Fluorescence in situ hybridization for detecting transitional cell carcinoma: implications for clinical practice

OBJECTIVE: To determine the diagnostic sensitivity of genetic studies using fluorescence in situ hybridization (FISH) for detecting both new and recurrent cases of transitional cell carcinoma (TCC) in a routine clinical practice setting, as bladder cancer has a significant risk of recurrence and progression to invasive disease and thus sensitive surveillance testing is very important. PATIENTS AND METHODS: FISH was performed using the UroVysion kit (Vysis Inc., Downers Grove, IL, USA) Consecutive patients were assessed using FISH, both to evaluate those with a history of TCC or with suspicious symptoms, and the FISH results were compared with concurrent biopsy and cytological assessments. RESULTS: In all, 521 consecutive FISH tests from 300 patients were evaluated; 47% had a history of bladder cancer and 53% had suspicious symptoms. Of the 521 FISH tests, 24% were positive; concurrent cytology was available for 84% of the FISH tests, with a concordance rate of 78% (6% were positive for both and 72% were negative by both tests). For the discordant cases, FISH was positive and cytology negative in 21% of cases, and cytology was positive with a negative FISH for 1%. In all, 99 FISH tests had concurrent biopsy data. Of the 44 cases histologically positive for TCC, 32 were FISH-positive, resulting in an overall sensitivity (95% confidence interval) of 73 (60-88)%. FISH detected 95% of cases with high-grade carcinoma, while only seven of these 17 were positive by concurrent cytological assessment. FISH detected 56% and cytology detected 32% of low-grade lesions. FISH detected all nine new cases with positive histology. Overall, the specificity of FISH was 65 (53-78)%. Of 112 patients with previous TCC, 28 had a recurrence; 22 of these had positive FISH results. CONCLUSION: FISH analysis has a high sensitivity for detecting new cases of TCC, as well as recurrences. From the present data FISH is considerably more sensitive and only slightly less specific than cytology in diagnosing TCC. Therefore, we recommend FISH as a useful initial diagnostic tool in patients suspected of both new and recurrent TCC.     

荧光原位杂交技术检测膀胱尿路上皮癌尿液的临床应用研究

目的：评价荧光原位杂交技术（fluorescence in situ hybridization,FISH）检测膀胱尿路上皮癌患者尿液的应用价值。方法：收集我院2007年10月-2009年4月期间77例膀胱尿路上皮癌患者、43例非尿路上皮癌的血尿患者（通过膀胱镜检查排除尿路上皮癌）和泌尿系良性疾病患者的晨尿,同时行FISH检测和尿脱落细胞学分析,再结合病理结果将两种方法进行比较。FISH检测使用荧光标记DNA探针混合物与细胞核上3、7、17号染色体着丝粒和9p16位点进行杂交。结果：FISH总的敏感度和特异度分别为89．6％和95．3％,G1-3各级的敏感度分别为76．1％、90．9％、100％,Ta、Tis、T1、T2-4各期的敏感度分别为55．6％、100％、88．9％、97．4％。尿脱落细胞学分析总的敏感度和特异度分别为37．7％和93．0％,G1-3各级的敏感度分别为0％、33．3％、78．3％,Ta、Tis、T1、T2-4各期的敏感度分别为11．1％、100％、14．8％、56．4％。结论：FISH比尿脱落细胞学提高了膀胱癌患者检测的敏感度,而特异度两者相近。FISH使低级别浅表型膀胱癌的准确率明显提高,几乎能检测出所有高级别的浸润型膀胱癌。相对于尿脱落细胞学,FISH检测更佳。     

荧光原位杂交技术在膀胱尿路上皮癌诊断中的应用价值

目的:评估荧光原位杂交技术(FISH)在膀胱尿路上皮癌诊断中的应用价值。方法:收集60例疑似膀胱癌的血尿患者的尿液标本,分别作尿细胞学检测和荧光原位杂交分析。20例正常人尿液标本,用于建立FISH阀值,作为阳性判断的标准。结果:细胞学和FISH的总敏感性分别为42.0%、82.2%,特异性分别为:93.3%、86.7%。细胞学和FISH在低级别及非肌层浸润性肿瘤等敏感性的均差异有统计学意义(P<0.05)。结论:FISH技术能明显提高膀胱尿路上皮癌的检出率,尤其是早期和低级别病变,可以成为筛查膀胱尿路上皮癌的一种新的无创性检查方法。     

