G3 Transitional Cell Carcinoma Research Articles

Diagnostic random bladder biopsies: Reflections from a population-based cohort of 538 patients

To assess whether diagnostic random bladder biopsies and the detection of concomitant carcinoma in situ (CIS) have an impact on the frequency of intravesical bacille Calmette-Guérin (BCG) instillations or radical cystectomy; and whether this affects the cancer-specific survival in patients with pTaG3 or pT1G1-G3 transitional cell carcinoma of the urinary bladder. A population-based cohort of 538 patients with newly diagnosed bladder cancer was prospectively registered in the Stockholm County during 1995 and 1996 and followed for more than 5 years. Random biopsies were recommended in all patients but the decision to take biopsies was made by the treating urologist and hence performed in 326 out of 538 patients (61%), which revealed concomitant CIS in 47 patients(14%). Sixty out of 103 (58%) patients with pTaG3 or pT1G1-G3 tumours, in whom random biopsies were performed, received intravesical BCG compared with five out of 22 patients (23%) where random biopsies were not taken (p = 0.004). Moreover, 23 out of 103 patients (22%) with pTaG3 or pT1G1-G3 tumours in whom random biopsies were performed underwent radical cystectomy compared with none out of 22 patients (0%) without random biopsies (p = 0.013). The Cox proportional hazard ratio for death due to bladder cancer in patients with pTaG3 or pT1G1-G3 tumours among patients not having versus having undergone random biopsies was 2.5 (95% confidence interval 1.1-5.6). Patients diagnosed in Stockholm in 1995 or 1996 with pTaG3 or pT1G1-G3 bladder tumours having undergone random bladder biopsies more frequently underwent BCG treatment and radical cystectomy and had higher cancer-specific survival than patients who did not undergo random biopsies.

Erection‐ and Ejaculation‐Preserving Cystectomy With Orthotopic Urinary Diversion: Is It Feasible?

Nerve-sparing techniques to preserve sexual function in men undergoing cystoprostatectomy have been documented by different centers. We evaluated the results of the first 4 erection- and ejaculation-preserving cystectomies performed in our department. The ages of patients ranged between 36 and 43 years. In all cases, patients wished to maintain sexual function. Of the cases, 3 patients had pT1 G3 transitional cell carcinoma (TCC) refractory to treatment and one had pT2a adenocarcinoma of the bladder. Extirpation of the bladder and anterior proximal prostate en bloc with preservation of the vasa deferentia, seminal vesicles, posterior prostate, and neurovascular bundles was performed after pelvic lymphadenectomy. W-ileal neobladder was performed by using 40 cm of ileum. All patients had erections at the third month. Of the cases, 2 patients had antegrade ejaculation. The ejaculate volumes were 0.8 and 1.2 mL in patients with antegrade ejaculation. Patients in the other cases had retrograde ejaculation. All patients were continent day and night. We started clean intermittent catheterization in 1 case because of residual urine. There were no local recurrences. One patient with TCC died because of systemic disease in the postoperative 32nd month. The most important drawback of potent cases in cystectomy decision is erectile dysfunction after radical cystectomy. This drawback causes delay of the operation and sometimes mortality. As was the case in other reports, our limited number of cases in this study demonstrated that erection and ejaculation could be preserved in selected groups of patients.

Laparoscopic Radical Cystoprostatectomy: Our Experience in A Consecutive Series of 10 Patients with a 3 Years Follow-Up

