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1.  Cytological findings in routine voided urine samples with hematuria from a tertiary care center in south India 
Regardless of the availability of newer and more sophisticated modalities of investigation, urinary tract cytology still remains the most commonly used non-invasive test for the diagnosis of bladder cancer.
As hematuria is the commonest presenting symptom in patients with malignancy of urinary tract, we undertook this study to know the usefulness of urine cytology in evaluation of the hematuric patients for malignancy.
Materials and Methods:
A total of 21,557 fresh voided urine samples received at our tertiary care referral centre over a period of three years were included in the study. Of these, 1428 cases had hematuria, criteria of either gross or microscopic.
Among these hematuric cases included in the study, 32.5% (464 cases) were found to have positive finding of atypical cells. In these cases with atypia, 9.5% (136 cases) were proved to have malignancy both with the histopathological biopsy and cystoscopic findings. Other cases of atypia were found to be of reactive origin, either due to instrumentation or foreign body. A large number of hematuric cases, that is, 964 cases (67.5%) were negative for atypical cells.
The limited ability of urine cytology to detect low grade bladder tumors, its subjectivity and lack of uniformity in reporting, all render urine cytology a less than perfect tool. With added collaboration between clinician and cytopathologist, urine cytology can be used an adjunct tool in evaluation of patients with hematuria.
PMCID: PMC3307445  PMID: 22438611
Atypical cells; hematuria; urine cytology
2.  Accurate Risk Assessment of Patients with Asymptomatic Hematuria for the Presence of Bladder Cancer 
World journal of urology  2012;30(6):847-852.
Bladder cancer is frequently diagnosed during a workup for hematuria. However, most patients with microscopic hematuria and many with gross hematuria are not appropriately referred to urologists. We hypothesized that in patients presenting with asymptomatic hematuria, the risk of having bladder cancer can be predicted with high accuracy. Towards this end, we analyzed risk factors in patients with asymptomatic hematuria and developed a nomogram for the prediction of bladder cancer presence.
Data from 1,182 consecutive subjects without a history of bladder cancer undergoing initial evaluation for asymptomatic hematuria were collected at three centers. Clinical risk factors including age, gender, smoking status, and degree of hematuria were recorded. All subjects underwent standard workup including voided cytology, upper tract imaging, and cystourethroscopy. Factors associated with the presence of bladder cancer were evaluated by univariable and multivariable logistic regression analyses. The multivariable analysis was used to construct a nomogram. Internal validation was performed using 200 bootstrap samples.
Of the 1,182 subjects who presented with asymptomatic hematuria, 245 (20.7%) had bladder cancer. Increasing age (OR=1.03, p<0.0001), smoking history (OR=3.72, p<0.0001), gross hematuria (OR=1.71, p=0.002), and positive cytology (OR=14.71, p<0.0001) were independent predictors of bladder cancer presence. The multivariable model achieved 83.1% accuracy for predicting the presence of bladder cancer.
Bladder cancer presence can be predicted with high accuracy in patients who present with asymptomatic hematuria. We developed a nomogram to help optimize referral patterns (i.e., timing and prioritization) of patients with asymptomatic hematuria.
PMCID: PMC4004026  PMID: 23124847
urinary bladder neoplasms; hematuria; nomograms; early detection of cancer; carcinoma
3.  Commentary: the role of cytologic analysis of voided urine in the work-up of asymptomatic microhematuria 
BMC Urology  2009;9:13.
Microscopic hematuria is a common finding in patients presenting to both primary care doctors as well as urologists. Sources of microscopic hematuria include infection, stones, inflammatory disorders as well as cancer of the genitourinary tract, particularly urothelial cancer. A primary focus in the urologic workup of hematuria is to rule out cancer. This is done using radiographic studies as well as procedures such as cystoscopy and bladder biopsy. As the authors state in their article titled "The utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria", cytologic analysis of voided urine, though attractive due to its noninvasive nature, has been found to have the neither the sensitivity, cost-effectiveness, nor the ease of administration necessary to replace more invasive diagnostics in the evaluation of microscopic hematuria.
PMCID: PMC2753578  PMID: 19744318
4.  High Risk Patients with Hematuria Are Not Evaluated According to Guideline Recommendations 
Cancer  2010;116(12):2954-2959.
To determine whether high risk patients with hematuria receive evaluation according to guideline recommendations.
