: Histologically proven malignancy was found in 54 of 105 patients at first high-risk quantitative bladder wash cytologic findings. Invasive TCC was found in 16 patients, and another 10 patients had progression during a median follow-up of 3.7 years. In univariate analysis, the presence of carcinoma in situ (CIS), highest tumor grade, 2cDI, and highest tumor stage were significant predictors of progression. The presence of CIS proved to be the only predictor of progression in the multivariate analysis. A 2cDI of 2.00 c(2) or higher was a significant predictor of CIS, invasive TCC, and progression. At follow-up analysis after negative cystoscopy, 2cDI showed a tendency toward predicting progression., Conclusions: These data confirm earlier findings that CIS is an important marker of progression. 2cDI as assessed by quantitative cytology is a practical tool to predict CIS, invasive TCC, and subsequent progression. A 2cDI of 2. 00 c(2) can be used to further stratify high-risk quantitative bladder wash cytologic findings.

The management of superficial bladder cancer is characterized by early recognition of recurrences and the prevention of progression. Several clinical markers are used to divide patients into risk groups determining treatment and follow-up schemes. Although only a small fraction of patients will progress to invasive disease, survival of these patients is largely dictated by their bladder cancer. Whether early aggressive treatment of 'high-risk' superficial bladder cancer improves survival is not the issue of this article. Here we discuss the markers available for predicting tumour recurrence and progression. Clinical markers remain the most practical in decision-making and can identify high-risk patients. Molecular markers may be useful, but as yet insufficient evidence exists on their efficacy for daily use.

Bladder cancer is seen mainly in men. The incidence in women is increasing, but is still approximately three to four times lower than in men. In particular transitional cell cancers seem relatively more common in men then in women (ratio 4:1), but non-transitional cell cancer is also more frequent in men (ratio 2.7: 1). As for men, smoking is the most important known factor for bladder cancer in women. Coffee-drinking also showed a weak correlation, the odds ratio being found to be twice as high for women (5.2) as for men (2.6). It was estimated that the percentage of bladder cancers attributed to occupational exposure in the United States is 11% in women, compared to 21% in men. Urinary tract infections are related to bladder cancer. The role of human papilloma virus infections, important in cervical cancer, is unclear in bladder cancer development. Surprisingly, bladder cancer is more often of a higher stage at initial diagnosis in women. With current tumor markers no explanation for the different prognosis in men and women can be postulated. The treatment of superficial bladder cancer tumors is similar for men and women. In recent years orthotopic bladder replacement has improved quality of life after cystectomy in invasive disease.

Mutations in the tumor suppressor gene p53, analyzed in bladder washings, have positive predictive value for the progression of superficial bladder cancer to invasive disease. Bladder washings reflect the general status of the urothelium, and because sampling of bladder washings can be performed as an outpatient procedure, patients can be monitored more carefully. To determine the actual value of bladder washing specimens in assessing the p53 status of histologic specimens, we used the technique of polymerase chain reaction-single-strand conformation polymorphism to analyze bladder washings and the synchronous tumors of 15 patients for the presence of p53 mutations. A significant correlation (2-tailed Fisher's exact test) between the p53 status of bladder washings and histologic specimens was observed if the 2 were compared among the specimens of a single patient. Overall, in 2 patients the mutation present in the tumors was not detected in the bladder washings, and in 1 patient the mutation in the bladder washing was not detected in the histologic specimens. These conflicting results obtained with bladder washings and histologic specimens could be explained mainly by the architecture of the tumors. The observed specificity of 86% and sensitivity of 75% emphasizes that although the correlation between the 2 methods is good, in a number of cases they are complementary to each other. The analysis of p53 mutations in at least 2 bladder washings gives insight into the p53 status of the synchronous tumors.

