Carcinoma in situ of the urinary bladder with and without associated vesical neoplasms

Of 99 patients who had carcinoma-in situ (TIS) at least once between 1970 and 1980, 84 were subjected to detailed analysis and pathologic review. They may be classified into four groups: (Group 1) 14 patients, who presented with invasive bladder carcinoma (TCC) associated with TIS; (Group 2) 15 patients who, subsequent to the diagnosis of TIS with or without another superficial TCC developed muscle invasion (12 patients) or metastases without muscle invasion (three patients); (Group 3) 29 patients who underwent cystectomy for superficial TCC (Ta or T1, or TIS alone). Twenty (69%) had extravesical superficial extension. Two patients developed metastases subsequent to undergoing cystectomy; and (Group 4) 26 patients with TIS proven at least once who have not developed muscle invasion, metastases nor have undergone cystectomy. Nineteen had previous non-TIS superficial TCC. All patients in Groups 2 and 4 were treated conservatively (TUR +/- intravesical chemotherapy) when the initial diagnosis of TIS was made. Twelve patients in Group 3 underwent cystectomy within a month of the diagnosis of TIS. When 38 patients found to have TIS in association with the first diagnosis of superficial transitional cell carcinoma of the bladder were compared with 32 patients who had TIS diagnosed subsequent to their initial diagnosis of transitional cell carcinoma, the former group fared significantly worse (P less than 0.01) in regard to muscle invasion, metastases, or clinical indications for cystectomy.     

Expression of UPA and UPAR is associated with the clinical course of urinary bladder neoplasms

The expression of urokinase plasminogen activator (uPA) and its receptor (uPAR) mRNA was determined in 194 subjects with newly detected bladder neoplasms, selected from a larger population-based series. An association was found between uPA and uPAR expression (n = 172; Spearman r(s) = 0.60, p < 0.001). Both uPA and uPAR mRNA levels were higher in muscle invasive (T2+) tumors than in noninvasive mucosal tumors (Ta) or those invading submucosa (T1). The relative hazard ratios (RHRs) for cancer-specific death associated with elevated expression (95% CI), adjusted for age and gender in a Cox proportional hazard model, were 1.8 (1.0-3.3) for uPA (upper quartile cut-line), 2.2 (1.3-4.0) for uPAR (median quartile cut-line) and 2.5 (1.3-4.9) for uPA + uPAR. An RHR for metastatic disease of 4.0 (1.6-9.9) was observed for uPAR. Restricting the analyses to T2+ tumors, the corresponding figures were: 2.1 (1.1-3.9) for uPA, 1.6 (0.8-3.3) for uPAR and 2.5 (1.1-5.6) for both. We conclude that expression of uPA and uPAR is associated with the clinical behaviour of bladder neoplasms, possibly providing means for refined staging of muscle invasive tumors and target proteins for novel therapies.     

膀胱病变组织中 ILK 激酶的表达及临床意义简

目的：探讨整合素连接激酶（integrin—linked kinase,ILK）在膀胱癌发生、发展中的作用。方法：采用免疫组化SP法,检测30例膀胱浸润性尿路上皮癌、25例非浸润性尿路上皮癌、20例膀胱内翻性乳头状瘤和5例正常膀胱黏膜组织中ILK激酶蛋白的表达。结果：浸润性尿路上皮癌ILK激酶阳性表达及阳性细胞率显著高于非浸润性尿路上皮癌、膀胱内翻性乳头状瘤和正常膀胱黏膜（P〈0．05）。结论：ILK激酶的表达水平与肿瘤发生、发展关系密切,高表达的ILK激酶预示着膀胱癌高度恶性、高侵袭性和预后不良。     

Tissue polypeptide antigen in normal and neoplastic urinary bladder. Preliminary reports

Tissue polypeptide antigen (TPA) both in normal and neoplastic urinary bladders has been studied by immunocytochemistry. A comparison of TPA with epithelial membrane antigen (EMA), keratins and carcinoembryonic antigen (CEA) in various tumor grades and stages has been performed better to define TPA role in bladder carcinomas. Well-differentiated tumors were strongly stained for TPA with a uniform staining intensity. Undifferentiated tumors were weakly stained for TPA with an uneven staining intensity. There was no relation between TPA findings and stages of invasion. However, TPA seems to be a very helpful diagnostic tool for tumor grading and staging.     

