Papillary Urothelial Neoplasm Research Articles

Multicenter Validation of Cyclin D1, MCM7, TRIM29, and UBE2C as Prognostic Protein Markers in Non-Muscle–Invasive Bladder Cancer

Transcripts from the four genes encoding cyclin D1, MCM7, TRIM29, and UBE2C have previously been included in gene expression signatures for outcome prediction in stage Ta/T1 urothelial carcinomas. We investigated the prognostic value of the protein expressions in Ta/T1 urothelial carcinomas patients. We used four different tissue microarrays (TMAs) with a total of 859 Ta/T1 urothelial carcinomas from Danish, Swedish, Spanish, and Taiwanese patient cohorts with long-term follow-up. Protein expression was measured by IHC, and antibody specificity was validated by Western blotting. We found the expression of cyclin D1, MCM7, TRIM29, and UBE2C to be significantly associated with progression to muscle-invasive bladder cancer (log-rank test; P < 0.001) in the Danish training cohort (n = 283). Multivariate Cox regression analysis identified cyclin D1 (P = 0.003), TRIM29 (P = 0.001), and UBE2C (P < 0.001) as independent prognostic markers. The prognostic value of the four proteins was validated in a joint validation cohort from Sweden, Spain, and Taiwan (n = 576). Computer-assisted image analysis of the prognostic markers produced results comparable to those obtained by manual scoring. Finally, a four-protein maximum-likelihood classifier was trained on the Danish training cohort and applied to the validation cohort. The four protein markers may help optimize treatment of patients with Ta/T1 bladder cancer. Additional prospective studies are needed for further validation of their clinical relevance.

Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium

Changes in the expression of the mismatch repair (MMR) genes hMSH2, hMLH1, hMSH6 and hPMS2 reflect dysfunction of the DNA repair system that may allow the malignant transformation of tissue cells. The aim of the present study was to address the mRNA expression profiles of the mismatch DNA repair system in cancerous and precancerous urothelium. This is the first study to quantify MMR mRNA expression by applying quantitative real-time PCR (qPCR) and translate the results to mRNA phenotypic profiles (r, reduced; R, regular or elevated) in bladder tumors [24 urothelial cell carcinomas (UCCs) and 1 papillary urothelial neoplasm of low malignant potential (PUNLMP)] paired with their adjacent normal tissues (ANTs). Genetic instability analysis was applied at polymorphic sites distal or close to the hMSH2 and hMLH1 locus. Presenting our data, reduced hMSH2, hMSH6 and hPMS2 mRNA expression profiles were observed in cancerous and precancerous urothelia. Significantly, the ANTs of UCCs revealed the highest percentages of reduced hMSH2 (r(2)), hMSH6 (r(6)) and hPMS2 (p(2)) mRNA phenotypes relative to their tumors (P<0.03). In particular, combined r(2)r(6) (P<0.02) presented a greater difference between ANTs of low-grade UCCs vs. their tumors compared with ANTs of high-grade UCCs (P= 0.000). Reduced hMLH1 (r(1)) phenotype was not expressed in precancerous or cancerous urothelia. The hMSH6 mRNA was the most changed in UCCs (47.8%), while hMSH2, hMLH1 and hPMS2 showed overexpression (47.8, 35 and 30%, respectively) that was associated with gender and histological tumor grading or staging. Genetic instability was rare in polymorphic regions distal to hMLH1. Our data reveal a previously unrecognized hMSH2 and hMSH6 mRNA combined phenotype (r(2)r(6)) correlated with a precancerous urothelium and show that hMLH1 is transcriptionally activated in precancerous or cancerous urothelium. In the present study, it is demonstrated that reduction of hMSH6 mRNA is a frequent event in bladder tumorigenesis and reflects a common mechanism of suppression with hMSH2, while alterations of hMSH2 or hMLH1 mRNA expression in UCCs does not correlate with the allelic imbalance of polymorphic regions harboring the genes.

Her2 amplification distinguishes a subset of non-muscle-invasive bladder cancers with a high risk of progression

BackgroundSeveral studies have employed immunohistochemistry to detect Her2/neu overexpression in urothelial carcinomas, yielding a tremendous range of positive expression rates. Few studies have examined Her2 status in non-muscle invasive bladder...

