Natural history of urothelial dysplasia of the bladder

Urothelial dysplasia is the putative precursor of urothelial carcinoma in situ (CIS) and invasive urothelial carcinoma of the urinary tract. Urothelial dysplasia is frequently identified in patients with urothelial CIS and cancer. However, very little is known about the clinical presentation and natural history of urothelial dysplasia in the absence of urothelial CIS or invasive cancer. The authors studied 36 patients with isolated urothelial dysplasia at the Mayo Clinic between 1969 and 1984. None of these patients had previous or concurrent urothelial CIS or invasive cancer, and none received treatment for dysplasia. The histopathologic features of urothelial dysplasia were examined, and long-term clinical follow-up was obtained. Progression was defined as the development of urothelial CIS or carcinoma. The male-to-female ratio was 2.6:1, and the mean patient age at the time of diagnosis was 60 years (range 25-79). Urothelial dysplasia has a predilection for the posterior wall. Eleven patients had urinary irritative symptoms, 10 had hematuria, 3 had both irritative symptoms and hematuria, and 12 were found to have dysplasia incidentally. The mean follow-up was 8.2 years (range 0.1-25.5). Seven (19%) of 36 patients developed biopsy-proven progression, including 4 with CIS and 3 with invasive cancer, and 1 of them died of bladder cancer. The intervals from diagnosis to progression ranged from 6 months to 8 years (mean 2.5 years). One of the remaining 29 patients had positive cytologic results 2.5 years after the initial diagnosis of dysplasia. The authors conclude that urothelial dysplasia is a significant risk for the development of CIS and invasive urothelial carcinoma, and patients with urothelial dysplasia should be followed up closely.     

The significance of urothelial dysplasia as diagnosed by cup biopsies

A prospective study was carried out in which four quadrant cold cup biopsies of the bladder were taken from patients with either a bladder tumour (57) or irritative bladder symptoms (44), and a control group (23). Five histopathological patterns were recognized: normal urothelium, mild, moderate and severe dysplasia, and carcinoma in situ (CIS). In the control group, 22 of the 23 patients had normal urothelium, giving a 4% incidence of mild dysplasia. Of the 57 patients with all stages and grades of transitional cell carcinoma, 38 (67%) had dysplastic urothelium. This association is significant (P less than 0.01, chi-squared). Thirty-seven patients had Ta or T1 tumours, and 24 (65%) of these had dysplasia, including four (11%) with CIS. Twenty patients had T2-T4, Grade 111 tumours and 14 (70%) of these had dysplasia, including five (25%) with CIS. There was no statistical difference between these two groups. The recurrence rate was evaluated for all patients presenting with a first bladder tumour. Seventy-three percent of patients with normal cup biopsies remained recurrence free during a mean follow-up of 3 years (s.d. 1.15 years). Of patients with dysplastic urothelium, 72% remained recurrence free over a mean follow-up of 3.25 years (s.d. 1.23 years). Hence, the presence of dysplasia did not predict the likelihood of tumour recurrence. Thirty patients had dysuria or suprapubic pain for which there was no explanation. Sixteen (53%) had dysplasia on cup biopsy including three (10%) with CIS (P less than 0.01, chi-squared). It seems clear, therefore, that the dysplasia was the cause of these symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical significance of urothelial dysplasia concomitant with superficial bladder cancer]

OBJECTIVE: Retrospective analysis was carried out to evaluate the prognostic value of urothelial dysplasia with superficial bladder cancer. PATIENTS AND METHODS: 62 patients with bladder cancer of pTa or pT1 who had been treated by transurethral resection (TUR-Bt), underwent random mucosal biopsies in the urinary bladder. The results of random biopsies were classified into 3 groups: negative group, dysplasia group and CIS group. The recurrence rate, progression rate and type of recurrences (true recurrence/new occurrence) were compared among the 3 groups. RESULTS: The results of random biopsies were as follows; negative group was found in 42 (68%), dysplasia group in 17 (27%) and CIS group in 3 (5%). There were no significant difference in the characteristics of the patients among the 3 groups. The recurrence rates at 1, 2 and 5 years after TUR-Bt were 3%, 12% and 21%, respectively, for negative group, and 37%, 51% and 67%, respectively, for dysplasia group (p < 0.01). For CIS group, 2 of 3 cases (67%) recurrenced within 1 year after TUR-Bt. Non of negative group progressed to muscle invasion, whereas 57% of dysplasia group invaded bladder muscle after 6 years post operatively (p < 0.001). No significant relationship was observed between the absence or presence of concomitant dysplasia and the rate of true recurrence. Dysplasia group revealed a higher rate (47.1%) of new occurrence than negative group (2.4%) (p = 0.0001). CONCLUSION: The presence or absence of concomitant dysplasia of superficial bladder cancer seems to be an important prognostic factor for future new ocurrence and progression after TUR-Bt.     

