Sten Holmäng

MICROPAPILLARY BLADDER CARCINOMA: A CLINICOPATHOLOGICAL STUDY OF 20 CASES

PURPOSE Micropapillary bladder carcinoma is rare, with only 18 cases reported to date. We report 20 additional cases with long-term followup. MATERIALS AND METHODS A total of 680 patients with an initial diagnosis of bladder carcinoma in western Sweden in 1987 and 1989 were prospectively registered. The clinical records of all 816 patients with bladder cancer treated at Sahlgrenska University Hospital with external beam irradiation between 1962 and 1989 were reviewed. The histopathological material was reviewed and immuno-histochemical analyses were performed on 20 cases identified with micropapillary bladder carcinoma. RESULTS The incidence of micropapillary bladder carcinoma was 0.7%. Mean patient age at diagnosis was 69 years (range 45 to 82) and the male-to-female ratio was 2.3:1. All but 5 patients had stage T3a disease or higher. There was no difference in stage or prognosis between the 5 prospectively identified patients and those treated with external beam irradiation. Only 2 patients had micropapillary bladder carcinoma as the only pattern, while 1 had 10% and the remainder had 20 to 95% micropapillary bladder carcinoma. Transitional cell carcinoma was noted in 17 patients and 5 had areas of gland forming adenocarcinoma. Carcinoma in situ was noted in 13 patients and 15 had lymphatic invasion. Only 5 patients survived 5 years, 1 of whom died of bladder cancer after 7 years. Radiation and chemotherapy did not seem to be effective. CONCLUSIONS The light microscopic appearance, which is strikingly similar to ovarian papillary serous carcinoma, and immunohistochemical staining pattern lend some support to the theory that micropapillary bladder carcinoma is a variant of adenocarcinoma. Since even the focal presence of micropapillary bladder carcinoma is associated with a poor prognosis, recognition of this entity is important. Due to its rarity, the optimal treatment of micropapillary bladder carcinoma needs to be determined in a multicenter study.

FOUR BLADDER TUMOR MARKERS HAVE A DISAPPOINTINGLY LOW SENSITIVITY FOR SMALL SIZE AND LOW GRADE RECURRENCE

PURPOSE We determine the sensitivity and specificity of 3 bladder tumor markers in urine, including NMP22 assay (Matritech, Newton, Massachusetts), BTA stat test (Bion Diagnostic Sciences, Inc., Redmond, Washington) and UBC antigen (IDL Biotech, Sollentuna, Sweden), and bladder wash cytology for new and recurrent bladder cancer. We examine whether tumor size, grade, and stage influence sensitivity and specificity of the markers. MATERIALS AND METHODS A total of 304 samples in 250 patients were studied. There were 174 patients who had a history of bladder cancer, including 93 with and 81 without recurrent tumor at cystoscopy. The other group of patients consisted of 66 with newly diagnosed bladder tumor and 64 investigated for microscopic hematuria that was found to be idiopathic. BTA stat was assayed according to manufacturer instructions. NMP22 and UBC were measured in urine with an enzyme-linked immunosorbent assay. A cutoff level of 4 for NMP22 and 1 for UBC was chosen to get the same specificity for new tumors as BTA stat (75%) RESULTS There was a highly significant difference (p <0.001) in all markers between patients with new bladder tumors and those without. The difference was less pronounced for tumor recurrence for NMP22, UBC and BTA stat (p=0.002, 0.016 and 0.244, respectively). The difference between new and recurrent tumors disappeared when corrected for tumor size, grade and stage. The sensitivity for new tumors was 65%, 75% and 60% for NMP22, BTA stat and UBC, respectively. Cytology had a sensitivity of 41% for new tumors at a specificity of 94%. The specificity for recurrence was 64% for NMP22, 54% BTA stat and 72% UBC. The sensitivity was 45% for NMP22, 55% BTA stat and 40% UBC. CONCLUSIONS Tumor size, grade and stage have a strong impact on sensitivity, and specificity for all 3 tested tumor markers as well as bladder wash cytology. The tumor markers or any combination of them cannot replace followup cystoscopy, mainly because most recurrences are small. The role of the markers for screening high risk populations and as a complement to followup cystoscopy remains to be evaluated.

