Animals ; Carcinoma, Large Cell ; physiopathology ; Carcinoma, Transitional Cell ; classification ; Humans ; Urologic Neoplasms ; classification ; Urothelium ; metabolism ; pathology

Antigens, CD20 ; metabolism ; Carcinoma in Situ ; classification ; diagnosis ; metabolism ; pathology ; Diagnosis, Differential ; Humans ; Hyaluronan Receptors ; metabolism ; Hyperplasia ; Precancerous Conditions ; diagnosis ; metabolism ; pathology ; Tumor Suppressor Protein p53 ; metabolism ; Urinary Bladder ; metabolism ; pathology ; Urinary Bladder Neoplasms ; classification ; diagnosis ; metabolism ; pathology ; Urothelium ; metabolism ; pathology

Adenocarcinoma ; diagnosis ; metabolism ; pathology ; Adenocarcinoma, Clear Cell ; diagnosis ; metabolism ; pathology ; Carcinoma, Signet Ring Cell ; diagnosis ; metabolism ; pathology ; Diagnosis, Differential ; Humans ; Immunohistochemistry ; Urinary Bladder Neoplasms ; diagnosis ; metabolism ; pathology ; Urothelium ; pathology

Although germline mutations of met proto-oncogene on human chromosome 7q31-34 have been known as useful molecular markers of hereditary papillary renal cell carcinoma (RCC), the expression of MET, a product of met proto-oncogene, has not been fully studied in sporadic RCC, along with its clinical significance. We investigated the expression of MET by immunohistochemistry in 182 cases of renal neoplasm encompassing 145 RCC, 25 urothelial carcinomas of renal pelvis, and 12 oncocytomas. MET was diffusely and strongly expressed in 90% of papillary RCC, all collecting duct carcinomas, and 92% of urothelial carcinomas of renal pelvis. On the contrary, clear cell RCC, chromophobe RCC, and oncocytomas were negative or focally positive for MET expression. In clear cell RCC, MET expression was positively correlated with high nuclear grade, presence of infiltrative growth, tumoral necrosis, papillary architecture, sarcomatoid component, tumoral involvement of the renal pelvis or ureter, involvement of the calyx, and lymphatic invasion. In conclusion, diffuse and strong expression of MET in papillary RCC and collecting duct carcinoma might be helpful in discriminating from the other subtypes of RCC with tubular or papillary growth. In case of MET expression observed in clear cell RCC, it might correlate with those clinicopathological parameters implying aggressive behavior.
Urothelium/chemistry/pathology ; Receptors, Growth Factor/*biosynthesis ; Proto-Oncogene Proteins/*biosynthesis ; Neoplasm Staging ; Kidney Pelvis/chemistry/pathology ; Kidney Neoplasms/metabolism/*pathology ; Immunohistochemistry ; Humans ; Carcinoma, Renal Cell/metabolism/*pathology ; Adenoma, Oxyphilic/metabolism/pathology

Na+/K+-ATPase (NKA) is abundantly expressed in the basolateral membrane of epithelial cells, which is necessary for tight junction formation. The tight junction is an urothelial barrier between urine and the underlying bladder. Impairment of tight junctions allows migration of urinary solutes in patients with interstitial cystitis/painful bladder syndrome (IC/PBS). We evaluated NKA expression and activity in bladder samples from patients with IC/PBS. The study group consisted of 85 patients with IC/PBS, and the control group consisted of 20 volunteers. Bladder biopsies were taken from both groups. We determined the expression and distribution of NKA using NKA activity assays, immunoblotting, immunohistochemical staining, and immunofluorescent staining. The protein levels and activity of NKA in the study group were significantly lower than the control group (1.08 ± 0.06 vs. 2.39 ± 0.29 and 0.60 ± 0.04 vs. 1.81 ± 0.18 micromol ADP/mg protein/hour, respectively; P < 0.05). Additionally, immunofluorescent staining for detection of CK7, a marker of the bladder urothelium, predominantly colocalized with NKA in patients in the study group. Our results demonstrated the expression and activity of NKA were decreased in bladder biopsies of patients with IC/PBS. These findings suggest that NKA function is impaired in the bladders from patients with IC/PBS.
Adult ; Cystitis, Interstitial/*diagnosis/metabolism ; Female ; Fluorescent Antibody Technique ; Humans ; Keratin-7/metabolism ; Male ; Microscopy, Fluorescence ; Middle Aged ; Sodium-Potassium-Exchanging ATPase/*metabolism ; Urinary Bladder/metabolism/pathology ; Urothelium/metabolism/pathology

OBJECTIVETo study the clinicopathologic features of urothelial hyperplastic lesion with an endophytic growth pattern and the role of immunohistochemistry and multitargeted fluorescence in situ hybridization (FISH) in the differential diagnosis.