荧光原位杂交技术在膀胱尿路上皮癌诊断中的临床应用

目的 探讨荧光原位杂交(FISH)技术运用于膀胱尿路上皮癌的诊断价值.方法 收集20例健康志愿者的新鲜晨尿,运用荧光标记的3号、7号、17号染色体着丝粒探针及9号染色体p16位点探针,对尿液标本中的脱落细胞染色体进行FISH技术检测,建立正常人群的阈值.收集158例怀疑为膀胱尿路上皮癌患者的新鲜晨尿,在行膀胱镜检查前,同期进行FISH技术与尿脱落细胞学检测,运用统计学方法,比较FISH技术与尿脱落细胞学检测的敏感性与特异性.结果 FISH与尿脱落细胞学的敏感性分别为84.8%和43.8%,FISH敏感性高于尿脱落细胞(P<0.05),FISH与尿脱落细胞学特异性分别为89.1%和87.0%,两者无统计学差异(P>0.05),在不同的肿瘤病理分级中,FISH的敏感性都高于尿脱落细胞,并且FISH敏感性随肿瘤分级逐级升高(P<0.05).结论 FISH技术具有较高的敏感性和特异性,可以作为国人膀胱尿路上皮癌筛查、诊断的新方法.     

A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma

PURPOSE: We determine the relative sensitivities of cytology and fluorescence in situ hybridization (FISH) for the detection of urothelial carcinoma. MATERIALS AND METHODS: A mixture of fluorescent labeled probes to the centromeres of chromosomes 3, 7 and 17, and band 9p21 (P16/CDKN2A gene) was used to assess urinary cells for chromosomal abnormalities indicative of malignancy. A total of 280 urine specimens from 265 patients, including 150 with a history of urothelial carcinoma and 115 without a history of urothelial carcinoma, were analyzed. FISH analysis was performed without prior knowledge of clinical findings, that is biopsy, cystoscopy and cytology results. A positive result was defined as 5 or more urinary cells with gains of 2 or more chromosomes. RESULTS: A total of 75 biopsies showed urothelial carcinoma at FISH analysis among the 265 patients. The sensitivity of urine cytology for pTa (36 cases), pTis (18) and pT1-pT4 (15) tumors was 47%, 78% and 60%, respectively, for an overall sensitivity of 58%. The sensitivity of FISH for pTa (37 cases), pTis (17) and pT1-pT4 (19) tumors was 65%, 100% and 95%, respectively, for an overall sensitivity of 81%. FISH was significantly more sensitive than cytology for pTis (p = 0.046), pT1-pT4 (p = 0.025), grade 3 (p = 0.003) and all tumors (p = 0.001). The specificity of cytology and FISH among patients without cystoscopic evidence of urothelial carcinoma and no history of urothelial carcinoma was 98% and 96%, respectively (p = 0.564). CONCLUSIONS: The sensitivity of FISH for the detection of urothelial carcinoma is superior to that of cytology, and the specificity of FISH and cytology for urothelial carcinoma are not significantly different. Further prospective studies are required but FISH has the potential to improve significantly the management of urothelial carcinoma.     

Clinical utility of a multiprobe FISH assay in voided urine specimens for the detection of bladder cancer and its recurrences,compared with urinary cytology

OBJECTIVES: To evaluate the clinical utility of a Multi-color FISH (fluorescence in situ hybridization) assay in voided urine specimens for the detection of bladder cancer and its recurrences, comparing the results with those afforded by urinary cytology. METHODS: Voided urine samples from 86 patients were obtained for urine cytology and FISH analysis. The latter was performed using a mixture of fluorescent labeled DNA probes for the centromeric regions of chromosomes 3, 7 and 17, and the 9p21 region. Cystoscopy with biopsy or tumor resection was performed in all patients, comparing the pathological results with the cytological and FISH findings. RESULTS: Urinary cytology affords an overall sensitivity of 63.8%, the figure being 25% for grade 1, 66.6% for grade 2 and 94.7% for grade 3 tumors. The sensitivities for FISH were 53.3% for grade 1, 83.3% for grade 2 and 100% for grade 3 tumors, with an overall sensitivity of 80.4%. The specificities of urinary cytology and FISH were 86.1 and 85.3%, respectively. CONCLUSIONS: FISH improves the sensitivity rates obtained with urine cytology for bladder cancer detection in all tumor grades and stages, and offers similar specificity. FISH doubles the accuracy of urinary cytology in application to low grade-stage tumors, and detects all high grade infiltrating tumors.     