Objective: Laparoscopic radical cystectomy is a feasible procedure but there is still controversy if laparoscopic treatment of transitional cell carcinoma (TCC) of the bladder is oncologically safe. We report our experience with laparoscopic radical cystectomy in a consecutive series of 10 male patients with a 3 years follow-up. Methods: Between June 2001 and July 2002, 10 men age 63 to 74 years (mean 68.8) underwent laparoscopic cystoprostatectomy with urinary diversion for muscle-invasive TCC or pT1 G3 TCC plus carcinoma in situ (Cis) after 2 cycles of intravesical bacille Calmette-Guerin therapy and three or more transurethral resections (delayed cystectomy). Results: Histopathology revealed 2 stage pT1N0 TCC G3 plus Cis, 1 stage pT2aN0 TCC G3 plus Cis, 1 stage pT2bN0 TCC G2, 4 stage pT2bN0 TCC G2-3, 1 stage pT2bN0 TCC G3, 1 stage pT3aN0 TCC G3. The mean follow-up is 30.4 months (range 23–36). No local recurrences, peritoneal carcinosis or trocar-site metastases occurred. Metastases presented in 4 of 10 cases (2 patients with a stage pT1N0 plus Cis and 2 patients with a stage pT2bN0 TCC) respectively after 7, 14, 16 and 28 months. These patients died respectively at 20, 18, 22 and 31 months later. One patient died for unrelated causes. Five patients are alive, free from disease. Conclusions: Laparoscopic radical cystectomy is feasible and accomplished with low morbidity. Up to now publishing data do not support a verified negative oncological effect of the laparoscopy in the treatment of bladder TCC, but our initial results seem worst than those achieved with open surgery. The experience of other Institutions will help to provide objective evaluation of this new and controvers technique because it is not clearly demonstrated that laparoscopic radical cystectomy is an oncologically safe procedure in the management of bladder TCC. Thus in our opinion it should be still considered experimental.

Curative surgery for solitary adrenal metastasis of pT1 G3 transitional cell carcinoma of the bladder

A preoperative computed tomography scan in a patient undergoing radical cystectomy for pT1N0 grade 3 transitional cell carcinoma revealed a tumor in the adrenal gland. Biopsy was negative, but 2 years later computed tomography showed progression, and adrenalectomy was performed, revealing transitional cell carcinoma. Four years after cystectomy, the patient had no evidence of other metastases. We discuss surgery for solitary metastasis of transitional cell carcinoma as a curative treatment option.

Clinical Outcome and Safety of Bacillus Calmette-Guérin Immunotherapy for Superficial Bladder Cancer

Background: The objectives of this study were to evaluate the effectiveness, the patients compliance and tolerability to bacillus Calmette-Guerin (BCG) intravesical instillation after transurethral resection of bladder tumor (TURBT) for stage Ta–T1, grade G1–G3 transitional cell carcinoma (TCC) of the urinary bladder. Methods: Between January 1995 and May 2002, 127 patients (110 males and 17 females) aged between 40 and 81 years 66.5±8.4 years) with Ta–T1, G1–G3 TCC of the urinary bladder were treated by TURBT and adjuvant intravesical instillation with BCG. The following details were recorded and evaluated: the disease-free survival rates, the tumor recurrence, age, gender, morphology, the size and number of tumors and side effects of BCG instillation. Results: 80 (63%) and 47 patients (37%) initially presented with multifocality and monofocality, respectively, were analyzed. Follow-up periods were 3–48 months (median, 18 months) for 110 of the 127 patients enrolled. At 3 months follow up, 40 multifocali...

Clinical Outcome and Safety of Bacillus Calmette-Guérin Immunotherapy for Superficial Bladder Cancer

Background: The objectives of this study were to evaluate the effectiveness, the patients compliance and tolerability to bacillus Calmette-Guerin (BCG) intravesical instillation after transurethral resection of bladder tumor (TURBT) for stage Ta–T1, grade G1–G3 transitional cell carcinoma (TCC) of the urinary bladder. Methods: Between January 1995 and May 2002, 127 patients (110 males and 17 females) aged between 40 and 81 years 66.5±8.4 years) with Ta–T1, G1–G3 TCC of the urinary bladder were treated by TURBT and adjuvant intravesical instillation with BCG. The following details were recorded and evaluated: the disease-free survival rates, the tumor recurrence, age, gender, morphology, the size and number of tumors and side effects of BCG instillation. Results: 80 (63%) and 47 patients (37%) initially presented with multifocality and monofocality, respectively, were analyzed. Follow-up periods were 3–48 months (median, 18 months) for 110 of the 127 patients enrolled. At 3 months follow up, 40 multifocali...

Laparoscopic radical cystoprostatectomy: a technique illustrated step by step.

