Low-grade Urothelial Carcinoma Research Articles

Utility of Fluorescence In Situ Hybridization (FISH) to Sub-Classify Low-Grade Urothelial Carcinoma for Prognostication.

BackgroundFluorescence in situ hybridization (FISH) is used widely to detect cancer levels, but its value in urothelial carcinoma remains unclear. The aim of this study was to use FISH to examine the urine specimens of low-grade urothelial carcinoma (UC) patients to determine the possibility of sub-classifying the prognosis of UC.Material/MethodsWe diagnosed 107 patients with low-grade UC using a UroVysion kit to detect chromosomes 3, 7, 17, and P16 in the urine. An average 46.6-month follow-up completed in January 2016 combined with the clinical follow-up data were evaluated with Spearman’s correlation analysis to analyze the aberration of chromosomes in relation to the prognostication. Univariate and multivariate analysis using the Mantel-Cox log-rank test for overall, cancer-specific, and disease-free survival were used to determine the prognostic significance of CSP7/CSP17 and CSP3/GLPp16.ResultsIn the 107 samples, 84 showed positive reaction in the FISH test. Furthermore, CSP7/CSP17 was found to be significantly related with age, tumor size, T stage, and tumor numbers, but not in CSP3/GLPp16. In addition, Kaplan-Meier analysis and Cox proportional hazards regression revealed a significant negative correlation between CSP7/CSP17 and survival, while CSP3/GLPp16 showed no significantly differences.ConclusionsCSP7/CSP17 positivity on FISH test appears to play a critical role in low-grade UC and may be considered as a high-risk and prognosis factor.

Nuclear features of infiltrating urothelial carcinoma are distinguished from low-grade noninvasive papillary urothelial carcinoma by image analysis.

Recent advances in computer technology have been made and image analysis (IA) has been introduced into pathological fields. The present study aimed to investigate the utility of IA for the evaluation of nuclear features and staining of immunohistochemistry (IHC) for Ki-67, p53 and GATA-binding protein 3 (GATA-3) in urothelial carcinoma tissue samples. A total of 49 cases of urothelial carcinoma tissue samples were obtained by transurethral resection of bladder tumors, which included 11 low-grade papillary urothelial carcinomas (LGPUCs), 1 non-invasive high-grade urothelial carcinoma and 37 infiltrating urothelial carcinomas (IUCs). Whole slide imaging (WSI) and IA were performed in Feulgen reaction and IHC-stained tissue samples. There was a significant difference in the average nuclear density, standard deviation (SD) of nuclear size and SD of nuclear minimum and maximum diameter between LGPUC and IUC, which is equivalent to the diagnostic features of IUC in nuclear variability, and hyperchromatic nuclei. In addition, the present study revealed that the SD of nuclear density was significantly different between the two groups. Regarding IA in IHC-stained tissue samples, Ki-67 was significantly overexpressed in IUC. Furthermore, the GATA-3 expression level in IUC samples with muscle invasion was significantly downregulated compared with that in non-muscle invasive tumors. The results of the present study suggest that IA in combination with WSI may be a beneficial tool for evaluating morphometric characteristics and performing semi-quantitative analysis of IHC.

Urinary tract washing specimens containing atypical urothelial tissue fragments are significantly associated with urothelial neoplasia.

We previously found that the presence of atypical urothelial tissue fragments (AUTF) was associated with an increased risk of high-grade urothelial carcinoma (HGUC) but not low-grade urothelial neoplasia (LGUN) in voided urine (VU) specimens. However, we subsequently found that patients with LGUN were more likely to have cytologic atypia in urinary washing (UW) specimens, suggesting that cytologic atypia found in UW specimens might be associated with both LGUN and HGUC. In this study, we retrospectively examined UW specimens containing AUTF to determine whether they were associated with HGUC, LGUN, or both HGUC and LGUN. 1173 UW specimens and any follow up biopsies were identified over a 10-year period and the presence of AUTF was recorded based on the original clinical diagnosis. The presence of AUTF in UW specimens was significantly associated with high-risk indeterminate diagnosis or definitive diagnosis of HGUC (P < .001). In addition, AUTF specimens were significantly associated with a neoplastic diagnosis of low-grade urothelial carcinoma (LGUC) or HGUC on subsequent biopsies when compared to specimens lacking AUTF (P = .047). The overall rate of CIS/HGUC in specimens with AUTF was 33.0 vs. 13.5% for specimens without AUTF (P = .051). Urothelial tissue fragments (UTF) found in UW specimens should be examined for the presence of cytomorphological atypia, as the presence of AUTF almost triples the risk of HGUC. As opposed to what has been found in VU specimens, AUTF in UW specimens is also associated with an increased risk of LGUN.

