Recent advances in urinary bladder cancer detection

Urinary bladder cancer (BCa) is the most common malignancy of the urinary tract. In recent decades, the overall incidence of BCa appears to be on the increase. Despite the increase in incidence, mortality rates in North America and Europe appear to have declined in the last decade, probably due to improved detection and treatment. The mainstay of diagnosis is by cystoscopy, aided with imaging and urine tests (e.g., cytology). This article reviews the recent advances made in detection of primary and recurrent bladder cancer.     

Urothelial tumors of the urinary bladder in manipur: a histopathological perspective

Objective: To study the histomorphological pattern of urothelial tumors of the urinary bladder in Manipurand to evaluate whether any correlation exists between tumor grade and muscle invasion. Methods: A 10 yearretrospective study of all consecutive cases diagnosed in the Department of Pathology RIMS – Imphal, between1st January 2001 to 31st December 2010. Results: The study included 26 cases of transitional cell tumors ofurinary bladder. The male to female ratio was 1.5: 1 and the ages ranged from 38 years to 73 years (mediansof 60 and 64 years, respectively). Of the total, 14 (53.9%) cases were low grade, 9 (34.6%) were high grade, 2(7.7%) were papillomas and 1 (3.9%) was a papillary urothelial neoplasm of low malignant potential (PUNLMP).Pathological staging showed that 14 (53.9%) of the cases were stage PTa, four (15.4%) PT1, and eight (30.9%)PT2. Some 18.2% of low grade tumors and 75% of high grade tumors were invasive to the detrusor musclelayer. Conclusion: Bladder cancer is an uncommon disease, transitional tumors being the only histological typeobserved. It was more common in males than females, with peak incidence in seventh decade. Most of the tumorswere non- invasive (PTa) and invasion to the detrusor muscle layer was seen in more than half of the high gradetumors. There is a definite correlation between advancing tumor grade and muscle invasion.     

The clinicopathological characteristics of muscle-invasive bladder recurrence in upper tract urothelial carcinoma

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.     

A review of upper urinary tract cytology performance before and after the implementation of The Paris System

Urinary cytology (UC) is one of the primary diagnostic modalities used for the screening and surveillance of urothelial carcinoma. Despite its widespread use, UC has suffered from a lack of standardized or reproducible criteria and wide interobserver variability, particularly of the designation of atypical urothelial cells. The Paris System for Reporting Urinary Cytology (TPS), published in 2016, aimed to provide a standardized approach for evaluating UC by creating diagnostic categories with specific cytomorphologic criteria. Recent studies have primarily investigated the application of TPS on lower urinary tract specimens and have mostly shown that TPS implementation has improved the performance of UC specimens. Only a few studies have reported the impact of TPS on upper urinary tract (UUT) cytology. Additionally, there is uncertainty as to which cytological features are most predictive of high-grade urothelial carcinoma (HGUC) in the UUT. This review summarizes the literature regarding the utility and performance of UUT cytology and highlights findings before and after the implementation of TPS.     

上尿路移行细胞癌术后预防性膀胱灌注的临床研究

目的:探讨上尿路移行细胞癌术后预防性膀胱灌注的有效性。方法:61例上尿路移行细胞癌患者行根治性切除术,其中34例患者术后预防性使用吡柔比星膀胱灌注,27例患者单纯随访,比较两组患者2年内膀胱肿瘤的发生率以及发生时间,并观察药物灌注毒副反应发生的情况。结果:吡柔比星灌注组膀胱癌发生率为14.7%,观察随访组膀胱癌的发生率为37.0%,差异有统计学意义(P<0.05),再发时间分别为20个月和14个月,二者比较差异有统计学意义(P<0.05)。患者灌注过程中均耐受,未出现中止灌注的情况。结论:本研究初步显示,吡柔比星预防性膀胱灌注可有效减少膀胱肿瘤的发生,毒副反应少,值得临床推广。     

长链非编码RNA HOTAIR抑制膀胱尿路上皮癌对阿霉素的敏感性

目的:研究长链非编码RNA HOTAIR在膀胱尿路上皮癌中的表达,明确其对膀胱尿路上皮癌对阿霉素敏感性的调控作用.方法:HOTAIR基因在膀胱尿路上皮癌及癌旁组织中的表达由实时定量PCR法检测.将HOTAIR基因的表达载体和沉默载体分别转染膀胱尿路上皮癌J82细胞,实时定量PCR验证转染效果.应用MTT法检测HOTAIR基因表达改变对于J82细胞的增殖能力及对阿霉素敏感性的调控作用.结果:HO-TAIR基因在膀胱尿路上皮癌表达显著上调.HOTAIR基因的表达载体和沉默载体能够显著上调或沉默HO-TAIR基因的表达.HOTAIR高表达能够促进J82细胞增殖,抑制J82细胞对阿霉素的敏感性;而HOTAIR表达沉默的J82细胞增殖能力下调明显,对阿霉素的敏感性明显增加.结论:长链非编码RNA HOTAIR在膀胱尿路上皮癌中高表达,HOTAIR能够作为癌基因促进膀胱尿路上皮癌的细胞增殖能力并抑制膀胱尿路上皮癌对阿霉素敏感性.     

