Urinary Large Cell Neuroendocrine Carcinoma: A Clinicopathologic Analysis of 22 Cases.

Large cell neuroendocrine carcinoma (LCNEC) of the urinary tract is a rare disease. We present a relatively large retrospective cohort of urinary LCNEC, 20 from the urinary bladder, and 2 from the ureter, from a single institution. The patients included 16 men and 6 women with a median age of 74.5 years. Most LCNEC presented at an advanced stage with tumors invading the muscularis propria and beyond (21/22). Eight cases were pure LCNEC, while 14 cases were mixed with other histologic types, including conventional urothelial carcinoma (n=9), carcinoma in situ (n=7), small cell carcinoma (n=6), and urothelial carcinoma with glandular (n=3) features. Most LCNEC expressed neuroendocrine markers synaptophysin (22/22), chromogranin (13/16), CD56 (7/7), TTF1 (8/8), and INSM1 (2/3). They were negative for common urothelial markers including HMWCK (0/3), p40/p63 (0/6), CK20 (0/10), and had variable GATA3 staining (4/8). Ki-67 stained 25% to nearly 100% tumor cell nuclei. Patient survival was associated with cancer stage, and pure LCNEC showed worse survival than mixed LCNEC. Compared with small cell carcinoma at similar stages from a prior study, LCNEC had a worse prognosis only when patients developed metastatic disease. For organ-confined LCNEC, neoadjuvant chemotherapy followed by radical resection is the treatment option to achieve long-term survival.

Prognostic significance of BAP1 expression in high-grade upper tract urothelial carcinoma: a multi-institutional study.

PURPOSE: To evaluate the prognostic value of BRCA1-associated protein-1 (BAP1) expression in upper tract urothelial carcinoma (UTUC), as BAP1 mutations have been associated with prognostic implications in urologic and non-urologic malignancies. METHODS: We reviewed a multi-institutional cohort of patients who underwent radical nephroureterectomy (RNU) for high-grade UTUC from 1990-2008. Immunohistochemistry (IHC) for BAP1 was performed on tissue microarrays. Staining intensity was graded from 0-3, with BAP1 loss defined as an average intensity of < 1. Clinicopathologic characteristics and oncologic outcomes [recurrencefree (RFS), cancer-specific (CSS), and overall survival (OS)] were stratified by BAP1 status. The prognostic role of BAP1 was assessed using Kaplan-Meier (KM) and Cox regression analysis. Significance was defined as p < 0.05. RESULTS: 348 patients were included for analysis and 173 (49.7%) showed BAP1 loss. Median follow-up was 36.0 months. BAP1 loss was associated with papillary architecture and absence of tumor necrosis or CIS. On univariable analysis, BAP1 loss was associated with improved RFS (HR 0.60, p = 0.013) and CSS (HR 0.55, p = 0.007), although significance was lost on multivariable analysis (HR 0.71, p = 0.115 and HR 0.65, p = 0.071; respectively) after adjusting for other significant parameters. BAP1 expression was not significantly associated with OS. CONCLUSIONS: BAP1 loss was associated with favorable pathologic features and better oncologic outcomes in univariate but not multivariate analysis in patients with high-grade UTUC. In contrast to renal cell carcinoma, loss of BAP1 expression appears to confer a better prognosis in high-grade UTUC. The role of the BAP1 pathway in UTUC pathogenesis remains to be further elucidated.

Insulin-like growth factor-1 receptor expression in upper tract urothelial carcinoma.

Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor that plays a crucial role in cell proliferation, growth, differentiation, and apoptosis. IGF1R overexpression has been observed in several cancers, including invasive bladder carcinomas, as a potential prognostic factor. Given known biologic differences between upper and lower urinary tract urothelial carcinoma, we assessed the expression status and prognostic significance of IGF1R in upper tract urothelial carcinoma (UTUC). Two tissue microarrays (TMAs) were built from 99 Japanese patients with non-metastatic UTUC submitted to radical nephroureterectomy between 1997 and 2011. TMAs were constructed with triplicate tumor and paired benign urothelium. Membranous IGF1R staining was evaluated using immunohistochemistry. Two scoring methods were applied (Her2-score and H-score). The highest score was assigned to each tumor. IGF1R positivity was defined as Her2-score ≥ 1+. Association with clinicopathologic parameters and outcome was assessed using hazard ratios (HR) with 95% confidence intervals (CI) and adjusted P values. We found positive IGF1R expression in 70% of UTUC. Outcomes were as follows: tumor recurrence, 33%; tumor progression, 59%; overall mortality, 33%; and cancer-specific mortality, 30%. IGF1R was not associated with any clinicopathologic features. In addition, IGF1R expression was not associated with tumor recurrence (HR = 0.54, CI = 0.25-1.1, P = 0.11), tumor progression (HR = 1.6, CI = 0.8-3.1, P = 0.19), overall mortality (HR = 1.5, CI = 0.68-3.4, P = 0.31), or cancer-specific mortality (HR = 1.6, CI = 0.68-3.8, P = 0.27). Positive IGF1R expression was found in more than two thirds of UTUC. This finding provides a rationale to investigate IGF1R as a potential therapeutic target in UTUC. In contrast to bladder cancer, IGF1R expression in UTUC did not correlate with outcome, further pointing to biologic differences between UTUC and bladder cancer.

Frequency and Prognostic Value of PTEN Loss in Patients with Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy.

PURPOSE: To our knowledge the frequency and prognostic significance of PTEN protein expression in upper tract urothelial carcinoma have not yet been investigated in large studies. We analyzed PTEN protein status and its association with disease recurrence and survival outcomes in a large, multi-institutional upper tract urothelial carcinoma cohort. MATERIALS AND METHODS: We retrospectively analyzed the records of 611 patients with upper tract urothelial carcinoma treated with radical nephroureterectomy between 1991 and 2008 at a total of 7 institutions. Median followup was 23 months. Tissue microarrays and immunohistochemical PTEN staining (monoclonal antibody) were performed. Univariable and multivariable Cox regression models were created to address the association of PTEN protein expression with disease recurrence, and cancer specific and overall mortality. RESULTS: PTEN staining was absent in 45 cases (7.4%). Patients with PTEN loss had significantly advanced pathological tumor stage and grade (p <0.001), and higher rates of lymph node metastasis (p <0.01) and lymphovascular invasion (p <0.001) compared to patients with PTEN expression. PTEN loss was associated with disease recurrence, and cancer specific and overall mortality on univariable Cox regression analyses. However, on multivariable Cox regression analyses adjusted for the effect of standard clinicopathological features PTEN loss was only associated with overall mortality (HR 1.69, 95% CI 1.09-2.61, p = 0.02). CONCLUSIONS: In patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma loss of PTEN protein expression is rare but associated with features of biologically aggressive disease such as higher grade and stage as well as lymph node metastasis. Loss of PTEN expression was associated with overall mortality. PTEN loss seemed to promote worse outcomes in this relatively small group of patients.

Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma.

BACKGROUND: Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer. OBJECTIVE: To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses. DESIGN, SETTING, AND PARTICIPANTS: We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data. RESULTS AND LIMITATIONS: WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade

Diagnostic utility of Ki-67 immunohistochemistry in small endoscopic biopsies of the ureter and renal pelvis.

Diagnosis of upper urinary tract urothelial carcinoma in ureteroscopic biopsies is challenging. Therefore, an immunohistochemical marker that can differentiate between malignant and benign urothelium and predict final pathological features is necessary. In this study, we investigated Ki-67 expression in 26 ureteroscopic biopsies of the ureter and renal pelvis diagnosed with urothelial carcinoma (UC) and in 13 biopsies with non-neoplastic urothelium, using digital image analysis. The median Ki-67 labeling index was 1.5% (range: 0.2-13.9%) in non-neoplastic urothelial specimens and 15.0% (range: 0.2-61.3%) in UC specimens (p=0.0001). In 12 of 26 (46%) UC specimens, the Ki-67 labeling index was more than 20%. By contrast, the Ki-67 labeling index was less than 5% in 11 of 13 (85%) non-neoplastic urothelial specimens. Ki-67 expression in ureteroscopic biopsies was significantly correlated with high tumor grade (p=0.013), concomitant carcinoma in situ (p=0.011), and stromal invasion (p=0.048) in surgical resection specimens. Our data suggested that Ki-67 may provide supplemental, objective evidence that can aid diagnosis of upper urinary tract UC in ureteroscopic biopsy specimens. Determination of Ki-67 expression in ureteroscopic biopsy specimens is potentially helpful in clinical decision making for patients with suspected upper urinary tract UC.