The efficacy of urinary cytology in the detection of urothelial tumours

Summary The sensitivity and specificity of urinary cytology in the detection of urothelial tumours using voided urine and applying simple smear preparation and staining techniques have been assessed. Of the 2704 patients under investigation 207 had urothelial tumours. The first urine analysis was positive in 66% of the patients with urothelial carcinoma; an additional 23% of the patients showed positive cytology in repeat smears, resulting in a sensitivity of 89%. The efficacy of urinary cytology depends on the tumour type: for grade 2 tumours, 79% were cytologically positive, 92% of grade 3 and 98% of the grade 4 tumours. The diagnostic efficacy in cases of carcinoma-in-situ, squamous cell carcinoma and adenocarcinoma was comparable with that of grade 4 carcinomas. Grade 0–1 tumours did not result in positive cytology. In eleven cases of lithiasis and in two cases of cyclophosphamide therapy the cytological diagnosis was positive but no neoplasm could be established histologically; these represent true false positive diagnoses. Thus, the false positive rate, 13 out of 165, was 7.88% and the false negative rate, 61 out of 207, was 29.4% when grades 0–1 were included, but 8.75% (14 out of 160) when grades 0–1 were excluded.     

荧光原位杂交技术在尿路上皮癌预警诊断中的应用

目的：探讨使用荧光原位杂交技术对尿路上皮癌进行预警诊断的可行性和有效性。方法：采用3、7、17号染色体着丝粒探针和9p21区带探针对30例影像学检查、膀胱镜检查、尿脱落细胞学检查均为阴性的高度可疑的尿路上皮癌的血尿患者尿液脱落细胞核行荧光原位杂交检测。结果：30例血尿患者中,11例FISH结果阳性。随访3～13个月。有5例确诊为膀胱尿路上皮癌,2例确诊为肾盂癌。19例FISH检测阴性的患者无一例患病。结论：尿脱落细胞荧光原位杂交技术对膀胱镜和尿脱落细胞学检查阴性的早期尿路上皮癌患者有预警诊断作用．具有重要的临床应用价值。     

Utility of fluorescence in situ hybridization as a non-invasive technique in the diagnosis of upper urinary tract urothelial carcinoma

OBJECTIVES: To assess the clinical utility of a fluorescence in situ hybridization (FISH) assay as a non-invasive method for diagnosing and monitoring urothelial carcinoma (UC) in the upper urinary tract (UUT). METHODS: Urine specimens from 30 consecutive patients with UUT UC and 19 healthy controls were analyzed by means of cytology and FISH. For FISH analysis, labelled probes to chromosomes 3, 7, 9, and 17 were used to assess chromosomal abnormalities indicative of malignancy. Sensitivity and specificity of both techniques were determined and compared. The frequency of chromosomal aberrations of malignant cells from UUT was also determined. RESULTS: Overall sensitivity for FISH was significantly higher than the corresponding value for urine cytology (76.7% vs. 36%, respectively, p=0.0056). Specificities for FISH and cytology were 94.7% and 100%, respectively (p=ns). The positive and negative predictive values for FISH were 95.8% and 72%, whereas for cytology they were 100% and 54%, respectively. Of the genetically altered nuclei counted, 67%, 54%, and 43% presented polysomy in chromosomes 3, 7, and 17, respectively, and 21% presented a homozygous deletion of chromosome 9. CONCLUSIONS: FISH assay of chromosomes 3, 7, 9, and 17 performed on exfoliated cells from voided urine specimens has greater sensitivity than cytology for detecting UUT UC whilst maintaining a similar specificity. The non-invasive nature of this method and its higher sensitivity could contribute to improving the current diagnosis of UUT UC.     

