Reflex UroVysion testing in suspicious urine cytology cases

BACKGROUND:

UroVysion is a US Food and Drug Administration–approved fluorescence in situ hybridization (FISH) probe set for use in the detection of recurrent urothelial carcinoma and in patients with hematuria. The objective of the current study was to evaluate the usefulness of UroVysion as a reflex test in patients with a suspicious urine cytology diagnosis. The rationale was that a more aggressive workup might be indicated in patients with a suspicious cytology diagnosis and positive UroVysion test.

METHODS:

The study population included 161 urine specimens diagnosed as suspicious over a period of 12 months. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (NPV) were calculated based on the histologic and cystoscopic correlation.

RESULTS:

The results using the reporting criteria suggested by the manufacturer demonstrated a sensitivity of 68.3%, a specificity of 39.7%, a PPV of 56.8%, and a NPV of 51.9%. The results using the presence of any cytogenetic abnormality as a positive FISH test demonstrated a sensitivity of 82.9%, a specificity of 21.7%, a PPV of 54.8%, and an NPV of 51.7%.

CONCLUSIONS:

A negative UroVysion test did not rule out the presence of low‐grade or high‐grade urothelial carcinoma in urine specimens diagnosed as suspicious. The use of less strict criteria dramatically increased the sensitivity of UroVysion FISH; however, there was a marked decrease in specificity noted. The results in this current study appear to indicate that a more aggressive workup of patients with a suspicious cytology, positive UroVysion result, and negative cystoscopic evaluation is not currently justified. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Value of p16(INK4a) in the diagnosis of low-grade urothelial carcinoma of the urinary bladder in urinary cytology

BACKGROUND:

The sensitivity of urinary cytology for the diagnosis of urothelial carcinomas is low, particularly in low‐grade carcinomas. The UroVysion test is a fluorescent in situ hybridization multiprobe assay that increases the sensitivity of urinary cytology. However, this test is not widely available. P16^INK4a, a protein involved in cell cycle progression, is overexpressed in urothelial carcinoma. Immunocytochemical expression of p16^INK4a has been examined in biopsy samples from urothelial carcinomas, but few studies have addressed this protein in urine cytology.

METHODS:

The authors compared the results of p16^INK4a immunoreactivity in cytology and biopsy samples from 83 cases, including low‐grade urothelial carcinomas, reactive epithelial lesions, and negative cases.

RESULTS:

p16^INK4a assessment of in urine cytology samples showed a sensitivity of 66.7% and a specificity of 82.8% in the diagnosis of low‐grade urothelial carcinomas.

CONCLUSIONS:

On the basis of these results, the authors propose that immunocytochemical detection of p16^INK4a is a reliable tool in urine cytology, both for the diagnosis of low‐grade urothelial carcinomas and for follow‐up purposes. More retrospective and prospective studies are required to verify these results. Cancer (Cancer Cytopathol) 2012. © 2012 American Cancer Society.     

Combined morphologic and fluorescence in situ hybridization analysis of voided urine samples for the detection and follow‐up of bladder cancer in patients with benign urine cytology

BACKGROUND.

Bladder cancer is among the 5 most common malignancies worldwide. Patients with bladder cancer are closely followed with periodic cystoscopies and urine cytology analyses due to the significant risk of tumor recurrence. The UroVysion fluorescence in situ hybridization (FISH) test demonstrated higher sensitivity over urine cytology in detecting bladder cancer by most comparative studies.

METHODS.

In the current study, the diagnostic usefulness of a combined cytology and FISH analysis approach was tested using the Duet automatic scanning system in patients with benign urine cytology who were being monitored for recurrent urothelial carcinoma or being assessed for various urologic symptoms.

RESULTS.

By combining the benefits of conventional cytology with molecular diagnostics, a more sensitive detection of bladder cancer was attained. All patients who had positive cystoscopy concomitantly with urine sampling were detected by combined analysis. Additional patients that developed transitional cell carcinoma during a follow‐up period of 24 months had a previous positive result on combined analysis. Only 2 patients with a negative combined analysis result presented with late disease recurrence (20 months and 22 months, respectively, after the negative test). Therefore, negative combined analysis was found to be predictive of a lack of disease recurrence for at least 12 months. In this timeframe, the overall sensitivity, specificity, negative predictive value (NPV), and positive predictive values of the combined analysis test were 100%, 65%, 100%, and 44%, respectively.