Correlation Between Confocal Laser Endomicroscopy (Cellvizio®) and Histological Grading of Upper Tract Urothelial Carcinoma: A Step Forward for a Better Selection of Patients Suitable for Conservative Management

BackgroundDespite the recent growing interest in the conservative management of upper tract urothelial carcinoma (UTUC), the diagnostic process is still a challenge for the risk of tumor undergrading. Real-time confocal laser endomicroscopy (CLE) provides in vivo microscopic images of tissues using a low-energy laser light source. ObjectiveTo describe our initial experience with CLE for the real-time characterization of UTUC. Design, setting, and participantsFourteen flexible ureteroscopies (f-URS) were performed at our center with CLE for UTUC. Lesions were preoperatively identified at computed tomography-intravenous urography. Cellvizio system was used during f-URS to perform CLE on the targeted lesions. Biopsies were then performed. Interventionf-URS with CLE. Outcome measurements and statistical analysisSurgeon’s CLE readings (low-grade/high-grade/carcinoma in situ [CIS]) were documented in the operation notes. A dedicated genitourinary pathologist—blinded to the surgeon reading—examined all specimens. A third person collected prospectively the CLE readings and the histopathological reports. Cohen’s Kappa analysis was performed to test interobserver agreement. Results and limitationsThe mean diameter of tumors at computed tomography scan was 26mm (range, 5–50mm). In eight patients, CLE allowed to obtain images compatible with low-grade UTUC, in five patients with high-grade UTUC, and in one case with CIS. We found correspondence between the CLE images and the final histopathological results in seven out of seven cases of low-grade UTUC (100%), in five out of six cases of high-grade UTUC (83%), and in one out of one case of CIS (100%). Substantial agreement was found at interobserver agreement (k=0.64) between CLE and histological reading. No complications and/or limitations related to the use of CLE were recorded. ConclusionsCLE is a promising new technology in providing a reliable real-time histological characterization of UTUC lesions. Ideal targets might be UTUC patients potentially candidates for conservative management. Patient summaryWe believe that a conservative treatment for low-grade upper tract urothelial carcinoma is an option that must be considered. The diagnostic process is still lacking of accurate tools. In this study, we find that confocal laser endomicroscopy, using the Cellvizio system, seems to help the clinician to have a real-time histological characterization of upper tract urothelial carcinoma lesions. This could better select patients for a conservative treatment.

Contrast-Enhanced Ultrasound Differentiation Between Low- and High- Grade Bladder Urothelial Carcinoma and Correlation With Tumor Microvessel Density.

Time-intensity curves (TICs) of contrast-enhanced ultrasound (CEUS) were analyzed retrospectively to differentiate between low-grade and high-grade bladder urothelial carcinoma, and to investigate correlation with tumor microvessel density (MVD). The data of 105 patients with pathologically confirmed bladder urothelial carcinoma (55 low-grade and 50 high-grade) were reviewed. Lesions were examined before surgery using conventional ultrasound and CEUS with TIC analysis. The TIC parameters time from peak to one-half the signal intensity (TPH) and the corresponding descending slope (DS) of the low-grade and high-grade groups were compared, and receiver operating characteristic curves constructed. The MVDs of the resectioned tissue specimens were quantified via immunohistochemistry for CD34. Based on conventional ultrasound, the low-grade and high-grade groups were similar in tumor shape, number, topography, internal echo, height, width, and vascularity. The TPH of the high-grade group was significantly longer than that of the low-grade group, and the DS was lower. The cutoff points of TPH and DS for differentiating low-grade and high-grade bladder urothelial carcinoma were 48.06 seconds and 0.15 dB/seconds, respectively (area under the receiver operating characteristic curve = 0.79 for both). The mean MVDs per high-power field of the low-grade and high-grade groups were 41.39 16.65 and 51.03 20.16, respectively (P = .009). The TPH correlated linearly with MVD (P < .01), as did the DS (P < .01). Contrast-enhanced ultrasound can be used to differentiate low from high-grade bladder urothelial carcinoma. The TIC parameters of CEUS reflect the MVD of bladder urothelial tumors and may be helpful for evaluating tumor angiogenesis, with implications for clinical diagnosis, treatment, and prognosis.

