Prognostic markers in low-grade papillary urothelial neoplasms of the urinary bladder: an update

Papillary urothelial neoplasms of the urinary bladder comprise a heterogeneous spectrum of ‘continuous’ lesions in which the assessment of an accurate histological grade and tumour stage is mandatory for the clinical management of patients. The 1998 World Health Organization/International Society of Urologic Pathologists (WHO/ISUP) consensus classification and the 1999 WHO classification proposed new malignancy grading schemes, mainly based on morphometric studies for the replacement of the 1973 WHO grading system. In accordance with these novel grading systems, two major categories of papillary urothelial neoplasms were distinguished: low-grade and high-grade papillary urothelial neoplasms. Concerning the specific subgroup of low-grade tumours, two other entities were defined: papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade papillary urothelial carcinomas (LGPUC). In long-term follow-up programmes, PUNLMP have demonstrated low recurrence rates and minimal risk for tumour progression in comparison with LGPUC. However, grade assessment is a subjective decision and, on occasion, the use of reproducible criteria by urological pathologists is difficult due to tumour heterogeneity and to the existence of a variable number of cases situated between consecutive groups. As a result, to determine a better correlation with clinicopathological patient outcome, other predictive markers are being investigated. Among these, the prognostic significance of classical clinicopathological, morphometric, cytometric, immunohistochemical and molecular markers have been widely reported. This review summarizes the prognostic importance of all these markers in the prediction of tumour recurrences and progression in low-grade papillary urothelial bladder neoplasms.     

Cytologic diagnosis of low-grade papillary urothelial neoplasms (low malignant potential and low-grade carcinoma) in the context of the 1998 WHO/ISUP classification

The 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) classification of urothelial neoplasms introduced a category called papillary neoplasm of low malignant potential (LMP) and separated it from low-grade papillary urothelial carcinoma (LGPUC), which was thought to yield abnormal cells in cytology specimens. The objective of our study was to evaluate the effectiveness of urine cytology in diagnosing these lesions. Eighty-six paired transurethral surgical biopsy and corresponding urine cytology specimens representing the spectrum of urothelial papillary lesions were examined. Consensus diagnosis on each biopsy was made, and the distribution was as follows: 16 benign urothelium, 27 LMP, 28 LGPUC, and 15 high-grade papillary urothelial carcinoma (HGPUC). This was followed by a blinded independent review of the urine cytology specimens by three observers. Each cytology case was marked as negative, atypical, suspicious, or positive for malignant cells by using previously published cytologic criteria. When the negative and atypical diagnoses were grouped together as "benign" and the suspicious and malignant diagnoses as "malignant," the detection rate of "malignancy" of the lesions was as follows: LMP, 37%; LGPUC, 25%; and HGPUC, 53%. The false positive rate was 6%, and the positive predictive value (PPV) was 94%. Detection rates of cells that were at least "atypical" were as follows: LMP, 74%; LGPUC, 79%; and HGPUC, 100%. While most of the LMP and LGPUC cases yielded cells that were at least "atypical," there was no significant difference in the distribution of cytologic diagnoses for LMP and LGPUC cases (P > 0.05). Urine cytology in the context of the 1998 WHO/ISUP classification appears to be useful as a screening tool but does not appear to discriminate LMP effectively from LGPUC.     

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 infuenced 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.     

Aurora-A/STK-15 is a predictive factor for <Emphasis Type="Italic">recurrent</Emphasis> behaviour in non-invasive bladder carcinoma: a study of 128 cases of non-invasive neoplasms

