Uroplakin gene expression in normal human tissues and locally advanced bladder cancer

The uroplakins are widely regarded as urothelium-specific markers of terminal urothelial cytodifferentiation. This study investigated the expression of the four uroplakin genes, UPIa, UPIb, UPII and UPIII, in a wide range of normal human tissues to determine tissue specificity and in advanced transitional cell carcinoma (TCC) to examine gene expression in primary and metastatic disease. In the urinary tract, all four uroplakins were expressed by urothelium and UPIII was also expressed by prostatic glandular epithelium. UPIa and UPII appeared to be urothelium-specific, but UPIb was detected in several non-urothelial tissues, including the respiratory tract, where it was associated with squamous metaplasia of tracheal and bronchial epithelia. The ten cases of primary TCC and corresponding lymph node metastases demonstrated that each uroplakin gene could be expressed at the mRNA level. No single uroplakin gene was expressed in all primary tumours or metastases, but 80% of the primary tumours and 70% of the lymph node metastases expressed at least one uroplakin gene. UPIII mRNA was often expressed in the absence of UPIII protein. These results confirm that in human tissues the expression of UPIa and UPII genes is highly specific to urothelium and suggest that the tight differentiation-restricted expression of uroplakin genes in normal urothelium is lost following malignant transformation.     

Uroplakins, specific membrane proteins of urothelial umbrella cells, as histological markers of metastatic transitional cell carcinomas.

Uroplakins (UPs) Ia, Ib, II, and III, transmembrane proteins constituting the asymmetrical unit membrane of urothelial umbrella cells, are the first specific urothelial differentiation markers described. We investigated the presence and localization patterns of UPs in various human carcinomas by applying immunohistochemistry (avidin-biotin-peroxidase complex method), using rabbit antibodies against UPs II and III, to paraffin sections. Positive reactions for UP III (sometimes very focal) were noted in 14 of the 16 papillary noninvasive transitional cell carcinomas (TCCs) (88%), 29 of the 55 invasive TCCs (53%), and 23 of the 35 TCC metastases (66%). Different localization patterns of UPs could be distinguished, including superficial membrane staining like that found in normal umbrella cells (in papillary carcinoma), luminal (microluminal) membrane staining (in papillary and invasive carcinoma), and, against expectations, peripheral membrane staining (in invasive carcinoma). Non-TCC carcinomas of various origins (n = 177) were consistently negative for UPs. The presence of UPs in metastatic TCCs represents a prime example of even advanced tumor progression being compatible with the (focal) expression of highly specialized differentiation repertoires. Although of only medium-grade sensitivity, UPs do seem to be highly specific urothelial lineage markers, thus operating up interesting histodiagnostic possibilities in cases of carcinoma metastases of uncertain origin.     

E-cadherin expression in urothelial carcinoma in situ,superficial papillary transitional cell carcinoma,and invasive transitional cell carcinoma

Flat urothelial carcinoma in situ (CIS) is a precursor of invasive transitional cell carcinoma (TCC). High-grade TCCs frequently are accompanied by CIS in surrounding urothelium. In contrast, superficial, noninvasive papillary TCCs are often low grade and generally are unaccompanied by CIS. E-cadherin (E-CD) is a member of a family of transmembrane glycoproteins involved in intercellular adhesion. Loss or decreased expression of E-CD has been linked to the invasive phenotype of a wide variety of human neoplasms, including bladder tumors. The objective of this study was to compare the expression of E-CD in high-grade urothelial dysplasia (HD)/CIS, superficial papillary TCC, benign urothelium, and invasive TCC. Staining for E-CD was performed in formalin-fixed, paraffin-embedded sections using a Ventana NexES immunostainer (Tuscon, AZ). Percentage and intensity of cell membrane staining for E-CD was calculated for the 4 groups using the quantitative Automatic Cellular Imaging System (ChromaVision, San Juan Capistrano, CA). The results were as follows: The CIS group (n = 23) had percentage and intensity (92.8%, 120.0 U) of E-CD expression similar to the superficial noninvasive papillary TCC group (n = 16, 97.8%, 123.0 U) and the benign urothelium group (n = 17, 87.9%, 104.6 U), but it had statistically significant higher percentage and intensity than the invasive TCC group (n = 15, 45.4%, and 39.2 U, P <.05). Our data indicate that CIS and superficial, noninvasive papillary TCCs strongly express E-CD. In contrast, loss of E-CD expression is associated with the invasive TCC phenotype. Only when TCCs become invasive does E-CD expression decrease in directly proportion to the depth of invasion.     