CONCLUSIONS.

Given the absolute sensitivity and NPV of the combined analysis test, the management of patients with a negative combined analysis result might be revised and allow for more flexible assessment and management of bladder cancer patients relying more on urine bound tests. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.     

Examination of Diagnostic Accuracy of UroVysion Fluorescence In Situ Hybridization for Bladder Cancer in a Single Community of Japanese Hospital Patients

Objective: UroVysion (Abbott Molecular, Inc., Illinois, USA) is based on multicolor fluorescence in situ hybridization(FISH). It has been used successfully in the USA following its Food and Drug Administration approval in 2001. However,the technology was not approved for use in Japan until 2017. Cystoscopy and urine cytology are the most frequentlyused examinations to detect bladder cancer in Japan, and there are only a few reports regarding the performance ofUroVysion. Therefore, the aim of this study is to examine the diagnostic accuracy of UroVysion FISH in Japanesepatients whose tumors are detected by cystoscopy before transurethral resection of bladder tumor (TURBT). Methods:From April 2018 to July 2018, a total of 40 patients who were diagnosed as having bladder tumors by cystoscopy, andtherefore underwent TURBT were registered in this study. One day before TURBT, urine cytology and UroVysionFISH were used in order to compare the accuracy with which they could detect bladder carcinoma, as confirmed bypathological results of TURBT. Results: The pathological results of TURBT showed urothelial carcinoma in 33 cases.Urine cytology showed positive results for 0 cases (0%), suspicious results for 10 cases (30.3%), and negative resultsfor 23 cases (69.7%). On the other hand, UroVysion FISH indicated 9 positive cases (27.3%) and 24 negative cases(72.7%). There were 19 cases of urothelial carcinoma (57.6%) that were not detected by either method. Conclusion:We conclude that UroVysion FISH alone is insufficient to detect bladder cancer and that cystoscopy is essential for theoptimum detection or follow up of bladder cancer cases in our hospital.     

A multicolor fluorescence in situ hybridization assay: A monitoring tool in the surveillance of patients with a history of non-muscle-invasive urothelial cell carcinoma: A prospective study

BACKGROUND:

Non–muscle‐invasive urothelial cell carcinoma (NMIUCC) has a high tendency to recur and affected patients must be monitored regularly using invasive cystoscopies. The aim of the current study was to compare a multicolor fluorescence in situ hybridization (FISH) assay (UroVysion) with routine follow‐up (cystoscopy and cytology) in the monitoring of patients with a previous history of NMIUCC.

METHODS:

An unselected cohort of patients under surveillance for a previous history of NMIUCC was prospectively studied. A total of 248 examinations in 223 patients were analyzed. Each exploration was comprised of cytological and FISH microscopic examination of voided urine samples and cystoscopy. The sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values for tumor recurrence of all 3 techniques were determined.

RESULTS:

The sensitivities of FISH and cystoscopy were not found to be significantly different (92.9% and 82.1%, respectively). The specificities of FISH and cystoscopy were 92.7% and 89.7%, respectively. The PPV and NPV of FISH were 53.5% and 97.2%, respectively, whereas those of cystoscopy were 63.4% and 98.9%, respectively. No significant differences were found between these 2 tests. In contrast, the sensitivity and specificity of cytology were 14.3% and 99.5%, respectively.

CONCLUSIONS:

Given the lack of statistically significant differences with regard to FISH and cystoscopy results, the authors propose that FISH could be a useful monitoring tool in the surveillance of patients with a previous history of NMIUCC. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

A review of reporting systems and terminology for urine cytology

Urine cytology continues to play an important role in the diagnosis and management of urothelial carcinoma, a common cancer of adults with significant morbidity and mortality. Because of its high sensitivity for high‐grade urothelial tumors, including lesions that may be cystoscopically occult, urine cytology nicely compliments cystoscopic examination, a method that detects most low‐grade tumors. Over the decades, several reporting schemes for urine cytology have been published in the literature, each of which has relative strengths and weaknesses. Unlike cervical cytology, there has not been widespread acceptance and use of any particular reporting scheme for urine cytology studies. Thus, terminology and criteria for urine cytology reporting are not uniform among pathologists, which can frustrate clinicians and hinders interlaboratory comparisons. Cancer (Cancer Cytopathol) 2013;121:9–14 © 2012 American Cancer Society.     

