Bladder cancer: translating molecular genetic insights into clinical practice

Transitional cell (urothelial) carcinoma of the bladder is the second most common urologic malignancy and is one of the best understood neoplasms, with relatively well-defined pathogenetic pathways, natural history, and tumor biology. Conventional clinical and pathologic parameters are widely used to grade and stage tumors and to predict clinical outcome of transitional cell carcinoma; but the predictive ability of these parameters is limited, and there is a lack of indices that could allow prospective assessment of risk for individual patients. In the last decade, a wide range of candidate biomarkers representing key pathways in carcinogenesis have been reported to be clinically relevant and potentially useful as diagnostic and prognostic molecular markers, and as potential therapeutic targets. The use of molecular markers has facilitated the development of novel and more accurate diagnostic, prognostic, and therapeutic strategies. FGFR3 and TP53 mutations have been recognized as key genetic pathways in the carcinogenesis of transitional cell carcinoma. FGFR3 appears to be the most frequently mutated oncogene in transitional cell carcinoma; its mutation is strongly associated with low tumor grade, early stage, and low recurrence rate, which confer a better overall prognosis. In contrast, TP53 mutations are associated with higher tumor grade, more advanced stage, and more frequent tumor recurrences. These molecular markers offer the potential to characterize individual urothelial neoplasms more completely than is possible by histologic evaluation alone. Areas in which molecular markers may prove valuable include prediction of tumor recurrence, molecular staging of transitional cell carcinoma, detection of lymph node metastasis and circulating cancer cells, identification of therapeutic targets, and prediction of response to therapy. With accumulating molecular knowledge of transitional cell carcinoma, we are closer to the goal of bridging the gap between molecular findings and clinical outcomes. Assessment of key genetic pathways and expression profiles could ultimately establish a set of molecular markers to predict the biological nature of tumors and to establish new standards for molecular tumor grading, classification, and prognostication. The main focus of this review is to discuss clinically relevant biomarkers that might be useful in the management of transitional cell carcinoma and to provide approaches in the analysis of molecular pathways that influence the clinical course of bladder cancer.     

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.     

The many faces of urothelial carcinoma: an update with an emphasis on recently described variants

Urothelial carcinoma is well known for its divergent differentiation. Several "variant" morphologies have been described in the literature in recent years and have additionally been recognized in the recent World Health Organization classification of urothelial neoplasms. The importance of recognizing these variant histologies lies in the potential diagnostic, prognostic, or therapeutic implications that accompany these diagnoses. The range of variant morphology seen in the urinary bladder may also be seen in urothelial tumors of the renal pelvis. Herein we review select variants of urothelial carcinoma focusing on the relatively recently recognized variants, outlining the diagnostic features, common differential diagnostic dilemmas, and clinical relevance. This review also includes a discussion on variants on which there is recent information available.     

High-grade prostatic sarcoma seen in a catheterized urine specimen: case report and differential diagnosis

Urine cytology has been effectively used in the diagnosis and management of epithelial bladder tumors, particularly high-grade urothelial carcinoma. Indeed it is the gold standard for bladder cancer screening. Although urothelial carcinoma is the most frequently identified bladder tumor by urine cytology, metastatic carcinomas from the kidney, colon, and a variety of other regional organs have been detected. Stromal lesions such as inflammatory myofibroblastic tumor, gastrointestinal stromal tumor, and leiomyosarcoma are other much rarer entities occurring within the bladder. Few to no case reports exist documenting their identification within urine cytology specimens. Herein we report the detection of a high-grade prostatic sarcoma within a catheterized urine specimen of a young male having a diffusely enlarged prostate. The specimen consisted of numerous fragments of relatively uniform spindle cells having ovoid nuclei with rounded ends and finely dispersed chromatin. Cytoplasmic borders were indistinct. No mitoses or significant atypia was present. The background consisted of numerous red blood cells, cellular debris, and a few clusters of unremarkable urothelial cells. Followup surgical biopsy of the patient's prostate revealed a high-grade spindle-cell sarcoma. Further immunohistochemical and molecular delineation of the tumor was not informative for a more definitive diagnosis. Although rare, sarcomas and other mesenchymal tumors involving the bladder are unique entities with a broad differential diagnosis.     