Materials and Methods
We recently performed a screening study for bladder cancer using a urine-based tumor marker in 1502 subjects at high risk based on age over 50, ≥10-year smoking history, and/or a 15 year or more environmental exposure. We evaluated use of urinalysis (UA) within 3 years preceding the screening study. Chart review was performed to determine if this subset with microhematuria received any additional evaluation.
Of 1502 study participants, routine urinalysis was performed in 73.2% and 164 (14.9%) subjects had documented hematuria (>3 RBCs/HPF) prior to inclusion. Of these, 42.1% had no further evaluation. Additional testing included repeat urinalysis (36%), urine culture (15.2%), cytology (10.4%), imaging (22.6% overall: 15.9% CT, 4.3% IVP; 2.4% MRI) and cystoscopy (12.8%).
Three subjects with microscopic hematuria (2%) were subsequently found to have bladder cancer during the screening study but were not referred for evaluation based on their hematuria. The source of hematuria was unknown in 65%, infection in 22%, benign prostatic enlargement in 10% and renal stone disease in 4% but these results are based on incomplete evaluation since only 12.8% underwent cystoscopy.
Subjects at high risk for bladder cancer based on ≥10 years of smoking or environmental exposure with microscopic hematuria are rarely evaluated thoroughly and only 12.8% were referred for urologic evaluation. Further studies are needed to evaluate both the utilization and effectiveness of guidelines for hematuria.
PMCID: PMC2940122  PMID: 20564400
Hematuria; Guidelines Recommendations; bladder cancer
5.  Utility of urine cytology in evaluating hematuria with sonographically suspected bladder lesion in patients older than 50 years 
Urology Annals  2014;6(3):212-217.
Investigate the utility of urine cytology (UC) in patients older than 50 years with hematuria and sonographically suspected bladder lesion.
Patients and Methods:
Between April 2010 and June 2012, 152 patients above 50 years suffering from hematuria were included in this study. In all patients, ultrasound revealed a lesion suspected to be bladder cancer. Voided urine specimens were taken from all patients and transported to Pathology laboratory and processed within 1-3 h. All patients have undergone a cystoscopy examination and biopsy was taken from any suspicious lesion. The cytological diagnosis was reported as one of three categories, positive or negative or suspicious for malignancy.
One hundred thirty three (87.5%) patients in this study proved to have bladder carcinoma in histopathological examination. The sensitivity of UC was 53.4% and only five patients were suspicious. Percentage of positive cytology was highest among patients having gross hematuria (51.3%), posterior wall lesions (75%), papillonodular configuration (81.8%), invasive cancer (59.1%) and bilharzial affection (52.5%).
Hematuria in patients older than 50 years with sonographically suspected bladder lesion mandates cystoscopy and biopsy. UC does not add more significant information in this group of patients.
PMCID: PMC4127857  PMID: 25125893
Bladder cancer; hematuria; urine cytology
6.  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
7.  Clinical impact of bladder biopsies with TUR-BT according to cytology results in patients with bladder cancer: a case control study 
BMC Urology  2010;10:12.
There seems to be no consensus concerning taking bladder biopsies during transurethral resection of bladder tumor (TUR-BT). We investigate the clinical significance of bladder biopsy with TUR-BT and the relationship between urinary cytology and the biopsy results.
We reviewed a total of 424 patients with non-muscle invasive bladder cancer treated with TUR-BT between 1998 and 2005. Of the total, 293 patients also underwent a bladder biopsy. Biopsies from suspicious-appearing urothelium (N = 59) and those from normal-appearing urothelium (N = 234) were evaluated separately.
Bladder cancer was observed in 23 cases (39.0%) who underwent a biopsy of suspicious-appearing urothelium. Among these 23 cases, 9 cases with visible tumor resection had carcinoma in situ (CIS) only in the biopsies from suspicious-appearing urothelium. Urinary cytology was negative in 3 of the 9 cases. Bladder cancer was observed in 26 cases (11.1%) who underwent a biopsy of normal-appearing urothelium. Of them, 5 cases with visible tumors had CIS only in the multiple biopsies from normal-appearing urothelium. Urinary cytology was positive in all of the 5 cases. No upstaging or upgrading cases were found in these patients by the addition of these two types of biopsy. Furthermore, therapy was not altered in these patients. With or without bladder biopsy was not a significant factor for tumor recurrence in either the univariate or multivariate analysis.
Based on the results, it is concluded the multiple biopsies from normal-appearing urothelium are not necessary in patients with negative cytology results because of the low detection rate and lack of influence on therapeutic decisions. Meanwhile, biopsy of suspicious-appearing urothelium is needed in patients with negative cytology results in order to detect CIS due to staging properties. This result supports a recent EAU guideline.