Fluorescence in situ hybridization for detecting urothelial carcinoma

BACKGROUND:

Because urothelial carcinoma (UC) is associated with a significantly high risk of disease recurrence and progression, patients with UC require long‐term surveillance. Fluorescence in situ hybridization (FISH) has been shown to be more sensitive than cytology in the detection of UC. The current study evaluated the use of FISH for detecting UC.

METHODS:

A pathology database was used to identify patients who had urine cytology and FISH performed at the study institution between 2004 and 2006. Urinary specimens were analyzed using UroVysion FISH probes for abnormalities in centromeric chromosomes 3, 7, and 17 and locus‐specific 9p21. FISH results were correlated with cytologic findings and a minimal clinical follow‐up of 24 months.

RESULTS:

A total of 1006 consecutive urinary specimens from 600 patients (448 men and 152 women) who were monitored for recurrent UC (915 specimens) or evaluated for urinary symptoms (91 specimens) were identified. On FISH analysis, 669 specimens were found to be negative for UC and 272 specimens were positive for UC. Sixty‐five (6%) specimens were insufficient for FISH analysis. The sensitivity and specificity of FISH for UC were 58% and 66%, respectively, and 59% and 63%, respectively, when FISH and cytology results were combined. Factors contributing to decreased FISH sensitivity included the paucity or absence of tumor cells, low‐grade tumors, degenerated cells, method of specimen collection, type of specimen, and obscuring inflammatory cells or lubricant.

CONCLUSIONS:

UroVysion FISH appeared to have good sensitivity and specificity for detecting UC in urinary specimens. It is important to correlate the FISH results with the cytologic findings. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.     

Evaluation of chromosomal aberrations in patients with benign conditions and reactive changes in urinary cytology

BACKGROUND:

Fluorescence in situ hybridization (FISH) is routinely used to help clarify atypical urinary cytology. However, to the authors' knowledge, little is known regarding the frequency of chromosomal aberrations in non‐neoplastic conditions that could potentially lead to false‐positive FISH results. The objective of the current study was to evaluate the frequency of chromosomal aberrations in benign cells of the urinary tract using the UroVysion FISH test.

METHODS:

The authors analyzed 77 Papanicolaou‐stained benign urine cytology specimens with reactive epithelial atypia using a FISH assay detecting the chromosomes 3, 7, and 17 and the gene locus 9p21. A positive test result was defined as an increased copy number of at least 2 chromosomes in ≥ 4 of 25 cells, or > 10 cells with a tetraploid or octaploid pattern, or homozygous or heterozygous deletion of 9p21 (≥ 12cells).

RESULTS:

FISH was positive in 27 of 77 bladder washings (35.1%) including 25 of 65 bladder washings (40.5%) and 2 of 15 voided urines (13.5%) from patients with irritative bladder (15 of 36 patients), a history of radiotherapy (7 of 12 patients), nonspecific cystitis (3 of 11 patients), hematuria (3 of 8 patients), and lithiasis (1 of 4 patients) . In 7 of 27 FISH‐positive urothelial specimens, the positivity was solely due a polyploid pattern (tetraploid/octaploid pattern) in > 10 of the cells.

CONCLUSIONS:

Chromosomal aberrations can occur in reactive urothelial cells, with a tetraploid pattern being the most common. Even an aneuploid pattern of FISH signals does not always prove malignancy because it rarely occurs in reactive urothelial cells. Correlation of FISH results with cytomorphology and patient history is crucial to avoid false‐positive diagnoses. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

uCyt+/ImmunoCyt in the detection of recurrent urothelial carcinoma: an update on 1991 analyses