H-ras p21 and peanut lectin immunoreactivity of hyperplastic, preneoplastic and neoplastic urinary bladder lesions in rats

Hyperplastic, preneoplastic and neoplastic urinary bladder lesions induced by bladder carcinogens and toxins in the rat were evaluated for immunoreactivity with polyclonal or monoclonal antibodies to H-ras p21 or binding to peanut lectin with avidin-biotin immunocytochemistry. A low proportion (less than 20%) of hyperplastic and neoplastic bladder lesions induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine and fixed in Bouin's fixative only were immunoreactive on the cell membrane with the antibodies to H-ras p21. Lectin binding was found for these lesions, as well, even in formalin-fixed tissue and for lesions induced by other carcinogens, but not in regenerative bladder hyperplasias after cyclophosphamide exposure or in bladder exposed to bladder tumor promoters. The latter lesions were also not immunoreactive with antibodies to p21. Our results suggest that this relatively simple technique might be used for identification and screening of tumors for involvement of ras oncogenes and carcinogen initiation.     

Rare lesions and tumors of the urinary bladder. Selected issues

Morphological variants of urothelial cancer have been recently described. The timely identification and recognition of these histological variants should avoid their misinterpretation as benign lesions. We emphasize the peculiar features of these variants because some may require different/specific therapeutic approaches.     

Flat intraepithelial lesions of the urinary bladder

BACKGROUND: In the 1998 World Health Organization and International Society of Urologic Pathology (WHO/ISUP) classification system for bladder neoplasms, flat intraepithelial lesions of the urinary bladder were categorized as reactive atypia, atypia of unknown significance, dysplasia, and carcinoma in situ. The clinical outcomes of patients diagnosed with these atypical urothelial proliferations are uncertain. METHODS: The authors studied a series of patients who were diagnosed with reactive atypia of the urinary bladder (25 patients), urothelial atypia of unknown significance (35), or urothelial dysplasia (26) between 1985 and 1993. All histologic slides were reviewed and classified according to the 1998 World Health Organization and International Society of Urologic Pathology classification system. Patients with a concomitant or prior history of carcinoma in situ or urothelial carcinoma were excluded. RESULTS: Patient age at diagnosis ranged from 24 to 88 years (mean, 65 years). The male-to-female ratio was 3:1. The mean follow-up was 3.9 years (range, 0.1-13.4 years; median, 3.5 years). None of the patients with reactive atypia or atypia of unknown significance developed dysplasia, carcinoma in situ, or urothelial carcinoma. Four patients (15%) with urothelial dysplasia developed biopsy-proven cancer, including 3 patients with muscle-invasive cancer. The mean interval from the diagnosis of urothelial dysplasia to the development of cancer was 4.5 years. CONCLUSIONS: Patients with a diagnosis of urothelial atypia of unknown significance or reactive atypia do not have adverse clinical outcomes, whereas patients with urothelial dysplasia of the bladder have an increased risk for the development of carcinoma in situ and urothelial carcinoma.     

Survival of patients with carcinoma in situ of the urinary bladder.

BACKGROUND: To the authors' knowledge, the long term follow-up of patients with carcinoma in situ of the urinary bladder is limited. METHODS: The authors studied 138 patients diagnosed with urothelial carcinoma in situ of the bladder at the Mayo Clinic between 1972-1979. All the histologic slides were reviewed and fulfilled the diagnostic criteria for carcinoma in situ according to the newly proposed World Health Organization and International Society of Urologic Pathology classification system. None of these patients had previous or coexisting invasive urothelial carcinoma at the time of diagnosis. Cox proportional hazards models were used to determine the prognostic significance of numerous clinical and pathologic findings using progression free, cancer specific, and all-cause survival as the endpoints for analysis. Progression was defined as the development of invasive carcinoma, distant metastases, or death from bladder carcinoma. RESULTS: The patients ages at the time of diagnosis ranged from 32-90 years (mean, 65.6 years). The male to female ratio was 7:1. Carcinoma in situ usually was multifocal (50%) with a predilection for the trigone, lateral wall, and dome. The mean follow-up after surgery was 11.0 years (range, 0.7-25 years). Actuarial progression free, cancer specific, and all-cause survival rates were 63%, 79%, and 55%, respectively, at 10 years, and 59%, 74%, and 40%, respectively, at 15 years. The mean interval from the time of diagnosis to cancer progression was 5 years. Patient age at diagnosis was significant in predicting progression free (P = 0.01) and all-cause survival (P = 0.002). Cystectomy performed within 3 months after the initial diagnosis was associated with improved all-cause survival (P = 0.03). After controlling for age, there was no difference in survival between patients who received immediate cystectomy and those did not (P = 0.16). CONCLUSIONS: Patients with carcinoma in situ of the bladder are at significant risk of cancer progression and death from bladder carcinoma. Cystectomy does not appear to offer a significant survival advantage in patients with carcinoma in situ of the bladder after adjusting for age.     