The 1973 WHO Classification Is More Suitable than the 2004 WHO Classification for Predicting Prognosis in Non-Muscle-Invasive Bladder Cancer

BackgroundPredicting the recurrence and progression of Non-muscle-invasive bladder cancer(NMIBC) is critical for urologist. Histological grade provides significant prognostic information, especially for prediction of progression. Currently, the 1973 and the 2004 WHO classification co-exist. Which system is better for predicting rumor recurrence and progression still a matter for debate.Methodology/Principal Findings348 patients diagnosed with Non-muscle invasive bladder cancer were enrolled in our retrospective study. Paraffin sections were assessed by an experienced urological pathologist according to both the 1973 and 2004 WHO classifications. Tumor recurrence and progression was followed-up in all patients. During follow-up, corresponding 5-year recurrence-free survival rates of G1, G2 and G3 were 82.1%, 55.9%, 32.1% and the 5-year progression-free survival rates were 95.9%, 84.4% and 43.3%, respectively. The 5-year recurrence-free survival rates of papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade papillary urothelial carcinoma(LGPUC) and high-grade papillary urothelial carcinoma (HGPUC) were 69.8%, 67.1% and 42.0% respectively and the 5-year progression-free survival rates were 100%, 90.9% and 54.8% respectively. In multivariate analysis, the 1973 WHO classification significantly associated with both tumor recurrence and progression(p = 0.010 and p = 0.022, respectively); the 2004 WHO classification correlated with tumor progression(p = 0.019), while was not proved to be a variable that can predict the risk of recurrence(p = 0.547). Kaplan-Meier plots showed that both the 1973 WHO and the 2004 WHO classifications were significantly associated with progression-free survival (p<0.0001, log-rank test). For prediction of recurrence, significant differences were observed between the tumor grades classified using the 1973 WHO grading system (p<0.0001, log-rank test), while a significant overlap was observed between PUNLMP and LG plots using the 2004 WHO grading system(p = 0.616, log-rank test).Conclusion/SignificanceBoth the 1973 WHO and the 2004 WHO Classifications are effective in predicting tumor progression in Non-muscle invasive bladder cancer, while the 1973 WHO Classification is more suitable for predicting tumor recurrence.

Pulmonary Carcinoid and Papillary Urothelial Neoplasm in a Patient with Crohnʼs Disease

Pulmonary Carcinoid and Papillary Urothelial Neoplasm in a Patient with Crohnʼs Disease

Neoplasias uroteliais papilíferas superficiais da bexiga (pTa e pT1): correlação da expressão do p53, KI-67 E CK20 com grau histológico, recidiva e progressão tumoral

To investigate the immunohistochemical expressions of p53, ki67, CK20 in superficial papillary urothelial neoplasms of the bladder and correlate them with histological grade, tumor progression and recurrence. We selected samples of 43 patients with superficial transitional cell carcinoma of the bladder. They were divided into two groups, one called Recurrent (R), with 18 individuals, and other Non-Recurrent (NR), with 25. Multi-sampling blocks were prepared. The immunohistochemical technique employed was immunoperoxidase, and the antibodies were: p53: Novocastra (clone DO7) at a dilution of 1/100; Ki67: Spring (clone SP6) at a dilution of 1/100; and CK20: Dako (clone K20 .8) at a dilution of 1/50. The expression of p53 was observed in 11 cases, six in the Recurrent group and five in the Non-Recurrent, all high-grade tumors (p = 0.0001). The histological progression occurred in six patients (p = 0.0076). Of the 18 Recurrent cases, six showed immunoreactivity for p53 and 12 were negative for this antibody (p = 0.1715). Ki67 was positive in 17 of the 18 cases from the Recurrent group (p = 0.0001) and, from 20 high-grade tumors, 18 showed reaction to this antibody (p = 0.0001). Of the 18 individuals who had recurrence, 13 showed anomalous expression for CK20 (p = 0.0166). In high-grade carcinomas, of the 20 cases, 16 showed anomalous expression for this antibody, while 18 of the 23 patients with low-grade tumors showed normal expression for CK20 (p = 0.0002). The p53 showed good correlation with histological progression and histologic grade. Ki67 was strongly associated with recurrence and histological grade, and CK20 was also associated with these variables.

Hexaminolevulinate-induced Fluorescence versus White Light During Transurethral Resection of Noninvasive Bladder Tumor: Does It Reduce Recurrences?

