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1.  Incidence of Benign Results After Laparoscopic Radical Nephroureterectomy 
Background and Objectives:
Studies of patients with benign pathologic lesions who underwent laparoscopic radical nephroureterectomy (RNU) with preoperative suspicion of upper urinary tract urothelial carcinoma are lacking. The aim of this retrospective cross-sectional study was to evaluate the incidence of benign pathologic lesions on laparoscopic RNU for upper urinary tract tumors that are presumed to be urothelial carcinoma. The clinicopathologic characteristics of these lesions were also determined.
Between January 2004 and December 2010, 244 patients underwent laparoscopic RNU for possible upper urinary tract urothelial carcinoma at our institute. Seven (2.9%) had benign lesions at the final pathologic examination. The preoperative features of these patients were investigated, including imaging findings, urine cytologic results, and ureteroscopic findings.
The 7 patients comprised 5 men and 2 women. The lesions were located in the ureter in 5 patients and in the renal pelvis in 2. All patients underwent preoperative voided urine cytology and cystoscopy. Two patients underwent preoperative ureteroscopy. In 1 patient, definite pathologic lesions were not identified in the surgical specimen. Urinary tract tuberculosis was diagnosed in 1 patient, inflammatory pseudotumor in 2, and fibroepithelial polyps in 1. In 2 patients, stones were detected (stone with atypical papillary urothelial hyperplasia and polypoid ureteritis with ureter stone, respectively) after laparoscopic RNU.
Benign pathologic lesions were detected in 7 patients (2.9%) who had undergone laparoscopic RNU for upper urinary tract tumors that were presumed to be urothelial carcinoma. The description of these false-positive cases will help improve the preoperative counseling of these patients.
PMCID: PMC4232409  PMID: 25408605
Benign; Nephroureterectomy; Upper urinary tract; Urothelial carcinoma
2.  Prognostic factors in laser treatment of upper urinary tract urothelial tumours 
Journal of Medicine and Life  2012;5(1):33-38.
Introduction. The standard treatment for upper urinary tract urothelial cell carcinoma (UUT-UCCs) is radical nephroureterectomy with bladder cuff excision. The endoscopic treatment was introduced with promising results in selected cases. The purpose of this study was the retrospective analysis of the factors that can influence the prognosis of the patients with UUT-UCCs who underwent endoscopic treatment.
Patients and method. We identified 187 patients who where diagnosed and treated for UUT-UCCs, between 1998 – 2011, in the Urology Department of “Sf. Ioan” Clinical Emergency Hospital, Bucharest. The endoscopic treatment was used in 65 cases. The indications for endoscopic treatment were imperative (41 cases) or elective (24 cases). The retrograde approach (rigid or flexible) was used in 47 cases, while the anterograde approach was preferred in 18 cases. Tumor ablation was performed using electroresection or Nd:YAG laser. The mean follow-up period was 60 months (range between 6 and 120 months). The follow-up protocol included computed tomography or intravenous urography, urinary cytology (selected cases), cystoscopy and ureteroscopy. The recurrence rates were reviewed by retrospective analysis.
Results. During follow-up 31 patients (47.6%) presented upper urinary tract recurrence. In 20 cases (30.7%) bladder recurrence was present. The median time from diagnosis to first recurrence was of 12.6 months. 18 patients (27.69%) underwent subsequent nephroureterectomy. The survival rates without recurrence at 1, 3 and 5 years were 61% (40 patients), 55.3% (36 patients) and 52.3% (34 patients). The most significant prognostic factors were: history of bladder tumour, tumour location and size, tumour stage and grade. The recurrence rate for pyelocaliceal tumours was 53.84% (21 out of 39 cases) and only 45.45% (10 out of 26 cases) for ureteral tumours. The recurrence rate for low-grade tumours was 36,36% (16 out of 44 cases) and 71.42% (15 out of 21 cases) for high-grade tumours. The tumours over 1.5 cm were associated with a higher recurrence rate compared with tumours below 1.5 cm (64.2 versus 43.13%).
Conclusions. Endoscopic management of UUT-UCCs offers the advantage of preserving of renal function. Laser treatment of malignant urothelial lesions in the upper urinary tract should be reserved for a selected patient. The most important prognostic factors for UUT-UCCs evolution are tumours location, size and mostly tumour grade. The patients’ compliance is very important for detecting recurrences.
Abbreviations UUT-UCCs - Upper urinary tract urothelial cell carcinomas
PMCID: PMC3307078  PMID: 22574085
laser; upper TCC; urothelial tumour; endoscopic treatment
3.  Upper Tract Urothelial Carcinomas in Patients with Chronic Kidney Disease: Relationship with Diagnostic Challenge 
BioMed Research International  2014;2014:989458.
Chronic kidney disease and upper tract urothelial carcinomas display a bidirectional relationship. Review of the literature indicates that early diagnosis and correct localization of upper tract urothelial carcinomas in dialysis patients and kidney transplant recipients are important but problematic. Urine cytology and cystoscopy have limited sensitivity for the diagnosis of upper tract urothelial carcinomas in dialysis patients. Enhanced computed tomography and magnetic resonance imaging could prove useful for the detection and staging of upper tract urothelial carcinomas in dialysis patients. Renal ultrasound can detect hydronephrosis caused by upper tract urothelial carcinomas in kidney transplant recipients but cannot visualize the carcinomas themselves. High detection rates for upper tract urothelial carcinomas in kidney transplant recipients have recently been demonstrated using computed tomography urography, which appears to be a promising tool. To detect carcinomas in dialysis patients and kidney transplant recipients as early as possible, regular screening in asymptomatic patients and diagnostic work-up in symptomatic patients should be performed using a combination of urological and imaging methods. Careful assessment of subsequent recurrence within the contralateral upper urinary tract and the urinary bladder is necessary for dialysis patients and kidney transplant recipients with upper tract urothelial carcinomas.