Objectives: Application of immunocytology directed against antigens of urothelial tumor cells or tumor-associated breakdown products intends to improve the sensitivity of the diagnosis of superficial transitional cell carcinoma (TCC) of the urinary bladder. In this study, the mode of action, sensitivity and specificity of the Bard(R) BTA test, detecting a tumor-associated release of a basement membrane complex, was addressed and compared with voided urine cytology (VUC)., Results: Contrary to grade, a significant (p = 0. 003) relationship between tumor stage and BTA test sensitivity was observed, being 23.8, 33.3 to 100% for Ta (n = 42), T1 (n = 6) to >/=T2 (n = 5), respectively. These data suggest an association between an increase of the BTA test sensitivity with an increase of basement membrane degradation or interruption. With regard to this mechanism, the BTA test may be of special importance for monitoring tumor progression or increase in tumor invasiveness. Detection of low-stage, low-grade tumors by noninvasive techniques remains a challenge. The sensitivity of the BTA test for the presence of TCC was 32.3%, while that of VUC was 17.7%, but in this study the difference was not statistically significant. Furthermore, the BTA test was not more effective in identifying the various tumor grades, stages or stage/grade groupings. However, dividing the patients in two groups of low risk (TaG1/TaG2) and high risk (TaG3 to >/=T2) leads to a significant (p = 0.008) increased sensitivity of the BTA test (27.3%) in detecting patients with low-risk tumors compared to VUC (3.0%). The specificity of the BTA test in patients with a history of TCC was 81.6%, while that of VUC was 98.9%., Conclusion: The sensitivity of the BTA test is at least equivalent to VUC and may be suited to monitor increase in stage in patients suffering from bladder carcinoma, but cannot replace cystoscopy in patients suspected for a bladder tumor.

For this study, bladder washings of 923 patients with a follow-up for superficial bladder cancer were used. For the prognostication of each case (follow-up period up to 20 mo), two parameters were used: tumor recurrence and the event of (progressing) invasive growth. Each sample was classified as negative, low grade or high grade, based on confocal-aided architectural cytology. The feature architecture was based on the images of the epithelial fragments as seen in the Feulgen stain, which also could be visualized in confocal microscopy. The same three classes were also used for grading the samples according to the QUANTICYT system, in which DNA and morphometry of nuclei were automatically assessed. The 532 cases graded as QUANTICYT high had a worse prognosis than the 391 cases with QUANTICYT low. In addition, architectural cytology contributed significantly for the prognostication of cases classified as QUANTICYT high, the 228 nonconcording cases faring better than the 304 concording ones. For QUANTICYT low, the 156 nonconcording cases had also a lower recurrence rate than the 235 concording ones, but this difference was only significant in patients followed for up to 8 mo. These findings indicate that QUANTICYT grading supplemented by architectural cytology supplies the clinician with valuable prognostic information which can be used to limit cystoscopies.

Objective: To study the value of two outpatient urine tests with regard to the diagnosis and recurrence of bladder tumors., Methods: Fifty patients with a history of superficial bladder cancer were evaluated with urinary NMP22 levels (cutoff level 10 U/ml), bladder wash karyometry (low versus intermediate and high risk) and cystoscopy. All patients were followed for 1 year., Results: Diagnostic negative and positive predictive values (NPV and PPV) of the tests were, respectively: NMP22 91.2 and 56.3%, and karyometry 80 and 33.3%. Prognostic NPV and PPV with regard to a subsequent recurrence were, respectively: NMP22 77.8 and 27.3%, and karyometry 82.6 and 50%., Conclusion: The diagnostic value of NMP22 is good. Since the 3 false-negative results were in low-stage and low-grade lesions, this test could be used as a prescreening for cystoscopy. The NPV of these tests with regard to tumor recurrence is around 80%, but only karyometry has a significant PPV. Change in the follow-up policy on the basis of these tests remains difficult. In patients with neobladders NMP22 appears to be of little use, because of the high urinary NMP22 levels in the absence of malignancy.