To evaluate the effect of hexaminolevulinate (HAL)-induced fluorescence during resection of noninvasive bladder cancer on tumor recurrence compared with resection under white light. Between 2008 and 2010, 102 consecutive patients with suspected bladder cancer were randomized to undergo transurethral resection with either conventional white light or combination of white light and HAL-induced fluorescence. Difference in tumor recurrence rate and recurrence-free survival between the 2 groups was evaluated. Subgroup analysis on recurrence-free survival was performed for different tumor parameters. Cystoscopy at 3 months revealed tumor recurrence in 6 of 45 (13.3%) patients of the white light group compared with only 1 of 41 patients of the HAL group (2.4%) (P < .001). The recurrence-free rates in white light patients at 12 and 18 months were 56.3% and 50.6%, respectively, compared with 91% and 82.5% in HAL patients (P = .0006). In subgroup analyses, recurrence-free survival was similar between the 2 groups when solitary tumors were treated (P = .3525). However, the HAL group had a favorable recurrence-free survival compared with the white light group when multifocal tumors (P < .001), primary tumors (P = .0237), recurrent tumors (P = .0189), nonaggressive (papillary urothelial neoplasm of low malignant potential and low grade) tumors (P = .0204), or aggressive (high grade and carcinoma in situ) tumors (P = .0134) were treated. HAL significantly aids resection of non-muscle-invasive bladder cancer with the result of reduction in tumor recurrence rates.

Urothelial Tumors of the Urinary Bladder in Manipur: A Histopathological Perspective

To study the histomorphological pattern of urothelial tumors of the urinary bladder in Manipur and to evaluate whether any correlation exists between tumor grade and muscle invasion. A 10 year retrospective study of all consecutive cases diagnosed in the Department of Pathology RIMS - Imphal, between 1st January 2001 to 31st December 2010. The study included 26 cases of transitional cell tumors of urinary bladder. The male to female ratio was 1.5: 1 and the ages ranged from 38 years to 73 years (medians of 60 and 64 years, respectively). Of the total, 14 (53.9%) cases were low grade, 9 (34.6%) were high grade, 2 (7.7%) were papillomas and 1 (3.9%) was a papillary urothelial neoplasm of low malignant potential (PUNLMP). Pathological staging showed that 14 (53.9%) of the cases were stage PTa, four (15.4%) PT1, and eight (30.9%) PT2. Some 18.2% of low grade tumors and 75% of high grade tumors were invasive to the detrusor muscle layer. Bladder cancer is an uncommon disease, transitional tumors being the only histological type observed. It was more common in males than females, with peak incidence in seventh decade. Most of the tumors were non- invasive (PTa) and invasion to the detrusor muscle layer was seen in more than half of the high grade tumors. There is a definite correlation between advancing tumor grade and muscle invasion.

Histologic grading of urothelial carcinoma: a reappraisal

A uniform grading system for bladder cancer will allow for valid comparison of treatment results among different centers. The introduction of the World Health Organization (2004)/International Society of Urological Pathology classification is a welcome step toward standardization of treatment and follow-up regimens. The greatest source of controversy with the World Health Organization (2004)/International Society of Urological Pathology classification system centers on the diagnosis of papillary urothelial neoplasm of low malignant potential. Some feel that papillary urothelial neoplasm of low malignant potential terminology increases the complexity of histologic grading and does not accurately reflect biologic potential. Papillary urothelial neoplasm of low malignant potential is a low-grade papillary urothelial neoplasm with a substantial incidence of recurrence and progression. In the distinction of papillary urothelial neoplasm of low malignant potential from noninvasive low-grade papillary urothelial carcinoma, there is considerable interobserver variability. For these reasons, some investigators believe that papillary urothelial neoplasm of low malignant potential is, in essence, an entity that was previously designated grade 1 urothelial carcinoma in the World Health Organization 1973 grading system. In addition, treatment and follow-up regimens for patients with papillary urothelial neoplasm of low malignant potential do not typically differ from those prescribed for low-grade, noninvasive urothelial carcinoma, further minimizing the clinical need for the papillary urothelial neoplasm of low malignant potential distinction to be made. We propose abandonment of the terminology "papillary urothelial neoplasm of low malignant potential" in bladder tumor classification. Full-genome searches for prognostic and predictive molecular gene expression signatures as cancer markers have shown significant promise. Recent advances in the molecular grading of these tumors may eventually supplant traditional morphologic grading systems, allowing a more precise and objective assessment of the tumors' biologic potentials.