PMCID: PMC4142288  PMID: 25177705
4.  Molecular grading of tumors of the upper urothelial tract using FGFR3 mutation status identifies patients with favorable prognosis 
Mutations in FGFR3 have been shown to occur in tumors of the upper urothelial tract and may be indicative of a good prognosis. In bladder tumors, the combination of FGFR3 mutation status and Ki-67 level has been used to define a tumor’s molecular grade and predict survival. Pathological evaluation of upper urothelial tumors is currently the best predictor of prognosis, but suffers from variability in pathological assessments. This study investigated the association with prognosis of FGFR3 mutations alone and in combination with Ki-67 in this patient population.
Genomic DNA was isolated from tumor samples of 80 patients with upper urothelial cancer. The presence of mutation in FGFR3 was evaluated using real-time polymerase chain reaction. Ki-67 protein expression was determined by immunohistochemistry. Kaplan–Meier survival analysis evaluated the relationship of FGFR3 mutations and Ki-67 levels with survival.
FGFR3 mutations were identified in 40% of tumors and were predominantly associated with noninvasive tumors. Overall survival was higher in patients with FGFR3 mutant tumors (P = 0.02) and in molecular grade 1 tumors as determined by FGFR3 and Ki-67 (P = 0.02).
In this study, we confirm the occurrence of FGFR3 mutations in tumors of the upper urothelial tract and its association with a good prognosis. Both FGFR3 and molecular grading are predictors of overall survival. Molecular grading can help to assess the prognosis of patients with upper urinary tract cancer and may represent a new tool for managing this population of patients.
PMCID: PMC3806446  PMID: 24199183
upper tract; urothelial carcinoma; ureter; renal pelvis; Ki-67; survival
5.  Nephroureterectomy for Transitional Cell Carcinoma – The Value of Pre-Operative Histology 
Nephroureterectomy with excision of a cuff of bladder remains the standard for managing upper tract transitional cell carcinoma (TCC). Increasing use of diagnostic upper tract endoscopy has underlined the importance of obtaining a pre-operative histological diagnosis in order to avoid under-treating high-grade or multifocal disease and over-treating low-grade disease, which could, in selected cases, be managed conservatively. We review nephroureterectomy at our institution over a 10-year period with particular reference to a pre-operative histological diagnosis.
Nephroureterectomy was performed in 113 patients from February 1994 to February 2004. Of these cases, 58 were for upper tract TCC and 50 of these 58 had intravenous urography (IVU): 9 had only IVU, 28 had an additional CT scan, 5 had an additional ultrasonography and 8 had additional CT + ultrasonography for pre-operative work-up. Thirty-four of the 58 cases had retrograde pyelography. Nineteen (32.7%) of the 58 cases had a pre-operative ureteroscopy (URS) and biopsy; 14 of these had rigid URS for tumours in the lower (11) and middle (3) thirds of the ureter and 5 had flexible URS for pelvicalyceal tumours by an experienced endourologist. Thirty-one (53%) of the 58 tumours were within the pelvicalyceal system and 27 within the ureter (upper, 5; middle, 3; lower, 19). Forty-eight patients underwent a total nephroureterectomy: 40 had a two incision approach and 8 had an endoscopic resection of the lower ureter. Five of the 58 cases had a sub-total nephroureterectomy and 5 a laparoscopic nephroureterectomy with open excision of lower ureter.
Nineteen (32.7%) of the 58 patients had a pre-operative histological diagnosis – 17 G2pTa, 1 G1pTa, and 1 G2pT1. Fourteen (74%) biopsies matched the final postoperative histology, but 1 was down-staged, 3 up-staged and 1 up-graded compared to the original histology. Five (12.8%) of 39 patients without pre-operative histology had no TCC in the final surgical specimen: 4 (10.25%) had benign pathology such as capillary haemangioma, urothelial cysts and reactive urothelial changes while one had renal cell carcinoma (RCC).
This study underlines the importance of obtaining a pre-operative histological diagnosis in cases with presumed upper tract TCC. Failure to do so can result in unnecessary ablative surgery for benign disease. Such an approach can also help identify multifocality and grade of disease so that treatment of upper tract TCC can be tailored more appropriately with ablative surgery for high-grade or multifocal disease and conservative (endoscopic) therapy for low-grade disease in selected cases. Patients with suspected TCC of the upper tract should be managed at centres where facilities for the comprehensive evaluation of such tumours exist.
PMCID: PMC2216716  PMID: 18201500
Transitional cell carcinoma; Ureter; Nephroureterectomy; Ureteroscopy; Histology
6.  Somatic mutation of Fibroblast Growth Factor Receptor-3 (FGFR3) defines a distinct morphologic subtype of high-grade urothelial carcinoma 
The Journal of pathology  2011;224(2):270-279.
