人尿脱落细胞FISH检查与尿脱落细胞学检查和膀胱镜检查在尿路移行细胞癌诊断中的应用及对比研究
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摘要
目的：尿路移行细胞癌在泌尿系肿瘤中比较常见，发病率高，复发率高，死亡率也较高，疾病的治疗占用了大量的医疗资源。而大量数据表明，越是能够获得早期的诊断治疗，预后就越好。本实验比较尿脱落细胞荧光原位杂交（FISH）检查、尿脱落细胞学检查和膀胱镜检查对以恶性血尿为主要症状的尿路移行细胞癌诊断的临床有效性，为完善血尿病因诊断提供数据支持。
材料与方法：河北医科大学第二医院泌尿外科2010年8月至2011年8月可疑尿路移行细胞癌的血尿患者100例，其中男性71例，女性29例，中位年龄为61岁。对100例患者均行FISH检查、尿脱落细胞学检查和膀胱镜检查。共有72例诊断为膀胱移行细胞癌，临床病理情况：Ta10例，T126例，T225例，T3/411例。13例诊断为上尿路肿瘤，其中6例肾盂移行细胞癌，6例输尿管移行细胞癌，1例肾盂神经内分泌癌。2例诊断为膀胱腺癌。10例患者诊断为腺性膀胱炎。1例间质性膀胱炎。1例肾结核。1例前列腺癌。
荧光原位杂交技术（FISH）是起源于20世纪80年代末的一种分子遗传学技术，探针为已知的荧光标记的核酸，按照碱基互补配对原则，将待检标本中的未知的单链核酸与探针特异性结合，形成杂交双链核酸，再应用荧光显微镜检测荧光信号，从而得出结果。FISH可以检测染色体数目异常和染色体畸变，在分子水平表现为基因片段扩增、缺失、碱基改变等。本实验使用GLPp16/CSP17组合探针进行检测。
通过对20例正常人（男10例、女10例）的尿液样本，使用相同方法进行FISH实验，两组探针组合分别观察100个细胞。统计出不同类型异常细胞的百分比，建立阈值。阈值=平均值（M）+3×标准差（SD）。分别建立17号染色体≥3个信号点、p16位点0个信号点、1个信号点的阈值。此阈值为本实验室前期实验确定。
100例患者的FISH结果与阈值相比较进行FISH判读。FISH阳性判读标准为17号染色体、p16位点1个信号点均异常或者17号染色体的复杂异常或者p16位点0个信号点。100例患者同时行尿脱落细胞学检查和膀胱镜检查，以膀胱镜活检病理或手术切除标本病理为最终确诊依据，并对疾病进行分期，比较三种诊断方法的敏感性和特异性（尿脱落细胞学诊断为可疑按阳性结果处理）。在膀胱镜检查前取不少于200ml尿液标本，否则影响细胞计数，膀胱镜活检病理结果与手术切除标本病理结果不一致时，以手术切除标本病理结果为准。
结果：FISH检查、尿脱落细胞学检查及膀胱镜检查对72例膀胱移行细胞癌的总的敏感性分别为62/72（86.1%）、14/72（19.1%）、67/72（93.1%）。FISH和膀胱镜比较，P=0.057>0.05，无统计学意义；FISH与尿细胞学比较P=0<0.05，有统计学意义。尿脱落细胞学与膀胱镜比较，P=0<0.05，有统计学意义。FISH对膀胱移行细胞癌Ta、T1、T2、T3/4各分期敏感性分别为60.0%、86.5%、94.1%、100%。尿脱落细胞学各分期敏感性分别为0%、13.5%、23.4%、62.5%。膀胱镜各分期敏感性分别为80.0%、91.9%、100%、100%。Ta、T1、T2期，FISH与尿脱落细胞学比较，P<0.05，有统计学意义；T3/4期，P>0.05，无统计学意义。各分期FISH与膀胱镜比较，P>0.05，无统计学意义。三者对于膀胱移行细胞癌总的特异性分别为10/12(83.3%)、12/12（100%）、12/12（100%），三者比较，P=0.314>0.05，无统计学意义。
FISH检查及尿脱落细胞学检查对于12例上尿路移行细胞癌总的敏感性分别为12/12（100%）、3/12（25.0%），进行比较，P<0.05，有统计学意义。两种检查对于整个84例尿路移行细胞癌总的敏感性分别为74/84(88.1%)、17/84(20.2%)，两者比较，P<0.05，有统计学意义。FISH对于整个尿路移行细胞癌Ta、T1、T2、T3/4各分期敏感性分别为60.0%、86.8%、95.2%、100%。尿脱落细胞学对于各分期敏感性分别为0%、15.8%、23.8%、40.0%。两种方法不同分期进行比较，均P<0.05，有统计学意义。两种方法总的特异性分别为13/16（81.3%）、16/16（100%），P>0.05，没有统计学意义。
结论：对于膀胱移行细胞癌，FISH检查的敏感性与膀胱镜检查相当，而二者明显高于尿脱落细胞学检查，三者在特异性上无明显差别。FISH和尿脱落细胞学还可以有效检测上尿路移行细胞癌，而FISH的敏感性明显高于尿脱落细胞学。因此，对于恶性血尿为主要症状的患者，FISH可以作为筛查移行细胞癌的有效手段；FISH可以有效的对整个尿路移行细胞癌进行早期诊断，作为一种重要的主要或辅助手段应用于临床。
Objective： Urinary tract transitional cell carcinoma is morecommon tumor of the urinary tract，which is with high incidence ofrecurrence rate and high mortality. The treatment of diseases occupy alot of medical resources. Large amounts of data showed that patientsaccepted more earlier diagnosis and treatment, the prognosis would bebetter. In this study, we compared the clinical effectiveness of fluorescencein situ hybridization (FISH) examination, urine cytology and cystoscopefor malignant hematuria as the main symptoms of urinary tract urinarytract cells in tumor diagnosis. We Provided data for improving thehematuria diagnosis from our study.