PMCID: PMC2912875  PMID: 20591189
8.  The role of FISH and cytology in upper urinary tract surveillance after radical cystectomy for bladder cancer☆ 
Urologic oncology  2011;30(6):821-824.
Cytology and fluorescence in situ hybridization (FISH) (Urovysion) assay are often used during upper urinary tract surveillance in patients following radical cystectomy with urinary diversion, without much available data regarding efficacy in this population. Here, we evaluate the value of FISH and cytology in detecting upper tract recurrence in the face of a urinary diversion.
Materials and methods
A review of our cystectomy database revealed 270 patients who had at least one FISH and/or cytology assay performed during surveillance after radical cystectomy. Workup included upper tract imaging in all patients and upper tract endoscopy as indicated. A total of 163 FISH assays and 474 urinary cytology examinations were included in the analysis. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FISH and cytology were assessed.
Ten patients (3.4%) developed upper tract recurrence after a median follow-up time of 31 months (2–202). All but 1 patient presented either with gross hematuria or positive finding on imaging; 6 had positive FISH and cytology, and 2 had positive cytology only (no FISH done). For detection of upper tract recurrence, sensitivity, specificity, PPV, and NPV of cytology were 80.0%, 85.6%, 10.7%, and 99.5%, respectively; and that for FISH were 85.7%, 86.5%, 23.1%, and 99.2%, respectively.
The FISH assay and urinary cytology both demonstrate high rates of false positivity and are useful mainly for their negative predictive ability in patients with a urinary diversion. Unless prospective trials show otherwise, both— or at least the more expensive test— can be omitted from surveillance strategies.
PMCID: PMC3931457  PMID: 21396845
Bladder cancer; Urinary diversion; FISH; Cytology; Surveillance; Urothelial cancer
9.  The value of cystoscopy as an initial diagnostic modality for asymptomatic microscopic hematuria. 
Journal of Korean Medical Science  2001;16(3):309-312.
For the patients who visit outpatient clinics due to asymptomatic microscopic hematuria, cystoscopy has been looked upon as rather invasive compared to other diagnostic methods. We tried to elucidate the actual diagnostic value of cystoscopy in the initial evaluation of asymptomatic microscopic hematuria. We reviewed the results of cystoscopic examinations in 213 patients who visited our hospital due to asymptomatic microscopic hematuria. No definite lesion that could explain the microscopic hematuria was detected by means of IVP, urine cytology, and other nephrologic evaluations for all the patients. Among the abnormal cystoscopic findings in 55 patients, the lesions suspected to be directly related to microscopic hematuria were classified as 'significant lesions' (31 patients, 17.6%) which include entities such as bladder cancer (1.31%). 27 of 31 patients with significant lesions (85.2%) were over 50 yr old, and furthermore, 3 patients who were diagnosed as bladder tumor by cystoscopy were over 60 yr. Cystoscopy should be utilized as initial diagnostic modality in older patients with asymptomatic microscopic hematuria to rule out any possibility of bladder cancer occurrence. Further studies are needed to justify implementation of cystoscopy as an initial diagnostic modality in younger patients with asymptomatic microscopic hematuria.
PMCID: PMC3054750  PMID: 11410691
10.  Immunocytology Is Strong Predictor of Bladder Cancer Presence in Patients With Painless Hematuria: A Multicentre Study 
European urology  2011;61(1):185-192.
Although the performance of immunocytology has been established in the surveillance of patients with urothelial carcinoma of the bladder (UCB), its value in the initial detection of UCB in patients with painless hematuria remains unclear.
To determine whether immunocytology improves our ability to predict the likelihood of UCB in patients with painless hematuria. Further, to test the clinical benefit of immunocytology in this setting using decision curve analysis.
Design, setting, and participants
The subjects were 1182 consecutive patients without a history of UCB presenting with painless hematuria and were enrolled at three centres.
All patients underwent upper-tract imaging, cystourethroscopy, voided urine cytology, and immunocytology analysis. Bladder tumors were biopsied and histologically confirmed as UCB.
Multivariable regression models were developed. Area under the curve was measured and compared using the DeLong test. A nomogram was constructed from the full multivariable model. Decision curve analysis was performed to evaluate the clinical benefit associated with use of the multivariable models including immunocytology.
Results and limitations
Immunocytology had the largest contribution to a multivariable model for the prediction of UCB (odds ratio: 18.3; p < 0.0001), which achieved a 90.8% predictive accuracy. Decision curve analysis revealed that models incorporating immunocytology achieved the highest net benefit at all threshold probabilities.