Aurora-A, a member of serine/threonine kinase, is implied in mitosis and centrosome maturation. Increasing levels of Aurora-A have been shown to be present in several malignancies and especially in bladder cancer. No immunohistochemical marker has shown to be able to predict the clinical outcome of patients with superficial bladder cancer, except MIB-1, as a predictive marker of relapse and progression. The aim was to investigate the expression of Aurora-A and MIB-1 in tissue micro arrays of superficial bladder cancer representative of pTa papillary urothelial neoplasm with different degrees of aggressiveness (low malignant potential [PUNLMP], non-invasive papillary urothelial carcinoma low grade [NILGC], non-invasive papillary urothelial carcinoma high grade [NIHGC] and carcinoma in situ). We analysed predictive values of both markers, their specificity and sensitivity in tumor recurrence. Aurora-A was a sensitive marker to predict tumor recurrence especially for pTa (PUNLMP, NILGC; PUNLMP p < 0.001, NILGC p < 0.001) with statistical significant correlation between immunohistochemical staining and clinical outcome. MIB-1 expression displayed statistical difference p = 0.002 in the PUNLMP group and p = 0.03 in the NILGC group. Aurora-A is a more sensitive marker than MIB-1 to predict relapse in pTa bladder neoplasias. The combination of both markers seems to have a very powerful predictive value of recurrence (p < 0.001).     

High-grade papillary urothelial carcinoma of the urinary tract: a clinicopathologic analysis of a post-World Health Organization/International Society of Urological Pathology classification cohort from a single academic center

About one half of all bladder neoplasms are noninvasive, and in those, the histologic grade is a crucial prognosticator. Few single-center studies have assessed the recurrence, progression, and cancer-related mortality rates of noninvasive high-grade papillary urothelial carcinomas. With this aim, we evaluated the clinicopathologic and outcome features of 85 patients with high-grade papillary urothelial carcinoma. Median age was 68 years, and 80.5% were men. Tumor size ranged from 0.3 to 13.0 cm (median, 1.6 cm). Recurrence was found in 36.5% of the patients, whereas tumor progression, defined as invasion of lamina propria or beyond, was identified in 40% of all cases. When present, lesion reappearance involved mostly 1 to 2 episodes. Metastasis appeared in 20% of the patients, and 15% died of disseminated bladder cancer. All cancer-related deaths occurred in the group of patients with progression, whereas patients with recurrence showed similar outcomes to those with no recurrence. For patients with tumor progression, clinical stage was significantly associated with outcome (P = .002). As for prognosis, tumor size was strongly associated with progression (P < .01). In conclusion, recurrence, progression, and cancer-specific mortality rates were 36.5%, 40%, and 15%, respectively. All the patients who died of cancer had a history of tumor progression. Patients with recurrences showed similar outcomes to those with no recurrence. Tumor size was strongly associated with tumor progression and cancer-specific survival, whereas clinical stage was significantly associated with outcome in the progression group. In light of the high recurrence and progression rates of high-grade papillary urothelial carcinoma, strict clinical surveillance aimed to detect early recurrent lesions, especially in patients with larger tumors, is warranted.     

Measuring the dimension of invasive component in pT1 urothelial carcinoma in transurethral resection specimens can predict time to recurrence

Recurrences of nonmuscle-invasive urothelial bladder cancer are very common following resection. Predictive histopathologic variables in transurethral resection of bladder tumor (TURBT) specimens are of particular importance especially in determining the behavior of lamina propria-invasive tumors (high grade T1 stage). A total of 110 patients who underwent TURBT for urothelial carcinoma (1997-2005) from a single institution were retrospectively reviewed. Amount of tumor invasion by urothelial carcinoma was assessed in terms of percentage, focality (focal vs multifocal), and dimension (DI, aggregate length of invasion). Of 110 patients, 39 (35%) were found to have invasive high-grade urothelial carcinoma, including 9 females. Mean age was 70 years (range, 56-94 years). Twenty-three patients with high-grade T1 urothelial carcinoma had available follow-up information. Recurrence rate in these 23 patients was 96% (22/23). Nearly all of the recurences (221/22, 95%) occurred within 1 year of the initial TURBT. There was an inverse correlation of DI with time to recurrence (P < .05; correlation coefficient, −0.47). Urothelial carcinoma with a greater DI (>0.5 cm) had a mean time to recurrence of less than 6 months. Percentage of tumor invasion and focality was not associated with recurrence. The aggregate length of invasion may be a prognostic variable for high-risk nonmuscle-invasive bladder cancer. Measuring “aggregate length of invasive tumor,” if further validated in larger studies, could provide a practical alternative in substaging pT1 tumors in TURBT specimens.     