FGFR3 mutations are common in low grade urothelial carcinoma and represent a potential therapeutic target in this disease. Their incidence and functional role in high grade urothelial carcinoma (HGUC), which displays an increased propensity for recurrence and muscularis propria invasion, is less well defined. We developed a mass spectrometry based genotyping assay to define the incidence of FGFR3 mutations in a large clinically annotated set of urothelial carcinomas. FGFR3 mutations were found in 17% of HGUC versus 84% of low-grade lesions. Retrospective pathologic review of the class of FGFR3 mutant HGUC revealed unique histologic features characterized by a bulky, exophytic component with branching papillary architecture as well as irregular nuclei with a koilocytoid appearance. The predictive value of this histologic appearance was confirmed using a prospective set of 49 additional HGUC. Prospective histologic review was able to correctly predict for the presence of an FGFR3 mutation in 13 of 24 HGUC specimens that exhibited the distinct morphology (54%). All 25 specimens lacking the defined histologic features were FGFR3 wild-type for a negative predictive value of 100%. Macrodissection of individual tumors confirmed the presence of the FGFR3 mutant allele in non-invasive and invasive, low and high-grade regions of individual tumors and in the lymph node metastases of patients whose tumors possessed the characteristic morphologic signature, suggesting that FGFR3 mutations are not restricted to the more clinically indolent regions of HGUCs. These data suggest that histologic screening of HGUC followed by confirmatory genotyping can be used to enrich for the population of HGUC most likely to harbor activating mutations in the FGFR3 receptor tyrosine kinase. Histologic review could thus aid in the development of targeted inhibitors of FGFR3 by facilitating the identification of the subset of patients most likely to harbor activating mutations in the FGFR3 gene.
PMCID: PMC3235805  PMID: 21547910
fibroblast growth factor receptor-3; FGFR3; urothelial carcinoma; morphology
7.  TERT Promoter Mutations Occur Early in Urothelial Neoplasia and are Biomarkers of Early Disease and Disease Recurrence in Urine 
Cancer research  2013;73(24):7162-7167.
Activating mutations occur in the promoter of the telomerase reverse transcriptase (TERT) gene in 66% of muscle-invasive urothelial carcinomas. To explore their role in bladder cancer development, and to assess their utility as urine markers for early detection, we sequenced the TERT promoter in 76 well-characterized papillary and flat noninvasive urothelial carcinomas, including 28 pTa low-grade (pTa LG) transitional cell carcinomas (TCC), 31 pTa high-grade (pTa HG) TCCs, and 17 pTis carcinoma in situ (CIS) lesions. We also evaluated the sequence of the TERT promoter in a separate series of 14 early bladder neoplasms and matched follow-up urine samples to determine if urine TERT status was an indicator of disease recurrence. A high rate of TERT promoter mutation was observed in both papillary and flat lesions, as well as in low- and high-grade noninvasive urothelial neoplasms (mean: 74%). Additionally, among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urines in seven of eight patients that recurred but in none of 6 patients that did not recur (P <0.001). TERT promoter mutations occur in both papillary and flat lesions, are the most frequent genetic alterations identified to date in noninvasive precursor lesions of the bladder, are detectable in urine, and appear to be strongly associated with bladder cancer recurrence. These provocative results suggest that TERT promoter mutations may offer a useful urinary biomarker, for both early detection and monitoring of bladder neoplasia.
PMCID: PMC3966102  PMID: 24121487
TERT promoter; mutation; urine; diagnostics; sequencing
8.  TERT promoter mutations are associated with distant metastases in upper tract urothelial carcinomas and serve as urinary biomarkers detected by a sensitive castPCR 
Oncotarget  2014;5(23):12428-12439.
TERT promoter C228T and C250T mutations occur in various malignancies including bladder cancer (BC) and may serve as urinary tumor markers. However, the mutation association with clinical variables in upper tract urothelial carcinomas (UTUCs) is unclear. There is also a lack of sensitive tools to detect the minor mutant TERT promoter in bulk urinary DNA. Here we analyzed 220 UTUC patients [98 with renal pelvic carcinoma (RPC) and 122 with ureter carcinoma (UC)] and developed a Competitive Allele-Specific TaqMan PCR (castPCR) for urinary assay. We identified C228T or C250T mutations in 42 of 98 (43%) RPC and 23 of 122 (19%) UC tumors. Distant metastases were significantly correlated with UTUC patients harboring TERT promoter mutations (P = 0.001). C228T were detected in 6/10 and 9/10 of urine samples from patients with mutation-carrying tumors using Sanger sequencing and castPCR, respectively. When urine samples from 70 BC patients were analyzed together, the sensitivity of urinary C228T assay was 89% and 50% for castPCR and Sanger sequencing, respectively (P < 0.001). Collectively, TERT promoter mutations occur in UTUCs with a high frequency in RPCs and predict distant metastasis. castPCR assays of the mutation are a useful tool for urine-based diagnostics of urological malignancies.
PMCID: PMC4322995  PMID: 25474136
Cancer biomarkers; Promoter mutations; Telomerase; TERT; UTUC
9.  A Decade of FGF Receptor Research in Bladder Cancer: Past, Present, and Future Challenges 
Advances in Urology  2012;2012:429213.
Fibroblast growth factors (FGFs) orchestrate a variety of cellular functions by binding to their transmembrane tyrosine-kinase receptors (FGFRs) and activating downstream signalling pathways, including RAS/MAPK, PLCγ1, PI3K, and STATs. In the last ten years, it has become clear that FGF signalling is altered in a high proportion of bladder tumours. Activating mutations and/or overexpression of FGFR3 are common in urothelial tumours with low malignant potential and low-stage and -grade urothelial carcinomas (UCs) and are associated with a lower risk of progression and better survival in some subgroups. FGFR1 is not mutated in UC, but overexpression is frequent in all grades and stages and recent data indicate a role in urothelial epithelial-mesenchymal transition. In vitro and in vivo studies have shown that FGFR inhibition has cytotoxic and/or cytostatic effects in FGFR-dependent bladder cancer cells and FGFR-targeted agents are currently being investigated in clinical studies for the treatment of UC. Urine-based tests detecting common FGFR3 mutations are also under development for surveillance of low-grade and -stage tumours and for general population screening. Overall, FGFRs hold promise as therapeutic targets, diagnostic and prognostic markers, and screening tools for early detection and clinical management of UC.