NBR1 and KIF14 Downstream of the Mammarian Target of Rapamycin Pathway Predict Recurrence in Nonmuscle Invasive Low Grade Urothelial Carcinoma of the Bladder

NBR1 and KIF14 Downstream of the Mammarian Target of Rapamycin Pathway Predict Recurrence in Nonmuscle Invasive Low Grade Urothelial Carcinoma of the Bladder

Urothelial carcinoma involving the ureteral orifice: a clinicopathologic analysis of 93 cases

Although tumors involving the bladder and ureter have been well described, there are only few studies in the pathology literature specifically analyzing tumors involving the ureteral orifice (UO). A search was performed for biopsy and resection specimens (transurethral resection, radical cystectomy/cystoprostatectomy, nephroureterectomy and bladder cuff resection) of urothelial carcinoma (UCa) involving the UO. Ninety-three cases were identified. Sixty-two (67%) patients were male. Mean patient age was 71 years (range, 43-91 years). Forty-two of 93 (45%) cases were invasive UCa (41 high-grade UCa; 1 low-grade UCa); 17/42 (40%) were invasive into muscularis propria. Tumor laterality was as follows: right side, 43 (46% of cases); left side, 41 (44%); bilateral, 4 (4.5%); and in 5 cases (5.5%), the laterality was not specified by the urologist. Seven cases of UCa with variant histology were also identified. Five patients had lymph node (LN) metastasis at the time of resection, and another 3 presented with LN or distant metastasis after resection (range, 4-38 months). Although this study focused primarily on the index tumor involving the UO (Group 1 cases are those with only UO involvement), in 70/93 (75%) cases (Group 2 cases), at least one other tumor was located at another site within the bladder. The fact that the majority of cases (75%) had tumors located at other sites of the bladder, emphasizes that careful examination of the UO needs to be performed by both urologists and pathologists when examining cases of UCa of the bladder.

MP10-20 PROSPECTIVE EVALUATION OF A CLINICAL TOOL FOR SEGREGATION OF HEMATURIA PATIENTS AT RISK FOR HIGH-GRADE UROTHELIAL CARCINOMA

You have accessJournal of UrologyBladder Cancer: Epidemiology & Evaluation II1 Apr 2017MP10-20 PROSPECTIVE EVALUATION OF A CLINICAL TOOL FOR SEGREGATION OF HEMATURIA PATIENTS AT RISK FOR HIGH-GRADE UROTHELIAL CARCINOMA Jay D. Raman, Laimonis Kavaliers, Paul O'Sullivan, David Darling, Parry Guilford, and Jimmie Suttie Jay D. RamanJay D. Raman More articles by this author , Laimonis KavaliersLaimonis Kavaliers More articles by this author , Paul O'SullivanPaul O'Sullivan More articles by this author , David DarlingDavid Darling More articles by this author , Parry GuilfordParry Guilford More articles by this author , and Jimmie SuttieJimmie Suttie More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.348AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To-date there are no urine-based tests that provide clinical resolution of the severity or grade of urothelial carcinoma (UC) in patients presenting with primary hematuria. Such information permits timely diagnosis and specific management of hematuria patients identified with high grade and/or advanced UC disease. The objective of this study was, therefore, to develop and investigate the performance of Cxbladder Resolve, a new urine-based test offering identification and accurate segregation of patients with high-grade (HG) and/or late-stage disease at the time of initial urological investigation. METHODS Participants in the study (N=863) were recruited from patients presenting with micro-(n=66) or macrohematuria (n=797) across centers in the U.S., New Zealand and Australia. An index incorporating 2 clinical variables and 5 gene expression biomarkers measured in urine was developed to segregate patients into 3 groups: 1. Low risk of UC; 2. Elevated risk of low grade (LG) UC; and 3. High risk of high grade (HG) UC. RESULTS Of the 863 recruited patients, 89 (10.3%) primary cases of UC were observed including 40 LG and 49 HG. Cxbladder Resolve segregated the 863 participants into: low risk of UC (n=479; 55%), elevated risk of LG UC (n=288; 33%) and high risk of HG UC disease (n=96; 11%). (Table) Of the 40 patients with LG bladder tumors, 27 were correctly categorized as Elevated risk of low grade UC, with the remainder; 9 as High risk of HG UC, and 4 as Low risk of UC. Of the 49 patients with HG UC, 47 (96%) were correctly identified as having High risk of HG UC and the remaining 2 patients were classified as elevated risk of LG UC. No patients with HG UC were classified as low risk of UC. Overall a negative predictive value [NPV] of =99% was observed. CONCLUSIONS Cxbladder Resolve accurately identifies over 95% of HG UC patients with a reciprocal high NPV (99%) for low risk patients. The index has a low probability of incorrectly classifying pathologic HG UC patients as low risk. Clinical utility is demonstrated for stratifying hematuria patients into risk groups allowing for prioritization of high risk patients with aggressive disease requiring early investigative procedures. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e116 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Jay D. Raman More articles by this author Laimonis Kavaliers More articles by this author Paul O'Sullivan More articles by this author David Darling More articles by this author Parry Guilford More articles by this author Jimmie Suttie More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