Prognostic Significance in Substaging of T1 Urinary Bladder Urothelial Carcinoma on Transurethral Resection

T1 papillary urothelial carcinomas of the urinary bladder run a variable clinical course, and an effective substaging system has not been defined yet. This study was conducted to devise an easy-to-use substaging method and to validate its prognostic value in T1 cancer on transurethral resection specimens. A total of 103 cases of T1 low-grade papillary urothelial carcinoma and 406 cases of T1 high-grade papillary urothelial carcinoma from a series of 1515 non-muscle-invasive bladder tumors treated by transurethral resection were studied. Substaging was performed using 0.5, 1.0, and 1.5 mm as thresholds to distinguish extensive from focal invasion. Correlations to recurrence, progression, cancer-specific mortality, and all-cause mortality were explored and compared with Ta tumors. All lamina propria invasions in low-grade papillary urothelial carcinomas were confined to 1.0 mm. The proportions of T1 high-grade papillary urothelial carcinoma invading beyond 0.5, 1.0 (T1>1 mm), and 1.5 mm were 53%, 32%, and 27%, respectively. No prognostic differences were found between Ta and T1 low-grade papillary urothelial carcinomas. T1>1 mm high-grade papillary urothelial carcinomas were associated with significantly greater risks for recurrence, progression, cancer-specific mortality, and all-cause mortality compared with T1≤1 mm and Ta tumors. Comparable statistical results could be obtained using 0.5 and 1.5 mm as cutoff points, but we recommend using 1.0 mm for practical consideration. Taking all non-muscle-invasive urothelial neoplasms of the bladder into consideration, 5 prognostically distinct categories can be established: (1) papillary urothelial neoplasms of low malignant potential; (2) low-grade papillary urothelial carcinoma Ta/1; (3) high-grade papillary urothelial carcinoma Ta; (4) high-grade papillary urothelial carcinoma T1≤1 mm; and (5) high-grade papillary urothelial carcinoma T1>1 mm. Our study demonstrates that the substaging of T1 bladder cancer is feasible, based on the evaluation of transurethral resection specimens, and can provide more precise prognostic information to identify a subset of patients with a more unfavorable prognosis.

Nuclear matrix protein‐22: a prospective evaluation in a population at risk for bladder cancer. Results from the UroScreen study

What's known on the subject? and What does the study add? The prognosis of bladder cancer significantly depends on tumour stage and time of diagnosis so early diagnosis is desirable to decrease mortality and treatment costs. The NMP22 test is approved for clinical application by the Food and Drug Administration (FDA) of the US. Previous studies have reported values of 47-100% for sensitivity and 58-91% for specificity with this test, but there is no new data on the predictive value of NMP22 for screening bladder cancer (BC). The most important risk factor for BC is the tobacco consumption but occupational exposure to carcinogenic substances, especially aromatic amines, is regarded as another risk factor. The UroScreen study is a prospective longitudinal study for the early detection of BC. To our knowledge, it is the largest prospective validation study conducted over the longest period of time. The study results led us to conclude that, based on the currently available data, NMP22 should not be regarded as an alternative to endoscopy, and we could not make a general recommendation for screening or follow-up. The UroScreen results indicate that urine-based molecular markers could be a suitable addition to urine cytology and the detection of microhaematuria. To evaluate the value of nuclear matrix protein-22 (NMP22) in bladder cancer (BC) screening, and its effect on variables in a prospective study in a high-risk population. A total of 1772 chemical workers (mean age 62 years) exposed to carcinogenic aromatic amines were enrolled in the study. In all, 7091 screening check-ups in 1609 subjects were performed. Urine samples were collected for a quantitative NMP22 immunoassay, urine analysis and creatinine concentration assessment. Cystoscopy and subsequent transurethral resection were performed where there were suspicious findings. Histopathological analysis found three papillary urothelial neoplasms of low malignant potential, five recurrent BCs and 13 primary BCs. Three tumours were at a muscle-invasive stage (pT2, pT3a or pT3b). We found higher NMP22 concentrations (>10 U/mL) in 224 patients, which correctly predicted BC in six cases (sensitivity 97.29%, specificity 28.57%; negative predictive value 99.04%, positive predictive value 12.24%). Gross haematuria affected NMP22 results (odd ratio [OR] 3.49, 95% confidence interval [CI] 1.81-6.73). Infection also affected NMP22 results (OR 4.13, 95% CI 2.31-7.35). NMP22 was more frequently positive in urine with creatinine concentration >2.5 g/L (OR 1.61, 95% CI 0.91-2.86). NMP22 outcomes are affected by haematuria, infection and concentrated urine. NMP22 alone cannot be recommended for primary screening in a high-risk population nor as an alternative to cystoscopy during follow-up. A NMP22 test might be a useful adjunct to urine cytology.