Blood group isoantigen deletion in carcinoma in situ of the urinary bladder.

Blood group isoantigens A and H (O) were measured by the Secific Red Cell Adherence (SRCA) Test in nine radical cystectomy specimens removed from patients with extensive carcinoma in situ of the urinary bladder. All bladders had areas of histologically normal epithelium and areas of epithelial atypia in addition to the carcinoma in situ. In eight cases, tissue-associated blood group isoantigens were deleted in areas showing either atypia or carcinoma in situ. Isoantigens were present in these areas in the ninth case. Blood group isoantigens were absent in approximately half of the sections of histologically normal epithelium. We propose that areas of epithelium which appear benign according to conventional histological criteria but in which the blood group isoantigens are absent may represent areas of low grade carcinoma in situ.     

p53 mutations in early neoplastic lesions of the urinary bladder in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine

Rat experimental models using Ar-butyl-Af-(4-hydroxybutyl) nitrosamine(BBN) as an initiating agent have been widely used to studycarcinogenic processes in the urinary bladder. In this study,early neoplastic lesions from 10 male F344 rats treated with0.05% BBN for 16 weeks were analyzed for changes in the H-rasor p53 genes by polymerase chain reaction (PCR)-single strandconformation polymorphism (SSCP) analysis and subsequent DNAsequencing. Lesions were pooled for each of the 10 rats andsix showed point mutations in the p53 gene and one in the H-rasgene. These results would indicate that BBNinduced rat urinarybladder carcinomas are similar to human urinary bladder carcinomaswith respect to alterations in the p53 and H-ras genes and thatp53 gene alterations are relatively early events in rat urinarybladder carcinogenesis induced by BBN treatment     

Cystectomy: the treatment of choice in patients with carcinoma in situ of the urinary bladder?

Patients (n = 46) with carcinoma in situ (Tis) of the urinary bladder were treated by intravesical chemotherapy. The complete remission rate was 75%. After a mean interval of 17 months recurrent tumours were diagnosed in 47%. Radical cystectomy with urethrectomy was performed in eight patients. Distal ureterectomy and uretercystoneostomy was done in six patients because of a distal ureteric tumour. Based on this group of 46 patients and the current literature, the following criteria are essential in indicating cystectomy: (1) micro-invasion; (2) persistent Tis after adequate intravesical treatment; (3) progressive tumour; (4) Tis of ureter and/or prostate; (5) tumour recurrence at more advanced stage.     

Uracil-induced calculi and proliferative lesions of the mouse urinary bladder

Uracil fed as 3% of the diet to rats produces urinary calculiand consequent proliferative lesions of the bladder epithelium,including papillomatosis. We evaluated the effects of dietaryuracil in two strains of mice and compared the results in malesand females. Uracil was fed as 3 or 1% of the diet to male andfemale Swiss and C3H mice for up to 20 weeks. The 3% dose producedmarked proliferative changes in the bladder epithelium by 10weeks of administration, the earliest time at which the animalswere processed for microscopic evaluation. These lesions progressedto severe nodular and papillary hyperplasia so that all of theanimals fed 3% uracil had to be killed by the end of the 15thweek. These animals had uracil-formed calculi. In contrast,mice fed 1% uracil rarely developed uracil calculi, and alsorarely developed proliferative changes in the bladder epitheliumas observed by light microscopy. Also, the labeling index wasdetermined and showed quantitatively the degree of cell proliferationsimilar to that qualitatively observed by light microscopicexamination. At 10 weeks of administration, there was an increasedlabeling index in the males compared to females in both strainsof mice fed 3% uracil, but this difference was not significantat 15 weeks. Similarly, the males tended to have more severehistologic changes than the females. The results of feedinghigh doses of uracil are similar in mice to those previouslyobserved in rats.     