Transurethral Resection of Non–Muscle-Invasive Bladder Transitional Cell Cancers With or Without 5-Aminolevulinic Acid Under Visible and Fluorescent Light: Results of a Prospective, Randomised, Multicentre Study

BACKGROUND Fluorescent light (FL)-guided cystoscopy induced by 5-aminolevulinic acid (5-ALA) has been reported to detect more tumours compared with standard white-light (WL) cystoscopy. Most reports are from single centres with relatively few patients. OBJECTIVE To evaluate whether 5-ALA-induced FL and WL cystoscopy at transurethral resection (TUR) is superior compared with standard procedures under WL only with respect to tumour recurrence and progression in patients with non-muscle-invasive bladder cancer. DESIGN, SETTING, AND PARTICIPANTS This randomised, multicentre, observer- and pathologist-blinded, prospective phase 3 clinical trial enrolled 300 patients, and of those patients, 153 were randomised to FL cystoscopy and 147 were randomised to standard WL cystoscopy. INTERVENTION All patients were first inspected under WL and all lesions were recorded. Patients randomised to FL underwent a second inspection. TUR was carried out in both groups. MEASUREMENTS Control cystoscopy under WL was performed in all patients every 3 mo during the first year after randomisation and biannually thereafter. RESULTS AND LIMITATIONS At the first TUR, the mean number of resection specimens per patient was 2.5 (FL: 2.5; WL: 2.4; p=0.37) and the resulting mean number of resected tumours was 1.7 with FL and 1.8 with WL (p=0.85). More patients were diagnosed with carcinoma in situ (CIS) in the WL group (13%) than in the FL group (4.2%). Within-patient comparison of FL patients only showed that FL detected more lesions than WL. Tumour lesions solely detected by FL cystoscopy that would not otherwise be detected by WL cystoscopy included 52% dysplasia, 33% CIS, 18% papillary neoplasms, 13% pT1, and 7% pTa. Outcome at 12 mo did not show any difference between groups with regard to recurrence-free and progression-free survival rates. CONCLUSIONS In this prospective, randomised, multi-institutional study, we found no clinical advantage of FL cystoscopy compared with WL cystoscopy and TUR.

INTRAVESICAL BACILLUS CALMETTE-GUERIN AND DIMETHYL SULFOXIDE FOR TREATMENT OF CLASSIC AND NONULCER INTERSTITIAL CYSTITIS:: A PROSPECTIVE, RANDOMIZED DOUBLE-BLIND STUDY

PURPOSE We conducted a prospective, double-blind study with a crossover design of intravesical bacillus Calmette-Guerin (BCG) and dimethyl sulfoxide to determine whether patients with classic and nonulcer interstitial cystitis, respectively, might benefit from either regimen. MATERIALS AND METHODS A total of 21 patients, including 11 with classic and 10 with nonulcer interstitial cystitis, randomly underwent treatments with intravesical BCG or dimethyl sulfoxide and, if not improved, were treated with the other substance after a washout period. All 21 patients were evaluated with symptom questionnaires, including a visual analog pain scale and voiding diaries. RESULTS Regardless of regimen, there was no improvement in maximal functional capacity. There was a reduction in urinary frequency following dimethyl sulfoxide treatment but only in the classic subtype (p <0.05), whereas no reduction was seen following BCG in either subtype. A substantial pain decrease was noted in classic (p <0.05) as well as nonulcer (p <0.05) interstitial cystitis following dimethyl sulfoxide. CONCLUSIONS Intravesical BCG has been presented as a promising new option for treatment of interstitial cystitis. We failed to demonstrate benefit from this treatment. Dimethyl sulfoxide had no positive effect on maximal functional capacity but resulted in a significant reduction in pain and urinary frequency, although only in patients with classic interstitial cystitis.

Combined treatment with temporary short-term high dose rate Iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma

PURPOSE To evaluate the treatment outcome after radical radiotherapy of localized prostate cancer in 50 patients (38 patients with stage T1-2 and 12 patients with stage T3) after a median follow-up time of 45 months (range 18-92 months). METHODS The treatment was given by combination of external beam radiotherapy (50 Gy) and brachytherapy (2 x 10 Gy). The brachytherapy was given using TRUS-guided percutaneously inserted temporary needles with a high dose rate remote afterloading technique with Ir-192 as the radionuclide source. Three target definitions and dose levels inside the prostate gland were used. Local control was evaluated by digital rectal examination, TRUS-guided biopsies and serum PSA evaluations. RESULTS Clinical and biopsy verified local control was achieved in 48 of the 50 (96%) patients; for stage T1-2 in 37 of 38 (97%) patients and for stage T3 in 11 of 12 (92%) patients. A posttreatment serum PSA level < or =1.0 ng/ml was seen in 42 (84%) patients, values from >1.0 to < or =2.0 ng/ml were seen in four (8%) patients and values exceeding 2.0 were seen in four (8%) patients. The late toxicity was minimal. CONCLUSION The local control results and the minimal toxicity after the combined radiotherapy treatment are promising. However, long term results are necessary before general use.

Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder

Background:The European Organization for Research and Treatment of Cancer (EORTC) risk tables and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model are the two best-established predictive tools to help decision making for patients with non-muscle-invasive bladder cancer (NMIBC). The aim of the current study was to assess the performance of these predictive tools in a large multicentre cohort of NMIBC patients.Methods:We performed a retrospective analysis of 4689 patients with NMIBC. To evaluate the discrimination of the models, we created Cox proportional hazard regression models for time to disease recurrence and progression. We incorporated the patients calculated risk score as a predictor into both of these models and then calculated their discrimination (concordance indexes). We compared the concordance index of our models with the concordance index reported for the models.Results:With a median follow-up of 57 months, 2110 patients experienced disease recurrence and 591 patients experienced disease progression. Both tools exhibited a poor discrimination for disease recurrence and progression (0.597 and 0.662, and 0.523 and 0.616, respectively, for the EORTC and CUETO models). The EORTC tables overestimated the risk of disease recurrence and progression in high-risk patients. The discrimination of the EORTC tables was even lower in the subgroup of patients treated with BCG (0.554 and 0.576 for disease recurrence and progression, respectively). Conversely, the discrimination of the CUETO model increased in BCG-treated patients (0.597 and 0.645 for disease recurrence and progression, respectively). However, both models overestimated the risk of disease progression in high-risk patients.Conclusion:The EORTC risk tables and the CUETO scoring system exhibit a poor discrimination for both disease recurrence and progression in NMIBC patients. These models overestimated the risk of disease recurrence and progression in high-risk patients. These overestimations remained in BCG-treated patients, especially for the EORTC tables. These results underline the need for improving our current predictive tools. However, our study is limited by its retrospective and multi-institutional design.

The nested variant of transitional cell carcinoma-a rare neoplasm with poor prognosis

The “nested” variant of transitional cell carcinoma is a rare variant composed of apparently clusters of urothelial cells, of benign appearance, which often simulate von Brunn’s nests and invade into the lamina propria or deeper. Only 36 cases have been reported to date and herein we report an additional 10 cases. Of these 10 cases treated with locoregional therapy, seven died of disease or treatment complications 4–40 months after diagnosis while one patient died of unrelated disease after 90 months. Follow-up is μ1 year for the remaining two patients. Our data and a review of the literature supports the assertion that the nested variant of transitional cell carcinoma is an aggressive neoplasm.

Systematic Review and Individual Patient Data Meta-analysis of Randomized Trials Comparing a Single Immediate Instillation of Chemotherapy After Transurethral Resection with Transurethral Resection Alone in Patients with Stage pTa-pT1 Urothelial Carcinoma of the Bladder: Which Patients Benefit from the Instillation?