Immunocytology is a strong predictor of the presence of UCB in patients who present with painless hematuria. Incorporation of immunocytology into predictive models improves diagnostic accuracy by a statistically and clinically significant margin. The use of immunocytology in the diagnostic workup of patients with hematuria appears promising and should be further evaluated.
PMCID: PMC3628750  PMID: 21924544
Cystoscopy; Decision curve analysis; Early detection of cancer; Hematuria; Immunocytology; Nomograms; Urinary bladder neoplasms
11.  Biomarkers for detection and surveillance of bladder cancer 
Bladder cancer is the fourth most common cancer in men and the ninth most common cancer in women in Canada. Early detection of tumours is essential for improved prognosis and long-term survival. The standard method for detection and surveillance is cystoscopy together with urine cytology. Cystoscopy is relatively sensitive but is expensive and invasive. Urinary cytology is a noninvasive method that has poor sensitivity but high specificity; it is relied on for the detection of carcinoma in situ. Currently, several urinary-based bladder tumour biomarkers with USFDA/Health Canada approval are available commercially, but none have been widely adopted by urologists despite their offering high sensitivity and/or specificity. We present here a review of recent studies evaluating 7 commercial biomarker assays for the detection and/or surveillance of bladder cancer.
Sensitivity and specificity ranges, respectively, for each marker were reported as follows: BTA Stat (Polymedco), 52.5%–78.0% and 69.0%–87.1%; BTA Trak (Polymedco), 51%–100% and 73%–92.5%; cytology, 12.1%–84.6% and 78.0%–100%; hematuria dipstick, 47.0%–92.6% and 51.0%–84.0%; NMP22 Bladder Cancer Test (Matritech), 34.6%–100% and 60.0%–95.0%; NMP22 BladderChek (Matritech), 49.5%–65.0% and 40.0%–89.8%; ImmunoCyt/uCyt+ (DiagnoCure), 63.3%–84.9% and 62.0%–78.1%; ImmunoCyt/uCyt+ and cytology, 81.0%–89.3% and 61.0%–77.7%; and UroVysion (Abbott Molecular)/florescence in situ hybridization, 68.6%–100% and 65.0%–96.0%.
We find that no currently available bladder cancer urinary marker is sensitive enough to eliminate the need for cystoscopy. In addition, cytology remains integral to the detection of occult cancer. However, owing to their relatively high sensitivities, these markers may be used to extend the period between cystoscopies in the surveillance of patients with transitional cell carcinoma. Further study is required to determine which markers, alone or in panel, would best accomplish this.
PMCID: PMC2494897  PMID: 18682775
12.  High-grade microscopic hematuria in adult men can predict urothelial malignancy 
Microscopic hematuria in men younger than 40 is a confusing issue to urologists, especially when these men have normal radiological findings. We report our experience in looking for urologic malignancy in this group of patients.
We conducted a prospective study for men with vague urological symptoms. We included men under 40 years old, men with microscopic hematuria greater than 25 red blood cells/high power field in 2 properly collected mid-stream urine samples, and men with free urine culture and normal multiphasic computed tomography abdomen and pelvis studies. All patients underwent diagnostic cystoscurethroscopy. If there were no lesions, multiple random biopsies were taken. In cases of apparently normal cystoscopic findings and associated renal colic, uretroscopy was done to the suspected side.
Only 20 patients fulfilled our inclusion criteria. The mean age of the patients were 34; 2 patients presented with pain. The other 18 patients were presenting with mild recurrent lower urinary tract symptoms. Cystoscopy showed small papillary low-grade tumour in 3 patients. All random biopsies were free of malignancy. Unilateral uretroscopy for the 2 cases presented with pain detected carcinoma in situ in one of them.
Cystoscopy is highly recommended for young adult men, with significant levels of microscopic hematuria, due to the 20% incidence rate of associated urological malignancy. Random bladder biopsies, in the absence of suspicious lesions, have no diagnostic role, and should not be done. Uretroscopy is advised for patients with microscopic hematuria and loin pain, even in the absence of suspicious radiological findings.
PMCID: PMC4113579  PMID: 25132893
13.  Noninvasive Electromagnetic Detection of Bladder Cancer 
ISRN Urology  2014;2014:802328.