PMCID: PMC3415141  PMID: 22899908
10.  Prospective evaluation of fluorescence-guided cystoscopy to detect bladder cancer in a high-risk population: results from the UroScreen-Study 
SpringerPlus  2014;3:24.
To prospectively evaluate the role of fluorescence-guided cystoscopy in a high-risk bladder cancer population undergoing screening based on a multi-marker panel of urine-tests (UroScreen-study).
Patients and methods
UroScreen was conducted as a validation study for tumor markers within the frame of a health surveillance program of workers with occupational exposure to aromatic amines. Voluntary annual screens were done in 1,609 men. Cytology, quantitative NMP22® assay, and UroVysion (FISH) were applied to 7091 urine samples. Subjects with at least one positive urine-based tumor marker and/or persisting microscopic hematuria were offered fluorescence-guided (PDD) instead of white light cystoscopy. In case of suspicious findings histopathological evaluation by transurethral biopsy was performed. Data were statistically summarized and compared to tumors found by the standard algorithm of the screening study.
Twenty-two subjects with a mean age of 58 years (39–72) underwent PDD cystoscopy. Of those 3 had positive NMP22 tests, 14 positive FISH tests and 9 suspicious cytologies. Two had persisting microscopic hematuria only. PDD cystoscopy revealed enhanced unifocal fluorescence in 14. All had subsequent transurethral biopsy or resection. In total, 1 urothelial carcinoma (pTaG1, low grade) was diagnosed. In the other participants urothelial cancer of the bladder was ruled out. Chronic cystitis was revealed in 8 of 14 biopsies. No higher detection rate was found using PDD than with the standard algorithm of the UroScreen study in which 17 tumors were detected by white light cystoscopy.
The use of PDD does not lead to a higher cancer detection rate in a high-risk screening population. Larger sample sizes may be needed to ultimately asses the value of PDD for bladder cancer screening.
PMCID: PMC3905106  PMID: 24478941
Urothelial cancer of the bladder; Urine based tumor marker; Bladder cancer screening; NMP22; UroVysion; UroScreen; Cytology; Photodynamic diagnostics; Cystoscopy
11.  FGFR1 promotes proliferation and survival via activation of the MAPK pathway in bladder cancer 
Cancer research  2009;69(11):4613-4620.
Fibroblast growth factor receptors (FGFRs) play key roles in proliferation, differentiation and tumorigenesis. Many urothelial carcinomas (UC) contain activating point mutations or increased expression of FGFR3. However, little is known about the role of other FGFRs. We have examined FGFR expression in immortalised normal human urothelial cells (TERT-NHUC), UC cell lines and tumor samples and demonstrated that FGFR1 expression is increased in a high proportion of cell lines and tumors independent of stage and grade. To determine the role of FGFR1 in low-stage bladder cancer we over-expressed FGFR1 in TERT-NHUC, and examined changes in proliferation and cell survival in response to FGF2. FGFR1 stimulation increased proliferation and reduced apoptosis. To elucidate the mechanistic basis for these alterations we examined the signaling cascades activated by FGFR1. FRS2α and PLCγ were activated in response to FGF2, leading to activation of the MAPK pathway. The level of MAPK activation correlated with the level of cyclinD1, MCL1 and phosphorylated BAD, which also correlated with FGFR-induced proliferation and survival. Knockdown of FGFR1 in UC cell lines revealed differential FGFR1-dependence. JMSU1 cells were dependent on FGFR1 expression for survival but 3 other cell lines were not. Two cell lines (JMSU1 and UMUC3) were dependent on FGFR1 for growth in soft agar. Only one of the cell lines tested (UMUC3) was frankly tumorigenic and here FGFR1 knockdown inhibited tumor growth. Our results indicate that FGFR1 has significant effects on urothelial cell phenotype and may represent a useful therapeutic target in some cases of UC.
PMCID: PMC2737316  PMID: 19458078
FGFR1; urothelial cell carcinoma; therapeutic target
12.  Aristolactam-DNA Adducts in the Renal Cortex: Biomarker of Environmental Exposure to Aristolochic Acid 
Kidney international  2011;81(6):559-567.
Balkan endemic nephropathy is a chronic tubulointerstitial disease frequently accompanied by urothelial cell carcinomas of the upper urinary tract. This disorder has recently been linked to exposure to aristolochic acid, a powerful nephrotoxin and human carcinogen. Following metabolic activation, aristolochic acid reacts with genomic DNA to form aristolactam-DNA adducts that generate a unique TP53 mutational spectrum in urothelium. The aristolactam-DNA adducts are concentrated in the renal cortex, thus serving as biomarkers of internal exposure to aristolochic acid. Here, we present molecular epidemiologic evidence relating carcinomas of the upper urinary tract to dietary exposure to aristolochic acid. DNA was extracted from the renal cortex and urothelial tumor tissue of 67 patients that underwent nephroureterectomy for carcinomas of the upper urinary tract and resided in regions of known endemic nephropathy. Ten patients from non-endemic regions with carcinomas of the upper urinary tract served as controls. Aristolactam-DNA adducts were quantified by 32P-post-labeling, the adduct was confirmed by mass spectroscopy, and TP53 mutations in tumor tissues were identified by chip-sequencing. Adducts were present in 70% of the endemic cohort and in 94% of patients with specific A:T to T:A mutations in TP53. In contrast, neither aristolactam-DNA adducts nor specific mutations were detected in tissues of patients residing in non-endemic regions. Thus, in genetically susceptible individuals, dietary exposure to aristolochic acid is causally related to endemic nephropathy and carcinomas of the upper urinary tract.