In situ detection of global DNA hypomethylation in exfoliative urine cytology of patients with suspected bladder cancer

Global DNA hypomethylation is a common phenomenon in bladder cancer. Therefore we investigated whether it is possible to detect and assess global DNA hypomethylation in bladder cancer using a specific monoclonal antibody for 5-methyl-cytosine. Cytospins from exfoliative urine cytology specimens of patients with bladder cancer or a history of bladder cancer, control patients with benign urological diseases and of young healthy volunteers were analyzed. Urothelial carcinoma (UC) cells showed various degrees of nuclear destaining indicating global DNA hypomethylation whereas all specimens from healthy volunteers showed granular nuclear staining indicating regular methylation of repeated DNA sequences. Lowest 5-methylcytosine immunostaining scores were observed in carcinoma cells and a statistically significant difference was observed between urothelial cells of healthy controls or patients with benign disease compared to bladder cancer patients (p<0.01, p<0.05, respectively). In UC cases even morphologically normal urothelial cells often displayed evident hypomethylation. Likewise, in patients with a history of UC, but no cystoscopic evidence of recurrence, morphologically non-malignant urothelial cells presented with some degree of demethylation. Our results strongly support the hypothesis of early global demethylation in bladder cancer. Immunocytochemical staining with the 5-methylcytosine antibody allows simultaneous individual assessment of nuclear morphology and methylation status of a given sample.     

Pathology of flat bladder lesions with emphasis on putative precursors

Flat bladder lesions comprise a spectrum of morphologic changes ranging from reactive atypia to carcinoma in situ (CIS). Differentiating these lesions is important because of differences in patient management and clinical outcome. The precise nature of precursor lesions of bladder cancer remains incompletely understood. Urothelial CIS is the most definitely characterized precursor lesion of high grade bladder cancer. Atypia of unknown significance (AUS) is somewhat controversial. For practical purposes, AUS and reactive urothelial changes should be considered a single entity, since neither lesion has established preneoplastic potential. Simple hyperplasia and papillary hyperplasia are recently identified putative preneoplastic lesions. More recent molecular data also support the precursor nature of intestinal metaplasia and keratinizing squamous metaplasia. In this review, we also discuss the utility of molecular ancillary studies in establishing premalignant lesions, diagnosis, and differential diagnosis of flat bladder lesions.     

Improved clonality analysis of multifocal bladder tumors by combination of histopathologic organ mapping, loss of heterozygosity, fluorescence in situ hybridization, and p53 analyses

The clonality status of multifocal bladder tumors is still controversially discussed with experimental evidence for both monoclonality and field cancerization. Methodologically, loss of heterozygosity (LOH) and genomic sequencing analyses are widely used in clonality analysis of malignant tumors. In the present study, we used LOH analysis and genomic sequencing in combination with fluorescence in situ hybridization (FISH) and extensive histopathologic whole-organ mapping to determine the clonal relationship of multifocal bladder cancer disease. Tissue sections (1 cm(2)) covering the entire urothelial lining were systematically dissected from 2 cystectomy specimens (cystectomy 1, no urothelial lesions, bladder infiltration by a leiomyosarcoma of the vaginal wall; cystectomy 2, multifocal pT3G3 tumors). The location of each sample was documented (bladder mapping). Urothelial cells were microdissected for LOH (chromosomes 9, 17p) and FISH analysis (CDKI2 (9p21), FACC (9q22), p53 (17p13.1), and centromeric probes for corresponding chromosome). Exons 5 to 9 of the p53 gene were sequenced in all tumor samples. No chromosomal alterations were detected in the cystectomy specimen without urothelial malignancies. The tumor-bearing bladder showed an increasing frequency of deletions with increasing malignancy of the investigated lesions. LOH analysis detected deletions only on chromosomes 9p and 17p. In contrast, FISH analysis revealed deletions of all investigated genes at chromosomes 9p, 9q, and 17p in all samples analyzed (preneoplastic and neoplastic tissue). An identical p53 mutation in codon 281 was found in all 7 analyzable tumor samples. Combination of molecular data with histopathologic bladder mapping suggested a monoclonal development of the multifocal lesions mostly via intraurothelial migration. Our data strengthen the results from recently published studies that patients with advanced urothelial carcinoma seem to have a monoclonal panurothelial disease in most cases. FISH showed a much higher sensitivity for detection of chromosomal losses than classical LOH analysis, especially in preneoplastic and small lesions. Combining 3 molecular approaches together with histopathologic organ mapping presents a valuable tool to determine the clonality status of multifocal bladder tumors.     

