Risk of concomitant carcinoma in situ determining biopsy candidates among primary non-muscle-invasive bladder cancer patients: Retrospective analysis of 173 Japanese cases

Objectives:   To determine candidates for bladder biopsies among Japanese primary non-muscle-invasive bladder cancer patients according to the risk of concomitant carcinoma in situ (CIS).
Methods:   Between January 1992 and August 2006, 173 primary non-muscle-invasive bladder cancer cases underwent transurethral resection of the bladder tumor with bladder biopsies for the detection of CIS. Correlations between biopsy results and preoperative/pathological features were retrospectively analyzed.
Results:   Positive cytology was statistically associated with the presence of concomitant CIS in multivariate analysis ( P  < 0.01). Abnormal cystoscopic appearance outside the tumor almost achieved statistical significance in multivariate analysis among preoperative factors ( P  = 0.06). In our series, one (12.5%) of eight low-risk, 18 (24.7%) of 73 intermediate-risk and 41 (59.4%) of 69 high-risk cases had CIS in normal-looking sites, respectively. In cases with a single papillary tumor and negative cytology, one of 16 (6.3%) had concomitant CIS in their biopsy specimens at the normal-looking sites.
Conclusions:   All non-muscle-invasive bladder cancer patients with positive cytology are candidates for additional random biopsies. Targeted biopsies should be performed for all suspicious areas in the bladder mucosa. Random biopsies should be considered in cases with the macroscopic types of cancer for predicting intermediate- and high-risk cancer.     

Prognostic significance of biopsy results of normal-looking mucosa in cases of superficial bladder cancer

Quadrant biopsies of normal-looking mucosa were used as part of the assessment of cases with superficial Ta,T1 transitional cell cancer of the bladder. Patients with one or more abnormal biopsies were shown to have a significantly greater chance of developing recurrent tumour compared to patients with normal mucosal biopsy findings. Other factors noted at the time of initial assessment, such as size, number of tumours, Ta,T1 category or grade of tumour did not predict recurrence, although recurrences that invaded muscle were associated with G3 histology in the primary tumour. The results of mucosal biopsy identified patients at risk for recurrence and it is possible that this group would derive particular benefit from adjuvant chemotherapy.     

Significance of random bladder biopsies in superficial bladder cancer

OBJECTIVES: We investigated to what extent biopsies of normal-appearing urothelium taken from patients with superficial bladder cancer (Ta, T1, Tis) showed malignant disease and whether those findings had impact on therapeutical decisions. PATIENTS AND METHODS: 1033 consecutive patients presenting with Ta, T1 or Tis (carcinoma in situ) superficial bladder tumors at increased risk for recurrence underwent multiple random biopsies from normal-appearing urothelium during transurethral resection (TUR). Patients with small, primary, singular tumors (smaller or equal to 1cm) were excluded from random biopsies. RESULTS: No tumor was found in the random biopsies of 905 patients (87.6%). 128 patients (12.4%) showed urothelial bladder cancer in their random biopsies (Tis: 74, Ta: 41, T1: 12, T2: 1). In 14 patients, where transurethral resection of the primary tumor revealed no signs of malignancy, urothelial bladder cancer was detected in the random biopsy material: Ta 8 patients, Tis 5 patients and T1 one patient. 21 patients with Ta tumors and 29 patients with T1 disease showed concomitant Tis. Upstaging of the primary, resected tumor by histological examination of the random biopsy material occurred in 75 patients (7%). Altogether, due to the random biopsy results therapy was altered in 70 patients (6.8%) of our series: It changed intravesical chemotherapy to BCG in 45, provoked a second TUR in 48 and cystectomy in 15 patients. CONCLUSIONS: While the clinical significance of random biopsies is still controversial, random biopsy results had strong impact on therapeutical decisions in our series. Regarding random bladder biopsies a simple tool for the urologist to identify high risk groups of patients, we recommend them as part of the routine management of superficial bladder cancer.     

Do normal mucosal biopsies predict prognosis in patients with transitional cell carcinoma of bladder treated by radical radiotherapy?