PMCID: PMC3560912  PMID: 22071594
13.  Urinary cytology with acridine orange fluorescence is highly valuable for predicting high-grade upper urinary tract urothelial carcinoma 
Objectives: To evaluate the clinical value of acridine orange fluorescent staining in urinary cytology for the diagnosis of upper urinary tract urothelial carcinoma. Methods and materials: A retrospective analysis was conducted with 510 cases of upper urinary tract urothelial carcinoma (UTUC) in terms of the results of acridine orange fluorescence (AO-F) staining of the exfoliated cells in urine. The percentage of positive AO-F result and the positive predictive value of AO-F for high-grade and muscle invasive urothelial carcinoma were calculated and analyzed in terms of clinical characteristics. Results: The overall percentage of positive AO-F result was 49% in the 510 patients, 54.1% for males and 40.6% for females. AO-F was positive in 51.9% of the patients with hematuria and 36.2% of the patients without hematuria. AO-F was positive in 56.4% of the patients with renal pelvis carcinoma and 42.8% of the patients with ureteral cancer; in 44.6% of the patients with non-muscle invasive carcinoma and 53.5% of the patients with muscle-invasive carcinoma. AO-F was positive in 26.8% of the cases with low-grade carcinoma and 55.3% of the patients with high-grade carcinoma. The positive predictive value of AO-F was 88% for high-grade cancer, and only 53.6% for muscle invasive carcinoma. Conclusions: Acridine orange fluorescence microscopy cannot increase the sensitivity of urine exfoliative cytology in the diagnosis of UTUC. It may be used as a predictor of high-grade UTUC. Acridine orange fluorescence microscopy in urinary cytodiagnosis does not show high value in predicting muscle invasive UTUC.
PMCID: PMC3925926  PMID: 24551302
Urothelial carcinoma; upper urinary tract; acridine orange fluorescence; cytodiagnosis
14.  Correlation between the cytology of urine sediment in fresh sample and smears stained by Papanicolaou and Giemsa methods 
Urine excreted by the body has a variable composition in different physiological and pathological conditions. The cells that come from the renal pelvis, ureters, bladder, and urethra are carried by the urine, and therefore, they can be observed in fresh samples and in smears with Giemsa and Papanicolaou stain.
The aim of this study was to show that high correlation that exists between the cytological examination of fresh urine samples and smears stained with Papanicolaou and Giemsa methods.
Materials and Methods:
A total of 45 cases with no tumor of the urinary tract and 36 patients with lower urinary tract neoplasms were included in the study (20: Low-grade urothelial tumors; 16: High-grade urothelial tumors, squamous carcinomas, and adenocarcinomas). The sediments in the urine samples were observed in fresh specimen and in smears stained with Papanicolaou method.
The meticulous observation of fresh urinary sediments allowed identification of diverse cellular types associated with varied pathologies.
The cytological examination of urinary samples in fresh smears, and its later diagnostic confirmation with the Papanicolaou stain is important not only as a diagnostic procedure of tumoral or non-tumoral pathologies, but also as a method for the ‘screening’ of pre-cancerous lesions or carcinoma in situ, especially in high-risk populations.
PMCID: PMC4150338  PMID: 25190980
Fresh urine sediment; inflammatory bladder pathologies; stained urine sediment; urinary tract; urinary bladder tumors
15.  FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder 
Cancer Medicine  2014;3(4):835-844.
While fibroblast growth factor receptor 3 (FGFR3) is frequently mutated or overexpressed in nonmuscle-invasive urothelial carcinoma (UC), the prevalence of FGFR3 protein expression and mutation remains unknown in muscle-invasive disease. FGFR3 protein and mRNA expression, mutational status, and copy number variation were retrospectively analyzed in 231 patients with formalin-fixed paraffin-embedded primary UCs, 33 metastases, and 14 paired primary and metastatic tumors using the following methods: immunohistochemistry, NanoString nCounterTM, OncoMap or Affymetrix OncoScanTM array, and Gain and Loss of Analysis of DNA and Genomic Identification of Significant Targets in Cancer software. FGFR3 immunohistochemistry staining was present in 29% of primary UCs and 49% of metastases and did not impact overall survival (P = 0.89, primary tumors; P = 0.78, metastases). FGFR3 mutations were observed in 2% of primary tumors and 9% of metastases. Mutant tumors expressed higher levels of FGFR3 mRNA than wild-type tumors (P < 0.001). FGFR3 copy number gain and loss were rare events in primary and metastatic tumors (0.8% each; 3.0% and 12.3%, respectively). FGFR3 immunohistochemistry staining is present in one third of primary muscle-invasive UCs and half of metastases, while FGFR3 mutations and copy number changes are relatively uncommon.
PMCID: PMC4303151  PMID: 24846059
Biomarker; bladder cancer; FGFR3; metastatic urothelial carcinoma; muscle-invasive urothelial carcinoma; targeted therapy
16.  ROS generation via NOX4 and its utility in the cytological diagnosis of urothelial carcinoma of the urinary bladder 
BMC Urology  2011;11:22.
Reactive oxygen species (ROS) production via NADPH oxidase (NOX) contributes to various types of cancer progression. In the present research, we examined the pathobiological role of NADPH oxidase (NOX)4-mediated generation of reactive oxygen species (ROS) in urothelial carcinoma (UC) of the urinary bladder, and demonstrated the utility of ROS labeling in urine cytology.
NOX4 gene was silenced in vivo and in vitro by NOX4 siRNA transfection with or without atlocollagen. Cell cycle and measurement of ROS were analyzed by flowcytometry. Orthotopic implantation animal model was used in vivo experiment. NOX4 expression in urothelial carcinoma cells was observed by immunohistochemical analysis using surgical specimens of human bladder cancer. Urine cytology was performed after treatment with ROS detection reagents in addition to Papanicolaou staining.