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.     

Aberrant differentiation of urothelial cells in patients with ureteropelvic junction obstruction

Aim: To investigate the urothelial changes in the pathogenesis of ureteropelvic junction obstruction (UPJ-O). Methods: A total of 12 patients of UPJ-O were respectively studied. The expression of Annexin A7, Annexin A11, EGFR, Keratin 5, uroplakin III, and SMA in the urothelium of obstructed UPJ segment and of the normal ureter below the obstructed segment were determined by immunofluorescence. Transmission electron microscopy was used to determine the morphological changes in UPJ epithelium in compared to normal ureteral epithelium. Results: We found that Annexin A7, Annexin A11, EGFR, Keratin 5, and SMA were upregulated, while uroplakin III was downregulated in the urothelium of UPJ-O patients. Furthermore, ultrastructural analyses showed that intercellular spaces between urothelial cells were dilated and the number of microvilli on superficial cells was increased in UPJ-O patients. Conclusions: We propose that a disrupted urothelial barrier in UPJ-O may results in urothelial inflammatory response and truncated differentiated urothelial cells, which may play an important role in the development and pathogenesis of UPJO.     

Collecting duct carcinoma of the kidney: an immunohistochemical evaluation of the use of antibodies for differential diagnosis

Collecting duct carcinoma is a highly aggressive renal epithelial malignancy, although it accounts for less than 1% of the incidence of renal epithelial neoplasms. Differential diagnoses between collecting duct carcinoma, pelvic urothelial carcinoma with marked invasion to the renal parenchyma (invasive urothelial carcinoma), and papillary renal cell carcinoma is often challenging. In our current study, we examined the utility of using commercially available antibodies, in conjunction with lectin histochemistry, for such differential diagnoses. We examined 17 cases of collecting duct carcinoma, 10 cases of invasive urothelial carcinoma and 15 cases of papillary renal cell carcinoma (type 1, 6 cases; type 2, 9 cases) in these evaluations. Our results indicated that Ulex europaeus agglutinin 1, E-cadherin, and c-KIT were frequently positive in collecting duct carcinoma and invasive urothelial carcinoma, in comparison with papillary renal cell carcinoma, which had negative results for CD10 and α-methylacyl CoA racemase. We found, however, that collecting duct carcinoma showed positivity for high-molecular-weight cytokeratin and low-molecular-weight cytokeratin at a low frequency compared with invasive urothelial carcinoma, and that these distinctions need further careful evaluation. In addition, high-molecular-weight cytokeratin positivity was not a reliable marker for collecting duct carcinoma. We conclude that Ulex europaeus agglutinin 1 reactivity and positivity for E-cadherin and c-KIT are effective in distinguishing collecting duct carcinoma from papillary renal cell carcinoma, and that negative results for α-methylacyl CoA racemase and CD10 are potentially useful hallmarks of this distinction also. In contrast, a differential diagnosis for collecting duct carcinoma and invasive urothelial carcinoma will require careful examination of multiple routinely stained specimens, particularly in cases of in situ neoplastic lesions in the pelvic mucosa.     