Primary urothelial carcinoma of the upper tract: Important clinicopathological factors predicting bladder recurrence after surgical resection

The aim of the present study was to further characterize potential clinicopathological predictors for urinary bladder recurrence-free survival (UBRFS) in patients with primary urothelial carcinoma of the upper urinary tract (UUT-UC). The present series included 385 cases of surgically treated primary localized UUT-UC without previous or concurrent urothelial carcinoma of the urinary bladder. Among the 374 patients with follow-up information, clinicopathological features and therapeutic information including whether they received a laparoscopy-assisted nephroureterectomy (LNU) and adjuvant chemotherapy were correlated with UBRFS. After a median follow up of 69 months, 86 patients (23%) developed urinary bladder recurrence. The median time to develop urinary bladder recurrence was 12 months. At the univariate level, an increment in histological grade ( P = 0.0321), a prominent papillary configuration ( P = 0.0004), LNU ( P = 0.0397) and male gender ( P = 0.0401) significantly predicted an inferior UBRFS. At the multivariate level, increase of histological grade ( P < 0.0001, relative risk (RR) = 3.776), prominent papillary configuration ( P < 0.0001, RR = 3.244), and male gender ( P = 0.0463, RR = 1.444) independently predicted UBRFS. In conclusion, male patients and those with high-grade and papillary UUT-UC, and who received LNU had higher risks of urinary bladder recurrence. Accordingly, for these patients, more intensive follow up coupled with postoperative intravesical adjuvant therapy to prevent urinary bladder recurrence should also be considered.     

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.     

Histological grading of papillary urothelial carcinoma of the bladder: prognostic value of the 1998 WHO/ISUP classification system and comparison with conventional grading systems

AIM: To test the prognostic value of the 1998 WHO/ISUP (World Health Organisation/International Society of Urologic Pathology) consensus classification system in Ta papillary urothelial neoplasms of the bladder. METHODS: The histological slides of 322 patients with a primary Ta tumour were classified according to the consensus classification system, and recurrence free survival (RFS) and progression free survival (PFS) were assessed for a mean follow up period of 79 months. In the same patient group, the RFS and PFS rates for the 1973 WHO grading system and a low grade/high grade system were analysed. RESULTS: Recurrent tumours were seen in all categories of the 1998 WHO/ISUP classification system and five year RFS was not significantly different between the groups (p = 0.12). The five year PFS showed a small but significant difference (p = 0.04) between papillary neoplasms of low malignant potential (PNLMP) and high grade papillary urothelial carcinomas (HGPUCs). In the 1973 WHO classification, no significant difference was found in RFS and PFS between the different grades. In the low grade/high grade classification PFS was significantly better for low grade tumours (p = 0.01). CONCLUSION: The prognostic value of the 1998 WHO/ISUP classification system is limited to predicting PFS, especially between PNLMP and HGPUC. The prognostic value of this system over other grading systems is questionable.     

Prognostic significance of minor high grade component in non-invasive papillary urothelial carcinoma of urinary bladder: (A study of 273 consecutive cases over a period of 3 years)

PurposeOur study aimed to determine the prognostic significance of minor high-grade components (HGC) in non-invasive papillary urothelial carcinomas compared with pure low-grade and high-grade tumors.Material and methodsWe retrospectively retrieved 273 in-house cases of non-invasive papillary urothelial carcinomas (pTa) from 2016 to 2018 for which follow up data was available in hospital archives. We stratified our data into four main groups (G). G1, pure low-grade (n = 164); G2, HGC ≤5 % (n = 17); G3, HGC >5 % to ≤25 % (n = 14); and G4, pure high-grade (n = 78). Prognosis was assessed in terms of recurrence, grade and stage of progression, metastasis, and death. The mean follow up duration was 34.72 ± 20 months (range 20–60 months).ResultsAll four groups showed no difference in tumor recurrence (G1 81.7 %, G2 88.2 %, G3 92.9 %, G4 92.3 % p-value 0.183). In terms of grade progression, there was no significant difference in G2 35.3 % and G3 35.7 % and both groups showed worst prognosis compared to G1 16.5 % p-value 0.04. Regarding stage progression (G1 6.7 %, G2 23.5 %, G3 28.6 %, G4 41% p-value 0.001), metastasis (G1 5.5 %, G2 5.9 %, G3 7.1 %, G4 17.9 % p-value 0.01) and death (G1 4.3 %, G2 5.9 %, G3 7.1 %, G4 15.4 % p-value 0.02) there was no significant difference in G2 and G3 and both groups showed worst prognosis than G1 and better than G4.ConclusionUrothelial carcinomas with minor high-grade component ≤25 % behaved worst than pure low grade and better than pure high grade and should be treated as distinct grade entity.     