Materials and methods: In the second hospital of Hebei medicaluniversity, the department of urology surgery enrolled100haematuriapatients (71male and29female，median age61years) suspicious ofurinary tract urothelial tumors,from August2010to august2011. All ofthe patients received FISH、urine cytology and cystoscope.72patients ofthem were pathologically diagnosed as bladder transitional cellcarcinoma, the staging as follow:10cases of Ta,26cases of T1,25casesof T2,11cases of T3/4.13patients were diagnosed as upper urinary tracttumor, including6cases of carcinoma of renal pelvis,6cases of uretercancer and1cases of endocrine carcinoma of the renal pelvis nerve. Theother15cases included2cases of bladder adenocarcinoma,10cases ofcystitis glandularis,1cases of interstitial cystitis,1cases of renaltuberculosis,1cases of prostate cancer.
Fluorescence in situ hybridization (FISH) is a molecular geneticstechnology, originated in the late1980s. Probe is a known fluorescently labeled nucleic acid. In accordance with the complementary base pairingprinciple, we combined the probe and unknown single-stranded nucleicacid specificly to form a hybrid double-stranded nucleic acids. Then wecould use fluorescent microscopy to read out the outcome. FISH candetect abnormal number of chromosomes and chromosomal aberrations.The experimental use GLP p16/CSP17combination probe.
We used the same method for the urine samples of20normalsubjects(10males,10females)with FISH experiment to establish thethreshold by the statistics of the percentage of different types ofabnormal cells. Threshold=mean (M)+3×standard deviation (SD).Established the17th chromosome≥3signal、p16site0signal point and1point threshold. This threshold was early established in our laboratoryexperiments.(Results see Table1)
FISH-positive criteria included chromosome17and9abnormalitiesat the same time, or a complex chromosome17abnormality, or anexception of p16(-2) alone more than15%.100cases of patients alsowere detected by urine cytology and cystoscopy detection. Thecomparison of the specificity and sensitivity among the three diagnosticmethods were completed based on the tumor staging results of theureteroscopic biopsy or surgical specimens (suspicious of urine cytologydiagnosis as the positive results of treatment). Take urine samples beforecystoscopy, not less than200ml, and otherwise affect the cell count. Ifthe results of cystoscopic biopsy and surgical resection pathologicalexamination or pathological staging were inconsistent, the results of thepathology of surgical specimens shall prevail.