荧光原位杂交法和全自动图像细胞仪在膀胱尿路上皮癌诊断中的应用

目的 探讨荧光原位杂交法(FISH)和全自动图像细胞仪(ICM)在膀胱尿路上皮癌诊断中的应用.方法 在2008年8月至2009年3月共选取60例患者,包括20例非尿路上皮癌和40例膀胱尿路上皮癌的患者,取患者的尿液作常规尿细胞学检查、FISH和ICM检测.结果 FISH的敏感性显著高于ICM的敏感性(82.5%比62.5%,P＜0.05)和常规尿细胞学的敏感性(82.5%比25.0%,P＜0.05),同时ICM敏感性也高于常规尿细胞学的敏感性(62.5%比25.0%,P＜0.05);FISH、ICM和常规尿细胞学检查的特异性都为100%,三者在特异性方面差异无统计学意义(P＞0.05).FISH、ICM和常规尿脱落细胞学检测的敏感性与病理分期无相关性(P＞0.05),但与分级有相关性(P＜0.05).结论 FISH和ICM在膀胱尿路上皮癌诊断中,其特异性和常规尿细胞学检查一致,但敏感性显著高于常规尿细胞学检查;同时FISH在膀胱尿路上皮癌诊断中的敏感性高于ICM,所以FISH技术更有望成为膀胱尿路上皮癌无创性的诊断和检测手段.     

尿脱落细胞FISH检测在恶性血尿病因诊断中的应用

目的：比较尿脱落细胞荧光原位杂交（Fluorescence in situ hybridization，FISH）检测、细胞学分析和膀胱镜对恶性血尿诊断的临床有效性及应用价值，为建立或完善恶性血尿病因诊断提供理论基础。方法：10例正常人通过FISH技术检测9号染色体p16位点、3号染色体、7号染色体及17号染色体的变异情况，建立FISH检测尿脱落细胞的方法学平台及标准检测方法同时确立阈值。同时收集100例血尿患者晨尿同步进行细胞学分析、膀胱镜检查及FISH检测。以组织病理确诊为膀胱尿路上皮癌为金标准，评估FISH诊断的特异度和敏感度及与膀胱癌发生及发展的关系。结果：FISH诊断尿路上皮癌的特异度为86．1％，敏感度为89．1％；尿细胞学诊断的特异度为97．2％，敏感度为23．4％。两者相比，敏感度差异有统计学意义（P〈0．05），而特异度差异无统计学意义（P〉0．05）。结论：与尿细胞学相比，FISH在恶性血尿病因的诊断中具有较高的灵敏度和相似的特异度，同时无创快速，可作为筛查和诊断尿路上皮癌的新方法。     

荧光原位杂交在膀胱尿路上皮癌诊断中的应用

目的评价尿脱落细胞荧光原位交(fluorescenceinsituhybridization,FISH)检测在膀胱肿瘤诊断中的应用价值。方法分别对69例疑似膀胱尿路上皮癌及20例对照组的尿液标本进行FISH及细胞学检测,比较两者诊断的敏感性及特异性,统计膀胱尿路上皮癌各个染色体畸变的几率。结果 FISH诊断膀胱尿路上皮癌的总的敏感度高于尿脱落细胞学检查(分别为79.7%、22.0%,P<0.05),两者的特异度分别为93.3%、100%(P>0.05)。结论 FISH在诊断膀胱尿路上皮癌中敏感性高于尿细胞学检查,同时其特异性亦较高,在早期诊断中具有重要意义。     

Enhanced bladder cancer detection with the Lewis X antigen as a marker of neoplastic transformation