Objectives: Two new methods for the detection of transitional tumor cells in bladder wash (karyometry: QUANTICYT) and voided urine material (BARD BTA test) were compared with bladder wash cytology for the prediction of histology and tumor recurrence., Methods: Bladder wash material and voided urine were sampled from 138 patients. Bladder wash karyometric (BWK) image analysis and the BTA test were applied. A subsequent urethrocystoscopy was performed and a bladder tumor, when present, was resected. Moreover, each patient was followed for tumor recurrence and progression., Results: Sensitivities for the detection of tumors were 34.4%, 44.8%, and 69.0% for the BTA test, bladder wash cytology (BWC), and BWK, respectively (BTA versus BWC, P = 0.64; BTA versus BWK, P = 0.0002; BWC versus BWK, P = 0.0001, using the McNemar test). Specificities for the different tests were 81.3%, 92.5%, and 72.5%, respectively (BTA versus BWC, P = 0.096; BTA versus BWK, P = 0.031; BWC versus BWK, P = 0.001, using the McNemar test). Combinations of tests did not result in better prediction of the presence of tumor. Sensitivity of carcinoma in situ for the three tests was 0 of 3, 3 of 3, and 3 of 3, respectively. Follow-up analysis after a negative cystoscopy revealed comparable predictive values for BWC and BWK., Conclusions: The BTA test may be useful for patients with recurrent, low-grade papillary lesions. However, sensitivity for detection of these lesions, although higher than that for BWC, was only 42.9%. The highest specificity was found for BWC; however, this was accompanied by the lowest sensitivity of all three tests. The lower specificity of BWK was accompanied by a better prediction of tumor recurrence after a normal urethrocystoscopy. BWK is particularly sensitive for the recurrence of high-grade bladder lesions.

Bladder wash cytology provides superior results for the detection of bladder malignancies than does voided urine analysis. Image analysis systems have been developed for quantification of cytologic features. In this study, routine bladder wash cytology is compared with an automated image analysis system (QUANTICYT). We studied a random set of 100 bladder wash samples from a population of 1614 patients in follow-up after bladder cancer. Four experienced pathologists interpreted the same 100 Papanicolaou-stained slides. Cytologic and image analysis results were compared for prediction of a cystoscopic lesion, histologic abnormalities, and tumor recurrence. After application of receiver operating characteristic curves, prediction of a cystoscopic lesion by cytology and image analysis was comparable. Both the image analysis system and the cytologic examination detected all of the high-grade lesions. Image analysis was superior to cytologic analysis for the prediction of tumor recurrence after normal findings at cystoscopic examination.

Objectives: Quantitative cytology by image-analysis techniques enables objective interpretation of nuclear features in light microscopic images. QUANTICYT, a quantitative karyometric cytology system, was used in the follow-up of patients with superficial bladder cancer., Methods: From 1992 to 1995, 4137 samples from 1412 patients were obtained. At 1-year follow-up after the initial bladder washing, a tumor recurrence rate of 21% was found. In this period, tumor progression to invasive disease occurred in 1.6% of patients. Scoring of tumor by the QUANTICYT system was based on two nuclear features: the 2c deviation index and the mean of a nuclear shape feature: MPASS., Results: The method was found to be reproducible and superior to visual cytologic interpretation. QUANTICYT analysis of the bladder washings resulted in a score of low, intermediate, and high risk. In a multivariate analysis, highest grade of earlier tumor and QUANTICYT risk score were the best predictors of tumor recurrence and progression. For the easy application of QUANTICYT analysis in daily routine, a report form that included patient history and DNA histogram was developed., Conclusions: QUANTICYT karyometric analysis of bladder-wash material proved a useful, clinically applicable grading tool in the follow-up of patients with superficial bladder cancer, with sufficient power to be used in decision-making in the individual patient.

To assess the value of p53 mutations in predicting the progression of superficial bladder cancer [transitional cell carcinoma (TCC)] and to define exactly when p53 mutations occur in the process of tumor progression, 80 consecutive bladder washings from 26 high-risk (indicated by quantitative karyometric analysis) superficial TCC patients were examined by single-strand conformation polymorphism. Six of 13 patients who experienced clinical progression (progression to T2 or higher) were found to have a p53 mutation in one or more of their bladder washings. In the control group (no progression to invasive disease), only 1 of 13 patients had a p53 mutation. For these high-risk superficial TCC patients, the occurrence of a p53 mutation has a positive predictive value of 86% for the progression of disease. A negative predictive value of 63% was observed. Moreover, because p53 mutations were found in samples prior to progression (mean, 8 months), they could identify patients who need changes in their treatment strategies to prevent progression to invasive disease. Despite these promising results, it is obvious that to increase not only the positive predictive value but especially the negative predictive value of this procedure to predict progression, additional prognostic markers are still needed.

