Diagnostic algorithm for papillary urothelial tumors in the urinary bladder

Papillary urothelial neoplasms with deceptively bland cytology cannot be easily classified. We aimed to design a new algorithm that could differentiate between these neoplasms based on a scoring system. We proposed a new scoring system that enables to reproducibly diagnose non-invasive papillary urothelial tumors. In this system, each lesion was given individual scores from 0 to 3 for mitosis and cellular thickness, from 0 to 2 for cellular atypia, and an additional score for papillary fusion. These scores were combined to form a summed score allowing the tumors to be ranked as follows: 0–1 = UP, 2–4 = low malignant potential (LMP), 5–7 = low-grade transitional cell carcinoma (TCC), and 8–9 = high-grade TCC. In addition to the scoring system, ancillary studies of MIB and p53 indexes with CK20 expression pattern analyses were compared together with clinical parameters. The MIB index was strongly correlated with disease progression. Four of the 22 LMP patients (18.2%) had late recurrences, two of these four (9.1%) had progression to low-grade carcinoma. The MIB index for LMP patients was strongly associated with recurrence (recurrence vs. non-recurrence, 16.5 vs. 8.1, p < 0.001). The proposed scoring system could enhance the reproducibility to distinguish papillary urothelial neoplasms.     

Concurrent malakoplakia and papillary urothelial carcinoma of the urinary bladder

A case of malakoplakia and papillary urothelial carcinoma of the urinary bladder is reported. In this case, malakoplakia was an incidental finding in a biopsy of the urinary bladder of a 74-yr old female, who presented with hematuria. The biopsy showed a low-grade papillary urothelial carcinoma in close association with malakoplakia. This is a rare association of these lesions.     

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.     

Fascin-1 expression in papillary and invasive urothelial carcinomas of the urinary bladder

Fascin-1 is an actin-bundling protein that plays an important role in cell motility and adhesion. The level of fascin-1 is low or undetectable in normal epithelial cells. However, overexpression is reported in transformed epithelial cells and in several common types of carcinomas [Bioessays. 2002;24:359-361]. Up-regulation of fascin-1 is associated with higher grades and with aggressive tumors with poorer prognoses. We found no report on the role or the protein expression of fascin-1 in urothelial carcinomas (UCs) of the urinary bladder. In this study, we examined by immunohistochemistry the expression of fascin-1 in the normal human transitional epithelium, benign vesical lesions, and different types of UCs. We found no detectable fascin-1 in the normal transitional epithelium. There was no increase of fascin-1 expression in cystitis cystica, cystitis glandularis, nephrogenic adenoma (n = 10), inverted papilloma (n = 5), and classic exophytic papilloma (n = 4) or in adjacent transitional epithelia associated with these conditions. Patchy or diffusely weak fascin-1 expression was observed in 42% (5/12) of superficial papillary UCs (Ta), and 95% (19/20) of invasive UCs (T2 or higher) demonstrated diffuse strong staining for fascin-1. The microinvasive foci in the lamina propria of UC (T1, n = 8) were also positive for fascin-1, although they were not as strongly stained as in the deeply invasive tumors. Interestingly, the neoplastic cells in the tips of microinvasive carcinomas were distinctly positive for fascin-1. There were significant numbers of fascin-1-positive cells (>50% of the neoplastic cells) in UCs in situ (n = 10). These findings suggest an association between increased fascin-1 expression and increased invasiveness of carcinomas in the urinary bladder.     