A biopsy of normal-looking mucosa showed mucosal abnormalities in 48.9% of patients with transitional cell carcinoma of the bladder. The presence of dysplasia or carcinoma in situ was significantly associated with grade but not with tumour category. In 100 patients who completed a course of radical megavoltage X-ray therapy, the result of mucosal biopsy gave no significant prognostic information about tumour regression, durable local control, survival or the risk of subsequent metastases.     

The significance of random bladder biopsies in superficial bladder cancer

Introduction: Today, there is no consensus about taking random bladder biopsies during transurethral resection of superficial bladder tumors for staging and to determine the urothelial abnormalities like dysplasia and carcinoma in situ. The aim of our study was to evaluate the results and indications of random bladder biopsies for primary superficial bladder cancer.Patients and methods: Random bladder biopsies were taken from 84 patients with primary superficial bladder cancer after transurethral resection. 40 patients had Ta and 44 had T1 tumor. The random biopsies were taken from right and left bladder walls, anterior and posterior walls, dome, trigone and prostatic urethra. The incidence of urothelial abnormalities were evaluated according to the stage and grade of the tumor.Results: None of the patients had carcinoma in situ or dysplasia with Ta tumor. In T1 group, 4 patients (9.1%) had carcinoma in situ and 3 patients (6.8%) had dysplasia. There was a statistically significant difference with regard to urothelial abnormalities between groups Ta and T1. The same difference was also seen between low and high grade tumors.Conclusion: In our study, only 7/84 (8.3%) of patients with primary superficial bladder cancer had urothelial abnormalities like carcinoma in situ or dysplasia. All of these pathologies were seen in T1 tumors. According to our results, we believe that random biopsies are not useful in superficial bladder cancers to detect urothelial abnormalities and also do not help for the planning of further treatment.     

Reduced bladder tumour recurrence rate associated with narrow‐band imaging surveillance cystoscopy

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b What’s known on the subject? and What does the study add? Narrow‐band imaging cystoscopy is a new imaging modality developed to enhance conventional standard white‐light cystoscopy to evaluate bladder tumors. The current paper suggests that fulguration of low‐risk papillary bladder tumours using NBI cystoscopy results in fewer subsequent tumour recurrences than fulguration using standard cystoscopy. How, or if, NBI cystoscopy will become integrated into routine management of non‐invasive bladder tumours remains for further study.

OBJECTIVE

To evaluate frequency of recurrences among patients with papillary bladder tumours followed sequentially with conventional white‐light (WLI) cystoscopy and narrow‐band imaging (NBI) cystoscopy.

PATIENTS AND METHODS

A cohort of 126 patients with recurrent low‐grade papillary bladder tumours were followed every 6 months for 3 years by conventional WLI cystoscopy, and then over the next 3 consecutive years by NBI cystoscopy. Recurrent tumours detected were treated by outpatient fulguration or transurethral resection. We compared the tumour recurrence rate during follow‐up with WLI and NBI cystoscopy, using patients as their own controls.

RESULTS

Of the 126 patients, 94% had tumour recurrences during WLI cystoscopy vs 62% during NBI cystoscopy. The mean number of recurrent tumours was 5.2 with WLI cystoscopy vs 2.8 with NBI cystoscopy, and the median recurrence‐free survival time was 13 vs 29 months (P= 0.001).

CONCLUSION

Compared with follow‐up with WLI cystoscopy, NBI cystoscopy was associated with fewer patients having tumour recurrences, fewer numbers of recurrent tumours, and a longer recurrence‐free survival time.     

Recent clinical trials in superficial bladder cancer

The present review addresses literature regarding the management of superficial bladder cancer published since March 2000. There is no definitive winner among urinary markers of bladder cancer, because they lack specificity or are insufficiently tested. Pathologists continue in their efforts to improve prediction of evolution of superficial bladder cancer to recurrent or infiltrative disease. A few studies have confirmed the value of previously described prognostic factors for recurrence and progression, and have added some refinements. Transurethral resection is not as complete as was believed. Fluorescence detection of flat bladder carcinoma has been demonstrated to improve diagnosis and treatment. The necessity to perform a repeat transurethral resection in high-grade superficial bladder cancer became evident. Identification of the working mechanisms of bacille Calmette-Guérin on superficial bladder cancer remains an important objective, and may help to improve treatment schedules and avoid the morbidity associated with bacille Calmette-Guérin administration. Patients who are at high risk may benefit from long-term maintenance bacille Calmette-Guérin therapy. Valrubicin and keyhole limpet haemocyanin appear to be promising agents in the treatment of superficial bladder cancer.     