V12-02 CONFOCAL LASER ENDOMICROSCOPY FOR BLADDER CANCER DIAGNOSIS: HOW TO DO IT & OUR PRELIMINARY RESULTS

You have accessJournal of UrologyBladder Oncology and Diversion1 Apr 2017V12-02 CONFOCAL LASER ENDOMICROSCOPY FOR BLADDER CANCER DIAGNOSIS: HOW TO DO IT & OUR PRELIMINARY RESULTS Esmée Liem, Jan Erik Freund, Theo de Reijke, Joyce Baard, Guido Kamphuis, Pilar Laguna Pes, Martijn de Bruin, and Jean de la Rosette Esmée LiemEsmée Liem More articles by this author , Jan Erik FreundJan Erik Freund More articles by this author , Theo de ReijkeTheo de Reijke More articles by this author , Joyce BaardJoyce Baard More articles by this author , Guido KamphuisGuido Kamphuis More articles by this author , Pilar Laguna PesPilar Laguna Pes More articles by this author , Martijn de BruinMartijn de Bruin More articles by this author , and Jean de la RosetteJean de la Rosette More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3208AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cystoscopy is the cornerstone in bladder cancer diagnosis and monitoring. Although very effective, conventional white light cystoscopy has its limitations. New techniques have been developed to improve visualisation of tumours and suspicious lesions. However, no information can be given on grade of the disease during cystoscopy or per-operatively as no histopathologic information can be obtained real time. Confocal Laser Endomicroscopy (CLE) is a unique new imaging technique. It allows in vivo optical sectioning of tissue and provides real time microscopic images with high resolution. The objective of this study is to assess if we can take ′optical biopsies′ of the bladder using CLE. METHODS We performed CLE in 19 patients with a bladder tumour, during transurethral resection of the bladder tumour (TURB). At the beginning of the procedure, after initial evaluation of the bladder, 360 ml of 0.1% Fluorescein, a fluorescent contrast agent, was administered intravesical via an indwelling catheter. After 5 minutes CLE was performed using the Cystoflex UHD R (Cellvizio, Mauna Kea, Paris, France), which has a resolution of 1 μm, a field of view of 240 μm, and an imaging depth of 50-65 μm. The CLE probe was introduced via the working channel of the cystoscope (Olympus or Storz 0 - 12°). CLE images were obtained of healthy tissue and tumours, and correlated with histopathology and analysed afterwards. After obtaining CLE images, the tumour was resected en-bloc. Tumour grade was assessed according to the WHO 2004 classification. RESULTS We were able to obtain good CLE images when the probe was correctly positioned. The probe has to be in good contact with the tissue, and perpendicular to the surface. Of the 19 patients; 2 had a benign lesion, 12 low-grade urothelial carcinoma, and 5 high-grade carcinoma. Differences in CLE images could be seen between healthy tissue and tumour (figure 1). CONCLUSIONS During TURB it was possible to take ′optical biopsies′ of the bladder. The obtained CLE images could give real time histopathologic information, and has the potential to differentiate in tumour grade during cystoscopy. These ′optical biopsies′ may assist urologist in future clinical practice in bladder cancer diagnosis and follow-up. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1372 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Esmée Liem More articles by this author Jan Erik Freund More articles by this author Theo de Reijke More articles by this author Joyce Baard More articles by this author Guido Kamphuis More articles by this author Pilar Laguna Pes More articles by this author Martijn de Bruin More articles by this author Jean de la Rosette More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Cytopathologic differential diagnosis of low-grade urothelial carcinoma and reactive urothelial proliferation in bladder washings: a logistic regression analysis.