Urothelial carcinoma of the renal pelvis with choriocarcinomatous features: genetic evidence of clonal evolution

Urothelial carcinoma with choriocarcinomatous features is a rare malignancy arising in the urinary bladder or renal pelvis. We report the case of a 60-year-old man with a biphasic neoplasm of the right kidney composed of papillary urothelial carcinoma and choriocarcinoma. Widespread hepatic and pulmonary metastases with choriocarcinomatous features were found on autopsy 6 weeks after initial diagnosis. Chromosomal analysis revealed a close genetic relationship between the papillary urothelial and choriocarcinomatous tumor components, documenting for the first time that choriocarcinoma of the renal pelvis results from clonal evolution of urothelial carcinoma with acquisition of trophoblastic differentiation.     

The molecular-morphologic correlates of bladder cancer

Environmental exposure to carcinogens trigger molecular events that lay the background for the subsequent development of urothelial carcinoma from the basal and intermediate layers of urothelial lining. Clinical classes of non-muscle invasive bladder cancer and muscle invasive bladder cancer are broadly divided into basal and luminal subtypes each with their molecular, morphologic and outcome characteristics. Morphology of cancer represents the sum total of genetic and epigenetic changes. The current review highlights the molecular – morphologic correlates identifiable in our daily clinical practice, the knowledge of which will help develop a deeper understanding of 1) early evolving lesions, 2) grade heterogeneity, 3) importance of recognizing subtypes of urothelial carcinoma and 4) basis of treatment resistance of urothelial carcinoma.     

Gene discovery in bladder cancer progression using cDNA microarrays

To identify gene expression changes along progression of bladder cancer, we compared the expression profiles of early-stage and advanced bladder tumors using cDNA microarrays containing 17,842 known genes and expressed sequence tags. The application of bootstrapping techniques to hierarchical clustering segregated early-stage and invasive transitional carcinomas into two main clusters. Multidimensional analysis confirmed these clusters and more importantly, it separated carcinoma in situ from papillary superficial lesions and subgroups within early-stage and invasive tumors displaying different overall survival. Additionally, it recognized early-stage tumors showing gene profiles similar to invasive disease. Different techniques including standard t-test, single-gene logistic regression, and support vector machine algorithms were applied to identify relevant genes involved in bladder cancer progression. Cytokeratin 20, neuropilin-2, p21, and p33ING1 were selected among the top ranked molecular targets differentially expressed and validated by immunohistochemistry using tissue microarrays (n = 173). Their expression patterns were significantly associated with pathological stage, tumor grade, and altered retinoblastoma (RB) expression. Moreover, p33ING1 expression levels were significantly associated with overall survival. Analysis of the annotation of the most significant genes revealed the relevance of critical genes and pathways during bladder cancer progression, including the overexpression of oncogenic genes such as DEK in superficial tumors or immune response genes such as Cd86 antigen in invasive disease. Gene profiling successfully classified bladder tumors based on their progression and clinical outcome. The present study has identified molecular biomarkers of potential clinical significance and critical molecular targets associated with bladder cancer progression.     