Objectives. Normal and neoplastic human tissues have different electromagnetic properties. This study aimed to determine the diagnostic accuracy of noninvasive electromagnetic detection of bladder cancer (BC) by the tissue-resonance interaction method (TRIM-prob). Patients and Methods. Consecutive patients were referred for cystoscopy because of (i) microscopic or gross hematuria and/or irritative voiding symptoms and (ii) bladder ultrasounds and urinary cytology findings negative or just suspicious of malignancy. Patients were first submitted to TRIM-prob bladder scanning by a single investigator and then to cystoscopy by another investigator blind to TRIM-prob data. Results. In 125 evaluated patients cystoscopy was positive for BC in 47 and negative in the remaining 78; conversely, TRIM-prob bladder scanning was positive for BC in 53 and negative in 72. In particular, TRIM-prob scanning yielded 7 false positives and only one false negative; therefore, its overall sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 97.9%, 89.9%, 86.8%, 98.6%, and 93.6%, respectively. Conclusions. TRIM-prob bladder scanning was a simple and quite accurate method for non-invasive electromagnetic detection of BC. If the elevated positive and negative predictive values will be replicated in further well-designed studies, it could be used to screen asymptomatic patients at high risk of BC.
PMCID: PMC3915748  PMID: 24563795
14.  Suspicious urinary cytology with negative evaluation for malignancy in the diagnostic investigation of haematuria: how to follow up? 
Journal of Clinical Pathology  2004;57(4):365-368.
Aims: To define the natural history of patients with suspicious urinary cytology and negative initial evaluation for malignancy in the investigation of haematuria.
Patients and methods: Data from the hospital information support system on urinary cytology examinations carried out at one centre were audited over a period of 24 months. There were 102 patients who had suspicious urinary cytology for malignant cells with negative initial evaluation. Follow up investigations, treatment, and final outcome were noted.
Results: There were 102 patients with suspicious urinary cytology and negative initial evaluation for malignancy in 24 months, with a mean follow up of 15.7 months. Seventy patients had no obvious pathology on initial investigations. Forty one patients were found to have urological malignancies (29 bladder, eight ureteric, and four prostate) on follow up. All patients diagnosed as having urothelial malignancies on follow up had either persistent suspicious cytology (29) or recurrent haematuria (eight). The mean duration for appearance of lesions was 5.6 months (range, 3–12 months). Three patients had suspicious digital rectal examination and biopsies confirmed adenocarcinoma of the prostate. One patient had urinary retention and transurethral resection of prostate showed prostatic adenocarcinoma. The presence of suspicious cells on repeat urine analysis was the only significant factor in predicting the presence of urothelial tumours (p  =  0.002).
Conclusion: Patients with persistent suspicious/positive cytology or recurrent haematuria need further evaluation and follow up. Asymptomatic patients or patients with obvious benign pathology do not require repeat evaluation. Careful urological evaluation, including prostate, should be carried out in these patients.
PMCID: PMC1770277  PMID: 15047737
urinary cytology; urological follow up; suspicious cells in urine
15.  The influence of urine cytology on our practice 
Urology Annals  2012;4(2):80-83.
Bladder cancer is a common malignancy. It is ranked ninth among male population in Saudi Arabia. Urine cytology is used by some physicians routinely in the workup for diagnosis and follow-up of patients with urothelial cancer. Our objective is to determine whether urine cytology is still essential in the work up of suspected urothelial cancer patients and to measure its cost-effectiveness.
Materials and Methods:
We reviewed all urine cytology reports that were performed over a period of five years from 2006 to 2010 in the International Medical Center in Jeddah, Saudi Arabia. The medical records of patients with cytology reports of both positive for malignant cells and atypical cells suspicious of malignancy were retrospectively, studied for age, sex, nationality, cystoscopic findings, imaging results, and total cost.
A total of 563 urine cytology tests were done on 516 patients. Two patients were positive for malignant cell and 10 showed atypical cells suspicious of malignancy. All 12 patients underwent imaging and/or cystoscopy as part of their complete work up for hematuria. The two patients with positive cytology had a cystoscopic confirmation of bladder tumor. In the 10 patients with atypical cells, bladder tumor was identified in seven using cystoscopy and/or imaging. The mean age was 54.6±16 year (range 15-95). The total cost was 140,750 SR (37,533 USD) for a yield of 0.3% positive results and 2% atypical cytology.
Routine urine cytology did not affect the diagnostic strategy for urothelial cancer. It should be only used in selected patients.
PMCID: PMC3355705  PMID: 22629001
Hematuria; transitional cell carcinoma; urine cytology; urine markers; urothelial cancer
16.  Usefulness of the NMP22BladderChek Test for Screening and Follow-up of Bladder Cancer 
Korean Journal of Urology  2010;51(2):88-93.