Expression of blood-group-related antigens in carcinoma in situ of the urinary bladder

Expression of epithelial ABH blood group antigens and the T (Thomsen-Friedenreich)-antigen was quantitatively studied by immunoperoxidase techniques in nine cystectomy specimens containing extensive carcinoma in situ (CIS), and also histologically benign epithelium. CIS areas typically showed abnormal expression of both ABH and T-antigens and a distinctive vascular architecture, revealed by endothelial ABH staining. Histologically normal epithelium generally was antigenically normal, but occasionally showed abnormalities of either ABH or T-antigens. Antigen expression was variable in histologically atypical epithelium, with significant segments showing abnormalities of either ABH or T-antigen, and sometimes of both antigenic markers. It is postulated that histologically benign, but antigenically abnormal, epithelium may represent low-grade CIS of the urinary bladder. Assessment of blood-group-related antigen expression in flat atypical epithelium of the urinary bladder may be useful for predicting the biologic potential of these lesions.     

Further observations on carcinoma in situ of the urinary bladder: silent but extensive intraprostatic involvement.

Of seven patients with carcinoma in situ of the urinary bladder in the absence of an associated papillary carcinoma, five were found to have silent but extensive intraductal prostatic involvement. In three of these the carcinoma in situ was associated with microinvasion. The mean age at the time of diagnosis was 68 years. All had symptoms characteristic of carcinoma in situ, including hematuria, dysuria, and urgency. In three patients the prostatic involvement was diagnosed on transurethral resection. In two it was discovered only after radical cystectomy. The prostatic involvement was neither suspected clinically nor has it been previously emphasized. Although three patients are alive, apparently free of disease up to 15 months postcystectomy, two have died, one of disease. The importance of prostatic assessment in the evaluation of the patient with carcinoma in situ of the urinary bladder is emphasized.     

Combined treatment in patients with carcinoma in situ of the urinary bladder using intravesical pirarubicin, irradiation and hyperthermia

The treatment with hyperthermia in combination with radiation and intravesical pirarubicin (THP-ADM) was preliminary investigated in 5 patients with urinary bladder carcinoma in situ. Following intravesical administration of 30 mg THP-ADM, external irradiation of 3.0 Gy was delivered to the urinary bladder. Immediately then, hyperthermia using Thermotron RF-8 was performed for 50 min (intravesical temperature: 42-43 degrees C for 35 min). After five courses of the treatment, complete response has been maintained for 6, 8, and 9 months in 3 patients. However, in a patient with complete response, urinary cytology became positive in the 6th month after the treatment. In the remaining patient treatment was interrupted after only 3 courses due to urinary irritation, urinary cytology didn't become negative. The side effects of the combined treatment were limited to the transient symptoms of bladder irritation in all patients and thermal burn in 2 patients. These preliminary results suggest that this combined treatment may represent an effective conservative therapy for patients with urinary bladder carcinoma in situ.     

膀胱嗜铬细胞瘤的诊断及治疗

目的 探讨膀胱嗜铬细胞瘤的临床诊断及治疗方法.方法 回顾性分析了1995至2004年6例膀胱嗜铬细胞瘤患者的临床资料及随访结果,并复习相关文献.结果 6例术后病理均为嗜铬细胞瘤.4例术前未发现转移的膀胱嗜铬细胞瘤患者术后临床症状消失,随访至今未见复发.2例有淋巴结转移的病例中,1例行转移淋巴结切除术,术后行化疗,随访至今未见复发;另1例因转移的淋巴结与髂血管关系紧密,未能切除.术中放置银夹,术后行放疗,效果不佳.转移的淋巴结未见明显缩小,临床症状及体征也未见好转,2年后因全身多发转移死亡.结论 膀胱嗜铬细胞瘤典型的临床症状是排尿时头痛、头晕、心悸、出汗,血尿和高血压等,可用B超、CT、膀胱镜行定位诊断,血尿儿茶酚胺(catechol amine,CA)测定行定性诊断.手术治疗为主要的治疗方法.膀胱恶性嗜铬细胞瘤最常转移的部位为髂血管旁淋巴结.早期发现,早期手术,术后辅以化疗能取得较好的疗效.术后监测临床症状及血尿儿茶酚胺,可以了解有无转移或复发.