Laparoscopic surgery is expanding among urologists as a minimally invasive treatment and may now be applied to treat neoplasms of the pelvic organs. Laparoscopic cystoprostatectomy has still not been well codified and illustrated. We describe a technique of laparoscopic radical cystoprostatectomy that we have developed in 10 patients after practicing in laparoscopic radical prostatectomy. Between June 2001 and July 2002, 10 men with bladder cancer underwent laparoscopic cystoprostatectomy with urinary diversion. This report details step by step our 5-port transperitoneal technique with primary access to the seminal vesicles and Denonvillier's fascia, ureters detection after umbilical arteries incision, endopelvic fascia incision and dorsal vein complex control before division of the vesical and prostatic fibrovascular pedicles with a harmonic scalpel. We performed 6 orthotopic ileal neobladders, 2 sigmoid ureterostomies and 2 cutaneous ureterostomies. In all cases no conversion to open surgery was necessary. The mean time to perform the laparoscopic radical cystoprostatectomy, including the lymph node dissection, was 166 minutes (range 150-180). Mean estimated blood loss was 310 ml (range 220-440). Mean hospital stay was 8.1 days (range 7-9) for ileal orthotopic neobladder, 8 days (range 7-9) for sigmoid ureterostomy and 5 days for cutaneous ureterostomy. The mean follow up is 12.3 months (range 5-18). Two patients respectively with stage T2bN0 G2-3 and stage pT1N0 (plus carcinoma in situ) G3 transitional cell carcinoma and surgical margins tumor free had diffusive metastatic disease after 6 months. The other 8 patients are free from disease. Laparoscopic radical cystectomy is still an operation for pioneers but this procedure may be not strictly relegated to a few academic centers. In our opinion laparoscopic cystoprostatectomy is a feasible, fast, safe and easy procedure and urinary diversion may be performed with a laparoscopic, open or combined approach without reducing the advantages of laparoscopy.

Immunocyt Test Improves the Diagnostic Accuracy of Urinary Cytology: Results of a French Multicenter Study

The limitations of urinary cytology and the invasiveness of cystoscopy generate an increasing interest in noninvasive diagnostic tools for the management of transitional cell carcinoma. We assess the clinical performance of ImmunoCyt (DiagnoCure, Inc., Saint-Foy, Canada) in the detection of bladder cancer in a 10-center French trial. From October 2000 to April 2001, 694 patients undergoing cystoscopy were prospectively included in the study. Of the patients 458 (66%) had been previously treated for superficial transitional cell carcinoma and 236 (34%) were referred for symptoms suggestive of bladder cancer. All patients underwent ImmunoCyt test and standard urinary cytology from voided urine as well as a complete evaluation including cystoscopy and transurethral resection or biopsy of suspicious lesions. Sensitivity and specificity values of urinary cytology and ImmunoCyt whether or not combined were calculated using cystoscopy as the gold standard and histopathology when available. A total of 85 recurrent and 58 newly diagnosed bladder tumors were diagnosed by cystoscopy and histologicaly confirmed. Overall sensitivity of urinary cytology was 17.9%, 46.3% and 63.8% respectively, for G1, G2 and G3 transitional cell carcinoma, whereas that of ImmunoCyt was 60.7%, 75.6% and 76.8%. Sensitivity of the combined tests was 66.7%, 78% and 87%, respectively. Moreover, 10 of 55 (18.2%) new pT1 and pT2 or greater tumors were diagnosed by ImmunoCyt alone. Specificity of urinary cytology was 94.5%, whereas that of ImmunoCyt was 84.2%. Specificity of the combined tests was 80.7%. Marked variations in urinary cytology sensitivity were observed among the different centers (27.3% to 66.7%), whereas combined assays (urinary cytology and ImmunoCyt) enhanced the overall sensitivity in the 80% range at most centers. This prospective multicenter series confirmed a marked increase in sensitivity without significant loss in specificity when including ImmunoCyt in standard urinary cytology protocol. This increased sensitivity was observed in high grade lesions (with 100% sensitivity for carcinoma in situ) as well in low grade, low stage tumors.

Clinical study of G3 superficial bladder cancer without concomitant CIS treated with conservative therapy.