Transition between urothelial carcinoma in situ and non-invasive micropapillary carcinoma as a pivot connection between diverse morphologies of bladder carcinoma: a case report of urothelial carcinoma with villoglandular differentiation

Urothelial carcinoma has numerous histological variants, and these variants may coexist in a single case. Here, we present a case of a 70-year-old man with urothelial carcinoma of the bladder with a maximal diameter of 5 mm that involved micropapillary and plasmacytoid variants, with villoglandular differentiation. The presence of these variants was confirmed by pathological examination of a transurethral resection specimen, and high-grade urothelial carcinoma was found as a minor component. Although this bladder carcinoma was classified as pT1, cystoprostatectomy, urethrectomy, and lymphadenectomy were performed due to the presence of the micropapillary and plasmacytoid variants, which are known to be aggressive. Examination of a surgically resected specimen revealed no carcinoma. A transition between urothelial carcinoma in situ and non-invasive micropapillary carcinoma was found to be a pivot point connecting the diverse morphologies of this bladder carcinoma, from which there existed two pathways. One pathway was from urothelial carcinoma in situ to the plasmacytoid variant through invasive high-grade urothelial carcinoma, and the other was from non-invasive micropapillary carcinoma to urothelial carcinoma with villoglandular differentiation or to the micropapillary variant. This is the 16th reported case of urothelial carcinoma with villoglandular differentiation in the literature. As urothelial carcinoma with villoglandular differentiation is often associated with aggressive variants, as shown in our case, it should be reported whenever encountered in routine pathological practice.     

Clinicopathological analysis of recurrence and progression of low-grade papillary urothelial carcinoma of the urinary bladder: Predicting the outcome

BackgroundUrothelial carcinoma of the urinary bladder is the most common malignancy of the urinary system. Patients with low grade papillary urothelial carcinoma (LGPUC) usually have a low risk for tumor recurrence and progression; yet a subset of patients develop recurrence or grade/stage progression to high-grade papillary urothelial carcinoma (HGPUC). The clinicopathological and molecular factors that contribute to this progression are yet to be determined.ObjectivesIn our study, we aimed to assess the incidence and clinicopathological factors associated with tumor recurrence/progression of LGPUC.MethodsUsing a pathological database of surgical specimens from patients who underwent bladder biopsies and/or transurethral resection of bladder tumors (TURBTs) between August 01, 2011, and July 31, 2021, at a large academic medical center, a single-center retrospective cohort analysis was performed, and medical charts of patients were reviewed.ResultsOf the total 258 patients included, 157 (60.9 %) had “no recurrence”, 85 (32.9 %) had ≥1 “recurrence of LGPUC”, and 16 (6.2 %) had “grade progression to HGPUC”. The mean follow-up time was 31.5 ± 32 months. Patients with “grade progression” and “recurrence of LGPUC” had larger mean tumor size on initial biopsy and multiple lesions on initial cystoscopy compared to those with “no recurrence.” Interestingly, former smokers had 2.5- and 8.5-times higher risk of recurrence of LGPUC and grade progression, respectively.ConclusionSince the majority of our patients did not develop recurrence, we question whether there is tendency to overclassify the papillomas as LGPUC based on the 2004 WHO/ISUP consensus grading classification.     

Biomarkers in urothelial carcinoma of the bladder: The potential cross-talk between transforming growth factor-β1 and estrogen receptor β/androgen receptor pathways

Urothelial carcinoma of the bladder is nearly three times more common in men than in women. Although it has been primarily attributed to differences in exposure to smoking and industrial chemicals, it is evident now that hormonal factors also play a role. One of the explanations for the differential biologic aggressiveness of urothelial carcinoma of the bladder between genders has focused on sex steroid hormones and their receptors. Recent studies indicated that both estrogen receptor β and androgen receptor have a role within urothelial carcinoma of the bladder and their expression and activity are altered in the carcinogenesis and progression. Moreover, expression of transforming growth factor-β1 is a strong predictor of recurrence and specific mortality. We conjecture about the potential cross-talk between transforming growth factor-β1 and estrogen receptor β/androgen receptor pathways. Clinical significance of expression of transforming growth factor-β1 could be improved, when they are related with the determination of estrogen receptor β/androgen receptor status. Further subgrouping of transforming growth factor-β1 level combined with estrogen receptor β/androgen receptor status, would be more accurately determine the prognosis of patients. This hypothesis could be easily verified in corresponding clinical research, and combined analysis of expression of TGF-β1 and ERβ/AR signaling proteins may provide clinicians useful information regarding tumor initiation and progression, and guide patient prognosis and management with specific therapies.     