NOX4 was overexpressed in several UC cell lines and the NOX inhibitor, diphenylene iodonium reduced intracellular ROS and induced p16-dependent cell cycle arrest at the G1 phase. Moreover, silencing of NOX4 by siRNA significantly reduced cancer cell growth in vivo as assessed in an orthotopic mouse model. Immunohistochemistry demonstrated high expression of NOX4 in low grade/non-invasive and high grade/invasive UC including precancerous lesions such as dysplasia but not in normal urothelium. Then, we assessed the usefulness of cytological analysis of ROS producing cells in urine (ROS-C). Urine samples obtained from UC cases and normal controls were treated with fluorescent reagents labeling the hydrogen peroxide/superoxide anion and cytological atypia of ROS positive cells were analyzed. As a result, the sensitivity for detection of low grade, non-invasive UC was greatly increased (35% in conventional cytology (C-C) vs. 75% in ROS-C), and the specificity was 95%. Through ROS-C, we observed robust improvement in the accuracy of follow-up urine cytology for cases with previously diagnosed UC, especially in those with low grade/non-invasive cancer recurrence (0% in C-C vs. 64% in ROS-C).
This is the first report demonstrating that ROS generation through NOX4 contributes to an early step of urothelial carcinogenesis and cancer cell survival. In addition, cytology using ROS labeling could be a useful diagnostic tool in human bladder cancer.
PMCID: PMC3215170  PMID: 22032647
17.  Renal Function and Oncologic Outcomes of Parenchymal Sparing Ureteral Resection Versus Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma 
The Journal of urology  2011;187(2):429-434.
We compared renal function and oncologic outcomes of parenchymal sparing ureteral resection with radical nephroureterectomy for the treatment of upper tract urothelial carcinoma confined to the ureter.
Materials and Methods
Review of a large institutional database identified 367 patients treated for primary upper tract urothelial carcinoma with radical nephroureterectomy or parenchymal sparing ureteral resection from 1994 to 2009. Patients with known renal pelvis tumors, muscle invasive urothelial carcinoma, prior cystectomy, contralateral upper tract urothelial carcinoma, metastatic disease or chemotherapy were excluded, leaving 120 patients for analysis. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease equation. Recurrence-free, cancer specific and overall survival were estimated using Kaplan-Meier analysis.
Radical nephroureterectomy was performed in 87 patients and parenchymal sparing ureteral resection in 33. Median age at surgery was 73 years in the radical nephroureterectomy group (IQR 64 –76) vs 70 years (IQR 59 –77) in the parenchymal sparing ureteral resection group (p = 0.5). The radical nephroureterectomy and parenchymal sparing ureteral resection cohorts had several disparate clinicopathological variables including preoperative hydronephrosis (80% vs 45%, p = 0.0006), stage (pT3 or greater 26% vs 9%, p = 0.01) and baseline estimated glomerular filtration rate (51 vs 63 ml/minute/1.73 m2, p = 0.009). Patients who underwent radical nephroureterectomy experienced a significantly greater decrease in estimated glomerular filtration rate after surgery (median −7 vs 0 ml/minute/1.73 m2, p <0.001). Median followup was 4.2 years. Of the patients 79 experienced cancer recurrence and 44 died (28 of upper tract urothelial carcinoma). There were no obvious differences in the rates of recurrence, cancer specific death or overall death by procedure type. However, due to the limited number of events we cannot exclude the possibility that there are large differences in oncologic outcomes by procedure type.
Parenchymal sparing ureteral resection is associated with superior postoperative renal function. However, the impact on cancer control cannot be determined conclusively due to the small sample size and putative selection bias.
PMCID: PMC3689028  PMID: 22177163
carcinoma; transitional cell; kidney failure; chronic; ureter
18.  AB 50. Diagnostic value of urine cytology test in differential diagnosis in relapsed lung cancer to renal cell carcinoma 
Journal of Thoracic Disease  2012;4(Suppl 1):AB50.
Urine cytology test is a useful diagnostic tool in detection of urinary tract cancer. However, the presence of cancer cells in urine cytology sediment in patients with relapsed lung cancer and renal metastases could be used widely in order to avoid interventional procedures of the urothelial tract in a false positive diagnosis of a primary renal cancer.
Patients and methods
A 52 year-old smoker woman of 40 p/y was presented for examination of intermittent episodes of haematuria over a 2 months period. The patient had right lower lobectomy (3 years ago) due to well differentiated squamous cell lung cancer, treated with neo-adjuvant chemotherapy and local relapse at the coloboma, 19 months after the surgery. The patient received chemotherapy of 4500 Gy. Eleven months later because of the history of haematuria, the patient proceeded in Contrast enhanced computed tomography (CT) examination of the abdomen revealed a heterogeneous mass of the right kidney. Before of a prospective FNA right renal biopsy, the patient proceeded in an everyday urine cytology test and chest CT examination in order to exclude a new relapse of lung cancer.
The urine cytology test with Thin Prep technique was positive and detected squamous cell lung cancer well differentiated. Bronchoscopy followed chest CT defined and showed clear evidence of new lesions and tracheal invasion. We would like to notice that there is no histological existence of primary squamous renal cancer.
Every renal lesion detected in patients with lung cancer history must alert metastatic disease, especially if computed tomography of the mass demonstrates relative homogeneity and minimal enhancement. Recent studies strongly showed that renal metastases count maximum 19% and usually have occult radiological findings. Urine cytology could be valuable to patients with lung cancer and urinary tract signs, especially if there are radiological lesions from lower abdomen CT scan. The above mentioned may be used in order of detection of renal metastases and especially to differentiate metastatic lung disease from primary renal cancer.