Reciprocal expression of bcl-2 and p53 oncoproteins in urothelial dysplasia and carcinoma of the urinary bladder

In order to investigate if and when the bcl-2 oncoprotein is activated in bladder tumorigenesis and its relationship with p53 overexpression and patient survival, we studied bcl-2 and p53 expression immunohistochemically in matched normal urothelium, dysplasia and cancer specimens selected by step-sectioning from 54 radically resected bladders for non-metastatic transitional cell carcinoma (TCC). In normal urothelium and mild dysplasia, bcl-2 was restricted to the basal cell compartment, while in moderate and severe dysplasia its expression was detectable also in the upper regions. Excess bcl-2 immunoreactivity was found in 27 (50%) of carcinomas, and a larger proportion of high-grade TCCs showed bcl-2 expression compared with that of low-grade TCCs (P < 0.05). Overexpression of p53 protein showed a increasing trend toward the progression of bladder tumorigenesis (P < 0.01) and a significant reciprocal correlation was found between bcl-2 and p53 expression in either various dysplasias (P < 0.01) or carcinoma (P < 0.05). With the evolution from mild dysplasia to carcinoma in individual cases, loss of bcl-2 expression was more frequently observed in superficial (P < 0.02) or low-grade carcinoma (P < 0.05) than in muscle-invasive or high-grade carcinoma. Furthermore, patients with negative immunostaining for both bcl-2 and p53 in cancer lesions had a significantly more favorable prognosis compared with those with positive immunostaining for the oncoproteins (P < 0.05), although bcl-2 by itself did not predict patient survival. We suggest that aberrant activated bcl-2, which is seen earlier than p53, appears to facilitate bladder tumorigenesis and to enhance tumor aggression in some extent. Received: 22 October 1997 / Accepted: 2 January 1998     

Plasmacytoid and micropapillary urothelial carcinoma: rare forms of urothelial carcinoma

Plasmacytoid urothelial carcinomas (PUC) along with micropapillary urothelial carcinoma (MPC), small cell cancer, and nested-typed tumors are among the rare variations of urothelial carcinomas. The molecular characterization of PUC and MPC is currently the focus of our research on bladder cancer which we are conducting in cooperation with the Institute of Pathology in Erlangen. PUCs account for approximately 0.9% of all urothelial carcinomas. The diagnosis of these rare variants has acquired increasing importance since this may have prognostic and possibly therapeutic consequences for the patients. By analysis of 32 PUCs we were able to demonstrate the most comprehensive results available to date on the underlying molecular and clinical characteristics of these variants. Micropapillary cancers have already been described in multiple organs. Micropapillary breast cancer represent an individual entity with characteristic genomic aberrations and corresponding clinical and pathological features     

The long-term culture of porcine urothelial cells and induction of urothelial stratification.

OBJECTIVE: To assess porcine urothelial cell cultures and the in vitro induction of urothelial stratification in long-term cultures, to study their morphological, functional and genetic behaviour, and thus provide potential autologous urothelium for tissue-engineered substitutes for demucosalized gastric or colonic tissue. MATERIALS AND METHODS: Primary cultures of porcine urothelium were established and the cells passaged thereafter. Cell specificity was confirmed by cytokeratin analysis, cell membrane stability assessed using lactate dehydrogenase leakage, cell de-differentiation by gamma-glutamyl transferase activity and genomic stability by karyotype investigations. Histology and scanning electron microscopy were performed to study the cultured cells and the stratified constructs. Furthermore, collagen matrices were tested as cell scaffolds. RESULTS: The cells were cultured for 180 days; 10 subcultures were established during this period. Stratification was induced in a culture flask and on a collagen matrix. Cytokeratins 7, 8, 17 and 18 were expressed in all cultures, and cell membranes were stable, with no evident de-differentiation. The cultures were stable in their genotype and no chromosomal aberrations were found. The histology and immunohistochemistry of the stratified porcine constructs, and cell membrane stability and cell de-differentiation, were compared with those in the human system. CONCLUSION: Pig and human urothelial cells can be cultured over a long period with no signs of senescence. Urothelial stratification can be induced in vitro. The collagen matrix seems to be an excellent scaffold, allowing cell adherence and growth.     

Renal lithiasis and urothelial tumor

We report the cases of 4 patients with renal pelvis tumor associated with renal calculi. Sonography was correlated with gross pathology in three cases. The pre operative diagnostic can be made by sonography. The carcinogenic role of the lithiasis and infection is quite possible.     