Results: The overall sensitivity FISH examination, urine cytologyand cystoscopy in72patients with bladder transitional cell carcinomawere62/72(86.1%),14/72(19.1%),67/72(93.1%). Three methodspairwise comparison. FISH and cystoscopy, P=0.057>0.05, nostatistical significance; FISH and urine cytology, P=0<0.05,there wasstatistically significant. Urine cytology and cystoscopy, P=0<0.05, there was statistically significant. The sensitivity of FISH in bladdertransitional cell carcinoma of Ta, T1, T2, T3/4staging were60.0%,86.5%,94.1%,100%;urine cytology were0%,13.5%,23.4%,62.5%;and thecystoscope were80.0%,91.9%,100%,100%, respectively. At Ta, T1, T2stage, compare FISH with urine cytology, P <0.05, there was statisticallysignificant; at T3/4stage, there was not statistically significant. CompareFISH with cystoscopy for eath stage,there was not statisticallysignificant. The specificity of FISH, urine cytology, and urine cytologywere10/12(83.3%)、12/12（100%）、12/12（100%）.There was nostatistically significant of the three.
The sensitivity of FISH examination and urine cytology for12cases of upper urinary tract transitional cell carcinoma were12/12(100%),3/12(25.0%), P <0.05, there was statistically significant. Theoverall sensitivity of both tests for the84cases of entire urinary tracttransitional cell carcinoma were74/84(88.1%),17/84(20.2%),respectively, P <0.05, statistically significant. The sensitivity of FISH inthe entire urinary tract transitional cell carcinoma of Ta, T1, T2, T3/4staging were60.0%,86.8%,95.2%,100%,and urine cytology were0%,15.8%,23.8%,40.0%.For each stage, P <0.05, there was statisticallysignificant. The overall specificity of two methods were13/16(81.3%),16/16(100%), P>0.05, not statistically significant.
Conclusions: For bladder transitional cell carcinoma,the sensitivityof FISH was equal to cystoscopy,both significantly higher than urinecytology. There was no significant difference in specificity. FISH andurine cytology could detect upper urinary tract transitional cellcarcinoma. For upper urinary tract transitional cell carcinoma, thesensitivity of FISH was significantly higher than urine cytology.Therefore, FISH can be used as an effective means of screening oftransitional cell carcinoma for patients with malignant hematuria as the main symptoms. FISH as an important Method could effectivelydiagnose urinary tract transitional cell carcinoma earlier.
材料与方法：河北医科大学第二医院泌尿外科2010年8月至2011年8月可疑尿路移行细胞癌的血尿患者100例，其中男性71例，女性29例，中位年龄为61岁。对100例患者均行FISH检查、尿脱落细胞学检查和膀胱镜检查。共有72例诊断为膀胱移行细胞癌，临床病理情况：Ta10例，T126例，T225例，T3/411例。13例诊断为上尿路肿瘤，其中6例肾盂移行细胞癌，6例输尿管移行细胞癌，1例肾盂神经内分泌癌。2例诊断为膀胱腺癌。10例患者诊断为腺性膀胱炎。1例间质性膀胱炎。1例肾结核。1例前列腺癌。
荧光原位杂交技术（FISH）是起源于20世纪80年代末的一种分子遗传学技术，探针为已知的荧光标记的核酸，按照碱基互补配对原则，将待检标本中的未知的单链核酸与探针特异性结合，形成杂交双链核酸，再应用荧光显微镜检测荧光信号，从而得出结果。FISH可以检测染色体数目异常和染色体畸变，在分子水平表现为基因片段扩增、缺失、碱基改变等。本实验使用GLPp16/CSP17组合探针进行检测。
通过对20例正常人（男10例、女10例）的尿液样本，使用相同方法进行FISH实验，两组探针组合分别观察100个细胞。统计出不同类型异常细胞的百分比，建立阈值。阈值=平均值（M）+3×标准差（SD）。分别建立17号染色体≥3个信号点、p16位点0个信号点、1个信号点的阈值。此阈值为本实验室前期实验确定。
100例患者的FISH结果与阈值相比较进行FISH判读。FISH阳性判读标准为17号染色体、p16位点1个信号点均异常或者17号染色体的复杂异常或者p16位点0个信号点。100例患者同时行尿脱落细胞学检查和膀胱镜检查，以膀胱镜活检病理或手术切除标本病理为最终确诊依据，并对疾病进行分期，比较三种诊断方法的敏感性和特异性（尿脱落细胞学诊断为可疑按阳性结果处理）。在膀胱镜检查前取不少于200ml尿液标本，否则影响细胞计数，膀胱镜活检病理结果与手术切除标本病理结果不一致时，以手术切除标本病理结果为准。