BLCA-4 expression is related to MMP-9, VEGF, IL-1α and IL-8 in bladder cancer but not to PEDF, TNF-α or angiogenesis

AimBLCA-4 is a specific nuclear matrix protein found in bladder cancer and there is a dearth of study on functional analysis upon this factor. We aimed to discover whether BLCA-4 is related to angiogenesis in bladder cancer. MethodsFifty-three bladder cancer samples were included for immunohistochemical staining of BLCA-4, matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), interleukin-1α (IL-1α), IL-8, pigment epithelium-derived factor (PEDF), tumour necrosis factor-α (TNF-α) and von Willebrand factor (vWF) for microvessel density (MVD). Expressional levels were scored and grouped by clinicopathological parametres for statistical analysis for correlations. ResultsPositive correlations were identified between expression of BLCA-4 and IL-1α (p=0.038), IL-8 (p=0.001), VEGF (p=0.002), and MMP-9 (p=0.013). No correlation was found for PEDF (p=0.182), TNF-α (p=0.531) or MVD (p=0.932). Positive correlations were also obtained in cases of advanced grade or stage, larger, recurrent and multiple tumours. Positive correlation between BLCA-4 and MMP-9 was also found in papillary urothelial neoplasm of low malignant potential (PUNLMP). ConclusionBLCA-4 may not effect pro-angiogenic pathways in bladder cancer, it can however interact with IL-1α, IL-8, VEGF and MMP-9 to enhance tumourigenesis and tumour invasiveness.

Significance of tyrosine kinase receptor gene and its variant expressions in bladder tumor tissues