We evaluated the usefulness of the nuclear matrix protein 22 BladderChek (NMP22BC) test for the screening and follow-up of bladder cancer.
Materials and Methods
From February 2006 to September 2009, we enrolled 1,070 patients who had hematuria or who were being followed up for bladder cancer. We compared the sensitivity and specificity of the NMP22BC test with those of urine cytology.
The sensitivity of the NMP22BC test (77.5%) was significantly higher than that of urine cytology (46.3%). The specificity of the NMP22BC test was 88.8%, compared with 97.9% for urine cytology. The sensitivity of the NMP22BC test (81.8%) in non-muscle-invasive bladder cancer was higher than that of cytology (36.4%). However, the sensitivity of the NMP22BC test and of urine cytology in invasive bladder cancer were 57.1% and 92.9%, respectively. The sensitivity of the NMP22BC test was higher for low-grade bladder cancer (83.9%) than for high-grade (62.5%), and the sensitivity of cytology was higher for high-grade bladder cancer (66.7%) than for low-grade (37.5%). Follow-up bladder cancer was detected in 262 patients. The sensitivity of the NMP22BC test in that group (72.7%) was decreased and the specificity (91.7%) was increased. The sensitivity of cytology (54.5%) in the follow-up group was increased and the specificity (95.6%) was decreased. The presence of pyuria was significantly associated with the lower specificity of the NMP22BC test.
The greater sensitivity of the NMP22BC test may be more useful for the diagnosis of non-muscle-invasive bladder cancer and low-grade bladder cancer than for the diagnosis of invasive or high-grade bladder cancer. If the NMP22BC test is performed in the absence of pyuria, it may play a compensatory role for urine cytology.
PMCID: PMC2855476  PMID: 20414419
Nuclear matrix protein 22; Cytology; Urinary bladder neoplasms
17.  Bladder Tumor in Women with Microscopic Hematuria: An Iranian Experience and a Review of the Literature 
Advances in Urology  2009;2009:231861.
Aim. In this study we report our experience with microhematuria and its relation with bladder tumors in Iranian women. Materials and Methods. Overall 249 women were evaluated. Microscopic hematuria was defined as three or more red blood cells per high-power field on at least two different occasions. Patients with a history of gross hematuria or coagulation disorders, having organic diseases, urinary stones, urinary tract infections, nephrological diseases, and local lesions such as urethral caruncle were excluded from the study population. Final diagnosis of malignant tumors was done with cystoscopy and biopsy specimen pathological assessment in all cases. Results. Age for the study population was 49.7 ± 11.8 years. 95 (38%) of patients were identified during routine check up and presenting symptoms in other patients were frequency, dysuria, stress urge incontinence, urge incontinence, feeling of incomplete urine emptying, and flunk pain, respectively. Finally, 7 (2.8%) of study subjects were confirmed as having bladder tumors. One of tumor cases was diagnosed 24 months after initial assessments. Patients with bladder tumor were significantly older; more frequently had diverticulum in their bladder wall (P < .05). Conclusion. Female microscopic hematuria is relevant and deserves evaluations, especially in elderly patients. Patients whose reason for microhematuria would not be diagnosed at the initial evaluations should be followed.
PMCID: PMC2715568  PMID: 19639044
18.  Thin glomerular basement membrane disease: light microscopic and electron microscopic studies. 
Journal of Korean Medical Science  1997;12(3):234-239.
Benign recurrent hematuria usually indicates a good prognosis. This condition is associated with abnormally thin glomerular basement membranes. Of 680 renal biopsy cases in which lower urinary tract disease had been excluded by careful study, 25 cases from seven children and eighteen adults met the criteria for thin glomerular basement membrane disease, placing the incidence of the disease at 3.7%. The mean patient age was 32.4 years and the male to female ratio was 1 to 5.3. The primary finding was microscopic hematuria in eighteen patients and gross hematuria in five patients. Among eighteen patients who had microscopic hematuria, one patient also exhibited proteinuria and one patient suffered from acute renal failure due to acute drug-induced interstitial nephritis. Proteinuria was only found in one patient. All of the patients had normal renal function, with the exception of one who suffered from acute renal failure. The duration of hematuria from the time of detection to the date of biopsy ranged from 3 months to 30 years with a mean interval of 56.6 months. No apparent evidence of familial hematuria in any patient was noted. Under light microscopy most glomeruli were normal. However, five cases showed focal global sclerosis. Under immunofluorescence microscopy seventeen cases were negative for all immunoglobulins, for complement, and for fibrinogen. Eight cases showed nonspecific mesangial deposition of fibrinogen and/or IgM. Ultrastructurally, extensive diffuse thinning of the GBM was a constant finding. The mean thickness of the GBM was 203.2 +/- 28.3 nm (n = 25); the thickness in adult (201.4 +/- 27.5 nm; n = 18) did not differ from that in children (208.1 +/- 32.0 nm; n = 7).