BACKGROUND: The authors provide an update on the clinical value and role of the uCyt+/ImmunoCyt test as a noninvasive tool for the detection of recurrent urothelial carcinoma. METHODS: Between January 2002 and October 2004, 942 patients (mean age, 72.6 yrs; range, 32-87 yrs) were enrolled in this prospective study. These patients mostly had been followed for superficial urothelial carcinoma (UC) confined to the mucosa and lamina propria (pathologic tumor [pT] classification pTa, pT1, and pTis [carcinoma in situ]) for a mean of 15.62 months (range, 4-28 mos). Voided urinary cytology and the uCyt+/ImmunoCyt test for all patients were performed on liquid-based cytology slides. Patients underwent subsequent cystoscopy when cytology or uCyt+/ImmunoCyt results were positive and when they underwent biopsy evaluation of any suspicious lesion. Altogether, 1991 uCyt+/ImmunoCyt analyses were performed. RESULTS: Two hundred ninety-eight patients who had adequate samples available were diagnosed with histologically proven UC. The sensitivity of cytology increased from 8.3% for Grade 1 tumors to 75.3% for Grade 3 tumors; whereas, with the uCyt+/ImmunoCyt, the sensitivity was 79.3% for Grade 1 tumors, 84.1% for Grade 2 tumors, and 92.1% for Grade 3 tumors. For cytology and uCyt+/ImmunoCyt combined, the sensitivity was 79.3% for Grade 1 tumors, 90.9% for Grade 2 tumors, and 98.9% for Grade 3 tumors. CONCLUSIONS: The current data confirmed the clinical usefulness of the uCyt+/ImmunoCyt test in the follow-up of patients with recurrent UC. Used as a noninvasive tool, cytology escorted by uCyt+/ImmunoCyt may reduce the morbidity and cost of follow-up for patients who have a low risk of recurrence while avoiding superfluous cystoscopic examinations. However, additional studies will be necessary to establish and compare the morbidity and cost of each method.     

Digitized microscopy in the diagnosis of bladder cancer: analysis of >3000 cases during a 7-month period

BACKGROUND:

Fluorescent in situ hybridization (FISH) analysis of urine samples has proven to be a valuable adjunctive test to urine cytology for both diagnosis and monitoring recurrence of urothelial carcinoma. Automated FISH analysis has the potential to improve laboratory efficiency and to reduce interobserver and intraobserver variability, resulting in more accurate, reproducible, assay performance.

METHODS:

A total of 3200 slides containing urine specimens, hybridized with the UroVysion Bladder Cancer Kit (Abbott Molecular, Des Plaines, Illinois), a 4‐probe set for chromosomes 3, 7, 17, and 9p21, was evaluated at Acupath Laboratories. The slides were analyzed over a 7‐month period, using the Ikoniscope ‐ oncoFISH bladder Test System (Ikonisys, New Haven, Connecticut).

RESULTS:

Analysis included the incorporation of a “flagging” system developed by Acupath Laboratories to identify cases, based on specific criteria, likely to benefit from further manual review. By using US Food and Drug Administration (FDA)‐cleared scoring criteria, 96.3% of the slides could be reported directly from the automated scan, requiring no manual review of the slide. For the remaining 3.7% of the samples (all of which were very hypocellular), a manual review of each slide subsequently allowed diagnoses to be successfully reported. The average scan time was 31.7 minutes, and the average slide scan review time was 8.3 minutes.

CONCLUSIONS:

This study demonstrated the value of an automated approach to the analysis of FISH slides, affording the benefit of high‐throughput while providing the user with the necessary images and tools to quickly and accurately report a case. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.     

Diagnostic approach for cancer cells in urine sediments by 5‐aminolevulinic acid‐based photodynamic detection in bladder cancer

Bladder urothelial carcinoma is diagnosed and followed up after transurethral resection using a combination of cystoscopy, urine cytology and urine biomarkers at regular intervals. However, cystoscopy can overlook flat lesions like carcinoma in situ, and the sensitivity of urinary tests is poor in low‐grade tumors. There is an emergent need for an objective and easy urinary diagnostic test for the management of bladder cancer. In this study, three different modalities for 5‐aminolevulinic acid (ALA)‐based photodynamic diagnostic tests were used. We developed a compact‐size, desktop‐type device quantifying red fluorescence in cell suspensions, named “Cellular Fluorescence Analysis Unit” (CFAU). Urine samples from 58 patients with bladder cancer were centrifuged, and urine sediments were then treated with ALA. ALA‐treated sediments were subjected to three fluorescence detection assays, including the CFAU assay. The overall sensitivities of conventional cytology, BTA, NMP22, fluorescence cytology, fluorescent spectrophotometric assay and CFAU assay were 48%, 33%, 40%, 86%, 86% and 87%, respectively. Three different ALA‐based assays showed high sensitivity and specificity. The ALA‐based assay detected low‐grade and low‐stage bladder urothelial cells at shigher rate (68–80% sensitivity) than conventional urine cytology, BTA and NMP22 (8–20% sensitivity). Our findings demonstrate that the ALA‐based fluorescence detection assay is promising tool for the management of bladder cancer. Development of a rapid and automated device for ALA‐based photodynamic assay is necessary to avoid the variability induced by troublesome steps and low stability of specimens.     