METHODSForty-one cases of urothelial lesions exhibiting endophytic growth patterns were reviewed and reclassified as inverted papilloma, urothelial carcinoma with an endophytic growth pattern, and florid von Brunn nest. The gains of chromosomes 3, 7, and 17 and loss of 9p21 was detected by FISH, and performed immunohistochemical staining for CK20, p53, and Ki-67. Follow-up data of 12 cases were obtained.

RESULTS(1) Twelve inverted papillomas sized 1.2 cm in average, consisted of anastomosing cords and nests with uniform width distribution involving the lamina propria, the central portion contained streaming cells with squamous metaplasia, and the periphery showed palisading. No or rare atypia and mitosis were found. Focal exophytic papillary component lined by less than 6 layers of normal urothelium were observed in 4 cases. (2) Twenty-four urothelial carcinomas with an endophytic growth pattern sized 2.1 cm in average, demonstrated the similar architecture with inverted papilloma, but exhibited thick columns and variable thickness of the cords, irregular size and shape of large nests with transition into solids. Mild to moderate cytologic atypia was shown, and mitotic figures ranged 1 to 8 per 10 HPFs. Exophytic papillary component was not observed in 3 cases, but the superficial urothelium showed dysplasia, while coexisted exophytic component in other cases was associated with low malignant potential or low grade tumor. (3) Five florid von Brunn nests sized 0.9 cm in average, had normal or hyperplastic urothelium, variable nests with cysts compacted in lamina propria, no cytologic atypia and mitosis. Twenty-one of 24 (79.1%) urothelial carcinomas with an endophytic growth pattern displayed abnormally positive results by multitargeted FISH, whereas all inverted papillomas and florid von Brunn nests were negative. Immunohistochemically, CK20 was weakly positive in 2 cases of urothelial carcinoma with an endophytic growth pattern, and negative in all inverted papillomas and florid von Brunn nests. p53 weakly stained 5% to 50% nuclei of the tumor cells in 16 cases of urothelial carcinomas with an endophytic growth pattern and 1 inverted papilloma. 1%-5% tumor cells expressed Ki-67 in urothelial carcinoma with an endophytic growth pattern, and less than 1% in inverted papilloma and florid von Brunn nests. Follow-up study revealed that 2 cases of urothelial carcinoma with an endophytic growth pattern had developed invasive carcinoma, underwent cystectomy, and metastasized remotely. No recurrence occurred in cases of inverted papilloma.

CONCLUSIONSBenign and malignant urothelial lesions with an endophytic growth pattern present histologic overlapping. Urothelial carcinoma with an endophytic growth pattern displays unique characteristics in morphology and immunohistochemistry. Multitargeted FISH analysis is helpful in the differential diagnosis.

Adult ; Aged ; Aged, 80 and over ; Carcinoma, Transitional Cell ; genetics ; metabolism ; pathology ; surgery ; Chromosome Aberrations ; Diagnosis, Differential ; Follow-Up Studies ; Humans ; Hyperplasia ; In Situ Hybridization, Fluorescence ; Keratin-20 ; metabolism ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Papilloma, Inverted ; genetics ; metabolism ; pathology ; surgery ; Tumor Suppressor Protein p53 ; metabolism ; Urinary Bladder Neoplasms ; genetics ; metabolism ; pathology ; surgery ; Urothelium ; metabolism ; pathology

PURPOSE: To examine the usefulness of various receptor tyrosine kinase expressions as prognostic markers and therapeutic targets in muscle invasive urothelial cancer (UC) patients. MATERIALS AND METHODS: We retrospectively analyzed the data of 98 patients with muscle invasive UC who underwent radical cystectomy between 2005 and 2010 in Yonsei Cancer Center. Using formalin fixed paraffin embedded tissues of primary tumors, immunohistochemical staining was done for human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 3 (FGFR3). RESULTS: There were 41 (41.8%), 44 (44.9%), and 14 (14.2%) patients who have over-expressed HER2, FGFR1, and FGFR3, respectively. In univariate analysis, significantly shorter median time to recurrence (TTR) (12.9 months vs. 49.0 months; p=0.008) and overall survival (OS) (22.3 months vs. 52.7 months; p=0.006) was found in patients with FGFR1 overexpression. By contrast, there was no difference in TTR or OS according to the HER2 and FGFR3 expression status. FGFR1 remained as a significant prognostic factor for OS with hazard ratio of 2.23 (95% confidence interval: 1.27-3.90, p=0.006) in multivariate analysis. CONCLUSION: Our result showed that FGFR1 expression, but not FGFR3, is an adverse prognostic factor in muscle invasive UC patients after radical cystectomy. FGFR1 might be feasible for prognosis prediction and a potential therapeutic target after thorough validation in muscle invasive UC.
Adult ; Aged ; Aged, 80 and over ; Carcinoma/*metabolism/*mortality/surgery ; Cystectomy ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Muscles/pathology ; Neoplasm Invasiveness ; Prognosis ; Proportional Hazards Models ; Receptor, ErbB-2/metabolism ; Receptor, Fibroblast Growth Factor, Type 1/*metabolism ; Receptor, Fibroblast Growth Factor, Type 3/metabolism ; Retrospective Studies ; Survival Rate ; Urinary Bladder Neoplasms/*metabolism/*mortality/surgery ; Urothelium/pathology