The sensitivity and clinical implications of periodical bladder biopsy following transurethral resection of superficial bladder transitional cell carcinoma

The role of the periodical bladder biopsy after transurethral resection (TUR-Bt) of superficial bladder cancer (sBT) was evaluated. Sixty-four patients (85 TURs) with sBT who underwent TUR-Bt between 1993 and 1998 were divided into 14 (22 TURs) who had carcinoma in situ (CIS) at the first TUR (group A), and 50 (64 TURs) who had papillary tumors without concomitant CIS (group B). Post-TUR intravesical instillation was performed with bacillus Calmette-Guerin for the majority of group A, and mitomycin C for the majority of group B. The first biopsy was performed at 3 months postoperatively, and the second biopsy was done at 8 to 12 months postoperatively. The mean observation time was 4 years and 6 months. Residual cancer was detected in 7 out of 34 biopsies (20.6%) in group A, and 19 out of 94 (20.2%) in group B. Every residual lesion in group A was CIS with negative cytology. In group B, with exclusion of 11 recurrent papillary tumors, the detection rate was only 8/83 (9.6%). In both groups, even in the cases with no sign of disease in biopsies, the recurrence immediately after the termination of the biopsy protocol was common. The progression of the cancer was more frequent in group A (4 patients), than in group B (2 patients) (p < 0.01, log-rank test), and no case in group B showed local progression. The periodical biopsy may have a certain, but limited advantage over conventional examinations. A less invasive and more sensitive method in awaited.     

Risk factors for multiple intravesical recurrences of superficial bladder cancer

Objectives. To elucidate the risk factors for a second or third intravesical recurrence in patients with superficial bladder cancer.Methods. Of 84 consecutive patients newly diagnosed as having superficial bladder cancer in Sapporo Medical University Hospital, 30 patients who had at least one recurrent superficial bladder cancer and were followed up for more than 3 years were included in this study. Multivariate analysis by Cox’s proportional hazards model was used to determine which clinical and pathologic variables significantly affected the second and third recurrences. Stepwise regression analysis was used to determine which clinical and pathologic variables significantly affected multiple recurrences of bladder cancer.Results. The 1, 2, and 5-year recurrence-free rates as determined by the Kaplan-Meier method were 66.1%, 43.8%, and 29.8% for a second recurrence and 67.4%, 61.8%, and 39.2% for a third recurrence, respectively. Multivariate analysis revealed that only the interval between the initial transurethral resection of the bladder cancer and the first recurrence was a significant and independent factor affecting the second recurrence. In the study of the third recurrence, the interval between the first and second recurrences was the only definite risk factor for the third one. When multiple recurrences were considered, stepwise regression analysis revealed that a time of 6 months or less from the initial transurethral resection until the first recurrence was a significant factor that affected the total frequency of bladder cancer recurrence (R² = 0.220, P = 0.0078).Conclusions. The results of our study indicate that patients will have the potential for frequent recurrences if they have the disease with recurrence after a short interval. This result may contribute to the selection of patients with superficial bladder cancer to receive aggressive adjuvant treatments to prevent frequent recurrences.     

Value of random mucosal biopsies in the management of superficial bladder cancer.