Radiochemotherapy of urothelial carcinoma

Radical cystectomy is the current standard therapy for muscle invasive or locally advanced transitional cell carcinoma of the bladder. Organ-preservingmonotherapeutic alternatives (e.g. transurethral resection, radiotherapy) do not lead to similar cure rates. In selected cases, a trimodal approach using transurethral resection and combined radio- and chemotherapy can be as efficient as cystectomy.     

Epidemiology of urothelial carcinoma

The epithelium lining is defined as the mucosal surfaces of the renal collecting tubules, calyces and pelvis, as well as the ureter, bladder and urethra. The term “urothelium” is used to refer to these surfaces. Upper tract urothelial carcinoma is a rare subset of urothelial cancers with a poor prognosis. Urinary bladder cancer is the most common malignancy involving the urinary system. Upper tract urothelial carcinoma is more common in men than in women, with a male‐to‐female ratio of 2:1. The incidence of urinary bladder cancer is also higher in men. Cigarette smoking and occupational exposure are the main upper tract urothelial carcinoma and urinary bladder cancer risk factors, while other factors are more specific to the carcinogenesis of upper tract urothelial carcinoma (i.e. Balkan endemic nephropathy, Chinese herb nephropathy). In Egypt until recent years, urinary bladder cancer was the most frequently diagnosed cancer due to Schistosoma haematobium. Substantial knowledge exists regarding the causes of upper tract urothelial carcinoma and urinary bladder cancer, and epidemiological studies have identified various chemical carcinogens that are believed to be responsible for most cases of urothelial carcinoma. In the era of precision medicine, genetic effects might play a direct role in the initiation and progression of urothelial carcinoma.     

尿路上皮癌的免疫治疗

尿路上皮癌(UC)是我国最常见的泌尿系恶性肿瘤之一,其复发率高,侵袭性强,治疗效果不佳。近年来,以程序性死亡受体1(PD-1)/程序死亡受体配体1(PD-L1)抑制剂为代表的免疫治疗研究不断发展,为晚期UC的药物治疗打开了一扇新的大门。本文就目前UC免疫治疗的最新临床进展进行系统的整理和综述,并针对未来发展方向予以分析和展望。     

Hirudin and its reversal

Editor—I read the informative editorial on heparin resistanceby Anderson and Saenko¹ with interest. However, experience forcesme to point out a possible area for confusion. Currently, thereis no drug reversal available for r-hirudin and reversal ofits anticoagulant effect relies entirely on renal elimination(biological half-life of 1–1.5 h).² In patients with poorrenal function, r-hirudin has a prolonged half-life, which maylead to serious bleeding problems after cardiopulmonary bypass(CPB).³ Indeed, poor     

Bladder and upper tract urothelial cancer

PURPOSE: While there are data available indicating the incidence and prevalence of bladder and upper tract urothelial cancer, population level data on resource use, costs and patterns of care for these cancers are limited. We quantified the economic impact of caring for patients with bladder and upper tract urothelial cancer, and determined the primary drivers for such costs in the population in the United States. MATERIALS AND METHODS: The analytical methods used to generate these results have been described previously. RESULTS: An increasing proportion of patients with bladder and upper tract urothelial cancer were being treated in the outpatient setting. Most care was provided by urologists and visit frequency was directly related to disease stage. Only a small proportion of patients potentially eligible for chemotherapy, ie those with advanced disease, sought specialized care from oncologists. Office based diagnostic tests such as cytology were not commonly done, although a substantial number of patients with bladder cancer underwent cystoscopy. The use of excretory urography in these patients was decreasing, while the use of computerized tomography was increasing. Ileal conduits were the most frequently performed type of urinary diversion following cystectomy. The cystectomy rate remained unchanged for a decade. Intravesical therapy was done infrequently in patients with bladder cancer. Annual costs for treating bladder and upper urinary tract cancers were $1 billion and $64 million, respectively, in 2000. These costs represented a $164 million increase over 1994 levels, which outpaced inflation. CONCLUSIONS: The costs of treating bladder cancer increased steadily during a 6-year period despite a decrease in inpatient care. Coupled with a lack of substantial change in transurethral resection and cystectomy rates, this suggests that the primary cost drivers are increased outpatient testing, eg computerized tomography and cystoscopy, and an increase in the number of diagnosed cases. Greater focus on selective use of testing modalities, preventive care such as smoking cessation and earlier identification of patients at risk may help curtail further expenditure with regard to managing bladder and upper urinary tract cancers.