Surveillance of urothelial carcinoma

BACKGROUND:

Previous investigators have detected shifts to lower stages at diagnosis for renal cell carcinoma and prostate cancer. The authors investigated whether a similar pattern is seen for urothelial carcinomas of the bladder, ureter, and renal pelvis and sought to identify changes in cancer grade and survival trends from 1993 to 2005.

METHODS:

The National Cancer Data Base (NCDB) collects data on approximately 75% of all newly diagnosed cancer cases annually. The authors queried the database for cases of urothelial carcinomas diagnosed in 1993‐2005 in patients aged 18 years and older. All cancer stage data were forward converted to the sixth edition of the American Joint Committee on Cancer staging definitions.

RESULTS:

A total of 334,480 bladder cancer cases, 15,105 renal pelvis cancer cases, and 10,128 ureteral carcinoma cases were identified. Stage data were available for 84% of bladder cases, 83% of renal pelvis cases, and 82% of ureter cases. With the classification of early stage tumors as stage 0a, 0is, and I and late stage tumors as II, III, and IV, the percentage of early stage renal pelvis and ureter tumors increased slightly from 1993 to 2005, whereas no stage migration was seen in bladder tumors. In looking specifically at early stage tumors, a significant increase in the proportion of stage 0a and a significant decrease in the proportion of stage I tumors for each cancer site was seen between 1993 and 2005. The proportion of high grade tumors in each disease site significantly increased from 1993 to 2005. For cases diagnosed in 1993‐1996 and 1997‐2000, a significant decrease in 5‐year relative survival was observed for patients with stage I and stage II bladder cancer. The absolute change, however, was relatively small, and for bladder cases was not significantly different when adjusted for low or high grade tumors.

CONCLUSIONS:

When differentiating between early and late stage tumors, a slight stage migration was seen in renal pelvis and ureteral carcinomas, whereas no stage migration was seen in bladder tumors. Within early stage tumors of all sites, a stage shift was seen, most notably with the proportion of stage 0a tumors increasing and stage I tumors decreasing. The proportion of high grade tumors in all sites increased. No change in overall survival was observed, underscoring the need for new therapeutic advances. Cancer 2009. © 2009 American Cancer Society.     

Detection and clinical outcome of urinary bladder cancer with 5-aminolevulinic acid-induced fluorescence cystoscopy : A multicenter randomized, double-blind, placebo-controlled trial

BACKGROUND:

The medical community lacks results from prospective controlled multicenter studies of the diagnostic efficacy of 5‐aminolevulinic acid (5‐ALA) cystoscopy on tumor recurrence in patients with superficial bladder tumors.

METHODS:

A prospective randomized, double‐blind, placebo‐controlled study was conducted in 370 patients with nonmuscle‐invasive urinary bladder carcinoma who received either 5‐ALA (n = 187) or a placebo (n = 183) intravesically before cystoscopy. Each group underwent cystoscopy under visible white light and under fluorescent light followed by transurethral tumor resection. The primary study objective was to evaluate the 12‐month recurrence‐free survival.

RESULTS:

Slightly more patients with tumors were detected by using 5‐ALA than by using the placebo (88.5% vs 84.7%). The mean numbers of tumor specimens per patient were 1.8 (5‐ALA) and 1.6 (placebo). Intrapatient comparison of fluorescent light versus white light cystoscopy in patients randomized to receive 5‐ALA showed a higher tumor detection rate with fluorescent light than with white light cystoscopy. In patients receiving 5‐ALA cystoscopy, the percentage of lesions that would not have been detected in these patients by white light cystoscopy ranged between 10.9% (pT1) and 55.9% (atypia). Progression‐free survival was 89.4% (5‐ALA) and 89.0% (placebo) (P = .9101), and recurrence‐free survival 12 months after tumor resection was 64.0% (5‐ALA) and 72.8% (placebo) (P = .2216).

CONCLUSIONS:

In comparison to the placebo, 5‐ALA cystoscopy did not increase the rates of recurrence‐free or progression‐free survival 12 months after tumor resection. Although more tumors per patient were detected in the 5‐ALA group, the higher detection rate did not translate into differences in long‐term outcome. Cancer 2011. © 2010 American Cancer Society.     