结果：FISH检查、尿脱落细胞学检查及膀胱镜检查对72例膀胱移行细胞癌的总的敏感性分别为62/72（86.1%）、14/72（19.1%）、67/72（93.1%）。FISH和膀胱镜比较，P=0.057>0.05，无统计学意义；FISH与尿细胞学比较P=0<0.05，有统计学意义。尿脱落细胞学与膀胱镜比较，P=0<0.05，有统计学意义。FISH对膀胱移行细胞癌Ta、T1、T2、T3/4各分期敏感性分别为60.0%、86.5%、94.1%、100%。尿脱落细胞学各分期敏感性分别为0%、13.5%、23.4%、62.5%。膀胱镜各分期敏感性分别为80.0%、91.9%、100%、100%。Ta、T1、T2期，FISH与尿脱落细胞学比较，P<0.05，有统计学意义；T3/4期，P>0.05，无统计学意义。各分期FISH与膀胱镜比较，P>0.05，无统计学意义。三者对于膀胱移行细胞癌总的特异性分别为10/12(83.3%)、12/12（100%）、12/12（100%），三者比较，P=0.314>0.05，无统计学意义。
FISH检查及尿脱落细胞学检查对于12例上尿路移行细胞癌总的敏感性分别为12/12（100%）、3/12（25.0%），进行比较，P<0.05，有统计学意义。两种检查对于整个84例尿路移行细胞癌总的敏感性分别为74/84(88.1%)、17/84(20.2%)，两者比较，P<0.05，有统计学意义。FISH对于整个尿路移行细胞癌Ta、T1、T2、T3/4各分期敏感性分别为60.0%、86.8%、95.2%、100%。尿脱落细胞学对于各分期敏感性分别为0%、15.8%、23.8%、40.0%。两种方法不同分期进行比较，均P<0.05，有统计学意义。两种方法总的特异性分别为13/16（81.3%）、16/16（100%），P>0.05，没有统计学意义。
结论：对于膀胱移行细胞癌，FISH检查的敏感性与膀胱镜检查相当，而二者明显高于尿脱落细胞学检查，三者在特异性上无明显差别。FISH和尿脱落细胞学还可以有效检测上尿路移行细胞癌，而FISH的敏感性明显高于尿脱落细胞学。因此，对于恶性血尿为主要症状的患者，FISH可以作为筛查移行细胞癌的有效手段；FISH可以有效的对整个尿路移行细胞癌进行早期诊断，作为一种重要的主要或辅助手段应用于临床。
Objective： Urinary tract transitional cell carcinoma is morecommon tumor of the urinary tract，which is with high incidence ofrecurrence rate and high mortality. The treatment of diseases occupy alot of medical resources. Large amounts of data showed that patientsaccepted more earlier diagnosis and treatment, the prognosis would bebetter. In this study, we compared the clinical effectiveness of fluorescencein situ hybridization (FISH) examination, urine cytology and cystoscopefor malignant hematuria as the main symptoms of urinary tract urinarytract cells in tumor diagnosis. We Provided data for improving thehematuria diagnosis from our study.
Materials and methods: In the second hospital of Hebei medicaluniversity, the department of urology surgery enrolled100haematuriapatients (71male and29female，median age61years) suspicious ofurinary tract urothelial tumors,from August2010to august2011. All ofthe patients received FISH、urine cytology and cystoscope.72patients ofthem were pathologically diagnosed as bladder transitional cellcarcinoma, the staging as follow:10cases of Ta,26cases of T1,25casesof T2,11cases of T3/4.13patients were diagnosed as upper urinary tracttumor, including6cases of carcinoma of renal pelvis,6cases of uretercancer and1cases of endocrine carcinoma of the renal pelvis nerve. Theother15cases included2cases of bladder adenocarcinoma,10cases ofcystitis glandularis,1cases of interstitial cystitis,1cases of renaltuberculosis,1cases of prostate cancer.
Fluorescence in situ hybridization (FISH) is a molecular geneticstechnology, originated in the late1980s. Probe is a known fluorescently labeled nucleic acid. In accordance with the complementary base pairingprinciple, we combined the probe and unknown single-stranded nucleicacid specificly to form a hybrid double-stranded nucleic acids. Then wecould use fluorescent microscopy to read out the outcome. FISH candetect abnormal number of chromosomes and chromosomal aberrations.The experimental use GLP p16/CSP17combination probe.