Micropapillary Carcinoma of the Breast with Necrosis-like Cell Death: A Case Report

A primary invasive micropapillary carcinoma of the breast in a 46-year-old woman is reported. Histologically, it was composed predominantly of papillary tumor cell clusters without fibrovascular cores, surrounded by a clear space. Tumor cells were positive for cytokeratin (CK) 7, estrogen receptor (ER), and progesterone receptor (PR), but negative for p53, CK 20, CD34, c-Erb-B2, CK5, epidermal growth factor receptor (EGFR), vimentin, and c-kit. MUC1 expression was found at the reversed apical membrane of neoplastic cell clusters. Accordingly, electron microscopy showed the lack of basement membrane and presence of microvilli at the basal surface of the tumor cells. Moreover, ultrastructural examination revealed single tumor cell death characterized by patchy condensations of chromatin throughout the nucleus. These nuclear alterations were associated with the occurrence of empty cytoplasmic vacuoles, conferring a necrosis-like phenotype to this cell death. Alternative programmed cell deaths are reviewed and their morphologic distinction is discussed.     

Micropapillary carcinoma of the breast with necrosis-like cell death: a case report

A primary invasive micropapillary carcinoma of the breast in a 46-year-old woman is reported. Histologically, it was composed predominantly of papillary tumor cell clusters without fibrovascular cores, surrounded by a clear space. Tumor cells were positive for cytokeratin (CK) 7, estrogen receptor (ER), and progesterone receptor (PR), but negative for p53, CK 20, CD34, c-Erb-B2, CK5, epidermal growth factor receptor (EGFR), vimentin, and c-kit. MUC1 expression was found at the reversed apical membrane of neoplastic cell clusters. Accordingly, electron microscopy showed the lack of basement membrane and presence of microvilli at the basal surface of the tumor cells. Moreover, ultrastructural examination revealed single tumor cell death characterized by patchy condensations of chromatin throughout the nucleus. These nuclear alterations were associated with the occurrence of empty cytoplasmic vacuoles, conferring a necrosis-like phenotype to this cell death. Alternative programmed cell deaths are reviewed and their morphologic distinction is discussed.     

E-cadherin expression in invasive urothelial carcinoma

E-cadherin (E-CD) is a transmembrane glycoprotein involved in intercellular adhesion. A loss or reduction in E-CD expression has been linked to the invasive phenotype of a wide variety of human neoplasms, including bladder tumors. The objective of this study was to compare the E-CD expression at different depths of tumor invasion below the bladder's basement membrane in high- and low-grade urothelial carcinomas to investigate whether deeper tumor invasion and higher-grade invasive urothelial carcinomas are associated with decreased E-CD expression. E-cadherin staining was performed on 29 formalin-fixed, paraffin-embedded sections from high- and low-grade urothelial carcinoma specimens using an automatic immunohistochemical stainer. The sections were divided into three categories according to the depth of invasion below the basement membrane: upper, middle, and lower. The percentage and intensity of E-CD cell membrane staining for the three categories were calculated using a quantitative automated cellular imaging system. The percentage of cells that stained for E-CD was 82.6% +/- 1.4% (mean +/- SD) in the upper layer, 59.6% +/- 2.2% in the middle layer, and 29.4% +/- 2.7% in the lower layer. The intensity of E-CD expression was 64.7 +/- 3.2 units in the upper layer, 43.3 +/- 2.9 units in the middle layer, and 26.1 +/- 3.1 units in the lower layer. There were significant differences between the three layers in both the percentage and intensity of cellular E-CD staining (P<.05). Normal urothelium, high-grade urothelial dysplasia/carcinoma in situ, and superficial noninvasive papillary urothelial carcinoma maintained E-CD expression. However, once malignant cells infiltrated through the basement membrane, E-CD expression decreased. The more poorly differentiated urothelial carcinoma, the deeper the nests, and the smaller the clusters of neoplastic cells within the tumor were, and the more decrease in E-CD expression noted. The degree of decreased E-CD expression was directly proportional to the degree of tumor differentiation and depth of infiltration in invasive urothelial carcinoma. Down-regulation of E-CD may be one of the pathways responsible for tumor differentiation and may promote deeper invasion in urothelial carcinomas.     

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.     