The value of the ImmunoCyt/uCyt+ test in the detection and follow-up of carcinoma in situ of the urinary bladder

BACKGROUND: Urine bound tests, which have been developed for the early detection of urothelial cancer (UC), do not seem to match cytology in the detection of carcinoma in situ (CIS) as their sensitivity in the case of CIS is poor. ImmunoCyt/uCyt+ in CIS seems promising, but the number of analysed CIS is still small. The aim of the present study was to assess the value of this test in the detection and follow-up of carcinoma in situ of the urinary bladder. PATIENTS AND METHODS: Thirty-five patients, with histologically verified CIS of the urinary bladder, were included in the study. At the first diagnosis, patients underwent cytology, cystoscopy, bioptical bladder mapping and ImmunoCyt/uCyt+. All patients underwent BCG instillation therapy. The patients were followed with cytology, ImmunoCyt/uCyt+, cystoscopy and bladder mapping after every BCG cycle and then every 3 months. RESULTS: At the first CIS diagnosis, the sensitivity of cytology and ImmunoCyt/uCyt+ was 100%. At the first control after therapy, cytology detected 81.8% of recurrences and ImmunoCyt/uCyt+ detected 90.9%. At the second control, both tests each detected 50% of recurrences. At every control, the combination of both the tests together gave a sensitivity of 100%. The specificity of cytology after therapy improved from 88.2% at the first control up to 100% at the third control. The specificity of ImmunoCyt/uCyt+ after BCG initially decreased from 70.6% to 55.5% and finally increased to 88.9%. CONCLUSION: ImmunoCyt/uCyt+ is as sensitive as cytology in the first diagnosis of CIS. In the follow-up, even if it is less sensitive, its combination with cytology leads to detection of 100% of the recurrences. Despite decreasing specificity after therapy, the value remains acceptable and increases during maintenance therapy. The ImmunoCyt/uCyt+ test could play an important role in controlling the response of patients to instillation therapies or in the modification of their application schedules.     

The Johns Hopkins Hospital template for urologic cytology samples

BACKGROUND:

Urine cytology represents a major portion of testing volume in many cytopathology laboratories.

METHODS:

The authors previously reported a template designed to standardize urothelial diagnostic categories to enable clinicians to uniformly manage their patients. In this study, they examined the common cytomorphologic features observed in specimens diagnosed with atypical urothelial cells, cannot exclude high‐grade urothelial carcinoma (AUC‐H), which prove most predictive of high‐grade urothelial carcinoma (HGUC).

RESULTS:

The most common morphologic features observed in the AUC‐H specimens were hyperchromasia, irregular nuclear borders, increased nucleus‐to‐cytoplasm ratio, and anisonucleosis. Of the 58 patients who had specimens diagnosed with AUC‐H, 95% ultimately were diagnosed with HGUC on follow‐up biopsy over the study period. The small number of patients who had AUC‐H with non‐HGUC follow‐up did not allow for a statistical comparison to determine the predictive ability of the selected criteria for HGUC. Next, the authors used the same features to examine a subset of urine samples that were diagnosed with atypical urothelial cells of unknown significance (AUC‐US) in an attempt to improve the predictive value of this clinically frustrating category. A blind review was performed of 290 urine specimens from 217 patients. In contrast to the AUC‐H specimen cohort, the majority of specimens with AUC‐US did not contain atypical cells with the 4 common morphologic features. All 4 features significantly predicted HGUC in surveillance patients, but not in patients with hematuria.

CONCLUSIONS:

Hyperchromasia was the strongest predictor of HGUC by far in patients who were undergoing surveillance (odds ratio, 9.81). Hyperchromasia remained statistically significant in multivariate analysis, indicating its predictive strength even in the absence of other features. Cancer (Cancer Cytopathol) 2013;121:21–28 © 2012 American Cancer Society.     

Carbonic anhydrase IX in bladder cancer

BACKGROUND:

The objective of this study was to evaluate the role of carbonic anhydrase IX (CAIX) in urothelial carcinoma of the bladder.

METHODS:

A tissue microarray was constructed that contained 724 tissue samples from 340 patients. Immunohistochemical staining was performed using the antibody MN‐75, the percentage of positive cells was evaluated, and their association with tumor (T) classification, grade, and survival was assessed.