Prognostic significance of tumor budding in muscle invasive urothelial carcinomas of the urinary bladder

ObjectiveThe aim of the present study was to analyze the prognostic significance of tumor budding in muscle-invasive urothelial carcinomas of the urinary bladder, and also to determine an optimal threshold value in evaluation.Patients and methodsThe study included 108 patients diagnosed with muscleinvasive conventional urothelial carcinoma between 2010 and 2020. Tumor budding was evaluated on H&E-stained slides. The critical tumor budding number was determined with the “receiver operating characteristics (ROC)” curve. Cases with a tumor budding number of ≤6 were categorized as low, and cases with >6 as high tumor budding.ResultsThe univariate Cox proportional hazards regression model for recurrence-free survival showed that lymphovascular invasion (P = 0.001), tumor budding (P = 0.012), pT stage (T4 vs. T2) (P = 0.005), and lymph node metastasis (P = 0.009) were significantly associated with recurrence-free survival. The multivariate Cox proportional hazards regression model utilizing backward stepwise (wald) method revealed that only LVI (P = 0.001) was independent risk factor for recurrence-free survival. The univariate Cox analysis showed that lymphovascular invasion (P = 0.001), tumor budding (P = 0.004), pT stage (T4 vs. T2) (P = 0.003), and lymph node metastasis (P = 0.001) were significantly associated with overall survival. The multivariate Cox analysis (backward stepwise (wald) method) revealed that tumor focality (P = 0.018), pT stage (T4 vs. T2) (P = 0.015), and lymphovascular invasion (P = 0.002) were independent factors for overall survival.ConclusionsOur findings suggested that the evaluation of tumor budding may be a useful parameter for predicting outcome in patients with muscle-invasive bladder cancer.     

Urothelial eddies in papillary urothelial neoplasms: a distinct morphologic pattern with low risk for progression

We encountered an undescribed histologic feature of papillary urothelial neoplasms: “urothelial eddy”, which was histologically reminiscent of squamous eddy of irritated follicular keratosis of the skin. A review of 756 patients with transurethral resection of bladder tumor revealed 10 patients (1.3%) of papillary urothelial neoplasms with urothelial eddies. All cases were male with a median age of 65 years. Urothelial eddies were characterized by small ovoid nests of ovoid to spindle cells arranged in an onion-skin pattern with fine cytoplasmic processes within wide intercellular space. The cytoplasmic processes mimicked intercellular bridges but ultrastructurally were cytoplasmic microvillous projections. They were of papillary urothelial neoplasm of low malignant potential in seven patients and low-grade urothelial carcinoma in three patients. Nine patients presented as non-invasive tumor and one patient showed microinvasion within papillary stalks. Six patients showed an inverted growth pattern. Their immunoprofile was more similar to that of conventional urothelial carcinoma rather than squamous cell carcinoma: high expressions of GATA3, S100P, uroplakin III, and cytokeratin 7; and low expressions of high molecular weight cytokeratin and p53. The Ki-67 labeling index was low (mean and median values, 2% each). During the follow-up period (mean, 88.7 months), four patients, including the microinvasive patient, showed recurrence with the same grade and stage but neither progressed into muscle-invasive tumor nor caused death. Our results suggest that urothelial eddy is a rare aberrant histology of papillary urothelial neoplasms with indolent behavior and should be discriminated from squamous differentiation of urothelial carcinoma, which has a poor prognosis.     