Recent evidence indicates that the Lewis X determinant is a tumor-associated antigen in the urothelium. Immunohistochemical analyses on frozen and deparaffinized, formalin-fixed tissue sections have demonstrated that the Lewis X antigen is not detected in normal adult urothelium except for occasional umbrella cells. However, papillomas and transitional cell carcinomas express this blood group-related antigen in more than 90% of the cases regardless of the grade or stage of the tumor, or the blood type or secretor status of the individual. To determine the presence of Lewis X antigen on exfoliated bladder epithelial cells we used an anti-Lewis X monoclonal antibody (P-12) and the avidin-biotin-peroxidase technique on 129 bladder barbotage specimens. Of 40 controls 34 were negative for Lewis X antigen, for a specificity of 85%. The 89 bladder tumor patients consisted of 14 with papilloma, 13 with flat carcinoma in situ, 49 with transitional cell carcinoma, and 13 with a positive cytology and negative biopsy results. Of these 89 patients 76 were considered positive for Lewis X antigen, for an over-all sensitivity 85.4%. The sensitivity for cytology alone was 61.2%. However, the combination of a positive cytology and/or positive Lewis X antigen result yielded a sensitivity of 93.2%. The data suggest that immunocytological detection of the Lewis X antigen on exfoliated bladder cells enhances the detection of urothelial tumor cells, particularly from low grade and low stage neoplasms.     

荧光原位杂交技术对膀胱癌尿脱落细胞诊断价值的荟萃分析

目的通过荟萃分析比较荧光原位杂交技术（fluorescence in situ hybridization,FISH）和细胞学检测膀胱癌尿脱落细胞的灵敏度和特异度。方法从中国生物医学文献数据库、PubMed等专业数据库中收录的有关FISH、细胞学与膀胱癌尿脱落细胞检测相关分析文献中,纳入符合条件的文献,应用Revman5．0进行荟萃分析。结果HSH用于诊断膀胱癌尿脱落细胞的灵敏度为78．1％（0R值为4．98,95％CJ：3．63～6．83）,显著优于细胞学的46．3％（P〈0．00001）;HSH检查的特异度为93．9％（OR值为0．41,95％CI：0．193-0．930）,稍低于细胞学检查的96．3％（P=0．03）。结论荟萃分析肯定了FISH用于膀胱癌尿脱落细胞检测的价值,其灵敏度高,特异度接近细胞学检查。     

FISH analysis of washing urine from the upper urinary tract for the detection of urothelial cancers

Introduction

To evaluate FISH analysis of washing urine from the upper urinary tract (UUT) in comparison with cytology (Cyt) for the detection of urothelial cancers.

Patients and methods

In 82 patients with symptoms or abnormalities of the UUT sampling of washing urine for FISH and Cyt and a stepwise diagnostic work-up (e.g. retrograde ureteropyelography, ureterorenoscopy and endoscopic biopsy) were performed. In case of endoscopically and/or histologically proven malignancy patients either underwent nephroureterectomy, partial ureterectomy or local treatment. Sensitivity and specificity for FISH and Cyt as well as its combination were determined.

Results

Urothelial cancer of the UUT was detected in 20 patients. Eleven patients underwent nephroureterectomy, six partial ureterectomy and three endoscopic tumour treatment. This revealed nine pTa, three pT1 and seven muscle-invasive tumours. Twelve tumours were classified as low and seven as high-grade tumours. In one patient with a macroscopic unequivocal finding of tumour, endoscopic laser ablation without histologic confirmation was performed. FISH was evaluable in 76 patients and detected 16 tumours with a sensitivity and specificity of 84.2 and 91.1 %, respectively. Cyt was performed in 79 and was evaluable in 78 patients. It detected ten tumours with a sensitivity and specificity of 52.6 and 91.4 %, respectively. Cyt and FISH together detected 19 tumours with (sensitivity 100 % and specificity 83.6 %).

Conclusion

FISH was more sensitive than and equally specific to Cyt in the detection of urothelial cancers of the UUT. Both markers in combination revealed the best sensitivity, making it a possible approach in future settings.     

The role of FISH and cytology in upper urinary tract surveillance after radical cystectomy for bladder cancer