Objectives To explore the clinical significance of tyrosine kinase receptor RON mRNA expression and it's splicing variant in bladder tumors. Methods Sixty-three cases of transitional cell carcinoma of the bladder (TCCB), including 30 cases of pathological grade I , 15 cases of pathological grade Ⅱ and 18 cases of pathological grade Ⅲ (44 cases of clinical stage Tis + T1, 15 cases of T2 + T3 +T4), 7 inverted papilloma of the bladder ( IPB), 9 cases of papillary urothelial neoplasm of low malignant potential (PUNLMP) and 12 cases of normalbladder mucosa RT-PCR was employed with the internal standard (GAPDHmRNA) to detect the expression of RON mRNA. PCR and direct sequencing was then utilized to identify the potential RON mRNA splicing variants. Finally, the variants' positive rates of expression were analyzed among the different tissues, diverse TCCB pathological grades and clinical stages. Results The expression levels of RON mRNA/GAPDH mRNA among TCCB, IPB, PUNLMP and normal control were 4. 9 × 10-3 ( 1. 8 × 10-3-1.0 × 10-2 ), 3. 8 × 10-3 (2. 4 × 10-3-1.7 × 10-2 ), 4. 9 ×10 -3 ( 1.7 × 10 -3-1.1 × 10 -2 ) and 1.0 × 10-3 (4. 5 × 10-4-2. 8 × 10-3 ) respectively. The difference had a statistical significance (x2K-W = 17. 278 ,P ＜0. 05 ). The expression levels among pathological grade I, Ⅱ and Ⅲ were 3.7 × 10-3( 1.3 × 10-3-7.5 × 10-3) , 4. 9 × 10-3(1.9 × 10-3-1.1 × 10-2) and 8.9 × 10-3(2. 7 ×10 -3-8.0 × 10 -2 ) respectively. The erpression levels among the clinical stage Tis + T1 and T2 + T3 + T4were 3.5 × 10-3 ( 1.2 × 10 -3-7. 7 × 10-3 ) and 9. 7 × 10 -3 ( 2. 9 × 10-3-5. 3 × 10-2 ). The differences between expression levels were of statistical significance among the different pathological grades ( x2k-W =7. 341, P ＜0. 05 ) and clinical stages ( Z = - 2. 306, P ＜ 0. 05 ). The positive rates of exon 11deletion(E11△) in TCCB, IPB and PUNLMP were 71％ (45/63), 57％ (4/7) and 67％ (6/9) respectively, andthe total positive rate in bladder tumor tissues was 70％. Meanwhile, expression of the novel RON variant wesnot detected in the normalbladder mucosa. The positive expression rate of E1 1△ has no significant correlationamong the different clinical pathological tissues (x2 = 0. 620, P ＞ 0. 05 ). There was no statistical significancein expression positive rate between different pathological grades ( Z =0. 221, P ＞0. 05 ) and clinical stages( Z = 0. 538, P ＞ 0. 05) as well. A novel RON splice variant, deletion of RON exon 11 3 476 - 3 539 ( E3476 -3539△) was fond in the pathological tissue. The positive expression rates of E3 476 -3 539 in TCCB,IPB and PUNLMP were 57％ (36/63), 43％ (3/7) and 56％ (5/9) respectively, and the total positive expression rate was 56％ (44/79). The positive rates of E3 476 -3 539△ in pathological grade I , Ⅱ and Ⅲ were 40％ ( 12/30), 67％ (10/15) and 78％ (14/18), and it's positive rates in clinical stage Tis +T1and T2 +T3 + T4 were 48％ (21/44) and 80％ (12/15). The differences in each group had significantly statistical significance ( Z = 7. 285, 5. 041, P ＜ 0. 05 ) . However, the positive rates amongdifferent pathological tissues had no significance (x2 = 0. 517, P ＞ 0. 05 ). Conclusions The expression level of RON mRNA is significantly associated with histological grading and clinical stage. RON may play an important role in the progression ofTCCB. Compared with the normal control, the increased RON variant expression may contribute to the carcinogenesis of the bladder tumor. Key words: Urinary bladder neoplasms; Receptor protein-tyrosine kinases; Alternative splicing

UP-01.063 Outcome of Patients Affected by Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP): Single Centre Cohort

The present study evaluates behavior of de-novo primary bladder PUNLMP lesions (Primary-PUNLMP) and Surveillance-PUNLMP, diagnosed during follow-up of a higher grade urothelial neoplasm.

Expression of Claudins and Their Prognostic Significance in Noninvasive Urothelial Neoplasms of the Human Urinary Bladder

The members of the claudin family are major integral transmembrane protein constituents of tight junctions. Normal and neoplastic tissues can be characterized by unique qualitative and quantitative distribution of claudin subtypes, which may be related to clinicopathological features. Differential diagnosis and prognosis of nonmuscle invasive tumor entities of urinary bladder epithelium are often challenging. The aim was to investigate the expression profile of claudins in inverted urothelial papillomas (IUPs), urothelial papillomas (UPs), papillary urothelial neoplasms of low malignant potential (PUNLMPs), and intraepithelial (Ta), low-grade urothelial cell carcinomas (LG-UCCs) in order to reveal potential prognostic and differential diagnostic values of certain claudins. Claudin-1, -2, -4, and -7 protein expressions detected by immunohistochemistry and clinical data were analyzed in 15 IUPs, 20 UPs, 20 PUNLMPs, and 20 LG-UCCs. UPs, PUNLMPs, and LG-UCCs showed significantly decreased claudin-1 expression in comparison to IUPs. LG-UCCs expressing claudin-4 over the median were associated with significantly shorter recurrence-free survival. PUNLMPs expressing claudin-1 over the median revealed significantly longer recurrence-free survival. High claudin-1 protein expression might help to differentiate IUP from UPs, PUNLMPs, and LG-UCCs. High claudin-4 expression may determine an unfavorable clinical course of LG-UCCs, while high claudin-1 expression in PUNLMP was associated with markedly better clinical outcome.