PMCID: PMC3054286  PMID: 9250920
19.  How accurate is urine cytology? 
Exfoliative urinary cytology was performed on 260 new cases of histologically proven urothelial cancer. The site, size, shape and histological grade of the tumours were documented, and they were classified by the TNM system. Overall, urine cytology was positive in 135 (52%), suspicious in 28 (11%) and negative in 97 (38%) cases. Malignant cells were found most often when the urothelial tumours were large, papillary and solid, moderately or poorly differentiated and invasive (T2-4). Most upper tract tumours and those situated in bladder diverticula had positive urinary cytology. This study confirms that exfoliative urinary cytology is useful in detecting the more malignant bladder tumours including in-situ carcinoma, and other tumours in less accessible parts of the urinary tract.
PMCID: PMC1290343  PMID: 3723535
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.  Touch imprint cytology of prostate core needle biopsy specimens: A useful method for immediate reporting of prostate cancer 
Cytology plays an important role in the preoperative assessment of many cancers. It is used as a first-line pathological investigation in both screening and diagnostic purposes.
To determine the diagnostic value and accuracy of touch imprint cytology (TIC) smear of prostate core needle biopsy (CNB) specimens in the diagnosis of prostate carcinoma.
Materials and Methods:
One hundred and twenty-one patients had ultrasound-guided transrectal prostate CNB. A total of 1210 TIC smears were prepared from all CNB specimens.
Diagnoses of 1210 TIC smears were compared with the histopathological findings of the CNB specimens. One hundred and seventy (14%) TIC smears were found positive for malignancy, 35 (2.9%) were diagnosed as suspicious for malignancy and 1005 (83.1%) were found negative for malignancy. Twenty-five of 35 suspicious imprints and 150 of 170 malignant smears were confirmed to be malignant on histopathological evaluation. Although 20 malignant TIC smears were defined as benign in standard histological preparations, 10 of them had definitive diagnosis of malignancy following extensive serial sectioning. Last of all, there were 10 false-positive cytology results. Moreover, 10 of the 35 suspected TIC smears were false negative when compared with the histopathological diagnosis. The sensitivity, specificity, positive predictive value and negative predictive value of touch imprint smear results were 100%, 98%, 90.2% and 100%, respectively.
TIC smears can provide an immediate and reliable cytological diagnosis of prostate carcinoma. It may clearly help the rapid detection of carcinoma, particularly in highly suspected cases that had negative routine biopsy results for malignancy with abnormal serum prostate specific antigen (PSA) levels and atypical digital rectal examination.
PMCID: PMC3480765  PMID: 23112457
Carcinoma; core needle biopsy; prostate; touch imprint cytology
22.  Feasibility of telecytopathology for rapid preliminary diagnosis of ultrasound-guided fine needle aspiration of axillary lymph nodes in a remote breast care center 
In the recent years, the advances in digital methods in pathology have resulted in the use of telecytology in the immediate assessment of fine needle aspiration (FNA) specimens. However, there is a need for organ-based and body site-specific studies on the use of telecytology for the immediate assessment of FNA to evaluate its pitfalls and limitations. We present our experience with the use of telecytology for on-site evaluation of ultrasound-guided FNA (USG-FNA) of axillary lymph nodes in a remote breast care center.
Materials and Methods:
Real-time images of Diff-Quik-stained cytology smears were obtained with an Olympus digital camera attached to an Olympus CX41 microscope and transmitted via ethernet by a cytotechnologist to a pathologist who rendered preliminary diagnosis while communicating with the on-site cytotechnologist over the Vocera system. The accuracy of the preliminary diagnosis was compared with the final diagnosis, retrospectively.