Recent advances in the treatment of bladder cancer

Bladder cancer continues to provide urologists and researchers with a clinical and scientific challenge. Several urinary markers used in the detection and screening of patients with bladder cancer are currently under investigation. Improvements in intravesical therapy are proving to help decrease both tumor recurrence and progression in patients with high-risk disease. In patients with organ-confined, node-negative bladder cancer, radical cystectomy provides excellent local control and long-term disease-free survival. The use of an extended lymphadenectomy at the time of cystectomy may yield improved prognostic information as well as a potential survival benefit. Neoadjuvant chemotherapy and less toxic combination chemotherapy regimens are offering potential improvements in patients with extravesical or nodal extension. The current methods of detection, as well as available therapeutic treatment options are reviewed.     

腔内激光手术治疗肾盂输尿管肿瘤

目的:通过对无法行根治性手术的上尿路上皮肿瘤患者进行腔内红激光治疗情况进行总结,评价该术式的有效性与安全性.方法:对于我院2013年1月到2016年6月期间收治的肾盂、输尿管肿瘤,其中13例行腔内激光手术治疗,分别就术中情况、术后并发症及疗效进行总结.结果:13例患者中,肾盂肿瘤行经皮肾镜激光手术9例,输尿管肿瘤行输尿管镜激光手术4例,平均手术时间分别为(47.22±6.25)min、(25.0±4.84)min;平均出血量分别约为(133.33±24.94)ml、(40.0±7.07)ml;血尿及肾积水情况得到控制,5/13例呈现局部进展,1/13例术后10个月死亡;未出现严重并发症.结论:对于特殊情况下的肾盂、输尿管肿瘤患者,腔内激光手术具有创伤小,止血效果好,可以姑息性切除肿瘤,降低肿瘤负荷,保护肾脏功能,也能减缓肿瘤进展,可以作为这一类患者的首选治疗方案.     

Bladder recurrence of upper urinary tract cancer after laparoscopic surgery

PURPOSE: We reviewed our cases to determine whether laparoscopic nephroureterectomy is a risk factor for the bladder recurrence. MATERIALS AND METHODS: From 1996 to 2003, 65 nephroureterectomies were performed: 47 by open and 18 by laparoscopic surgery. In 43 (28 by open, 15 by laparoscopic surgery), bladder cancer was not observed at the time of the operation. Two laparoscopic operations were converted to open surgery because of technical problems. The other 13 with laparoscopic and 28 with open surgery were enrolled into this study. RESULTS: Significantly higher recurrence rate was observed in laparoscopic cases (69.2%) than that in open cases (35.7%, P = 0.0484) by log rank test. However, the operation time required in laparoscopic surgery (371.5 +/- 90.8 min) was significantly longer than that in the open surgery (229.9 +/- 46.6 min, P < 0.0001). In multivariate analysis (Cox proportional hazards model), only the longer operation time (>250 min) was a significant variable (P = 0.0305), and laparoscopic surgery in itself was not a significant risk factor (P = 0.5011). CONCLUSIONS: Although frequent bladder recurrence was observed in laparoscopic cases, the most important risk factor was the longer operation time. Technical improvements including shortening of operation time and earlier ureteral ligation may decrease the bladder recurrence.     

Glucocorticoid therapy and risk of bladder cancer

Background:

Use of immunosuppressive drugs post organ transplantation, and prolonged use of glucorticoids for other conditions have been associated with subsequent risk of certain malignancies, that is, skin cancers and lymphoma. There is evidence that the incidence of bladder cancer is also elevated among organ transplant recipients, however, it is unknown whether other groups of patients, that is, those taking oral glucocorticoids, likewise are at an increased risk.

Methods:

In a population-based case–control study in New Hampshire, USA, we compared the use of glucocorticoids in 786 bladder cancer cases and in 1083 controls. We used unconditional logistic regression analysis to compute adjusted odds ratios (ORs) associated with oral glucocorticoid use.

Results:

In our analysis, the risk of bladder cancer was related to a history of prolonged oral glucocorticoid use (OR=1.85, 95% CI=1.24–2.76, adjusted for age, gender and smoking). Associations with oral glucocorticoid use were stronger for invasive tumours (OR=2.12, 95% CI=1.17–3.85) and tumours with high (3+) p53 staining intensity (OR=2.35, 95% CI=1.26–4.36).