Fascin as an identifier of metastatic urothelial carcinoma: A retrospective study of fine-needle aspiration cell blocks and histologic tissue microarrays

Fascin, a marker of invasiveness in urothelial carcinoma, has not been correlated with metastatic disease. To enhance diagnostic accuracy and correctly identify primary site for appropriate patient management, fascin may be a useful marker in metastatic urothelial carcinoma. In this study, we evaluated twenty five cases with adequate cell block material for immunohistochemistry (IHC) staining in patients with either concurrent or previously resected urothelial carcinoma between 2005 and 2010. Fascin, thrombomodulin, uroplakin, cytokeratin 7, and cytokeratin 20 IHC were performed on paraffin-embedded cell block serial sections. Fascin was over-expressed in the majority (23/25, 92%) of metastatic urothelial carcinomas. We found concordant results in 22 of 25 (88%) cases for fascin and thrombomodulin IHC staining. Either fascin and/or thrombomodulin demonstrated positive staining in 25 of 25 (100%) cases. Histologic tissue microarrays of 72 genitourinary (GU) carcinomas of the kidney and prostate were stained with fascin to reveal all cases to be negative in the cells of interest. In comparing fascin with the traditional markers of urothelial carcinoma, fascin expression is of greater frequency and intensity than thrombomodulin. The combination of fascin and/or thrombomodulin identified all 25 (100%) cases of urothelial carcinoma. Fascin IHC staining is equivalent in frequency and intensity to cytokeratin 7. Fascin is an advantageous diagnostic complement, to thrombomodulin and/or cytokeratin 7, in the setting of metastatic urothelial carcinoma, and is highly specific and sensitive relative to GU malignancies.     

Comparison of the WHO/ISUP classification and cytokeratin 20 expression in predicting the behavior of low-grade papillary urothelial tumors. World/Health Organization/Internattional Society of Urologic Pathology.

It has not been possible to identify those low-grade papillary transitional cell bladder tumors that will recur based on conventional histopathologic assessment. Both the new World Health Organization/International Society of Urologic Pathology (WHO/ISUP) classification of transitional cell papillary neoplasms and the pattern of tumor cytokeratin 20 (CK20) immunostaining have been suggested as means of improving prognostication in low-grade transitional cell tumors. Forty-nine low-grade, noninvasive papillary transitional cell tumors were identified for the period between 1984 and 1993. The recently described WHO/ISUP classification was applied, and the tumors were classified histologically as papilloma, papillary neoplasm of low malignant potential (LMP) or low-grade papillary carcinoma. After CK20 immunostaining, the expression pattern in the tumor was classified as normal (superficial) or abnormal. Of 49 tumors, 20 were classified as papillary neoplasms of LMP and five of these patients (25%) experienced a recurrence. Of 29 tumors classified as low-grade papillary carcinoma, 14 (48.2%) recurred. In 46 of 49 cases, the CK20 immunostaining could be evaluated. Sixteen tumors showed normal (superficial) pattern of CK20 expression, and four (25%) of these patients experienced a recurrence. In contrast, of 30 patients with abnormal CK20 staining of their tumors, 15 (50%) patients had one or more recurrences. In this study, papillary neoplasms of LMP (as per the WHO/ISUP classification system) had a lower recurrence rate than low-grade papillary transitional cell carcinoma. Similarly low-grade urothelial tumors showing a normal CK20 expression pattern recurred less frequently than tumors with an abnormal pattern of CK20 staining. Neither of these differences was statistically significant, and recurrences were observed in 20% of patients whose tumors were both classified as papillary neoplasms of LMP and showed normal CK20 immunostaining; thus they do not allow a change in our current management of patients with low-grade papillary urothelial tumors, with close follow-up for all patients.     