RESULTS:

All normal urothelial tissue samples were negative for CAIX expression, whereas 71% of bladder cancers expressed CAIX. CAIX expression was higher in noninvasive (Ta) versus invasive (T1‐T4) tumors (P < .001), in low‐grade versus high‐grade bladder cancer (P < .001), and in metastases versus the corresponding primary tumor (P = .032). For patients with nonmuscle invasive carcinoma who underwent transurethral resection (TUR), higher CAIX expression was associated with poorer recurrence‐free survival (P = .001). In addition, for patients with T1 tumors who underwent TUR, higher CAIX expression conveyed a 6.5‐fold higher risk of progression into muscle‐invasive disease (P = .006). In patients who underwent cystectomy, higher CAIX expression was associated with worse overall survival (P = .003). Multivariate Cox models revealed that CAIX expression was the strongest, independent prognostic factor of recurrence‐free survival (hazard ratio, 2.29; P = .001) and overall survival (hazard ratio, 1.9; P < .001).

CONCLUSIONS:

CAIX was expressed differentially in noninvasive versus invasive tumors, in low‐grade versus high‐grade bladder cancer, and in primary tumors versus metastases. The current results indicated that CAIX is a strong predictor of recurrence, progression, and overall survival of patients with bladder cancer; and the integration of CAIX expression into conventional prognostic models significantly improved their predictive accuracy. The data suggest a tripartite role of CAIX as a diagnostic, prognostic, and therapeutic molecular marker in bladder cancer. Cancer 2009. © 2009 American Cancer Society.     

Compliance with guidelines for patients with bladder cancer: variation in the delivery of care

BACKGROUND:

Clinical practice guidelines for the management of patients with bladder cancer encompass strategies that minimize morbidity and improve survival. In the current study, the authors sought to characterize practice patterns in patients with high‐grade non–muscle‐invasive bladder cancer in relation to established guidelines.

METHODS:

Surveillance, Epidemiology and End Results (SEER)‐Medicare–linked data were used to identify subjects diagnosed with high‐grade non–muscle‐invasive bladder cancer between 1992 and 2002 who survived at least 2 years without undergoing definitive treatment (n = 4545). The authors used mixed‐effects modeling to estimate the association and partitioned variation of patient sociodemographic, tumor, and provider characteristics with compliance measures.

RESULTS:

Of the 4545 subjects analyzed, only 1 received all the recommended measures. Approximately 42% of physicians have not performed at least 1 cystoscopy, 1 cytology, and 1 instillation of immunotherapy for a single patient nested within their practice during the initial 2‐year period after diagnosis. After 1997, only use of radiographic imaging (odds ratio [OR], 1.19; 95% confidence interval [95% CI], 1.03‐1.37) and instillation of immunotherapy (OR, 1.67; 95% CI, 1.39‐2.01) were found to be significantly increased. Surgeon‐attributable variation for individual guideline measures (cystoscopy, 25%; cytology, 59%; radiographic imaging, 10%; intravesical chemotherapy, 45%; and intravesical immunotherapy, 26%) contributes to this low compliance rate.

CONCLUSIONS:

There is marked underuse of guideline‐recommended care in this potentially curable cohort. Unexplained provider‐level factors significantly contribute to this low compliance rate. Future studies that identify barriers and modulators of provider‐level adoption of guidelines are critical to improving care for patients with bladder cancer. Cancer 2011;. © 2011 American Cancer Society.     

Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis

BACKGROUND:

Several studies have demonstrated that abnormal levels of nuclear matrix protein 22 (NMP22) are associated with bladder cancer and have led to the approval of NMP22 as a urinary biomarker by the US Food and Drug Administration. Nonetheless, the clinical significance of NMP22 remains unclear. The objective of this study was to use decision analysis to determine whether NMP22 improves medical decision‐making.

METHODS:

The current study included 2222 patients who had a history of nonmuscle‐invasive bladder cancer and current negative cytology. The authors developed models to predict cancer recurrence or progression to muscle‐invasive disease using voided NMP22 levels, cystoscopy, age, and sex. Clinical net benefit was calculated by summing the benefits (true‐positives), subtracting the harms (false‐positives), and weighting these values by the threshold probability at which a patient or clinician would opt for cytoscopy.

RESULTS:

After cystoscopy, 581 patients (26%) had cancer identified. The NMP22 level was associated significantly with bladder cancer recurrence and progression (P < .001 for both). The use of NMP22 in a model with age and sex was associated with better patient outcomes than performing cystoscopy on everyone and produced threshold probabilities > 8% for recurrence and > 3% for progression. Only offering cystoscopy to those who had a risk > 15% reduced the number of cystoscopies by 229 while missing only 25 cancer recurrences per 1000 men with negative cytology. The current study was limited by its multicenter design.