Lymphoepithelioma-like carcinoma of the ureter: a rare presentation, synchronous with conventional urothelial carcinoma.

Lymphoepithelioma-like carcinoma (LELC) is a rare finding in the upper urinary tract. The presenting clinical findings mimic those of other more common upper-tract tumors, such as urothelial carcinoma. Preoperative imaging has not been shown to reliably predict the diagnosis of LELC. This tumor can be misdiagnosed as a reactive inflammatory lesion or lymphoma if the proper immunohistochemical stains for cytokeratin are not used.

[Metastatic lymph node collision of a prostatic adenocarcinoma and an urothelial carcinoma and review of the literature]. / Double métastase ganglionnaire d'un adénocarcinome prostatique et d'un carcinome urothélial et revue de la littérature.

INTRODUCTION: Tumor collision is the encounter of two tumors from two different topographical sites. Cases of metastatic lymph node collision are exceptional. We report the case of a metastatic lymph node collision of an urothelial carcinoma and a prostatic adenocarcinoma. OBSERVATION: A 61-year-old man was hospitalized for a right nephroureterectomy with peri-ureteral lymph node dissection. He was followed since 2004 for prostatic adenocarcinoma and treated with radical prostatectomy then radiation therapy 4 years later due to a new increase of PSA. In the follow-up, an urothelial carcinoma of the lower right ureter was discovered in 2014. Histological analysis of a peri-ureteral lymph node showed a double metastasis of urothelial and prostatic origin. The prostatic adenocarcinoma was composed of acinar and ductal subtypes. Immunohistochemical study including CK7, CK20, PSA, GATA3, P63 antibodies confirmed the distinct phenotype of the 2 tumors. DISCUSSION: Metastatic collision of urothelial carcinoma and prostatic adenocarcinoma has been reported in 4 cases only. Our review of literature shows that prostatic adenocarcinoma always precedes the urothelial carcinoma. Immunohistochemical study, when carried out for distinguishing both tumors, should include CK7, CK20 and PSA. GATA3, androgen receptor and P63 could be added in a second time.

Multi-institutional validation of the predictive value of Ki-67 in patients with high grade urothelial carcinoma of the upper urinary tract.

PURPOSE: We validate the independent predictive value of Ki-67 in patients with high grade upper tract urothelial carcinoma. MATERIALS AND METHODS: A total of 475 patients from the international Upper Tract Urothelial Carcinoma Collaboration who underwent extirpative surgery for high grade upper tract urothelial carcinoma were included in this study. Immunohistochemical staining for Ki-67 was performed on tissue microarray formed from this patient cohort. Ki-67 expression was assessed in a semiquantitative fashion and considered over expressed at a cutoff of 20%. Multivariate analyses were performed to assess independent predictors of oncologic outcomes and Harrell's C indices were calculated for predictive models. RESULTS: The median age of the cohort was 69.7 years and 55.2% of patients were male. Ki-67 was over expressed in 25.9% of patients. Ki-67 over expression was significantly associated with ureteral tumor location, higher pT-stage, lymphovascular invasion, sessile tumor architecture, tumor necrosis, concomitant carcinoma in situ and regional lymph node metastases. On Kaplan-Meier analyses over expressed Ki-67 was associated with worse recurrence-free survival (HR 12.6, p <0.001) and cancer specific survival (HR 15.8, p <0.001). On multivariate analysis Ki-67 was an independent predictor of recurrence-free survival (HR 1.6, 95% CI 1.07-2.30, p=0.021) and cancer specific survival (HR 1.9, 95% CI 1.29-2.90, p=0.001). Ki-67 improved Harrell's C index from 0.66 to 0.70 (p <0.0001) for recurrence-free survival as well as cancer specific survival in our preoperative model, and from 0.81 to 0.82 (p=0.0018) for recurrence-free survival and 0.81 to 0.83 (p=0.005) for cancer specific survival in our postoperative model. CONCLUSIONS: Ki-67 was validated as an independent predictor of recurrence-free survival and cancer specific survival in patients treated with extirpative surgery for high grade upper tract urothelial carcinoma in a large, multi-institutional cohort.