115 newly diagnosed patients with Ta-T1, G1-G2 superficial transitional cell carcinoma of the bladder underwent four quadrant biopsies of normal-looking bladder mucosa, in addition to the endoscopic treatment of the primary tumour or tumours. In 88 (77%) patients all the biopsies were normal; in the other 27 (23%) at least one biopsy revealed dysplasia or carcinoma in situ or G1-G2 carcinoma. 88 patients presented with a single tumour, of which 14 (16%) had abnormal biopsies compared to 13 (48%) of the 27 presenting with multiple tumours. The difference between the 2 groups was statistically significant (p < 0.01). The incidence of freedom from new tumours at 5 years was 68% in patients with normal biopsies compared to 33% in patients with abnormal biopsies (p = 0.002). In patients presenting with multiple tumours and in those with single tumours and abnormal biopsies, the incidence of freedom from new tumours was significantly lower than in those presenting with single tumours and normal mucosal biopsies (p = 0.002). The study shows that the exercise of performing random mucosal biopsies is particularly useful in patients presenting with single tumours, in order to identify those who are more likely to develop new tumours over the longer term. Such patients could be offered early prophylactic intravesical chemotherapy. The study did not substantiate tumour implantation as a factor for new tumour development in superficial bladder cancer.     

Active surveillance for low-risk bladder cancer

BackgroundMost newly diagnosed bladder cancers present as non–muscle invasive bladder cancer (NMIBC). NMIBC is a heterogeneous disease with varying treatment options, follow-up schedules, and oncologic outcomes. We sought to review the role of active surveillance for low risk bladder cancer in the literature.MethodsA PubMed search was performed using the following keywords: active surveillance, low risk, bladder, transurethral resection of bladder tumor, cost, and quality of life. Relevant articles were reviewed and utilized.ResultsLow-risk bladder cancer—defined as pTa low-grade papillary tumors—is the type of NMIBC with the most favorable oncologic outcome and which almost never progresses to muscle invasive disease or metastasizes. Bladder cancer has the highest per patient treatment costs of all cancers. One of the reasons is the high rate of recurrence. Patients with low-grade bladder tumors often experience a recurrence after primary transurethral resection. Many patients undergo multiple resections in the hospital.ConclusionsAppropriately selected patients with recurrent low-risk bladder cancer could be managed with either office fulguration or cystoscopic surveillance. Active surveillance for patients with low-risk bladder cancer avoids or delays the surgical and anesthetic risks of a TURBT, thus optimizing quality of life without compromising the patient's risk of cancer progression.     

A comparison of white-light cystoscopy and narrow-band imaging cystoscopy to detect bladder tumour recurrences

OBJECTIVE

To determine whether narrow‐band imaging (NBI) cystoscopy enhances the detection of non‐muscle‐invasive bladder tumours over standard white‐light imaging (WLI) cystoscopy, as surveillance WLI is the standard method used to diagnose patients with recurrent bladder tumours, but they can be missed by WLI cystoscopy, possibly accounting for early recurrences.

PATIENTS AND METHODS

We evaluated 427 patients for recurrent bladder tumours by WLI cystoscopy, followed by NBI cystoscopy as a further procedure, using the same video‐cystoscope. Recurrent tumours visualized by WLI or NBI cystoscopy were mapped, imaged, biopsied and subsequently treated by transurethral resection (TUR) or fulguration. Biopsies or TUR specimens obtained by WLI and NBI were examined separately for presence of tumour.

RESULTS

In all, 103 patients (24%) had tumour recurrences; 90 (87%) were detected by both WLI and NBI and another 13 (100%) only by NBI cystoscopy. NBI detected extra papillary tumours or more extensive carcinoma in situ in 58 (56%) patients found to have recurrences. The mean number of recurrent tumours visualized on WLI cystoscopy was 2.3, vs to 3.4 seen on NBI cystoscopy (P = 0.01).

CONCLUSION

NBI cystoscopy improved the detection of recurrent non‐muscle‐invasive bladder tumours over standard WLI cystoscopy.     

Monitoring endoscopic treatment of superficial bladder carcinoma by postoperative urinary cytology

Transurethral resection was the only modality of treatment in 39 patients with long-standing, recurrent, superficial bladder carcinoma. Postoperative urinary cytology was performed within 3 days of each endoscopy. Tumor recurrence was defined by the presence of a positive biopsy or visible papillary tumors on followup cystoscopic examination. Tumor recurred in 38 patients (97.4 per cent) and 1 patient (2.6 per cent) has remained free of disease 74 months following transient positive postoperative cytology. Among the 38 recurrences 15 (39.5 per cent) were positive, 3 (7.9 per cent) suspicious and 20 (52.6 per cent) negative at the postoperative cytological examination. The interval to recurrence did not differ significantly among the 3 groups. The failure of a negative postoperative cytology study to predict a durable response to treatment by transurethral resection reflects the polychronotopic nature of superficial bladder tumors in this select patient population and suggests the need for adjuvant therapy.     