We investigated how the dual inhibition of the molecular mechanism of the mammalian target of the rapamycin (mTOR) downstreams, P70S6 kinase (P70S6K) and eukaryotic initiation factor 4E (eIF4E), can lead to a suppression of the proliferation and progression of urothelial carcinoma (UC) in an orthotopic mouse non-muscle invasive bladder tumor (NMIBT) model. A KU-7-luc cell intravesically instilled orthotopic mouse NMIBC model was monitored using bioluminescence imaging (BLI) in vivo by interfering with different molecular components using rapamycin and siRNA technology. We then analyzed the effects on molecular activation status, cell growth, proliferation, and progression. A high concentration of rapamycin (10 microM) blocked both P70S6K and elF4E phosphorylation and inhibited cell proliferation in the KU-7-luc cells. It also reduced cell viability and proliferation more than the transfection of siRNA against p70S6K or elF4E. The groups with dual p70S6K and elF4E siRNA, and rapamycin reduced tumor volume and lamina propria invasion more than the groups with p70S6K or elF4E siRNA instillation, although all groups reduced photon density compared to the control. These findings suggest that both the mTOR pathway downstream of eIF4E and p70S6K can be successfully inhibited by high dose rapamycin only, and p70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression.
Animals ; Cell Line ; Cell Proliferation/drug effects/genetics ; Cell Survival/drug effects ; Disease Progression ; Eukaryotic Initiation Factor-4E/*antagonists & inhibitors/genetics ; Female ; Mice ; Mice, Nude ; Mucous Membrane/pathology ; Phosphorylation/drug effects ; RNA Interference ; RNA, Small Interfering ; Ribosomal Protein S6 Kinases, 70-kDa/*antagonists & inhibitors/genetics ; Signal Transduction/drug effects ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism ; Urinary Bladder Neoplasms/genetics/*pathology ; Urothelium/pathology

We investigated how the dual inhibition of the molecular mechanism of the mammalian target of the rapamycin (mTOR) downstreams, P70S6 kinase (P70S6K) and eukaryotic initiation factor 4E (eIF4E), can lead to a suppression of the proliferation and progression of urothelial carcinoma (UC) in an orthotopic mouse non-muscle invasive bladder tumor (NMIBT) model. A KU-7-luc cell intravesically instilled orthotopic mouse NMIBC model was monitored using bioluminescence imaging (BLI) in vivo by interfering with different molecular components using rapamycin and siRNA technology. We then analyzed the effects on molecular activation status, cell growth, proliferation, and progression. A high concentration of rapamycin (10 microM) blocked both P70S6K and elF4E phosphorylation and inhibited cell proliferation in the KU-7-luc cells. It also reduced cell viability and proliferation more than the transfection of siRNA against p70S6K or elF4E. The groups with dual p70S6K and elF4E siRNA, and rapamycin reduced tumor volume and lamina propria invasion more than the groups with p70S6K or elF4E siRNA instillation, although all groups reduced photon density compared to the control. These findings suggest that both the mTOR pathway downstream of eIF4E and p70S6K can be successfully inhibited by high dose rapamycin only, and p70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression.
Animals ; Cell Line ; Cell Proliferation/drug effects/genetics ; Cell Survival/drug effects ; Disease Progression ; Eukaryotic Initiation Factor-4E/*antagonists & inhibitors/genetics ; Female ; Mice ; Mice, Nude ; Mucous Membrane/pathology ; Phosphorylation/drug effects ; RNA Interference ; RNA, Small Interfering ; Ribosomal Protein S6 Kinases, 70-kDa/*antagonists & inhibitors/genetics ; Signal Transduction/drug effects ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism ; Urinary Bladder Neoplasms/genetics/*pathology ; Urothelium/pathology