Bladder washings can be used for simultaneous karyometry and proliferation analysis using MiB-1 as a proliferation marker. We analyzed 42 problem cases with a discordance between cytologic and karyometric classification (QUANTICYT), in which the karyometric classification was based on a combination of a nuclear shape parameter and DNA (2cDI). Moreover, 25 concordant cases were analyzed: 5 normal samples, 6 low-grade tumors and 7 high-grade tumors. All normal samples and all low-grade tumors had labelling indices below 10%, and all high-grade tumors over 10%. For the discordant low-grade tumors, the QUANTICYT classification correlated better with the MiB-1 labelling than the cytologic diagnosis. There was a clear correlation between 2cDI and MiB-1 labelling index. Slightly elevated MiB-1 labelling indices might have some prognostic value.

Transitional cell carcinoma of the bladder has a high recurrence rate after local treatment. Progression to a higher stage occurs in 10-30% of the recurrent tumors, and early detection of potentially progressive tumors is important. In the current study morphometric, densitometric, and chromatin textural features of nuclei of superficial bladder tumors (pTa-T1) were studied to determine the value of karyometric features in the prediction of tumor progression. Seventy-two histological samples from 36 patients, consisting of both the primary and the first recurrent superficial tumor, were analyzed. Patients were divided into two groups: those with tumor progression, defined as an increase in tumor stage or occurrence of metastatic disease, and those without. Discriminant analysis on four karyometric features resulted in correct prediction of prognosis of 78% and 97% in the primary and recurrent tumors, respectively (P < 0.001). Tumor grade and stage did not offer additional information concerning prognosis. Karyometric analysis of recurrent superficial transitional cell tumors can be useful in selecting patients who need a more aggressive therapy. However, tumor characteristics of recurrent tumors varied and continuous evaluation of the karyometric features is necessary for early detection of an increase in the malignant potential of the tumor.

An image analysis method of grading histologic sections of bladder carcinoma was tested. The method was new in four respects. First, for fixation of the biopsies a coagulant fixative was used. Second, 2-microns plastic sections were used to ensure the reproducibility of nuclear imaging. Third, a new stereologic approach was used for calculation of the nuclear volume and DNA content. Fourth, for the classification rule the morphometric, densitometric and texture features were used in concert. The IBAS 2000 instrument was used for the measurements. Texture analysis of the chromatin patterns was performed using Markovian texture features. Using discriminant analysis, of 22 parameters, 2 morphometric, 2 densitometric and 3 texture features were selected for the classification rule. With them, 89% of the bladder carcinomas were correctly classified into the three grades. All grade III tumors were classified correctly. Among the features tested, the densitometry of the DNA had the highest F values. All of the grade III tumors and 45% of the grade II tumor group had DNA histograms indicating aneuploidy. This study showed that plastic-embedded material is well suited to morphometry and densitometry and can be used for quantitative grading of bladder carcinoma.

The reproducibility of cytomorphometrical nuclear area measurements on transitional cell carcinoma is studied. The inter-individual consistency is low (r = 0.55, P = 0.0005) when nuclei for measurement are chosen at random. When we use a systematic analysis based on cell situation and cytological features of malignancy to select the 50 nuclei for measurement per slide, the consistency between two technicians appears to be significantly higher (r = 0.90, P = 0.015). Not only interindividual consistency increases using the selection, but the correlation with histological tumour grade also improves significantly for both technicians. The results show that cytomorphometry is a method of grading bladder carcinoma when an accurate selection of nuclei to measure is used. Cytomorphometrical studies should contain a clear description of the way the nuclei for measurement are chosen.

Cytomorphometry, using various cytopreparatory techniques on bladder washings and histomorphometry on the resected bladder tumours, was used in an attempt to answer the question: Can cytomorphometry replace histomorphometry for grading of bladder tumours? For the analysis of quantitative data, a probit model was used. Three out of the four cytomorphometric methods provided data supportive to the histomorphometry. Using one of the four cytomorphometric methods was sufficient to enhance grading accuracy and all were equally good. Two cases of high grade carcinoma in situ were properly identified by cytomorphometry (as judged on the follow-up data) but the concurrent resected papillary tumours were low grade. These findings indicate that cytomorphometry is a useful method in bladder tumour grading. In some cases it is preferable to histomorphometry.