Evidence for the early onset of aberrant promoter methylation in urothelial carcinoma

There is evidence that carcinoma in situ (CIS) is the precursor of invasive urothelial carcinoma, a tumour characterized by frequent gene promoter methylation. The timing of altered DNA methylation is unknown in this pathway. Here we investigate gene methylation in 196 consecutive samples of normal urothelium, CIS, and tumours from 104 patients with both CIS and invasive urothelial carcinoma using quantitative methyl-sensitive polymerase chain reaction for six genes (p16, p14, E-cadherin, RARbeta2, RASSF1a, and GSTP1). Control normal urothelial samples from 15 patients with no history of urothelial carcinoma were also analysed. Immunohistochemistry established the expression of well-characterized CIS markers p53 and cytokeratin 20. Promoter methylation occurred frequently in both normal urothelium and CIS samples from patients with urothelial carcinoma, and increased with progression from normal to invasive urothelial carcinoma, at both specific loci (chi2 test: E-cadherin, p=0.0001; RASSF1a, p=0.003, RARbeta2, p=0.007, p16, p=0.024) and in general (methylation indices [t-test, p<0.0001]). Methylation was associated with cytokeratin 20 expression (t-test, p=0.004) and poor prognosis, and with increased progression to tumour death in patients whose CIS samples showed methylation, in comparison with those without methylation (log rank p<0.03). Promoter methylation occurs early in the urothelial carcinogenic pathway and appears to be a good biomarker of the invasive urothelial carcinoma phenotype.     

Highly invasive transitional cell carcinoma of the bladder in a simian virus 40 T-antigen transgenic mouse model

Transitional cell carcinoma (TCC), a neoplasm of urinary bladder urothelial cells, generally appears in either of two forms, papillary non-invasive or invasive TCC, although intermediate forms can occur. Each has a distinctive morphology and clinical course. Altered expression of the p53 and pRb genes has been associated with the more serious invasive TCC, suggesting that the loss of activity of these tumor suppressor proteins may have a causal role in this disease. To test this hypothesis directly, transgenic mice were developed that expressed the simian virus 40 large T antigen (TAg) in urothelial cells under the control of the cytokeratin 19 gene (CK19) regulatory elements. In one CK19-TAg lineage, all transgenic mice developed highly invasive bladder neoplasms that resembled invasive human bladder TCCs. Stages of disease progression included development of carcinoma in situ, stromal invasion, muscle invasion, rapid growth, and, in 20% of affected mice, intravascular lung metastasis. Papillary lesions never were observed. Western blot analysis indicated that TAg was bound to both p53 and pRb, which has been shown to cause inactivation of these proteins. Our findings support suggestions that (i) inactivation of p53 and/or pRb constitutes a causal step in the etiology of invasive TCC, (ii) papillary and invasive TCC may have different molecular causes, and (iii) carcinoma in situ can represent an early stage in the progression to invasive TCC.     

Immunohistochemical expression of keratin proteins in urinary bladder carcinoma

Transitional carcinomas of the urinary bladder were examined immunohistochemically for keratin proteins with the use of polyclonal antiserum (TK, 41-65 kDa) and 3 monoclonal antibodies (KL 1, 55-57 kDa; PKK 1, nos. 19, 18, 8; and K 8.12, nos. 16, 13). Umbrella cells gave particularly strong staining for TK, KL 1 and PKK 1, whereas they were negative for K 8.12. Basal- and intermediate-layer cells in urothelial epithelium were moderately positive for all keratins. Brunn's nests cells showed comparatively slight or moderate keratin staining, and K 8.12 staining of Brunn's nests was higher than in urothelial epithelial cells. Transitional carcinoma (grades I and II) indicated uniform keratin distribution, and staining was strong with TK, while that of KL 1, PKK 1 and K 8.12 varied, and grade III tumors showed the lowest intensity of staining. K 8.12 staining in papillary transitional carcinomas was strongly positive in basal located tumor cells, as compared with apical tumor cells. Squamous cell carcinoma was varying positive to keratin reactions dependent on the degree of keratinization. Heterogenity of keratin distribution in papillary transitional carcinomas was given between basal tumor cells and well differentiated tumor cells including umbrella-like cells.     

Expression of CD15 antigen in urinary bladder transitional cell carcinoma.