CONTEXT The European Association of Urology non-muscle-invasive bladder cancer (NMIBC) guidelines recommend that all low- and intermediate-risk patients receive a single immediate instillation of chemotherapy after transurethral resection of the bladder (TURB), but its use remains controversial. OBJECTIVE To identify which NMIBC patients benefit from a single immediate instillation. EVIDENCE ACQUISITION A systematic review and individual patient data (IPD) meta-analysis of randomized trials comparing the efficacy of a single instillation after TURB with TURB alone in NMIBC patients was carried out. EVIDENCE SYNTHESIS A total of 13 eligible studies were identified. IPD were obtained for 11 studies randomizing 2278 eligible patients, 1161 to TURB and 1117 to a single instillation of epirubicin, mitomycin C, pirarubicin, or thiotepa. A total of 1128 recurrences, 108 progressions, and 460 deaths (59 due to bladder cancer [BCa]) occurred. A single instillation reduced the risk of recurrence by 35% (hazard ratio [HR]: 0.65; 95% confidence interval [CI], 0.58-0.74; p<0.001) and the 5-yr recurrence rate from 58.8% to 44.8%. The instillation did not reduce recurrences in patients with a prior recurrence rate of more than one recurrence per year or in patients with an European Organization for Research and Treatment of Cancer (EORTC) recurrence score ≥5. The instillation did not prolong either the time to progression or death from BCa, but it resulted in an increase in the overall risk of death (HR: 1.26; 95% CI, 1.05-1.51; p=0.015; 5-yr death rates 12.0% vs 11.2%), with the difference appearing in patients with an EORTC recurrence score ≥5. CONCLUSIONS A single immediate instillation reduced the risk of recurrence, except in patients with a prior recurrence rate of more than one recurrence per year or an EORTC recurrence score ≥5. It does not prolong either time to progression or death from BCa. The instillation may be associated with an increase in the risk of death in patients at high risk of recurrence in whom the instillation is not effective or recommended. PATIENT SUMMARY A single instillation of chemotherapy immediately after resection reduces the risk of recurrence in non-muscle-invasive bladder cancer; however, it should not be given to patients at high risk of recurrence due to its lack of efficacy in this subgroup.

IRRADIATION OF LOCALIZED PROSTATIC CARCINOMA WITH A COMBINATION OF HIGH DOSE RATE IRIDIUM-192 BRACHYTHERAPY AND EXTERNAL BEAM RADIOTHERAPY WITH THREE TARGET DEFINITIONS AND DOSE LEVELS INSIDE THE PROSTATE GLAND

PURPOSE Localized prostate cancer was treated with combined external beam radiotherapy and high dose rate Ir-192 brachytherapy with the purpose of a high dose. The technical aspects of a modified treatment are described. METHODS The brachytherapy was given in two sessions preceded and succeeded by external beam radiation. The radioactive source was temporarily implanted by a remote afterloading device through six to 15 needles inserted transperineally guided by transrectal ultrasound. The entire prostate gland was included in the clinical target volume. The urethra and the tumour volume could be defined and irradiated to different dose levels in more than 90% of the patients. RESULTS Fifty-four patients were treated. The total dose to the prostate was approximately 70 Gy and to the tumour volume 80 Gy. By calculating the corresponding dose given by 2.0 Gy fractions, considering the radiobiology by using the LQ formula and assuming an alpha/beta value for prostate tissue of 10, the dose to the prostate was approximately 84 Gy and to the tumour volume 112 Gy. For the late effects to the urethra an alpha/beta value of 3 was used, which corresponds to 85 Gy. The brachytherapy could be given with accuracy except when the dorsal border of the prostate was concave. The dose distribution then tended to be less satisfactory. Post-treatment calculations showed that the maximum dose to the rectum was 67 Gy (radiobiologically corrected to 88 Gy), given in a small volume. The early side effects from the brachytherapy were minimal. The treatment could not be performed as intended in four patients; three patients had a narrow pelvis and in one patient the prostate was unusually resilient, preventing the needles from being positioned properly. CONCLUSIONS This modification of a previously reported brachytherapy technique for prostate carcinoma permits a high radiation dose to the tumour and to the prostate gland, which ultimately may improve local control.

The Cost of Bladder Tumour Treatment and Follow-up

Objective: To evaluate the costs of bladder tumour treatment and follow-up. Material and Methods: The incidence of bladder tumours, both new and recurrences, and the cost of bladder tumour treatments with curative intent were registered during a 4-year period (1994-97). Results: The incidence of new tumours varied from year to year, in contrast to the number of recurrent tumours, which remained remarkably stable. The total cost of bladder cancer diagnosis, treatment and follow-up was almost 7000000 SEK per year (2800000 SEK per 100000 inhabitants per year). The number of therapeutic events per year remained stable at 256 - 17 (102 per 100000 inhabitants per year). Cystectomies were responsible for 34% of the expenditure and transurethral procedures for 40%. Follow-up cystoscopies accounted for only 13% of the total cost. One-third of the routine follow-up cystoscopies resulted in a therapeutic procedure. The cost of transurethral resections and extirpations was approximately five times higher when performed with the patient hospitalized compared to when performed as day-care surgery. Conclusions: A reduction in the number of follow-up cystoscopies will only produce marginal economic savings. Further savings could be made if more transurethral resections and extirpations/fulgurations were performed on an outpatient basis. Another important goal is to reduce the median cost per cystectomy.