膀胱乳头状尿路上皮肿瘤中CD10和CK20的表达

目的探讨CD10与CK20在膀胱乳头状尿路上皮肿瘤中的表达及临床病理意义。方法以19例正常尿路上皮为对照,采用免疫组化法检测74例膀胱乳头状尿路上皮肿瘤中CK20和CD10染色分布模式和强度以及二者之间的关系。结果CD10与CK20的阳性率分别为51.4%和54.4%,两者的染色分布和强度差异无显著性(P0.05)。CK20的染色分布模式在尿路上皮乳头状瘤(urothelial papilloma,UP)和非浸润性乳头状尿路上皮癌(non-invasive papillary urothelial carcinoma,NIPUC)中差异有显著性(P0.05)。CD10与CK20的染色强度整体比较差异有统计学意义(P0.05),且UP、低度恶性潜能未定的乳头状尿路上皮肿瘤(papillary urothelial neoplasm of law malignant potential,PUNLMP)与NIPUC组间相比差异均有统计学意义(P0.05)。两者联合检测阳性率达74.3%,癌组织中阳性率为84.9%。结论 CD10与CK20在膀胱乳头状尿路上皮肿瘤中的表达极其相似,联合使用明显提高阳性率;对鉴别尿路上皮乳头状肿瘤表浅病变的类型以及该类肿瘤的良恶性有意义。     

Inverted urothelial papilloma of the urinary bladder with focal papillary pattern: a previously undescribed feature

We report 2 examples of inverted urothelial papillomas with a focal papillary pattern. Both patients, a 43-year-old man and a 13-year-old adolescent boy, presented with hematuria. In addition to the characteristic trabecular endophytic growth pattern and bland cytologic features, the tumors showed focal papillary architecture in the endophytic component. Because of this feature, both tumors were misinterpreted as papillary urothelial carcinoma with inverted pattern. However, the papillary fronds were similar to those of exophytic urothelial papilloma. They were lined by 3 to 8 layers of normal-appearing urothelial cells often covered by a continuous or discontinuous layer of superficial (umbrella) cells. Although follow-up is limited, the 2 patients have remained asymptomatic. The recognition of papillary structures in urothelial inverted papilloma broadens the morphological spectrum of this unusual benign urothelial neoplasm and complicates the microscopic interpretation of urothelial lesions with inverted growth patterns. Surgical pathologists should be aware of this unusual feature of inverted urothelial papilloma of the urinary bladder to avoid misinterpretation with urothelial carcinoma with an inverted pattern.     

Expression of miRNAs and ZEB1 and ZEB2 correlates with histopathological grade in papillary urothelial tumors of the urinary bladder

Histopathological grading of papillary urothelial tumors (PUTs) of the urinary bladder is subjective and poorly reproducible. We investigated the relationship between the expression of frequently deregulated microRNAs (miRNAs) as well as their target genes (ZEB1/ZEB2) and bladder cancer histopathological grade in an attempt to find a miRNA that might allow more reliable grading of PUTs. We measured the expression levels of four miRNAs (miR-145, miR-205, miR-125b, and miR-200c) in 120 formalin-fixed, paraffin-embedded bladder tumor tissue samples using real-time PCR assays. ZEB1 and ZEB2 expression was assessed in the same bladder tissues by immunohistochemistry. MiR-205 distinguished low-grade papillary urothelial carcinoma (LG) from high-grade papillary urothelial carcinoma (HG), and miR-145 distinguished HG from infiltrating carcinoma (CA) with an area under the receiver operator characteristic curve (AUC) of 0.992 and 0.997, respectively (sensitivity/specificity of 95.8/96.7 % and 100/91.7 %, respectively; p?<?0.05). The expression level of miR-125b was significantly lower in LG than in PUNLMP, with an AUC value of 0.870 (93.3 % sensitivity and 84.2 % specificity; p?<?0.05). ZEB1 immunoreactivity was more frequently detected in HG than in LG (57 % vs 13 %, p?<?0.01) and in HG than in CA (57 % vs 17 %, p?<?0.01). ZEB2 immunoreactivity was more frequent in CA than in HG (83 % vs 54 %, p?<?0.05). ZEB1/ZEB2 and miRNAs expression seems to reliably distinguish between different grades of PUTs of the urinary bladder. They might well serve as useful complementary diagnostic biomarkers for grading of papillary urothelial tumors.     

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.     