PMCID: PMC3537402
19.  Bladder Cancer Diagnosis and Identification of Clinically Significant Disease by Combined Urinary Detection of Mcm5 and Nuclear Matrix Protein 22 
PLoS ONE  2012;7(7):e40305.
Urinary biomarkers for bladder cancer detection are constrained by inadequate sensitivity or specificity. Here we evaluate the diagnostic accuracy of Mcm5, a novel cell cycle biomarker of aberrant growth, alone and in combination with NMP22.
1677 consecutive patients under investigation for urinary tract malignancy were recruited to a prospective blinded observational study. All patients underwent ultrasound, intravenous urography, cystoscopy, urine culture and cytologic analysis. An immunofluorometric assay was used to measure Mcm5 levels in urine cell sediments. NMP22 urinary levels were determined with the FDA-approved NMP22® Test Kit.
Genito-urinary tract cancers were identified in 210/1564 (13%) patients with an Mcm5 result and in 195/1396 (14%) patients with an NMP22 result. At the assay cut-point where sensitivity and specificity were equal, the Mcm5 test detected primary and recurrent bladder cancers with 69% sensitivity (95% confidence interval = 62–75%) and 93% negative predictive value (95% CI = 92–95%). The area under the receiver operating characteristic curve for Mcm5 was 0.75 (95% CI = 0.71–0.79) and 0.72 (95% CI = 0.67–0.77) for NMP22. Importantly, Mcm5 combined with NMP22 identified 95% (79/83; 95% CI = 88–99%) of potentially life threatening diagnoses (i.e. grade 3 or carcinoma in situ or stage ≥pT1) with high specificity (72%, 95% CI = 69–74%).
The Mcm5 immunoassay is a non-invasive test for identifying patients with urothelial cancers with similar accuracy to the FDA-approved NMP22 ELISA Test Kit. The combination of Mcm5 plus NMP22 improves the detection of UCC and identifies 95% of clinically significant disease. Trials of a commercially developed Mcm5 assay suitable for an end-user laboratory alongside NMP22 are required to assess their potential clinical utility in improving diagnostic and surveillance care pathways.
PMCID: PMC3392249  PMID: 22792272
20.  Is Routine Urine Cytology Useful in the Haematuria Clinic? 
The objective of this study was to determine the value of routine urine cytology in the initial evaluation of patients presenting to a one-stop haematuria clinic.
A total of 1000 consecutive patients who attended the haematuria clinic between June 2003 and November 2004 were studied prospectively. A standard protocol was used to investigate these patients. This included urine cytology, upper tract imaging and flexible cystoscopy.
Overall, 986 samples of urine were sent for cytology. In 126 patients, the report was abnormal; of these, 71 patients were found to have bladder transitional cell carcinoma by flexible cystoscopy and a further 3 had upper tract transitional cell carcinoma diagnosed radiologically. The remaining 52 patients with abnormal cytology were not found to have cancer on further investigations. The total cost for urine cytology and additional investigations was £50,535.
In this study of the initial evaluation of patients with haematuria, no case of urothelial malignancy was diagnosed on the basis of urine cytology alone. Therefore, urine cytology need not be used routinely in the initial diagnostic workup for haematuria.
PMCID: PMC2443314  PMID: 18325219
Haematuria; Urine cytology; Urothelial malignancy; Diagnosis
21.  Primary large cell neuroendocrine carcinoma of the ureter 
Large cell neuroendocrine carcinoma (LCNEC) is the rarest type of urinary tract malignancy. Herein, we report a case of LCNEC that arose in the ureter of a 78-year-old Japanese man with a history of ascending colon cancer that had been excised by a right hemicolectomy. Left-sided hydronephrosis associated with the ureteral tumor was discovered during follow-up. A left nephroureterectomy combined with a partial resection of the urinary bladder was performed because atypical cells were detected using voided urine cytology. A histopathological examination revealed that the ureteral tumor contained large atypical epithelial cells of neuroendocrine morphology without a urothelial carcinomatous component. The neoplastic cells were immunohistochemically positive for synaptophysin, chromogranin A, CD56, and cytokeratins, but they were negative for uroplakin III and thyroid transcription factor-1. The Ki-67 labeling index of the neoplastic cells was 50%. Transmission electron microscopy demonstrated the presence of numerous dense granules in the cytoplasm of the neoplastic cells. The ureteral lesion was finally classified as stage III, pT3 cN0 cM0. The patient’s postoperative course was uneventful without chemoradiotherapy, and LCNEC did not recur in the subsequent nine months. This case demonstrates that LCNEC can occur in the ureter, which normally does not contain neuroendocrine cells in the urothelium.
PMCID: PMC3606864  PMID: 23573321
Colon cancer; immunohistochemistry; large cell neuroendocrine carcinoma; transmission electron microscopy; ureter; voided urine cytology
22.  Evaluation of a triple combination of cytokeratin 20, p53 and CD44 for improving detection of urothelial carcinoma in urine cytology specimens 
CytoJournal  2013;10:25.
Atypical urine cytology results trigger cystoscopy or molecular tests, both of which are costly, complex and difficult to perform tests. Several immunostains are being investigated to improve cancer detection; however, cytology material is limited and restricts the use of multiple immunostains. This study was designed to determine the utility of a cocktail of three stains, cytokeratin (CK20), p53 and CD44 in urine cytology samples for improving the detection of urothelial carcinoma.