Conclusion:

Our results raise the possibility of an increased risk of bladder cancer from systemic use of glucocorticoids, and a potential role of immune surveillance in bladder cancer aetiology.     

Potential of urinary biomarkers in early bladder cancer diagnosis

Carcinoma of urinary bladder ranks among the top ten most common cancers worldwide. Approximately 80% of the disease is superficial (limited to mucosa and lamina propria) at the time of presentation. However, the majority of these tumors recur and 15–20% progress into muscle-invasive disease. Cystoscopic surveillance of the urinary bladder remains the standard of care to identify these recurrences on follow-up. Not only is this an invasive procedure, but the sensitivity of cystoscopy can be as low as 70%, so there can be up to 30% of tumors that are missed. Urinary cytology, with recognized limitations, has been used as an adjunct to this procedure, pending discovery of alternate urinary biomarkers. In the past decade there has been tremendous advancement in producing urinary biomarkers for urinary bladder cancer research, reflecting advancements in genomics and proteomics. An ideal biomarker should be able to replace cystoscopic examination and be cost effective. Unfortunately, most of the identified protein or molecular biomarkers have failed this test. This article critically appraises the status of these urinary biomarkers in urinary bladder cancer, in addition to highlighting some of the difficulties in this research area.     

改良全膀胱切除和原位新膀胱术重建下尿路功能

背景与目的:全膀胱切除原位新膀胱术是治疗浸润性膀胱癌最有效的手段.但由于手术繁杂、时间长、出血和并发症较多,以及相当一部分患者控尿不佳等缺点,我们对全膀胱切除和原位新膀胱术进行了反复改良,获得了比较满意的效果,本文报告我们的经验.方法:采用改良的全膀胱切除和原位新膀胱术治疗119例临床诊断为浸润性膀胱癌的患者.男性109例,女性10例.年龄33～78岁,平均55岁.统计手术时间、术中出血和输血量,对新膀胱功能、并发症、肿瘤控制和生存情况进行随访分析.结果:对全膀胱切除和原位新膀胱术一共进行了八处改良.从2000年1月至2007年2月用改良术治疗119例,无围手术期死亡.手术时间150～330 min,平均245 min.输血39例(32.8%).术后病理分期浅表性膀胱癌(T1N0M0) 9例,浸润性110例(其中T2N0M0 102例、T3aN0M0 3例、T3aN1M0 2例、T3bN1M0 2例,、T4N1M0 1 例).随访6～72个月,平均45个月,108例生存,10例因肿瘤死亡,1例非肿瘤原因死亡.术后白天控尿良好113例(95%),夜间控尿良好97例(81.5%).主要并发症有切口裂开5例,二次缝合后治愈;输尿管新膀胱吻合口漏1例,经再次手术作输尿管再植治愈;肠梗阻3例需住院处理.输尿管末端粘连引起肾积水8例,经内镜下切断粘连后积水消退.无肠瘘和新膀胱尿道吻合口瘘或狭窄,无膀胱输尿管返流.结论:全膀胱切除后采用改良原位新膀胱术重建下尿路功能,手术时间短、出血少和并发症少,新膀胱控尿和排尿满意,是目前全膀胱切除后最理想的下尿路重建方式.     

Value of p16(INK4a) in the diagnosis of low-grade urothelial carcinoma of the urinary bladder in urinary cytology

BACKGROUND:

The sensitivity of urinary cytology for the diagnosis of urothelial carcinomas is low, particularly in low‐grade carcinomas. The UroVysion test is a fluorescent in situ hybridization multiprobe assay that increases the sensitivity of urinary cytology. However, this test is not widely available. P16^INK4a, a protein involved in cell cycle progression, is overexpressed in urothelial carcinoma. Immunocytochemical expression of p16^INK4a has been examined in biopsy samples from urothelial carcinomas, but few studies have addressed this protein in urine cytology.

METHODS:

The authors compared the results of p16^INK4a immunoreactivity in cytology and biopsy samples from 83 cases, including low‐grade urothelial carcinomas, reactive epithelial lesions, and negative cases.

RESULTS:

p16^INK4a assessment of in urine cytology samples showed a sensitivity of 66.7% and a specificity of 82.8% in the diagnosis of low‐grade urothelial carcinomas.

CONCLUSIONS:

On the basis of these results, the authors propose that immunocytochemical detection of p16^INK4a is a reliable tool in urine cytology, both for the diagnosis of low‐grade urothelial carcinomas and for follow‐up purposes. More retrospective and prospective studies are required to verify these results. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.     