Expression of RNA-binding protein IMP3 (KOC) in benign urothelium and urothelial tumors

RNA-binding protein IMP3 is a KH-domain-containing protein and a member of the insulin-like growth factor messenger RNA-binding protein family. It is identical to K-homology protein overexpressed in cancer that was identified through screening for genes differentially expressed between benign pancreatic tissue and pancreatic cancer. Several studies have shown that IMP3 is associated with aggressive and advanced tumors in various organs. We studied the expression of IMP3 in benign urothelium and urothelial tumors by immunohistochemistry. The expression pattern of IMP3 was further compared with that of p53 and p16. Our study shows that IMP3 is generally not expressed in benign urothelium or low-grade urothelial tumors including urothelial dysplasia, papillary urothelial neoplasm of low malignant potential, and low-grade papillary urothelial carcinoma. The expression of IMP3 is significantly increased in high-grade urothelial tumors including high-grade papillary urothelial carcinoma, urothelial carcinoma in situ, and invasive urothelial carcinoma. Expression of IMP3 in urothelial tumors parallels the accumulation of nuclear p53, although there is not always a one to one correlation. In contrast, expression of p16 in the different groups of urothelial tumors is more variable. Urothelial carcinomas with invasion of muscularis propria appear to express IMP3 more frequently than lower-stage tumors. These findings suggest that IMP3 may be involved in the progression of urothelial tumors from low grade to high grade in both papillary and flat lesions. Immunohistochemical detection of the combined expression of IMP3 and p53 is useful in the diagnosis of high-grade urothelial tumors, particularly in small, superficial materials.     

Upper tract urothelial carcinoma: a clinicopathologic study including microsatellite instability analysis.

Urothelial carcinoma of the renal pelvis and ureter may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome that is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability. In this study, we examined microsatellite instability and the clinicopathologic features of urothelial carcinoma of the renal pelvis (n = 61) and ureter (n = 53) from 114 consecutive patients surgically treated from 1985-1992. Clinical data were obtained through chart review. Matched normal and tumor DNA was extracted from paraffin-embedded tissue, and a panel of six microsatellite loci was analyzed. The male-female ratio was 2.8:1 with a median age of 70 years (range, 28 to 92 y). Microsatellite analysis was successful in 67 tumors, and 21 (31.3%) patients had tumors that exhibited microsatellite instability. Patients with microsatellite-unstable tumors were significantly more likely to have additional nonurologic cancers (P =.015) including colorectal carcinoma (P =.001) compared with patients with tumors that did not exhibit microsatellite instability. In addition, patients with microsatellite-unstable tumors showed more colorectal cancers in their family (P =.026) and were more likely to have higher grade urothelial carcinoma of the upper tract (P =.028). Grade and stage, but not microsatellite status, were the strongest predictors of cancer-specific survival. This study found the highest frequency of microsatellite instability in upper urothelial tract carcinomas reported to date and highlights upper tract urothelial carcinoma as a marker of the hereditary nonpolyposis colorectal cancer syndrome in some patients. These findings reinforce the importance of obtaining cancer histories in patients with upper tract urothelial carcinoma to subsequently identify individuals with the hereditary nonpolyposis colorectal cancer syndrome and at-risk relatives for surveillance and management programs.     

Clonality and genetic divergence in multifocal low-grade superficial urothelial carcinoma as determined by chromosome 9 and p53 deletion analysis