The treatment for superficial G3 transitional cell carcinoma (TCC) of the urinary bladder remains controversial. It is important to reveal the clinical features of superficial G3 bladder cancer that can be treated conservatively. A total of 39 patients with primary superficial bladder cancer (Ta, T1) with G3 components but without concomitant carcinoma in situ (CIS), who had been treated initially with transurethral resection (TUR), were retrospectively analyzed for factors related to tumor recurrence, progression and survival. The patients were 34 males and five females whose age ranged from 49 to 85 years (average, 68 years). Initial tumor stages were Ta in one patient and T1 in 38. Initial treatments were TUR alone in 18 patients and TUR with adjuvant therapy (intravesical chemotherapy or BCG therapy) in 21. Factors examined included age, gender, morphology, size and number of tumors and adjuvant therapies. Follow-up periods were 3-138 months (median, 37 months). Tumor recurrence, progression and cancer death were observed in 23, seven and four cases, respectively. The 5-year progression-free rate (75%) and survival rate (83%) in 39 patients with G3 did not show a statistically significant difference from those of the 109 patients with G1 or the 187 patients with G2 superficial bladder cancer who were treated with TUR initially. Only the rate of recurrence of patients with G3 was significantly higher than that of patients with G2 or G1. Adjuvant therapies reduced the recurrence rate of the patients with G3. Only tumor morphology, papillary or non-papillary, affected both the progression-free rate and the survival rate of patients with G3. There were no statistically significant differences associated with other factors. The results suggest that superficial G3 bladder cancer could be treated with TUR initially, especially for papillary tumors.

Prognostic significance of platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in stage pT1 G3 bladder cancer.

The management of patients with pT1 G3 bladder cancer remains controversial because of the high incidence of recurrence with muscle invasion. Thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and has angiogenic activity. The aim of this study was to determine whether the expression of PD-ECGF/dThdPase in bladder cancer tissue was associated with tumor progression and recurrence in patients with pT1 G3 bladder cancer. Fifteen patients who were pathologically diagnosed as having pT1 G3 transitional cell carcinoma of the bladder were treated with transurethral resection. Sections of paraffin-embedded bladder tissue were immunohistochemically stained with either mAb654-1, a monoclonal antibody against human PD-ECGF or anti-CD34 monoclonal antibody, respectively. When more than 10% of tumor cells were positively stained with mAb654-1, this section was defined as positive in this study. Eight of 15 sections from patients with pT1 G3 bladder cancer (53%) were positive with PD-ECGF/dThdPase. During follow up, patients in the negative group had no disease progression and only two patients had local recurrence. In contrast, seven of eight positives had recurrence (P < 0.05) and progression was also observed in four recurrent patients. However, there was no statistical relationship between PD-ECGF and CD34 expression in any of the patients. The expression of PD-ECGF/dThdPase appears to be an important prognostic factor of pT1 G3 bladder cancer and did not show any significant relationship between PD-ECGF/dThdPase expression and vascular density.

URETHRAL RECURRENCE OF TRANSITIONAL CELL CARCINOMA IN A FEMALE PATIENT AFTER CYSTECTOMY AND ORTHOTOPIC ILEAL NEOBLADDER

A 63-year-old woman presented elsewhere with a unifocal pT1, G3 transitional cell carcinoma at the bladder base in 1995. She underwent urethral sparing cystectomy and ileal neobladder. Intraoperative frozen section from the proximal urethra did not demonstrate tumor involvement. Final histological examination revealed pT1, pN2, G3 transitional cell carcinoma. Adjuvant chemotherapy was not given. In 1998 the patient had symptoms of obstructive voiding due to a 3 3 3 cm. solid mass at the neobladder-urethra anastomosis (see figure). After 6 cycles of methotrexate, vinblastine, doxorubicin and cisplatin and a transient tumor size reduction, the patient was referred to us for local tumor progression. Endoscopy identified a tumor at the neobladder-urethra anastomosis. Magnetic resonance imaging demonstrated a 2.5 3 1 cm. tumor infiltrating the anterior vaginal wall. With a combined abdominovaginal approach complete removal of the tumor was accomplished, including removal of the introitus and vagina, lower third of the ileal neobladder and entire urethra. The ileal neobladder was converted to a continent cutaneous urinary diversion with umbilical stoma. Histopathological examination revealed poorly differentiated transitional cell carcinoma and tumor-free margins of resection. Two months later multiple hepatic metastases were diagnosed and the patient died 3 months later.