Diagnosis of urothelial carcinoma of the bladder using fluorescence endoscopy

Bladder cancer is a frequent disease and represents the second most common genitourinary neoplasm. Although many aspects of the management of superficial bladder cancer are now well established, significant challenges remain, which influences patient outcome. Early detection and treatment of recurrent disease is required to optimize bladder preservation, reduce patient morbidity, and increase quality of life and survival. Fluorescence endoscopy, often referred to as 'photodynamic diagnosis' (PDD), with intravesical application of photosensitizing agents, has been developed to enhance the early detection of bladder cancer. There is growing evidence that PDD using 5-aminolaevulinic acid (ALA), hexyl-ALA ester or hypericin enhances the detection of bladder cancer, particularly of high-grade flat lesions. Furthermore, transurethral resection of bladder tumour under fluorescence guidance reduces the risk of recurrent tumours. However, the impact on the progression of disease remains unclear and must be investigated in prospective randomized trials.     

Bladder cancer in cystoscopically normal‐appearing mucosa: a case of mistaken identity?

Study Type – Diagnosis (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To test the frequency of malignancy in normal‐appearing urothelium in patients with high‐risk bladder cancer, as biopsy of normal‐appearing mucosa using standard white‐light cystoscopy (WLC) reportedly shows carcinoma in situ (CIS) in some patients with bladder tumours.

PATIENTS AND METHODS

Cold‐cup biopsies of normal‐appearing mucosa were obtained by two experienced oncological urologists from 63 patients during transurethral resection of bladder cancers. Each biopsy labelled as ‘normal’ was interpreted by two expert uropathologists.

RESULTS

Each of the biopsies in all 63 patients was interpreted by both urological pathologists as showing normal or benign histology, except that one showed focal CIS.

CONCLUSIONS

Bladder urothelium appearing normal to expert urological oncologists using standard WLC rarely shows CIS when biopsies are evaluated by experienced uropathologists.     

Exfoliative cytology after transurethral resection of superficial bladder tumours

Fifty-one patients with predominantly superficial bladder tumours underwent prospective cytological examination at predetermined intervals following surgery in order to evaluate the prognostic reliability of bladder irrigation cytology. The results suggest that positive cytology 3 days after radical transurethral resection is a reliable indicator of incomplete resection or additional occult tumour foci. The implications for post-operative management and follow-up are discussed.     

Does cystoscopy correlate with the histology of recurrent papillary tumours of the bladder?

OBJECTIVE: To correlate the cystoscopic appearance of recurrent papillary bladder tumours with the histology after transurethral resection, and thus ascertain whether cystoscopy can reliably identify low-grade, noninvasive papillary tumours suitable for outpatient fulguration. PATIENTS AND METHODS: In all, 150 recurrent papillary tumours of the bladder identified at outpatient flexible cystoscopy were classified as either low-grade and noninvasive (TaG1), high-grade and noninvasive (TaG3), or invasive (TIG3) tumours, and correlated with urine cytology and histology of tumour stage and tumour grade after transurethral resection. RESULTS: Cystoscopy classified 84 of the 150 papillary tumours as TaG1 and 66 as either TaG3 or T1G3. Cystoscopy correctly predicted the histology of 78 of 84 (93%) TaG1 tumours, 71 of 72 (98%) TaG1 tumours associated with a negative urine cytology, and 92% of TaG3 or T1G3 tumours. CONCLUSIONS: A skilled urologist can identify noninvasive, low-grade recurrent papillary bladder tumours on follow-up cystoscopy that do not require biopsy and that may be treated by outpatient fulguration alone.     