CONCLUSIONS:

For clinicians who would perform a cystoscopy at a threshold of 5% for recurrence or 1% for progression, NMP22 did not aid clinical decision‐making. For less risk‐averse clinicians who would only perform a cystoscopy at a threshold probability >thinsp;8% for recurrence or > 3% for progression, NMP22 helped to indicate which patients required cystoscopy and which could be spared this procedure. Cancer 2011. © 2011 American Cancer Society.     

Diagnostic significance of ‘atypia’ in instrumented versus voided urine specimens

BACKGROUND.

Urine cytology plays an important role in monitoring patients with a history of urothelial carcinoma. Because it is difficult to reliably discriminate artifacts induced by instrumentation, inflammation, or therapy those of from malignant cells, many of these specimens are categorized as atypical. The objective of the current study was to study the prevalence and significance of atypical urine cytology with regard to the effect of instrumentation and prior biopsy.

METHODS.

All urine cytology cases seen during a 4‐year period (2001‐2004) with a diagnosis of atypical urothelial cells (AU) were obtained from the cytopathology computer database. In all cases with available surgical follow‐up, the following data were extracted: total number and type of urine specimen, the primary histologic diagnosis, and follow‐up histologic diagnosis.

RESULTS.

In all, 1653 voided and 3502 instrumented urine specimens were examined. A diagnosis of AU was rendered in 115 (6.9%) of the voided urine specimens and in 277 (7.9%) of the instrumented specimens. Follow‐up histology was available in 70 cases, including 55 instrumented and 15 voided urine specimens. A nonbenign follow‐up diagnosis was observed in 18 of 55 (32.7%) cases in the instrumented group and in 7 of 15 (46.6%) cases in the voided group. Voided urine was marginally associated with a worse subsequent biopsy diagnosis (Pexact Monte Carlo = .09)

CONCLUSIONS.

An AU diagnosis is more predictive of a subsequent adverse biopsy diagnosis in voided urine specimens compared with instrumented urines. In the absence of a benchmark for the atypia rate, it is prudent to keep the atypia rate low to keep it more meaningful. This important category should be used by the pathologist to convey concern and recognize the difficulty in interpretation of specimens that may require close follow‐up. Cancer (Cancer Cytopathol) 2008. © 2008 American Cancer Society.     

Comparison of American Joint Committee on Cancer pathologic stage T3a versus T3b urothelial carcinoma: Analysis of patient outcomes

BACKGROUND:

The radical cystectomy experience at Vanderbilt University Medical Center was scrutinized to determine whether there was a difference in survival between patients with lymph node‐negative pathologic T3a versus pathologic T3b urothelial carcinoma of the bladder.

METHODS:

Pathologic and clinical data were reviewed on patients who underwent radical cystectomy for urothelial carcinoma between 1995 and 2005. We excluded patients with nontransitional cell cancer, lymph node disease, or with unknown lymph node status. Of the 790 reviewed patients, 75 patients (9.4%) were diagnosed with pathologic T3 urothelial cancer of the bladder. The impact of pathologic substaging (pT3a vs pT3b) was examined to determine the effect on overall, disease‐specific, and recurrence‐free survival.

RESULTS:

The mean age was 68.6 years (36 years to 83 years). Median overall follow‐up was 25.3 months (1.13 months to 130.17 months). Median follow‐up for patients alive at last follow‐up was 55.9 months (25.3 months to 130.2 months). Actuarial overall survival at 5 years was 29.5% for pT3a and 29.3% for pT3b (P = .79). Actuarial disease‐specific survival at 5 years was 54.1% for pT3a and 42.4% for pT3b (P = .21). Actuarial recurrence‐free survival at 5 years was 68.1% for pT3a and 71.9% for pT3b (P = .53).

CONCLUSIONS:

There were no significant differences in overall, disease‐specific, or recurrence‐free survival when comparing lymph node‐negative pT3a versus pT3b urothelial cancer of the bladder following radical cystectomy. Simplification of pathologic staging for urothelial carcinoma of the bladder should be considered at future revisions of the American Joint Committee on Cancer staging system. Cancer 2009. © 2009 American Cancer Society.