Conventional cytomorphologic assessment is the first step to establish an accurate diagnosis in urinary cytology. In cytologic preparations, the separation of low-grade urothelial carcinoma (LGUC) from reactive urothelial proliferation (RUP) can be exceedingly difficult. The bladder washing cytologies of 32 LGUC and 29 RUP were reviewed. The cytologic slides were examined for the presence or absence of the 28 cytologic features. The cytologic criteria showing statistical significance in LGUC were increased numbers of monotonous single (non-umbrella) cells, three-dimensional cellular papillary clusters without fibrovascular cores, irregular bordered clusters, atypical single cells, irregular nuclear overlap, cytoplasmic homogeneity, increased N/C ratio, pleomorphism, nuclear border irregularity, nuclear eccentricity, elongated nuclei, and hyperchromasia (p˂0.05), and the cytologic criteria showing statistical significance in RUP were inflammatory background, mixture of small and large urothelial cells, loose monolayer aggregates, and vacuolated cytoplasm (p˂0.05). When these variables were subjected to a stepwise logistic regression analysis, four features were selected to distinguish LGUC from RUP: increased numbers of monotonous single (non-umbrella) cells, increased nuclear cytoplasmic ratio, hyperchromasia, and presence of small and large urothelial cells (p=0.0001). By this logistic model of the 32 cases with proven LGUC, the stepwise logistic regression analysis correctly predicted 31 (96.9%) patients with this diagnosis, and of the 29 patients with RUP, the logistic model correctly predicted 26 (89.7%) patients as having this disease. There are several cytologic features to separate LGUC from RUP. Stepwise logistic regression analysis is a valuable tool for determining the most useful cytologic criteria to distinguish these entities.

A rare case of synchronous association of chromophobe renal cell carcinoma with urothelial carcinoma of urinary bladder

IntroductionChromophobe renal cell carcinoma accounts for 3–5% of all RCCs. However, its association with urothelial carcinoma of urinary bladder has never been reported. We report a case of synchronous association of chromophobe RCC with low grade urothelial carcinoma of urinary bladder. ObservationsA 64-year old gentleman, presented with a dull aching pain in right loin region of one month duration. General physical and abdominal examinations were unremarkable. Ultrasonography of abdomen showed a well-defined hypoechoic mass lesion involving the lower pole of right kidney. CECT abdomen revealed a partially exophytic mass lesion of size 4cm×4.3cm×5.1cm arising from lower pole of right kidney. Surprisingly, urinary bladder also showed a polypoidal mass lesion measuring 15mm×12mm×13mm in posterior wall inferior to right vesico-ureteric junction. We proceeded with right partial nephrectomy followed by transurethral resection of bladder tumor. Histopathology report revealed chromophobe RCC and low grade urothelial carcinoma of urinary bladder. The patient is under regular follow-up. ConclusionSynchronous association of chromophobe RCC with urothelial carcinoma of urinary bladder has not been reported so far, hence there is no scientific consensus in the management of these lesions.

Urothelial Carcinoma in a 22-Year-Old Female with Angelman Syndrome

A 22-year-old nulligravid white female with Angelman syndrome was noted to have a 4-month history of premenstrual nausea, vomiting, and abdominal pain. She had an echogenic focus in her bladder noted on ultrasound. She was diagnosed with low grade urothelial carcinoma after cystoscopic evaluation with biopsy and was sent to urology for further treatment. Urothelial carcinoma is rare in individuals younger than age 40. Patients may present with gross hematuria. There is often a delay in diagnosis in younger individuals with different genetic mutations noted upon diagnosis.

Evaluation of MUC1 and P53 expressions in noninvasive papillary urothelial neoplasms of bladder, their relationship with tumor grade and role in the differential diagnosis.