Transurethral Resection of Non–muscle-invasive Bladder Cancer

Transurethral resection of the bladder (TURB) is the initial and critical step in the management of bladder tumours. The aim of the procedure is to establish the histologic diagnosis, determine the tumour stage and grade, and achieve complete removal of papillary non–muscle-invasive tumours. Although TURB is a frequently performed procedure, its results are limited by the high recurrence rate and by the risk of tumour understaging. The major prerequisite for optimal outcomes is a systematically and meticulously performed procedure by a well-trained urologist. Smaller tumours can be resected en bloc; tumours >1 cm should be resected separately in fractions. Deep resection, including the detrusor muscle, is essential for correct staging. The biopsy should be taken from all areas suggestive of carcinoma in situ (CIS), and biopsies from normal-looking mucosa are recommended only in patients with positive cytology or non-papillary tumours. TURB should be performed with modern equipment, including new telescopes and video systems. Moreover, urologists should be aware of promising innovations, including new imaging techniques, and their possible benefits.Re-TUR can improve recurrence-free survival (RFS) and tumour staging. It is recommended in any patient with a T1 or high-grade tumour at initial resection and when the pathologist has reported that the specimen contained no muscle. It should also be considered in cases where the urologist is not sure that the initial resection was complete, especially in extensive and multiple tumours.     

Thulium laser resection via a flexible cystoscope for recurrent non‐muscle‐invasive bladder cancer: initial clinical experience

OBJECTIVE

To present our initial experience of thulium laser resection via a flexible cystoscope for recurrent non‐muscle‐invasive bladder cancer (ThuRBT), as transurethral resection for bladder tumour (TURBT) is regarded as the reference standard for treating this disease, but alternative laser resection or ablation is suitable especially for recurrent tumours.

PATIENTS AND METHODS

From January 2005 to October 2005, 32 patients with early recurrent bladder tumour (recurrent within a year after TURBT) were treated with ThuRBT via a flexible cystoscope. The follow‐up included urine analysis, ultrasonography and cystoscopy every 3 months.

RESULTS

All patients were treated successfully with ThuRBT in one session, with no bladder haemorrhage, obturator nerve reflex or vesicle perforation. Randomized biopsies taken after surgery on and adjacent to the resection surface revealed no residual tumours. The mean (range) tumour diameter was 1.5 (0.5–3) cm and the mean operative duration was 25 (15–35) min. During the first year of follow‐up, local and heterotopic recurrences were found in three and six patients, respectively. The accumulated recurrence rates at 3, 6 and 12 months were 9%, 22% and 28%, respectively.

CONCLUSIONS

ThuRBT is a reliable therapy with minimal morbidity and invasiveness for selected patients with bladder cancer.     

CD44 standard form expression as a predictor of progression in high risk superficial bladder tumors

Objective: The purpose of this study was to assess the significance of the standard CD44 adhesion molecule expression in predicting progression of high risk superficial bladder carcinoma in the short term.Methods: Sixty-six patients (51 males and 15 females, aged 27 to 89 years (mean 64.75 years) with primary superficial transitional cell bladder cancer initially treated with transurethral resection (TURBT) were enrolled in the study. Only pTa/pT1 grade 2 multiple tumors as well as all grade 3 tumors were included in this study. All tumor samples obtained after the resection were immunohistochemically evaluated for the expression of the CD44 standard molecule. Fifty eight patients remained during the follow up period which ranged from 3 to 36 months (mean 11.8 months). Tumor progression in the short term was considered as the critical end point of interest in this study. The prognostic significance of tumor stage, grade, presence of carcinoma-in-situ (CIS) and expression of CD44 in determining the risk for progression, was studied with both univariate (log rank test) and multivariate (Cox proportional hazards) methods of analysis.Results: Kaplan-Meier survival curves indicated that a shorter median progression-free survival is expected for those patients with G3 bladder tumors (p = 0.0055), concomitant CIS (p = 0.0051), and loss of expression of CD44 (p = 0.0015), whereas a similar association with stage was not detected (p = 0.5793). The cox regression multivariate analysis did not yield a significant result for any of the studied parameters therefore no one of the factors taken into account can serve as an independent predictor of progression in superficial bladder cancer in the short term.Conclusion: The immunohistochemically detectable loss of the expression of CD44 standard form from superficial bladder tumor samples may be, complementary to the established prognostic factors, a useful predictor of tumor progression in the short term.