Reproducibility of the 1998 World Health Organization/International Society of Urologic Pathology classification of papillary urothelial neoplasms of the urinary bladder

Objectives This study assessed the diagnostic agreement and intra- and inter-observer reproducibility of the World Health Organization/International Society of Urologic Pathology Consensus Classification of Urothelial Neoplasms (1998 WHO/ISUP classification) and the 1973 WHO classification.Methods A teaching set with 5 slides of each papillary neoplasm of low malignant potential, low-grade papillary carcinoma, high-grade papillary carcinoma, and a guideline, as well as a study set of 30 slides containing ten cases of each category, were sent to participants. Six pathologists expert in urological pathology reviewed the 30 slides of non-invasive papillary urothelial tumors in the study set. Diagnostic accuracy and reproducibility were evaluated using intra- and inter-rater techniques (kappa statistic).Results A moderate to substantial intra- and inter-observer reproducibility was achieved for both the 1998 WHO/ISUP and 1973 WHO classification. The results of the two classification systems were not different statistically (P>0.05). Reproducibility was lower in low-grade tumors for both classifications.Conclusions The new proposed classification system for non-invasive urothelial neoplasms does not increase the reproducibility. There is still a need for uniformity in grading in order to compare the different studies and therapies and to provide more accurate information for management.     

Spindle cell lesions of the bladder and urinary tract

Spindle cell lesions of the urinary tract encompass a variety of benign and malignant tumours as well as a group of lesions of controversial nomenclature that is the subject of ongoing debate. This review focuses on our current and evolving understanding of the lesion variably referred to as inflammatory myofibroblastic tumour, pseudosarcomatous myofibroblastic proliferation or inflammatory pseudotumour and the main differential diagnoses of sarcomatoid carcinoma and sarcoma. Other spindle cell lesions of the bladder are described.     

Myoepithelial cell staining patterns of papillary breast lesions: from intraductal papillomas to invasive papillary carcinomas

We evaluated 25 intraductal papillomas and 18 papillary carcinomas (invasive, 4; micropapillary ductal carcinoma in situ [DCIS], 5; cases originally classified as intracystic/intraductal papillary carcinoma, 9) by calponin, smooth muscle myosin heavy chain (SMM-HC), and p63 immunostains. Calponin, SMM-HC, and p63 labeled myoepithelial cells (MECs) in all intraductal papillomas and all micropapillary DCIS cases. The invasive papillary carcinoma cases were uniformly negative for all stains. The 9 cases originally diagnosed as intracystic/intraductal papillary carcinoma showed more variable results, with identification of an MEC layer in only 4 cases. Comparison of staining of MECs by these 3 stains showed that calponin was more sensitive and intense than SMM-HC; however, there was cross-reactivity with myofibroblastic cells. Staining with p63 was discontinuous, making interpretation of an intact myoepithelial layer difficult. Of 9 cases originally classified as intraductal papillary carcinoma, 5 showed absence of a basal MEC layer by immunohistochemical analysis. The lack of a basal MEC layer in these cases suggests a spectrum of progression from in situ to invasive disease and might help explain distant metastases from previously reported "intraductal papillary carcinoma."     

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.     

Histologic grading of noninvasive papillary urothelial tumors: validation of the 1998 WHO/ISUP system by immunophenotyping and follow-up

Cytokeratin (CK) 20, Ki-67, and p53 were applied to 84 noninvasive papillary urothelial tumors graded by the 1973 World Health Organization (WHO) and 1998 WHO/International Society of Urological Pathology (ISUP) systems. In the WHO/ISUP classification, all benign lesions showed normal CK20 staining and all carcinomas showed abnormal staining. The Ki-67 index was significantly different between benign and malignant lesions (P < .05) and between low- and high-grade carcinomas (P < .001). p53 was negative in all benign lesions, with a significant difference between low- and high-grade carcinomas (P < .001). Tumor recurrence was significantly different between low- and high-grade carcinomas (no recurrences among the papillary urothelial neoplasms of low malignant potential). By the 1973 WHO classification, normal CK20 staining was present both in benign lesions and in carcinomas. Ki-67 staining did not distinguish between grade 2 and grade 3 carcinomas (P > .05), and there was no difference in p53 staining in grades 1 and 2 carcinomas (P > .05). Recurrences were not different between grades 1, 2, and 3 carcinomas. All biologic markers studied and tumor recurrences were significantly different among papillary lesions classified by the WHO/ISUP system but not by the 1973 WHO system, validating the predictive value of the WHO/ISUP system and providing objective markers for the grading of papillary urothelial tumors.     