Overexpression of COX2 indicates poor survival in urothelial bladder cancer

BackgroundCOX2 is a cyclo-oxygenase enzyme expressed in the tumor cells, inflammatory cells, stromal and non-epithelial cells. The study was conducted to evaluate the expression of COX2 in Urothelial carcinoma and find the association with progression and recurrence.MethodsThe expression of COX2 was evaluated by real-time PCR and immunohistochemistry.ResultsGene expression of COX2 was found to be upregulated >28-fold in urothelial cancer compared to adjacent normal bladder mucosa. Inflammatory cell expression of COX2 was found in 92% cases whereas only 37% cases showed COX2 overexpression in tumor cells. Tumor cell COX2 overexpression was significantly associated with invasion and recurrence.ConclusionCOX2 expression is a marker of invasion, recurrence and poor survival and may have a role in predicting the cases which will benefit from additional treatment with COX2 inhibitors in urothelial carcinoma.     

Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder carcinoma. A tissue microarray study of 158 cases

P63 is a member of the p53 family, which plays a role in the differentiation of urothelium and is supposed to play a role in urothelial carcinogenesis. P53 and MIB-1 are recognised in many studies as predictive markers of progression, but few studies in the literature have examined p63. The aims of our study were to explore the expression of p63 in bladder carcinomas and to compare this expression to p53 and MIB-1, as well as to stage and grade. Tissue microarrays were performed on 158 urothelial carcinomas (56 pTa, 45 pT1 and 57≥pT2). Immunohistochemical studies were performed with p63, p53 and MIB-1 antibodies. In our study we observed that p63 immunostaining is present in all cell layers in papillary urothelial neoplasm of low malignant potential (PUNLMP), but partially lost in non-invasive papillary urothelial carcinoma low grade (NILGC) and in pT1/≥pT2 bladder cancers. P53 and MIB-1 displayed lower expression in PUNLMP/NILGC vs non-invasive papillary urothelial carcinoma high grade (NIHGC)/pT1, but there was no correlation between the expression of p63, p53 and MIB-1. Our study demonstrates that p63 expression distinguishes between PUNLMP/NILGC and NIHGC/pT1 (p=4.10⁵). A statistical difference disserving pTa and pT1/≥pT2 with a statistical significance (p<10⁻⁶) could also be observed. P63 should be considered as an additional biomarker that might help pathologists to classify their patients.     

Benign and low-grade papillary lesions of the urinary bladder: a review of the papilloma-papillary carcinoma controversy, and a report of five typical papillomas

The controversial topic concerning the most appropriate nomenclature for low-grade papillary lesions of the urinary bladder is reviewed on the basis of the literature and the authors' experiences. This undertaking was prompted by a recent report in which use of the designation "papilloma" was advocated for lesions that generally had been diagnosed as grade 1 papillary urothelial carcinoma. The literature indicates that 10% to 20% of patients with a noninvasive low-grade papillary tumor of the bladder will later have invasive bladder cancer. This significant outcome in a minority of such patients warrants very careful follow-up for the group as a whole, irrespective of the terminology used. The authors contrast the features of papillary urothelial carcinoma with a series of five cases, which they interpret as true papillomas. They believe that these low-grade papillary lesions can be distinguished from true papillomas and do not favor a change in terminology. Some of the problems in the evaluation of inverted papilloma and inverting urothelial carcinoma are briefly reviewed as are other selected papillary lesions of the urinary bladder.     

Clinicopathologic study of 60 cases of urothelial neoplasms with inverted growth patterns: Reclassification by international consultation on urologic disease (ICUD) recommendations