The aim of this study was to investigate the usability of MUC1 and p53 for differential diagnosis of noninvasive papillary urothelial neoplasias, especially for distinguishing papillary urothelial neoplasm of low malignant potential (PUNLMP) from low-grade papillary urothelial carcinoma (LGPUC) when the histologic signs are not obvious. Seventeen biopsy specimens of the patients with PUNLMP, 20 with LGPUC and 13 with high-grade papillary urothelial carcinoma (HGPUC) were stained for MUC1 and p53 protein by immunohistochemical methods. Histological grading was performed according to an algorithm, which allows histological parameters used in 2004 WHO/ISUP 1998. We had obvious statistical difference for aberrant expression pattern of MUC1 between PUNLMP and LGPUC-HGPUC (P = 0.007). Positivity of MUC1 expression in cytoplasm of basal cells was more observed in HGPUC and LGPUC, whereas PUNLMP was more often showing apical and superficial positivity of MUC1 expression (P = 0.001 and 0.011). Nuclear p53 protein in HGPUC was obviously more frequent than that in LGPUC and PUNLMP (P < 0.001). Measures showed statistical difference among aberrant MUC1 expression, p53 overexpression, and tumor grade (P < 0.001). MUC1 and p53 may be helpful immunohistochemical markers for distinguishing PUNLMP from LGPUC and HGPUC, when the histologic signs are not obvious.

Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP) After Initial TUR-BT: Comparative Analyses with Noninvasive Low-Grade Papillary Urothelial Carcinoma (LGPUC).

Purpose: To verify if the distinction between papillary urothelial neoplasm of low malignant potential (PUNLMP) and noninvasive low-grade papillary urothelial carcinoma (LGPUC) reflects a different biologic activity.Materials and Methods: We reviewed and analyzed the clinical data from 678 patients who had a diagnosis of PUNLMP (n=53) or noninvasive LGPUC (n=625) after initial TUR-BT for bladder neoplasm between 2000 and 2012.Results: The noninvasive LGPUC group showed a higher frequency of recurrence in comparison with the PUNLMP group (46.7% vs. 30.2%, p=0.022). In contrast, there were no significant differences in progression (15.2% vs. 18.9%, p=0.295) between the two groups. Grade progression was reported in 10 patients (LG: n=5; high grade: n=2; carcinoma in situ: n=3) and stage progression was reported in 2 patients (all: T1) in PUNLMP group. The Kaplan-Meier survival analysis showed significantly decreased 5-year recurrence-free survival (RFS) (50.3% vs. 74.6%, log-rank test, p=0.014) in the noninvasive LGPUC group compared to the PUNLMP group. However, there were no significant differences in progression-free survival (PFS) between the two groups. Multivariate analysis revealed that tumor grades according to 2004 WHO/ISUP classification system (PUNLMP vs. LG) were identified as significant predictors of RFS. However, it was not a significant predictor of both PFS and overall survival.Conclusions: PUNLMP had a substantial number of recurrences (30.2%), although RFS was better than noninvasive LGPUC. In addition, PUNLMP had a similar risk of progression compared with noninvasive LGPUC. Consequently, PUNLMP should be treated in a manner similar to noninvasive LGPUC, and long-term clinical follow-up should be recommended for patients with PUNLMP.

ProEx C as Diagnostic Marker for Detection of Urothelial Carcinoma in Urinary Samples: A Review.

The gold standard for the detection of urothelial carcinoma is represented by urethro-cystoscopy and biopsy. Both procedures are invasive and expensive and therefore cytology is often used as first approach to investigate on a possible neoplasia, being a safe and cost-effective diagnostic modality of evaluation. Because cytology alone is not highly sensitive for detection of low grade urothelial carcinoma and recurrence of the disease, several adjunct markers and urine based tests for urothelial carcinoma have been developed, which can help in the final diagnosis. In particular, ProEx C is an immunohistochemical cocktail containing antibodies direct against topoisomerase IIα (TOP2A) and minichromosome maintenance 2 (MCM2) proteins. It proved to be a valid biomarker especially in detecting squamous intraepithelial lesions in cervical liquid-based samples and in discerning these lesions from their mimickers, as well as in ovarian, endometrial, vulvar, primary and metastatic melanomas, breast, pancreatic and renal cell carcinomas. This brief review covers the effective utility of ProEx C as adjunct tool in assessing the urothelial lesions in urine cytology, also providing prognostic and therapeutic information to help in clinical decisions.