A total of 39 female patients (mean age: 50.5 years) seen at the breast care center underwent USG-FNA of 44 axillary nodes. Preliminary diagnoses of benign, suspicious/malignant, and unsatisfactory were 41, 52, and 7%, respectively. Only one of the 23 cases that were initially interpreted as benign was reclassified as suspicious on final cytologic diagnosis. Seventeen of 18 suspicious/malignant cases on initial cytology corresponded with a malignant diagnosis on final cytology. One suspicious case was reclassified as benign on final cytologic diagnosis. All unsatisfactory cases remained inadequate for final cytologic interpretation. The presence of additional material in the cell block and interpretative error were the main reasons for discrepancy, accounting for the two discrepant cases.
This retrospective study demonstrates that the on-site telecytology evaluation of USG-FNA of axillary lymph nodes in patients at a remote breast care center was highly accurate compared with the final cytologic evaluation. It allows pathologists to use their time more efficiently and makes on-site evaluation at a remote site possible.
PMCID: PMC3519010  PMID: 23243554
Axillary lymph nodes; FNA; telecytopathology; ultrasound-guided FNA
23.  The Use of Molecular Analyses in Voided Urine for the Assessment of Patients with Hematuria 
PLoS ONE  2013;8(10):e77657.
Patients presenting with painless hematuria form a large part of the urological patient population. In many cases, especially in younger patients, the cause of hematuria is harmless. Nonetheless, hematuria could be a symptom of malignant disease and hence most patients will be subject to cystoscopy. In this study, we aimed to develop a prediction model based on methylation markers in combination with clinical variables, in order to stratify patients with high risk for bladder cancer.
Material and Methods
Patients (n=169) presenting with painless hematuria were included. 54 patients were diagnosed with bladder cancer. In the remaining 115 patients, the cause of hematuria was non-malignant. Urine samples were collected prior to cystoscopy. Urine DNA was analyzed for methylation of OSR1, SIM2, OTX1, MEIS1 and ONECUT2. Methylation percentages were calculated and were combined with clinical variables into a logistic regression model.
Logistic regression analysis based on the five methylation markers, age, gender and type of hematuria resulted in an area under the curve (AUC) of 0.88 and an optimism corrected AUC of 0.84 after internal validation by bootstrapping. Using a cut-off value of 0.307 allowed stratification of patients in a low-risk and high-risk group, resulting in a sensitivity of 82% (44/54) and a specificity of 82% (94/115). Most aggressive tumors were found in patients in the high-risk group. The addition of cytology to the prediction model, improved the AUC from 0.88 to 0.89, with a sensitivity and specificity of 85% (39/46) and 87% (80/92), retrospectively.
This newly developed prediction model could be a helpful tool in risk stratification of patients presenting with painless hematuria. Accurate risk prediction might result in less extensive examination of low risk patients and thereby, reducing patient burden and costs. Further validation in a large prospective patient cohort is necessary to prove the true clinical value of this model.
PMCID: PMC3797079  PMID: 24143252
24.  The Clinical Usefulness of Nuclear Matrix Protein-22 in Patients with Atypical Urine Cytology 
Korean Journal of Urology  2011;52(9):603-606.
Difficulty exists in interpreting the significance of atypical urine cytology. This study was performed to assess the diagnostic utility of nuclear matrix protein-22 (NMP-22) testing when atypical cells are detected during urine cytology.
Materials and Methods
Among patients whose urine cytology was reported as atypical between January 2004 and December 2009, a total of 275 who also underwent NMP-22 testing were enrolled in the present study. These patients were further divided into the screening group (143 patients examined as outpatients for hematuria) and the follow-up group (132 patients followed up for previously diagnosed bladder cancer). The sensitivity, specificity, positive and negative predictive values, and accuracy were assessed for atypical cytology alone and in conjunction with NMP-22.
Of the 275 patients exhibiting atypical urine cytology, cancer was confirmed in 85, yielding a positive predictive value of 30.9% (85/275). Of the 96 patients testing positive for NMP-22, 58 were diagnosed with bladder cancer. The positive predictive value in conjunction with NMP-22 was 60.4% (58/96). The sensitivity, specificity, negative predictive value, and accuracy were 68.2% (58/85), 80.0% (152/190), 84.9% (152/179), and 76.2% (210/275), respectively. Testing for NMP-22 in the screening and follow-up groups increased the positive predictive value from 30.0% (43/143) to 64.0% (32/50) and from 31.3% (42/132) to 56.5% (26/46), respectively; there was no significant difference between the screening and follow-up groups (p=0.106).
When only cases with atypical urine cytology were examined, NMP-22 testing increased the detection rate of bladder cancer regardless of whether the test was used in screening hematuria or in following up patients.
PMCID: PMC3198232  PMID: 22025954
Cytology; Nuclear matrix; Urinary bladder neoplasms
25.  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

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