An approach to the classification of spindle cell proliferations in the urinary bladder

Spindle cell proliferations of the urinary bladder are uncommon but may cause significant diagnostic difficulty resulting from the degree of morphologic overlap between clinically benign and malignant lesions. These difficulties may be amplified in small biopsies because some of the more specific diagnostic features may not be present for evaluation. In addition, the number of different diagnostic terms applied to the same entity has added confusion to this diagnostic area. This review discusses the nomenclature, morphologic criteria, and immunohistochemical features used to classify spindle cell proliferations occurring in the urinary bladder, including those with myofibroblastic, smooth muscle, skeletal muscle, epithelial (sarcomatoid urothelial carcinoma), fibroblastic, and neural differentiation. A separate discussion of 5 challenging differential diagnostic scenarios is also presented.     

Primary multiple clear cell variant urothelial carcinomas of urinary bladder: a rare case report

Clear cell variant urothelial carcinoma of urinary bladder was very rare. There were only 6 report articles included by Pubmed and total 8 cases had been described till now. All of the past reports described single tumor of urinary bladder, but multiple carcinomas had not been reported. Here we reported a 65-years-old Chinese man who complained of intermittent gross hematuria and odynuria for more than 2 months in January 2013. Only one cauliflower-like tumor was detected approximately in the left wall of the urinary bladder with cystoscopy and the biopsy specimen was diagnosed as “urothelial carcinoma, high grade”. However, three tumors were found in anterior wall (×2) near neck of urinary bladder and posterior wall (×1) of the urinary bladder during transurethral resection of the bladder tumor. Typical urothelial carcinoma with partial clear cell appearance made it difficult to make a precise pathological diagnosis and immunohistochemical stain helped to diagnose the case as clear cell variant urothelial carcinoma, but not metastasis of the renal cell carcinoma. Finally, computerized tomographic scanning confirmed that there was no primary tumor in the kidney. The clinical and pathological characteristic had not been identified for the limited reports. More work should be done to know this kind of tumor well for guiding clinical therapy.     

Malignant glandular lesions and glandular differentiation in invasive/noninvasive urothelial carcinoma of the urinary bladder

Although the lumen of the urinary bladder is covered with only urothelial epithelium, malign glandular lesions (eg, nonurachal adenocarcinoma) and benign lesions (eg, cystitis cystica and cystitis glandularis) can also rarely occur in this site due to its characteristic embryologic development. Glandular differentiation is uncommon in urothelial carcinomas and is even less common in noninvasive urothelial cancers. In addition, in situ urothelial carcinomas are more likely to progress in the presence of glandular differentiation toward high-grade urothelial carcinomas and/or aggressive urothelial carcinomas. Pure nonurachal adenocarcinomas and mixed carcinomas (urothelial carcinoma and adenocarcinoma) are very rare, and their pathogenesis is not clear. Most of the nonurachal adenocarcinomas are thought to arise on the grounds of cystitis glandularus with intestinal metaplasia. Here, I present 2 cases with noninvasive urothelial carcinoma with substantial glandular differentiation showing progression to signet ring cell carcinoma and invasive urothelial carcinoma, one case with mixed carcinoma (urothelial carcinoma and adenocarcinoma) and another case with pure adenocarcinoma developing from cystitis glandularis with intestinal metaplasia, and discuss malign glandular lesions in the bladder and invasive/noninvasive urothelial carcinomas with glandular differentiation.