Utility of fluorescence in situ hybridization analysis for detecting upper urinary tract-urothelial carcinoma.

The objective of this study was to evaluate the clinical utility of fluorescence in situ hybridization (FISH) in the detection of upper urinary tract-urothelial carcinoma (UUT-UC). Between November 2011 and November 2015, voided urine specimens from 52 consecutive patients with UUT-UC and 26 controls were collected for both FISH test and cytology. Sensitivity and specificity of FISH test and cytology were determined and compared. The frequency of chromosomal aberrations was also analyzed. For FISH analysis, the sensitivity was 79.5% and specificity was 96.3%. For cytology, the sensitivity was 27.3% and specificity was 100%. The overall sensitivity for FISH was significantly higher than that of in single value-based urine cytology (79.5% vs. 27.3%, respectively, P < 0.001). The sensitivities of FISH and cytology by grade were 64.3% vs. 28.6% for low-grade urothelial carcinomas (P = 0.128) and 86.7% vs. 26.7% for high-grade urothelial carcinomas (P < 0.001), respectively. Twenty-seven (77.1%) cases were positive due to the gain of two or more chromosomes in five or more urinary cells, among which, 21 (60%) cases showed positivity in all the 4 chromosomes, 7 (20%) cases matched the criterion that 10 or more cells gained a single chromosome, whereas only 1 (2.9%) case was positive because of the homozygous deletion of 9p21 in 12 or more cells. FISH has superior sensitivity and similar specificity in the detection of UUT-UC, compared with cytology. The present findings indicated that FISH can be applied as a noninvasive diagnostic tool for suspected UUT-UC patients.

Histopathologic Evolution of Urothelial Carcinoma Recurrence in Transurethral Resection of the Urinary Bladder:35 Consecutive Cases And Literature Review

Background:Urothelial carcinoma (UC) is the malignancy most frequently encountered in the urinary bladder. The primary aim of this study was to make a reappraisal of histopathologic features, recurrence and progression.Materials and Methods:The records of cases consecutively diagnosed with UC in the state hospital pathology laboratory were collected. Cases were classified according to age, gender, histologic grade, pathologic staging [primary Tumor (pT)],tumor configuration, primary or recurrent status, and progression.Results:A total of 35 (29 male and 6 female) cases were examined. The mean age was 68.9 years with a male-to-female incidence ratio of 4.8:1. Low-grade UCs accounted for 20 (57.1%) and high-grade for 15 (42.9%). A papillary pattern was observed in 80% of the UCs, classified into the following pathological stages: 11 (31.4%) pTa, 22 (62.9%) pT1, and 2 (5.9%) pT2 cases. Eleven patients progressed to a higher stage (pT1 to pT2), and three cases from low to higher grade. We analyzed results for 26 (74.3%) cases aged 65 years or older.Conclusions:UCs have a great tendency for recurrence but potentially may be amenable to effective local or systemic treatments.

English

Objectives: Urine cytology is an easy to perform non-invasive screening test forpatients who are suspected of having urinary tract malignancy. Urothelial carcinoma constitutesapproximately 90% of all primary tumors of urinary bladder.1 High-grade urothelial carcinomasare represented by well characterized cytological features. Whereas cytological features forlow-grade urothelial carcinomas show considerable overlap with features secondary to chronicinflammation, calculi, indwelling catheters or effects of intra-vesical chemotherapy.2 Thepurpose of this study is to find an appropriate set of cytological features of shed urothelial cellsthat will be useful to differentiate low-grade urothelial carcinoma cells from atypical urothelialcells secondary to non-neoplastic conditions. Study Design: Retrospective study. Setting:Charsada Teaching Hospital affiliated with Jinnah Medical College Peshawar. Period: 2010to 2015. Methods: All cases of urine and bladder washing cytology were retrieved for threediagnostic categories namely: low-grade urothelial carcinoma (LGUC), high-grade urothelialcarcinoma (HGUC), and “atypical urothelial cells”; for which histological diagnoses were alsoavailable. These cases were reviewed for cell clusters with smooth or irregular communityborders, cytoplasm texture, nucleomegaly, high nucleus to cytoplasm ratios (N/C ratio),presence of nucleoli, nuclear membrane irregularity, and chromatin texture. Results: Cellclusters with smooth borders were common in reactive changes, whereas irregular communityborders were seen in low-grade urothelial carcinomas and dyscohesive pattern was a featureof HGUC. The increase in N/C ratio ›2:1 was always associated with malignancy. The nuclearmembrane irregularity was also a strong indicator of malignancy. Cytoplasmic homogeneityand nuclear hyperchromasia were more prominent and consistently seen in high-gradeurothelial carcinomas. Conclusions: The study showed that nuclear membrane irregularity,nucleomegaly and high N/C ratio of › 2:1 were the most consistent features found in LGUC.These features can be used with high certainty to differentiate LGUC (malignant) from atypicalurothelial cells (non-neoplastic).