Materials and Methods:
Urine cytology specimens with cell blocks containing adequate cytologic material between 2005 and 2010 and subsequent follow-up biopsy and/or Urovysion test (102 cases including 29 negative, 56 atypical and 17 malignant) were included in the study and evaluated with the triple stain. Results were first validated on the positive and negative cases and then applied to the atypical cases to determine the utility in the diagnosis of urothelial carcinoma.
Based on the validation and published literature, two distinct immunoprofiles were defined – malignant, characterized by at least five CK20 and/or p53 positive atypical cells and reactive, all other staining patterns. The malignant immunoprofile showed 88% sensitivity, 78% specificity, 74% positive predictive value (PPV) and 90% negative predictive value (NPV) for detecting urothelial carcinoma. These values improved to 95% sensitivity and 96% NPV when low-grade urothelial carcinoma cases were excluded.
Our results indicate that the triple stain is an inexpensive, easy to perform test most useful for differentiating high-grade urothelial carcinoma from its mimics. However Inclusion of CD44 in the cocktail did not provide additional value and is best excluded.
PMCID: PMC3927070  PMID: 24575145
Carcinoma cytokeratin 20; cytology; p53; urine
23.  Endoscopic Management of Upper Tract Urothelial Carcinoma 
Advances in Urology  2009;2009:620604.
Nephroureterectomy is currently the gold standard for management of upper urinary tract urothelial carcinoma despite it results. This review article in the loss of a renal unit. The ultimate aim of endoscopic management of this condition is cancer control whilst preserving renal function and the integrity of the urinary tract. Endoscopic treatments of upper tract TCC include the antegrade percutaneous and retrograde ureteroscopic approaches. This review article summarizes the endoscopic management of upper tract urothelial carcinoma, surveillance of the disease after endoscopic management and adjuvant therapy. The main message regarding endoscopic management of upper tract urothelial cancer is that patients must be carefully selected. Patient selection is based on tumour size, grade, and multifocality. Single low-grade tumours, less than 1.5 cm in size, generally have a good outcome with endoscopic treatment provided that they have regular ureteroscopic surveillance. Ureteroscopic treatment of high-grade tumours is essentially palliative. It is essential that patients are motivated and compliant as lifetime follow-up is necessary. However, until large randomized trials with long-term follow-up are performed, endoscopic management cannot be considered a standard treatment and should be limited to poor performance status patients.
PMCID: PMC2613442  PMID: 19132098
24.  Tumor-specific isoform switch of the fibroblast growth factor receptor 2 underlies the mesenchymal and malignant phenotypes of clear cell renal cell carcinomas 
We aim to identify tumor-specific alternative splicing events having potential applications in the early detection, diagnosis, prognosis, and therapy of cancers.
Experimental Design
We analyzed RNA-seq data on 470 clear cell renal cell carcinomas (ccRCC) and 68 kidney tissues to identify tumor-specific alternative splicing events. We further focused on the FGFR2 isoform switch and characterized ccRCCs expressing different FGFR2 isoforms by integrated analyses using genomic data from multiple platforms and tumor types.
We identified 113 top candidate alternatively spliced genes in ccRCC. Prominently, the FGFR2 gene transcript switched from the normal IIIb isoform (“epithelial”) to IIIc isoform (“mesenchymal”) in nearly 90% of ccRCCs. This switch is kidney-specific since it was rarely observed in other cancers. The FGFR2-IIIb ccRCCs show a transcriptome and methylome resembling those from normal kidney, whereas FGFR2-IIIc ccRCCs possess elevated hypoxic and mesenchymal expression signatures. Clinically, FGFR2-IIIb ccRCCs are smaller in size, of lower tumor grade, and associated with longer patient survival. Gene set enrichment and DNA copy number analyses indicated that FGFR2-IIIb ccRCCs are closely associated with renal oncocytomas and chromophobe RCCs. A re-examination of tumor histology by pathologists identified FGFR2-IIIb tumors as chromophobe RCCs and clear cell papillary RCCs.
FGFR2 IIIb RCCs represent mis-diagnosed ccRCC cases, suggesting FGFR2 isoform testing can be used in the diagnosis of RCC subtypes. The finding of a prevalent isoform switch of FGFR2 in a tissue-specific manner holds promise for the future development of FGFR2-IIIc as a distinct early detection biomarker and therapeutic target for ccRCC.
PMCID: PMC3644028  PMID: 23444225
alternative splicing; renal cell carcinoma; RNA-seq; FGFR2; TCGA
25.  Primary multiple clear cell variant urothelial carcinomas of urinary bladder: a rare case report 
Clear cell variant urothelial carcinoma of urinary bladder was very rare. There were only 6 report articles included by Pubmed and total 8 cases had been described till now. All of the past reports described single tumor of urinary bladder, but multiple carcinomas had not been reported. Here we reported a 65-years-old Chinese man who complained of intermittent gross hematuria and odynuria for more than 2 months in January 2013. Only one cauliflower-like tumor was detected approximately in the left wall of the urinary bladder with cystoscopy and the biopsy specimen was diagnosed as “urothelial carcinoma, high grade”. However, three tumors were found in anterior wall (×2) near neck of urinary bladder and posterior wall (×1) of the urinary bladder during transurethral resection of the bladder tumor. Typical urothelial carcinoma with partial clear cell appearance made it difficult to make a precise pathological diagnosis and immunohistochemical stain helped to diagnose the case as clear cell variant urothelial carcinoma, but not metastasis of the renal cell carcinoma. Finally, computerized tomographic scanning confirmed that there was no primary tumor in the kidney. The clinical and pathological characteristic had not been identified for the limited reports. More work should be done to know this kind of tumor well for guiding clinical therapy.
PMCID: PMC4097271  PMID: 25031765
Clear cell variant urothelial carcinoma; urinary bladder

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