RECURRENCE AND PROGRESSION OF STAGE T1, GRADE 3 TRANSITIONAL CELL CARCINOMA OF THE BLADDER FOLLOWING INTRAVESICAL IMMUNOTHERAPY WITH BACILLUS CALMETTE-GUERIN

We prospectively examined the incidence of recurrence and progression in patients with stage pT1, grade 3 carcinoma of the bladder following complete transurethral resection of the bladder tumor and adjuvant immunotherapy with bacillus Calmette-Guerin (BCG). Between July 1987 and March 1999, 123 patients presenting to our clinic with superficial urothelial carcinoma (stage pT1, grades 1 to 3) received adjuvant intravesical immunotherapy with BCG after histologically confirmed complete transurethral tumor resection. Disease was stage pT1, grade 3 in 44 patients (36%). Median followup was 28 months (mean 43, range 5 to 141). Of the patients 36 (82%) with bladder preservation remained tumor-free during followup after 1 or 2 cycles of BCG. Superficial tumor recurred in 5 patients (11%) and muscle invasive progression was noted in 7 (16%). Radical cystectomy was performed in 4 cases (9%). Of the patients 5 (11%) died of cancer. Tumor-free survival for all patients was 89% (39 of 44). Adjuvant immunotherapy with BCG after complete transurethral resection of bladder tumor represents a highly effective primary treatment of stage pT1, grade 3 carcinoma of the bladder. Immediate radical cystectomy does not appear necessary.

P53 Immunoreactivity in biopsy specimens of T1G3 transitional cell carcinoma of the bladder — a helpful parameter in guiding the decision for or against cystectomy?

The aim of this study was to determine whether p53 is helpful in making the decision to undergo cystectomy in T1, G3 transitional cell carcinoma (TCC) of the bladder, by prospectively comparing the p53 status of bladder biopsies with the histology and p53 status of the corresponding cystectomy specimens. From January 1996 to August 1997, 38 consecutive patients with T1G3 TCC at 6 different centres were enrolled into the study. Bladder biopsies and cystectomy specimens were examined with three different antibodies against p53. The p53 status of each bladder biopsy was compared with p53 status, tumour stage and grade of the cystectomy specimen. An independent evaluation of the histology and immunohistochemistry was carried out by two pathologists. 15 of 38 patients (39%) were found to have a higher tumour stage in the cystectomy specimen compared with the staging by transurethral resection of the bladder tumour (TUR-B). 3 patients did not show residual tumour in the cystectomy specimen. No differences in p53 positivity were noted between the different antibodies. 14 of 31 evaluable tumours (45%) were p53 positive at the time of the TUR-B. p53 staining of the TUR-B specimen did not correctly predict the residual tumour in the cystectomy specimen. We, therefore, concluded that compared with standard histopathology, the p53 status of the TUR-B specimen does not provide additional relevant information with regard to local tumour staging and, thus, is not helpful in making the decision for or against a cystectomy.

Expression of the multidrug resistance-associated protein (MRP) gene in urothelial carcinomas.