Papillary urothelial neoplasm of low malignant potential of the urinary bladder: clinicopathologic and outcome analysis from a single academic center

Few long-term single-center studies have addressed the outcome of patients with papillary urothelial neoplasms of low malignant potential. Our study evaluates the behavior of these tumors occurring as primary urinary bladder lesions. For this purpose, 34 primary in-house cases diagnosed and treated between 1998 and 2008 were identified from our medical records. Upon review, 3 cases were upgraded to noninvasive low-grade urothelial carcinomas and excluded from further evaluation. During follow-up (range, 3-108 months; mean, 42 months), 13 patients developed recurrences; and 9 patients progressed to a noninvasive higher grade lesion (8 to low-grade and 1 to high-grade urothelial carcinomas). None of our patients developed stage progression (>pTa) or died of bladder cancer. Size of the primary tumor was associated with the risk of recurrence (P = .043), whereas the number of episodes of recurrence was associated with the likelihood of grade progression (P = .034). In conclusion, recurrences were observed in 42% of all our patients, with a grade progression rate of 29%. None of our patients developed invasive carcinoma or died as a consequence of their disease. Considering the low but definitive risk of recurrence and grade progression, appropriate clinical follow-up of patients with primary papillary urothelial neoplasm of low malignant potential is warranted.

Histologic grading of urothelial papillary neoplasms: impact of combined grading (two-numbered grading system) on reproducibility

The clinical management of tumor patients is often strongly influenced by the tumor grade. The presence of heterogeneity is well recognized in a variety of tumors. Overall grade is based on highest grade area identified within a tumor. Urothelial carcinoma often contains different histological grades within the same tumor. This study investigates the impact of a combined grading system on the reproducibility of papillary urothelial neoplasms. A set prepared for an earlier study consisting of ten cases of each category (papillary urothelial neoplasm of low malignant potential (PUNLMP), LGPUC, and HGPUC) was used. Agreement between pairs of pathologists was evaluated using κ statistics for the combined scoring system. Interobserver agreement was fair to substantial as reflected by κ values ranging from 0.24 to 0.74 (mean κ = 0.43). The combined scores of 2 and 3 which included PUNLMP showed the lowest degree of agreement and when this category was excluded from the analysis, interobserver agreement increased significantly (mean κ = 0.65; ranging from 0.43 to 0.92) in terms of combined scores of 4, 5, and 6. PUNLMP has been shown to be the least reproducible component of a combined scoring system even among experienced observers. Exclusion of PUNLMP from grading scheme seems to improve interobserver variability.

1753 RECURRENCE AND PROGRESSION RATES OF UROTHELIAL PAPILLOMAS OF THE URINARY BLADDER

You have accessJournal of UrologyBladder Cancer: Superficial1 Apr 20111753 RECURRENCE AND PROGRESSION RATES OF UROTHELIAL PAPILLOMAS OF THE URINARY BLADDER Ali Amin, Sheila Faraj, Alcides Chaux, Turki Al-hussain, Roni Cox, Michael Nagar, and George J. Netto Ali AminAli Amin Baltimore, MD More articles by this author , Sheila FarajSheila Faraj Baltimore, MD More articles by this author , Alcides ChauxAlcides Chaux Baltimore, MD More articles by this author , Turki Al-hussainTurki Al-hussain Baltimore, MD More articles by this author , Roni CoxRoni Cox Baltimore, MD More articles by this author , Michael NagarMichael Nagar Baltimore, MD More articles by this author , and George J. NettoGeorge J. Netto Baltimore, MD More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.2080AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Urothelial papilloma (UP) is a rare tumor of the genitourinary tract, usually seen in younger patients as an isolated, small papillary lesion. A recurrence rate of 0–31% and a lower than 10% risk of progression have been previously reported in UP. The aim of this study is to evaluate the clinical outcome of patients with UP diagnosed in one institution. This is, to the best of our knowledge, the largest series on the long term follow up of urothelial papilloma. METHODS Fifty-three cases diagnosed between 1998 and 2009 as primary UP (without previous history of a higher grade lesion) were retrieved from the archives of our department. Medical records were reviewed and the primary care physician was contacted for follow-up information. Recurrence was defined as the subsequent development of any type of neoplastic urothelial lesion while progression was defined as the development of subsequent lesion of higher histological grade (urothelial dysplasia, papillary urothelial neoplasm of low malignant potential [PUNLMP], low or high-grade papillary urothelial carcinoma). Follow-up ranged from 1–60 months (mean 16.6, median 12 months). RESULTS The mean of age for the patients was 67.4 y (range 24–90 years). Overall recurrence was identified in 19 cases (35%); recurrence without progression was observed in 2 cases (3.7%) after a mean duration of 22.0 months (range 5–39 months), and recurrence with progression in 17 cases (32%) after a mean duration of 11.6 months (range 1–34 months) from initial UP diagnosis. The difference between the mean intervals of recurrence with and without progression was not statistically significant. None of the patients developed invasive urothelial carcinoma. Most frequent progression was to low-grade urothelial carcinoma in 7 cases (13%) followed by high-grade urothelial carcinoma (4 cases, 7%), urothelial dysplasia and PUNLMP (3 cases each, 5%). None of the 53 patients died of urothelial carcinoma; however seven patients died from unrelated causes. CONCLUSIONS Although none of our patients developed invasive urothelial carcinoma or died of urothelial carcinoma, we found a relatively high rate of recurrence and progression in our UP cohort compared to previous series. Additional studies are still needed to evaluate the current risk of recurrence and progression in urothelial papillomas. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e703 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ali Amin Baltimore, MD More articles by this author Sheila Faraj Baltimore, MD More articles by this author Alcides Chaux Baltimore, MD More articles by this author Turki Al-hussain Baltimore, MD More articles by this author Roni Cox Baltimore, MD More articles by this author Michael Nagar Baltimore, MD More articles by this author George J. Netto Baltimore, MD More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Expression of pigment epithelium-derived factor and tumor necrosis factor-α is correlated in bladder tumor and is related to tumor angiogenesis