BackgroundMost urothelial neoplasms of the bladder show an exophytic papillary pattern, but some show an inverted growth pattern. In 2004, the World Health Organization (WHO) released a detailed histologic classification system for papillary urothelial neoplasms, but not for inverted forms. The International Consultation on Urologic Disease (ICUD) recommendations of 2012 are applicable to inverted/endophytic papillary lesions as follows: 1) inverted papilloma (IP), 2) inverted papillary urothelial neoplasm of low malignant potential (IPUNLMP), 3) inverted papillary urothelial carcinoma, low grade, non-invasive (IPUCLG-NI), 4) inverted papillary urothelial carcinoma, high grade, non-invasive (IPUCHG-NI), 5) inverted papillary urothelial carcinoma, high grade, invasive (IPUCHG-I). However, only atypical cellular morphology was considered for classification in the 2012 ICUD recommendations, and data to support to validate this new grading system are lacking.MethodsSixty cases of inverted urothelial papillary tumors were classified into 5 categories according to 2012 ICUD and 2016 WHO/ISUP recommendations to evaluate their clinical, pathological, and immunohistochemical characteristics. Two subgroups were defined as subgroup 1, IP and IPUNLMP, and subgroup 2, IPUCLG-NI, IPUCHG-NI, and IPUCHG-I. Clinical features (age, sex, history of urothelial carcinoma, smoking history, size, and multifocality) and histologic features (nuclear pleomorphism, mitotic count, mitosis level, apoptosis, luminal necrosis, trabecular thickening, anastomosing trabeculae, hypercellularity, loss of polarity, peripheral palisading, palisading with central streaming, and discohesiveness) were evaluated. Immunohistochemical stains for CK20, CD44, P53, p16, Ki-67, cyclin D1 and c-erbB2 were performed.ResultsA total of 60 cases were classified as 10 cases of IP, 29 cases of IPUNLMPs, 15 cases of IPUCLG-NI, 4 cases of IPUCHG-NI, and 2 cases of IPUCHG-I. Compared to subgroup 1, subgroup 2 showed larger tumor size, more nuclear irregularity, higher mitotic count (hot spot and per 10 high power fields), more upper level mitosis (>1/2), and more frequent apoptosis, luminal necrosis, surface papillary component, trabecular thickening, anastomosing irregular trabeculae, hypercellularity, loss of polarity, peripheral palisading with central streaming, and discohesiveness, and absence of umbrella cells and urothelial eddies. CK20, Ki67, and c-erbB2 were the only markers that were differently expressed in the two subgroups, with more expression in subgroup 2.ConclusionsThe 2012 ICUD recommendations are valid to classify inverted papillary urothelial tumors. However, other histologic features besides atypical cellular morphology should also be considered to distinguish subgroup 1 and subgroup 2 inverted papillary urothelial tumors.     

Clinical significance of the reduction of UT-B expression in urothelial carcinoma of the bladder

Urea transporter B (UT-B) is a membrane protein and plays an important role in regulating urea concentration in bladder urothelial cells. It has been reported that UT-B gene mutations were related to bladder carcinogenesis, and UT-B deletion could induce DNA damage and apoptosis in bladder urothelium. However, the functions and clinical significance of UT-B in human bladder cancer remain unknown. The most common type of bladder cancer is urothelial carcinoma (UC). We hypothesized that UT-B expression was related to bladder UC progress. In this study, UT-B was detected using immunohistochemistry in 52 paraffin-embedded specimens of bladder UC and 10 normal urothelium specimens. The results showed that UT-B protein expression in UC tumor cells was significantly lower as compared with normal urothelial cells (P = 0.021). UT-B protein expression was significantly reduced with increasing histological grade (P = 0.010). UT-B protein expression in muscle-invasive stage was significantly lower than in non-muscle-invasive stage (P = 0.014). Taken together, our data suggest that the reduction or loss of UT-B expression may be related to the incidence, progression and invasiveness of bladder UC. UT-B may be a novel diagnostic or prognostic biomarker, as well as a potential therapeutic target in UC of the bladder.     