ObjectivesCytology and fluorescence in situ hybridization (FISH) (Urovysion) assay are often used during upper urinary tract surveillance in patients following radical cystectomy with urinary diversion, without much available data regarding efficacy in this population. Here, we evaluate the value of FISH and cytology in detecting upper tract recurrence in the face of a urinary diversion.Materials and methodsA review of our cystectomy database revealed 270 patients who had at least one FISH and/or cytology assay performed during surveillance after radical cystectomy. Workup included upper tract imaging in all patients and upper tract endoscopy as indicated. A total of 163 FISH assays and 474 urinary cytology examinations were included in the analysis. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FISH and cytology were assessed.ResultsTen patients (3.4%) developed upper tract recurrence after a median follow-up time of 31 months (2–202). All but 1 patient presented either with gross hematuria or positive finding on imaging; 6 had positive FISH and cytology, and 2 had positive cytology only (no FISH done). For detection of upper tract recurrence, sensitivity, specificity, PPV, and NPV of cytology were 80.0%, 85.6%, 10.7%, and 99.5%, respectively; and that for FISH were 85.7%, 86.5%, 23.1%, and 99.2%, respectively.ConclusionsThe FISH assay and urinary cytology both demonstrate high rates of false positivity and are useful mainly for their negative predictive ability in patients with a urinary diversion. Unless prospective trials show otherwise, both—or at least the more expensive test—can be omitted from surveillance strategies.     

膀胱移行细胞癌患者尿脱落细胞中生存素的检测及其意义

目的:探讨膀胱移行细胞癌(TCCB)患者尿脱落细胞生存素(Survivin)蛋白和mRNA表达及其临床意义。方法:采用免疫组化SP法和巢式逆转录聚合酶链反应方法,对TCCB患者32例(TCCB组)、非TCCB16例(对照组)尿脱落细胞Survivin的蛋白和mRNA进行检测,同时行尿脱落细胞学检查。结果:TCCB组尿脱落细胞Survivin的蛋白、mRNA阳性表达率分别为28例(87.5%),32例(100%);对照组仅1例mRNA阳性表达(6.2%)。两组Survivin阳性率比较差异有统计学意义(P<0.01);尿液中Survivin的敏感性和特异性,分别为87.5%,80%和96.9%,93.8%。而尿脱落细胞阳性率为18例(56.2%),其敏感性和特异性分别为56.2%和100%。结论:尿脱落细胞Survivin检测诊断TCCB的敏感性和特异性均较高,且对患者无创、无痛苦,可作为早期诊断TCCB的敏感指标,其中RT-PCR检测敏感性更高。     

Urinary cytology has a poor performance for predicting invasive or high-grade upper-tract urothelial carcinoma

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Accurate preoperative staging for upper‐tract urothelial carcinoma (UTUC) lesions is presently limited. Urinary cytology has shown promise for characterizing pathological features of bladder cancer. The role of cytology for UTUC is at present poorly defined. In this large multi‐institutional cohort of patients, urinary cytology was limited in its ability to accurately predict the grade and stage of upper‐tract lesions. Selective ureteral sampling improved the diagnostic accuracy of cytology when compared to bladder specimens. Improved preoperative surrogate markers for staging UTUC remain necessary.

OBJECTIVE

? To evaluate the diagnostic accuracy of urine cytology for detecting aggressive disease in a multi‐institutional cohort of patients undergoing extirpative surgery for upper‐tract urothelial carcinoma (UTUC).

METHODS

? We reviewed the records of 326 patients with urinary cytology data who underwent a radical nephroureterectomy or distal ureterectomy without concurrent or previous bladder cancer. ? We assessed the association of cytology (positive, negative and atypical) with final pathology. Sensitivity and positive predictive value (PPV) of a positive (± atypical) cytology for high‐grade and muscle‐invasive UTUC was calculated.

RESULTS

? On final pathology, 53% of patients had non‐muscle invasive disease (pTa, pTis, pT1) and 47% had invasive disease (≥pT2). Low‐grade and high‐grade cancers were present in 33% and 67% of patients, respectively. ? Positive, atypical and negative urine cytology was noted in 40%, 40% and 20% of cases. Positive urinary cytology had sensitivity and PPV of 56% and 54% for high‐grade and 62% and 44% for muscle‐invasive UTUC. ? Inclusion of atypical cytology with positive cytology improved the sensitivity and PPV for high‐grade (74% and 63%) and muscle‐invasive (77% and 45%) UTUC. Restricting analysis to patients with selective ureteral cytologies further improved the diagnostic accuracy when compared with bladder specimens (PPV > 85% for high‐grade and muscle‐invasive UTUC).