The biopsy specimens of 91 patients between the ages of 38 and 94 with transitional cell carcinoma of the bladder were retrospectively reviewed to determine if the expression of CD15 antigen detected by a monoclonal antibody MC2 was correlated with prognosis. Expression was variable, ranging from strong expression of the antigen by only the superficial cells in well differentiated papillary lesions to weak expression by most cells in solid or invasive tumours. In the invasive component there was a correlation between MC2 expression and tumour type, suggesting that the cell surface carbohydrate detected by MC2 may have a role in cell adhesion. There was no correlation between staining and survival. It is concluded that tumour type, grade, and stage remain the best prognostic indicators of urothelial tumours.     

Solid papillary ductal carcinoma in situ versus usual ductal hyperplasia in the breast: a potentially difficult distinction resolved by cytokeratin 5/6

The solid papillary variant of ductal carcinoma in situ is an uncommon entity, which usually presents in the seventh or eighth decade and may be associated with invasive mucinous carcinoma. Solid papillary ductal carcinoma in situ (SP-DCIS) shares many morphological features with usual ductal hyperplasia (UDH) involving a papilloma: papillary architecture, solid growth, cellular streaming, and low-grade nuclear features. These similarities can make the distinction between these 2 entities challenging. Recent studies have demonstrated that immunohistochemical staining for cytokeratin 5/6 can distinguish UDH from conventional forms of ductal carcinoma in situ. Most of the epithelial cells of UDH express cytokeratin 5/6, but the tumor cells of ductal carcinoma in situ do not. We tested the hypothesis that the results of staining for cytokeratin 5/6 can distinguish UDH from the solid papillary variant of ductal carcinoma in situ. Immunohistochemical staining of 14 cases of SP-DCIS and 9 cases of UDH (4 involving papillomas) was performed using cytokeratin 5/6 antibody clone D5/16 B4. Strong cytoplasmic or membrane staining was considered positive. The hyperplastic cells in all cases of UDH showed strong staining for cytokeratin 5/6. The percentage of positive cells ranged from 50% to 80%. None of the SP-DCIS tumor cells stained for cytokeratin 5/6; however, many cases did show staining of occasional entrapped, benign epithelial, and myoepithelial cells. We conclude that the absence of strong cytokeratin 5/6 expression by SP-DCIS distinguishes it from its morphological mimic, UDH. Pathologists must guard against misinterpreting SP-DCIS as UDH in those cases in which the carcinoma cells engulf cytokeratin 5/6-expressing residual, native epithelial cells.     

Aberrant expression of beta-catenin and mutation of exon 3 of the beta-catenin gene in renal and urothelial carcinomas

The present study attempted to clarify the significance of aberrant expression of beta-catenin protein and mutation of exon 3 of the beta-catenin gene in renal and urothelial carcinogenesis. beta-Catenin expression was examined immunohistochemically and mutation of the beta-catenin gene was analyzed by polymerase chain reaction-single strand conformation polymorphism (SSCP) and direct sequencing. beta-Catenin immunoreactivity was observed at the cell membrane in all 30 renal cell carcinomas (RCC) examined, and no RCC showed a mobility-shifted SSCP band. Of 46 transitional cell carcinomas (TCC) examined, there was reduced expression of beta-catenin, as compared with its expression in non-cancerous transitional epithelium, in 22 cases (48%) and beta-catenin accumulation in the nucleus in five cases (11%). Of four renal pelvis TCC examined, point mutation of exon 3 of the beta-catenin gene at codon 45 resulting in amino acid substitution (Ser to Phe) was detected in one (25%). The incidence of reduced expression of beta-catenin correlated significantly with the growth pattern (superficial type vs invasive type) of TCC (P < 0.05). These data indicate that: (1) aberrant beta-catenin expression may be at least partly involved in urothelial carcinogenesis, but less significantly so in renal carcinogenesis, and (2) it may be associated with the progression of TCC showing invasive growth.     

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.