Relationship of Ki67, TP53, MDM-2 and BCL-2 expressions with WHO 1973 and WHO/ISUP grades, tumor category and overall patient survival in urothelial tumors of the bladder

Using the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) (2004 WHO), 1999 WHO/ISUP, and 1973 WHO classifications, we examined Ki67, BCL-2, TP53, and MDM-2 expressions in invasive and noninvasive urothelial neoplasias of the bladder of 72 patients, and compared the results regarding tumor category and grade with clinical outcome to determine the clinicopathological relevance of these classifications. Ki67 and TP53 expressions were correlated with tumor grades of the 1973 WHO classification, and they also distinguished "papillary urothelial neoplasm with low malignant potential" from other WHO/ISUP grades (p < 0.05). No difference was observed for Ki67 and TP53 expressions between the other WHO/ISUP grades (p > 0.05). Neither tumor grade nor tumor category correlated with MDM-2 or BCL-2 expressions (p > 0.05). WHO/ISUP classifications are obviously not superior to the 1973 WHO classification for grading urothelial neoplasia of the bladder. However, if the "papillary urothelial neoplasm with low malignant potential" is distinguished from grade 1 tumors of the 1973 WHO classification, more precise prognostic information may be obtained.     

Clinicopathological characteristics and outcome of nested carcinoma of the urinary bladder

We present the clinicopathological features of 56 cases of the nested variant of urothelial bladder carcinoma. This is an uncommon variant of bladder cancer, recognized by the current WHO classification of urologic tumors. The nested component represented 100 % of the tumor in 24 cases. The architectural pattern of the tumor varied from solid expansile to infiltrative nests characterized by deceptively bland histologic features resembling von Brunn nests. Typical features of high-grade conventional urothelial carcinoma were present in 32 cases. Most neoplastic cells had nuclei of low to intermediate nuclear grade with occasional nuclear enlargement, most frequently seen in deep areas of tumor. The nested component expressed cytokeratins 7, 20, CAM5.2, and high molecular weight (34ßE12), p63, Ki67, p53, p27, and GATA3. Tumor extension was T1 (n?=?9), minimally T2 (n?=?10), T2a (n?=?1), T2b (n?=?4), T3a (n?=?8), T3b (n?=?13), and T4a (n?=?11). On follow-up, 36 of patients died of or were alive with disease from 2 to 80 months (mean 21 months). Four patients died of other causes. Eleven other patients remained disease free. Univariate survival analysis showed no differences for nested carcinoma compared with conventional urothelial carcinoma. As in conventional urothelial carcinoma, in nested carcinoma of the bladder pT category defined different survival groups. In summary, nested variant of urothelial bladder carcinoma is typically associated with advanced stage. In samples of limited volume, it may be misdiagnosed as proliferation of von Brunn nests or other nested-like bladder lesions, delaying definitive therapy.     

Bladder papillary urothelial neoplasm of low malignant potential in Chinese: a clinical and pathological analysis

Papillary urothelial neoplasm of low malignant potential (PUNLMP) had the incidence of low and definitive recurrence. Therefore, few studies showed that the relationship between pathological factors and the prognosis of patients with PUNLMP. The aim of this study assessed the linkage of pathological factors and prognosis of patients with PUNLMP including the presence or absence of mitoses and the thickness of urothelium. A retrospective analysis of 71 patients with PUNLMP was enrolled between January 2007 and June 2013. The clinicopathological factors consisting of tumor diameter, multifocality, the presence or absence of mitoses and cell thickness of urothelium were retrieved, Log-rank test and Cox proportional hazards regression models were used for univariate and multivariate analyses to evaluate the associations of these factors with recurrence-free survival (RFS) and progression-free survival (PFS).The incidence of recurrence and progression for PUNLMP was 19.7% and 16.9%, respectively. Patients with grade progression represented 85.7% in the recurrent patients. No patients had stage progression and no cases died from invasive urothelial carcinoma. Univariate analysis showed that the presence of mitoses, tumor diameter greater than or equal to 0.8 cm, multifocality were significantly correlated with worse RFS (P < 0.05) and PFS (P < 0.05). Multivariate analysis demonstrated that the presence of mitoses, tumor multifocality were significantly independent biomarkers for worse RFS (P < 0.05) and PFS (P < 0.05). Although the rare and infrequent mitoses were found for PUNLMP, the presence of mitoses and tumor multifocality were still the independent and poor predictors for the prognosis of PUNLMP. In addition, once the PUNLMP appeared to the recurrence, the inevitable grade progression could be determined, herein, long-term follow-up was necessary to be warranted, especially for patients with multiple lesions and the presence of mitoses.