CONCLUSIONS

? In this cohort of patients with UTUC treated with radical surgery, urine cytology in isolation lacked performance characteristics to accurately predict muscle‐invasive or high‐grade disease. ? Improved surrogate markers for pathological grade and stage are necessary, particularly when considering endoscopic modalities for UTUC.     

Role of fluorescence in situ hybridization in bladder cancer surveillance of patients with negative cytology

ObjectivesThe clinical utility of urine markers in urothelial cancer (UC) surveillance is not established. We previously evaluated the use of fluorescence in situ hybridization (FISH) in managing patients with atypical cytology at risk for UC. This study evaluates its role in patients with negative cytology with a history of UC.Materials and methodsBetween June 2007 and January 2009, every patient with a history of UC who underwent cystoscopy and cytology with UroVysion test were identified. A comprehensive chart review was performed on each patient with negative cytology.ResultsThe population comprised 142 patients undergoing cancer surveillance; 111 patients with negative cystoscopy, 19 with equivocal cystoscopy, and 12 with positive cystoscopy. In patients with negative cystoscopy, there was cancer in only 1 of 111 patients. UroVysion could detect the only patient with UC with sensitivity of 100% and had a negative predictive value (NPV) of 100%. In patients with equivocal cystoscopy, it detected 2 tumors that would be missed by cytology. There were 4 false negative results (sensitivity 33.3% and NPV 66.7%). In patients with obvious lesion on cystoscopy, there were 9 false negative results (sensitivity 10% and NPV 18.2%).ConclusionsFew patients with negative cystoscopy and negative cytology have cancer. Patients with equivocal and positive cystoscopy and negative cytology frequently have cancer and the UroVysion FISH assay was not helpful in these cases. The cost-effectiveness of the FISH assay needs to be assessed prior to widespread use in patients with negative cytology.     

Current bladder tumor tests: does their projected utility fulfill clinical necessity?

PURPOSE: We reviewed currently available bladder cancer tests in the context of the clinical expectations of a noninvasive bladder cancer test. MATERIALS AND METHODS: We reviewed the literature on bladder cancer tests that are commercially available or have shown clinical usefulness and examined how each test compares with standard methods of bladder cancer diagnosis. RESULTS: The clinical necessity for a noninvasive test for bladder cancer is 2-fold, including the early detection of high grade bladder tumors before muscle invasion and monitoring tumor recurrence or new onset. An ideal noninvasive test should be sensitive, specific, rapid, technically simple and have low intra-assay and interassay variability. Urine cytology has high specificity but limited applicability due to its relatively low sensitivity and subjective nature. Hematuria detection by Hemastix dipstick is sensitive but not specific for detecting bladder cancer. Molecules associated with bladder tumor growth and progression may serve as a basis for designing noninvasive diagnostic tests. The Food and Drug Administration approved BTA Stat and BTA TRAK tests, which detect human complement factor H and a related protein in urine, have 60% to 80% sensitivity and 50% to 70% specificity (lower in symptomatic patients) for bladder cancer. The Food and Drug Administration approved NMP22 test, which measures the level of nuclear mitotic apparatus protein in urine, has 50% to 100% sensitivity and 60% to 90% specificity. Accu-Dx detects fibrin degradation products, fibrin and fibrinogen in urine, although this test is no longer commercially available. The Immunocyt test combines cytology with an immunofluorescence technique to improve the sensitivity of cytology for detecting low grade tumors. The telomeric repeat amplification protocol assay for telomerase in exfoliated cells has 70% to 86% sensitivity and 60% to 90% specificity for bladder cancer. However, the low stability of telomerase in urine affects its sensitivity. The hyaluronic acid and hyaluronidase (HA-HAase) test, which measures the urinary level of hyaluronic acid and hyaluronidase, has 90% to 92% sensitivity and 80% to 84% specificity for bladder cancer. Quanticyt karyometry evaluates nuclear shape and DNA content of exfoliated cells to detect bladder cancer. The list of bladder tumor markers is growing rapidly and large multicenter trials are essential to assess their usefulness. CONCLUSIONS: Although currently noninvasive bladder cancer tests cannot replace cystoscopy, some have shown a promise of being clinically useful. One or a combination of these tests-markers may prove to be a prostate specific antigen for bladder cancer provided that patients and, more importantly, clinicians accept it.