Multifocality and recurrence are clinically important features of urothelial carcinomas of the urinary bladder. Recent molecular genetic studies have suggested that multifocal urothelial carcinomas are monoclonally derived from an identical transformed progenitor cell. However, most of these studies investigated advanced and poorly differentiated tumors. The study presented focuses on early papillary tumors, including 52 superficial well-differentiated multifocal and recurrent bladder carcinomas from 10 patients. Microdissection separating urothelium from stromal cells was considered essential to obtain pure tumor cell populations. Genetic analysis was carried out by applying two different methods. Dual color fluorescence in situ hybridization (FISH) with centromeric probes for chromosomes 9 and 17 and gene-specific probes for chromosome loci 9q22, 9p21, and 17p13 was carried out in parallel to loss of heterozygosity (LOH) analyses applying 5 microsatellite markers on these chromosomes. Overall, deletions on chromosome 9p were found in 47 tumors (90%), at chromosome 9q in 36 tumors (69%) and at chromosome 17p in 3 tumors (6%). There was a very high correlation of the results between FISH and LOH analysis. Ten early superficial papillary tumors showed deletion of chromosome 9p without deletion of 9q, suggesting 9p deletions as a very early event in the development of papillary urothelial carcinoma. Although in four patients, all investigated tumors showed identical genetic alterations and one patient showed no genetic alterations at the loci investigated, in five patients, two or more clones with different deletions were found. In four of these patients, the results are compatible with clonal divergence and selection of different cell subpopulations derived from a common progenitor cell. However, in one patient different alleles in two markers at chromosome 9 were deleted, favoring an independent evolution of two recurring tumor cell clones. In summary, we could show that there is considerable genetic heterogeneity in early multifocal and recurring urothelial carcinoma and demonstrated the occurrence of two independent clones in at least one patient as an indicator of possible initial oligoclonality of bladder cancer.     

Frequent FGFR3 mutations in urothelial papilloma

Activating point mutations in the FGFR3 gene occur frequently in low-grade and low-stage bladder carcinomas, whereas they are rare in high-grade carcinomas. This study investigates the incidence of FGFR3 mutations in 12 urothelial papillomas and 79 pTaG1 tumours which were regraded according to the 1998 WHO/ISUP classification system, resulting in 62 papillary urothelial neoplasms of low malignant potential (PUNs-LMP) and 17 low-grade papillary urothelial carcinomas (LG-PUCs). FGFR3 mutation analysis of 21 ovarian Brenner tumours was also performed. Seventy-seven cases were detected with a mutation in the FGFR3 gene. The mutations were exclusively found in bladder neoplasms. In urothelial papilloma, generally considered a benign lesion, 9/12 (75%) mutations were found. This report is the first to describe a genetic defect in urothelial papilloma. A comparable percentage of mutations was found in PUNs-LMP (85%) and LG-PUCs (88%). No mutations were found in matched normal DNA from bladder tumour patients. The mean follow-up was 5.78 years (range 0.21-17.60 years). Five patients developed high-grade papillary urothelial carcinoma from 2.5 to 12 years after first diagnosis. Two patients died of bladder cancer. The mean number of recurrences (recurrence rate) per year was 0.03, 0.21, and 0.46, respectively, for papilloma, PUN-LMP, and LG-PUC. Urothelial papilloma is a rare lesion with a benign natural behaviour compared with PUN-LMP and LG-PUC of the bladder, but from a molecular perspective, papillomas should be classified together with all well-differentiated urothelial neoplasms.     

膀胱尿路上皮癌组织中miR-133b的表达水平与其化疗敏感性的关系分析

目的 探讨膀胱尿路上皮癌组织中miR-133b的表达水平与其化疗敏感性的关系分析.方法 回顾性分析2011年2月至2012年2月于本院确诊为膀胱尿路上皮癌患者65例,根据癌组织中miR-133b表达水平将其分为高表达组(n=25)和低表达组(n=40),采用茎环实时荧光逆转录聚合酶链反应(stem-loop real-time,RT-PCR)检测膀胱尿路上皮癌组织和癌旁正常组织中 mi R-133b的表达水平,随访5年,统计分析所有患者化疗效果、5年存活情况.结果 膀胱尿路上皮癌组织中miR-133b的表达量(U6标准化后的) 低于癌旁正常组织,差异有统计学意义(P<0.05);高表达组患者化疗有效率高于低表达组,差异有统计学意义(P<0.05);所有患者随访0.5~5年,平均随访时间3.86年,最终有45例存活5年以上,高表达组患者5年存活率(88.00%)高于低表达组(57.25%),差异有统计学意义(P<0.05);存活组患者膀胱尿路上皮癌组织中miR-133b水平高于死亡组,差异有统计学意义(P<0.05).结论 与癌旁正常组织比较,膀胱尿路上皮癌组织中miR-133b呈明显低表达,且与术后化疗敏感性、预后有密切关系,有可能作为预测化疗疗效和判断预后的指标之一.     

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.