Analysis of papillary urothelial carcinomas of the bladder with grade heterogeneity: supportive evidence for an early role of CDKN2A deletions in the FGFR3 pathway.

The dual pathway model of urothelial carcinogenesis does not fully explain grade and stage progression in patients with initial low-grade, non-muscle invasive urothelial carcinomas. Fibroblast growth factor receptor 3 (FGFR3) mutations are a hallmark of the low-grade pathway, with subsequent progression to muscle invasion occurring when FGFR3 mutant tumours exhibit a homozygous CDKN2A deletion. We hypothesized that grade heterogeneity represents the morphological manifestation of molecular changes associated with disease progression. We identified retrospectively 29 non-muscle invasive papillary urothelial carcinomas with grade heterogeneity (<20% high grade). Nineteen had sufficient material for immunohistochemistry, CDKN2A fluorescence in-situ hybridization and FGFR3 mutation analysis. Eight pure low-grade urothelial carcinomas (PLGUC) were also analysed. FGFR3 mutation was seen in 10 of 19 cases. A homozygous CDKN2A deletion was identified in the low-grade areas of eight of nine (88%) technically suitable FGFR3 mutant cases (including five pTa cancers), in five of nine FGFR3 wild-type carcinomas and in none of the PLGUC. Increased MIB-1 expression was seen in low-grade areas of 12 of 19, in high-grade areas of 17 of 19 cases with grade heterogeneity and in none of the PLGUC. p53 staining was increased in one of 19 low-grade and seven of 19 high-grade areas. Our findings show that grade heterogeneity in urothelial carcinoma is characterized by increased MIB-1 labelling, and particularly in the FGFR3 mutant pathway, with homozygous deletions of CDKN2A in low- and high-grade areas. This would suggest that CDKN2A deletion occurs prior to grade progression and supports the current convention to assign the highest grade to urothelial carcinomas with grade heterogeneity.

Profiles of histopathological lesions of urinary bladder: A five years study

Background: Neoplastic and non-neoplastic urinary bladder lesions are the main reasons for morbidity and mortality throughout the world. Amongst these, urothelial carcinoma is a common primary tumor of urinary bladder (90%). The objective of this study is to determine the profile of various urothelial lesions received in Army Hospital within 5 years of period.Materials and methods: Five years retrospective study of cystoscopic biopsies and radical cystectomy specimens were carried out in Department of Pathology, Army hospital.Results: Out of 53 cystoscopic biopsies and radical cystectomy specimens, 42 were neoplastic and 11 were non neoplastic lesions. Thirty six urothelial carcinomas were observed out of which 20 were high grade urothelial carcinoma and 16 were low grade. Out of 20 high grade urothelial carcinoma, 17 had muscle invasion and 3 had invasion upto lamina propria. Of 16 low grade urothelial carcinoma, 12 were noninvasive, 2 had invasion upto lamina propria and 2 had muscle invasion. Papilloma was the commonest benign lesions found (7.1%) followed by papillary urothelial neoplasms of low malignant potential (PUNLMP) (2.4%) and hemangioma (2.4%).Conclusion: This article have highlighted upon the importance of histopathological study in evaluating urinary bladder lesions. Also, it has helped in determining that neoplastic lesions were more common than non-neoplastic lesions as seen in our study. A great majority of neoplastic lesions were of urothelial origin. Cystoscopic studies and biopsies help in early detection of bladder neoplasms and they form the mainstay of the diagnosis and follow up.