We used the same method for the urine samples of20normalsubjects(10males,10females)with FISH experiment to establish thethreshold by the statistics of the percentage of different types ofabnormal cells. Threshold=mean (M)+3×standard deviation (SD).Established the17th chromosome≥3signal、p16site0signal point and1point threshold. This threshold was early established in our laboratoryexperiments.(Results see Table1)
FISH-positive criteria included chromosome17and9abnormalitiesat the same time, or a complex chromosome17abnormality, or anexception of p16(-2) alone more than15%.100cases of patients alsowere detected by urine cytology and cystoscopy detection. Thecomparison of the specificity and sensitivity among the three diagnosticmethods were completed based on the tumor staging results of theureteroscopic biopsy or surgical specimens (suspicious of urine cytologydiagnosis as the positive results of treatment). Take urine samples beforecystoscopy, not less than200ml, and otherwise affect the cell count. Ifthe results of cystoscopic biopsy and surgical resection pathologicalexamination or pathological staging were inconsistent, the results of thepathology of surgical specimens shall prevail.
Results: The overall sensitivity FISH examination, urine cytologyand cystoscopy in72patients with bladder transitional cell carcinomawere62/72(86.1%),14/72(19.1%),67/72(93.1%). Three methodspairwise comparison. FISH and cystoscopy, P=0.057>0.05, nostatistical significance; FISH and urine cytology, P=0<0.05,there wasstatistically significant. Urine cytology and cystoscopy, P=0<0.05, there was statistically significant. The sensitivity of FISH in bladdertransitional cell carcinoma of Ta, T1, T2, T3/4staging were60.0%,86.5%,94.1%,100%;urine cytology were0%,13.5%,23.4%,62.5%;and thecystoscope were80.0%,91.9%,100%,100%, respectively. At Ta, T1, T2stage, compare FISH with urine cytology, P <0.05, there was statisticallysignificant; at T3/4stage, there was not statistically significant. CompareFISH with cystoscopy for eath stage,there was not statisticallysignificant. The specificity of FISH, urine cytology, and urine cytologywere10/12(83.3%)、12/12（100%）、12/12（100%）.There was nostatistically significant of the three.
The sensitivity of FISH examination and urine cytology for12cases of upper urinary tract transitional cell carcinoma were12/12(100%),3/12(25.0%), P <0.05, there was statistically significant. Theoverall sensitivity of both tests for the84cases of entire urinary tracttransitional cell carcinoma were74/84(88.1%),17/84(20.2%),respectively, P <0.05, statistically significant. The sensitivity of FISH inthe entire urinary tract transitional cell carcinoma of Ta, T1, T2, T3/4staging were60.0%,86.8%,95.2%,100%,and urine cytology were0%,15.8%,23.8%,40.0%.For each stage, P <0.05, there was statisticallysignificant. The overall specificity of two methods were13/16(81.3%),16/16(100%), P>0.05, not statistically significant.
Conclusions: For bladder transitional cell carcinoma,the sensitivityof FISH was equal to cystoscopy,both significantly higher than urinecytology. There was no significant difference in specificity. FISH andurine cytology could detect upper urinary tract transitional cellcarcinoma. For upper urinary tract transitional cell carcinoma, thesensitivity of FISH was significantly higher than urine cytology.Therefore, FISH can be used as an effective means of screening oftransitional cell carcinoma for patients with malignant hematuria as the main symptoms. FISH as an important Method could effectivelydiagnose urinary tract transitional cell carcinoma earlier.
引文
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33穆大为，周利群，丁义等。应用荧光原位杂交技术检测上尿路的尿路上皮癌可显著提高诊断敏感性。北京大学学报，2010，142（4），381-385
34Kruger S, Mess F, Bohle A, et al. Numerical aberrations ofchromosome17and the9p21locus are independent predictors oftumor recurrence in non-invasive transitional cell carcinoma of theurinary bladder [J]. Int J Oncol,2003,23(1):41-48
35包卿兵，刘军，林建中。17号染色体数目异常在预测浅表性膀胱癌复发中的研究。Journal of Clinical Urology,2008,23(9):660-663.
36Micheal F, Sarosdy MF, Schell hammer P, et al. Clinical evaluationof a multi-target fluorescent in situ hybridization assay for detectionof bladder cancer. J Urol,2002,168(5):1950-1954
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