ObjectiveAngiogenesis is a pivotal process on which solid tumor growth is substantially dependent. Pigment epithelium-derived factor (PEDF) is the most potent natural anti-angiogenic factor, which has seldom been studied in bladder tumor, and whose functioning pathway remains unclear. We have thus investigated PEDF expression in relation to tumor necrosis factor-α (TNF-α) and microvessel density (MVD) with immunohistochemistry. MethodsAntibodies of PEDF and TNF-α were examined by Western blotting before immunohistochemistry. Sixty-four urothelial tumor sections and 23 normal controls were stained and expression of PEDF, TNF-α, and MVD were studied. ResultsDecreased PEDF expression and increased TNF-α expression was noticed in tumorous tissue compared with healthy urothelium. Lower PEDF expression was related to higher tumor grade but stage. Increased TNF-α expression was noticed in recurrent, larger tumors as well as in tumors with progression in grade and stage. Expression of PEDF and TNF-α was correlated in bladder tumor. PEDF or TNF-α was correlated with MVD negatively or positively, respectively, in cancerous tissue and tumorous grouping without correlation in papillary urothelial neoplasm of low malignant potential. ConclusionExpressional change of PEDF and TNF-α is in relation to angiogenesis of bladder tumor, especially in bladder cancer development.

Expression of pigment epithelium-derived factor in bladder tumour is correlated with interleukin-8 yet not with interleukin-1α

Pigment epithelium-derived factor (PEDF) is an antiangiogenic factor which is effective in tumour inhibition in a variety of tumours and has not yet been studied in bladder tumour before. In this study the expression of PEDF, interleukin-1α (IL-1α) and -8 (IL-8) in bladder tumours was investigated. Immunohistochemistry was performed on 64 bladder tumour and 23 normal uroepithelium samples. Expression change of the factors was compared with clinicopathological parameters. Correlations between PEDF, IL-1α and IL-8 were analyzed. None of the factors was in relation to gender, tumour occurrence, and size or onset pattern. PEDF (P=0.014) and IL-1α (P=0.049) expression was down-regulated with grade progression. PEDF expression was lower in normal uroepithelium than in papillary urothelial neoplasm of low malignant potential (PUNLMP) (P=0.000) and carcinoma (P=0.009) whilst IL-1α (P=0.000 and P=0.000 respectively) and IL-8 (P=0.000 and P=0.023 respectively) expression was higher in the same grouping. PEDF expression had a negative correlation with IL-8 in PUNLMP (P=0.049, r=-0.578) as well as in tumour grouping (P=0.033, r=-0.276). Deranged expressional change of PEDF, IL-1α and IL-8 could be in relation to loss of differentiation from normal uroepithelium to papillary lesion and eventually to carcinoma.