Highly predictive survival nomogram after upper urinary tract urothelial carcinoma

BACKGROUND:

Nephroureterectomy is the surgical standard of care for patients with upper urinary‐tract urothelial carcinoma. The objectives of the current study were to identify the most informative predictors of cancer‐specific mortality after nephroureterectomy, to devise an algorithm capable of predicting the individual probability of cancer‐specific mortality, and to compare its prognostic accuracy to that of the International Union Against Cancer (UICC) staging system.

METHODS:

Within the Surveillance, Epidemiology, and End Results database, the authors identified 5918 patients who had been treated with nephroureterectomy. Within the development cohort (n = 2959), multivariate Cox regression models predicting cancer‐specific mortality were fitted by using age, stage, nodal status, sex, grade, race, type of surgery (nephroureterectomy with or without bladder‐cuff removal), and tumor location (renal pelvis vs ureter). Backward variable elimination according to the Akaike information criterion identified the most accurate and parsimonious model. Model validation and calibration were performed within the external validation cohort (n = 2959). External validation was also applied to the UICC staging system.

RESULTS:

The 5‐year freedom from cancer‐specific mortality rates in both the development and external validation cohorts was 77.3%. The most informative and parsimonious nomogram for cancer‐specific‐mortality–free survival relied on age, pT and pN stages, and tumor grade. In external validation, nomogram prediction of 5‐year cancer‐specific‐mortality–free rate was 75.4% accurate and was significantly better (P < .001) than the UICC staging system (64.8%).

CONCLUSIONS:

The current nomogram is capable of predicting the prognosis in patients with upper urinary‐tract urothelial carcinoma treated by nephroureterectomy with better accuracy than the UICC staging system. The authors recommend the application of this nomogram to routine clinical practice when counseling or making clinical decisions. Cancer 2010. © 2010 American Cancer Society.     

p53 mutations in urinary bladder cancer

We have screened for mutations in exons 5-8 of the p53 gene in a series consisting of 189 patients with urinary bladder neoplasms. 82 (44%) neoplasms were lowly malignant (Ta, G1-G2a) and 106 (56%) were highly malignant (G2b-G4 or > or = T1). Only one mutation was in a lowly malignant urinary bladder neoplasm, in total we found p53 mutations in 26 (14%) of the 189 patients. 30% of the samples had loss of heterozygosity (LOH) for one or both of the p53 exogenic (CA)n repeat and the p53 intragenic (AAAAT)n repeat markers. 31 samples (21%) showed LOH but were not mutated, suggesting other mechanisms inactivating p53 than mutations. 4 mutations were found at codon 280 and 2 mutations were found at codon 285, 2 previously reported hot spots for urinary bladder cancer. The study indicate a boundary between G2a and G2b tumours concerning the occurrence of genetic events affecting p53 function; moderately differentiated (G2) urinary bladder neoplasms probably are genetically heterogeneous which supports the suggestion that they should not be grouped together but instead, for example, be categorized as either lowly or highly malignant.     

Outcomes after adjuvant chemotherapy in the treatment of high-risk urothelial carcinoma of the upper urinary tract (UUT-UC): results from a large multicenter collaborative study

BACKGROUND:

Urothelial carcinoma of the upper urinary tract (UUT‐UC) was a rare, aggressive urologic cancer with a propensity for multifocality, local recurrence, and metastasis. High‐risk patients had poor outcomes. Because of the rarity of these tumors, randomized clinical trials and data regarding adjuvant chemotherapy in locally advanced tumors are currently unavailable. Our objective was to assess the effect of adjuvant chemotherapy and the impact of potential prognostic factors on survival in high‐risk, postsurgical UUT‐UC patients.

METHODS:

Using a multi‐institutional, international retrospective database, identified were 627 patients with high risk UUT‐UCs (pT3N0, pT4N0 and/or N+ and/or M+) who underwent surgical removal. Only patients who received adjuvant chemotherapy were included.

RESULTS:

Overall, 140 patients (22.6%) with a median age of 67 years were included. The median follow‐up was 22.5 months. The 5‐year, overall survival for the entire cohort was 43%, the 5‐year recurrence‐free survival was 54%, and metastasis‐free survival was 53% at 5 years. Positive surgical margins were an independent prognostic factor for recurrence (P = .06), cancer‐specific mortality (P = .05), and overall mortality (P = .02) of any cause. Adjuvant chemotherapy was not linked with overall or cancer‐specific survival in patients with high risk disease (adjuvant chemotherapy [n = 140] vs no treatment [n = 487]) (P >.5).

CONCLUSIONS:

Adjuvant postoperative chemotherapy did not offer any significant benefit to overall survival in our population. Additional data were necessary, and studies enrolling patients at high risk in clinical trials investigating neoadjuvant chemotherapy in conjunction with chemotherapy should have been highly encouraged. Cancer 2011;. © 2011 American Cancer Society.