The intrinsic or acquired resistance of urothelial cancer to chemotherapy is one major obstacle to successful treatment. Generally, the expression level of P-glycoprotein in urothelial cancer is low, so we accordingly investigated the expression of multidrug resistance-associated protein (MRP). We examined the expression of MRP mRNA by means of slot-blotting samples of 11 renal pelvic and/or ureteral tumors, 33 bladder tumors, one lung metastasis from a ureter tumor, 7 non-cancerous urothelia from patients with transitional-cell carcinoma (TCC) and one urothelium from a patient with renal-cell carcinoma (RCC). We also estimated, by Southern blotting, whether or not the MRP gene was amplified in clinical specimens that overexpressed MRP mRNA. MRP was detected immunohistochemically using a polyclonal antibody against MRP. In all, 5 of 11 renal pelvic and/or ureter tumors (45.5%), 17 of 33 bladder tumors (51.5%) and 4 of 7 non-cancerous urothelia of TCC patients (57.1%) expressed more than 2-fold the MRP mRNA levels of drug-sensitive human KB cells. There was no significant difference in the MRP mRNA level between primary and recurrent tumors. Low-grade urothelial carcinomas (G1 and G2 TCCs) expressed significantly higher levels of MRP mRNA than the high-grade G3 TCC. The MRP gene was not amplified in urothelial carcinomas, irrespective of their expression levels of MRP mRNA. Immunohistochemically, MRP was located mainly on the plasma membrane, but also detected on the cytoplasm of cancer cells. MRP may be one mechanism responsible for intrinsic drug resistance in low-grade urothelial cancer.

Results of conservative treatment (transurethral resection plus adjuvant intravesical chemotherapy) in patients with primary T1, G3 transitional cell carcinoma of the bladder

Objectives. To evaluate a selected population of 50 consecutive patients with primary T1, G3 bladder transitional cell carcinoma in the absence of carcinoma in situ (Tis) treated with a bladder-sparing approach.Methods. Between January 1983 and December 1992, all patients were treated by transurethral resection (TUR) plus adjuvant intravesical chemotherapy over 1 year. In most cases, doxorubicin, epirubicin, and mitomycin were used alone or in combination.Results. At a mean follow-up period of 52 months (range, 18 to 126), 16 of 50 patients (32%) showed a recurrent superficial tumor. The recurrent lesion was of Stage T1 in 11 (22%) cases, but was a T1, G3 tumor only in 5 cases (10%). In 2 additional patients (4%) a Tis developed during the observation period after TUR. The mean interval between TUR and first recurrence was 14.6 months (range, 3 to 38). At a mean time of 17 months after the initial TUR, 3 patients (6%) underwent a radical cystectomy due to a progression in T category and 3 additional patients (6%) developed distant metastases at a mean time of 23 months after TUR. In brief, 84% of the patients are alive and tumor-free. Five patients (10%) died of bladder cancer with a mean follow-up of 52 months.Conclusions. If no concomitant Tis exists, a conservative approach is a legitimate option as an initial treatment of patients with primary T1, G3 bladder tumors.

Transurethral resection and intra-arterial chemotherapy for muscle-invasive bladder cancer.

Thirty-three patients with muscle-infiltrating T2-T3a bladder carcinoma were treated by TUR through the full thickness of the bladder wall and extended into the perivesical fat. The solitary tumours were not more than 4 cm in diameter. Histology proved in every case tumour stages of pT2 (17 patients) or pT3a (16 patients), G2 or G3 transitional cell carcinoma and negative mucosal biopsies. After TUR the patients received 1 or 2 cycles of chemotherapy: 60 mg of doxorubicin, 50 mg of cisplatin, 1 g of 5-fluorouracil administered into the ipsilateral hypogastric artery. There was no perioperative mortality but one patient died of complications related to chemotherapy. During the first year of follow-up relapses of muscle-invasive cancer were observed in 3 patients (10%), two were subjected to cystectomy and one to repeated TUR. With a median follow-up of 34 months 27 patients are alive and have functional bladder. The actual 3-year and 5-year survival rates were 17/21 (81%) and 6/9 (67%), respectively. The results of this study suggest that in strictly selected patients extended TUR and intra-arterial chemotherapy may be a bladder-preserving treatment modality for muscle-invasive bladder cancer. Regular (three monthly cystoscopy, cytology, biopsy, CT) investigations and follow-up are necessary to detect recurrences.

Adjuvant Intravesical Chemotherapy in Patients with Primary T1 G3 Transitional Cell Carcinoma of the Bladder

The Authors present their experience with TUR plus adjuvant intravesical chemotherapy in 50 patients affected by primary T1 G3 bladder tumours without previous or concomitant carcinoma in situ. At a mean follow-up of 36 months, 84% of the patients are alive and tumour-free. Cystectomy was performed in three patients due to locally invasive disease. Five patients (10%) died of bladder cancer.