Invasive urothelial carcinoma with chordoid features of the ureter: a rare entity and review of literature.

Invasive urothelial carcinoma (UC) is characterized by some histologic variants that can sometimes lead to diagnostic difficulty. In addition to those described by the World Health Organization. Recently invasive urothelial carcinoma with chordoid features (UCC) has been described as a distinct entity and there are relatively few reported cases in the English-language literature. To date 13 cases of UCC have been reported in 2 case series, respectively in 2009 and 2015. We report the 14(th) case in an 80-year-old female, and to the best of our knowledge this is the second case report of UCC in the ureter. She was admitted to our hospital with macroscopic haematuria and unspecific left lower abdominal pain. Computed tomography scan revealed a soft tissue nodule in the middle of the left ureter. The left nephroureterectomy was performed. Morphologically, 85% areas had acellular myxoid stroma was associated with the neoplastic cells. The neoplastic cells had scant eosinophilic cytoplasm and were arranged into cords closely mimicking chordoma or extraskeletal myxoid chondrosarcoma. 15% areas was typical invasive urothelial carcinoma, and focal areas had transition phenomenon between them. Immunohistochemically, the tumor cells were positive for CK, 34ßE12 and p63, but were negative for S100, AFP, CD34, Syn and CgA. The final histopathological diagnosis was UCC of the ureter.

Insulin-like growth factor messenger RNA-binding protein 3 expression helps prognostication in patients with upper tract urothelial carcinoma.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is a clinically heterogeneous disease that lacks high-quality trials that provide definitive prognostic markers. Insulin-like growth factor messenger RNA binding protein 3 (IMP3) has been associated with outcomes in urothelial carcinoma of the bladder but was not yet studied in UTUC. OBJECTIVE: To evaluate the association of the oncofetal protein IMP3 with oncologic outcomes in patients with UTUC treated with radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: We investigated the expression of IMP3 and its association with clinical outcomes using tissue microarrays constructed from 622 patients treated with RNU at seven international institutions between 1991 and 2008. INTERVENTION: All patients were diagnosed with UTUC and underwent RNU. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: Uni- and multivariable Cox regression analyses evaluated the association of IMP3 protein expression with disease recurrence, cancer-specific mortality, and all-cause mortality. RESULTS AND LIMITATIONS: IMP3 was expressed in 12.2% of patients with UTUC (n=76). The expression was tumor specific and correlated with higher stages/grades. Within a median follow-up of 27 mo (interquartile range [IQR]: 12-53), 191 patients (25.4%) experienced disease recurrence, and 165 (21.9%) died of the disease. Patients with IMP3 demonstrated significantly worse recurrence-free survival (27.4% vs 75.1%; p<0.01), cancer-specific survival (34.5% vs 78.9%; p<0.01), and overall survival (15.6% vs 64.8%; p<0.01) at 5 yr compared with those without IMP3. In multivariable Cox regression analyses, which adjusted for the effects of standard clinicopathologic features, IMP3 expression was independently associated with disease recurrence (hazard ratio [HR]: 1.87; p<0.01), cancer-specific mortality (HR: 2.15; p<0.01), and all-cause mortality (HR: 2.07; p<0.01). Major limitations include the retrospective design and relatively short follow-up time. CONCLUSIONS: IMP3 expression is independently associated with disease recurrence, cancer-specific mortality, and all-cause mortality in UTUC. IMP3 may help improve risk stratification and prognostication of UTUC patients treated with RNU.

Immune expression of E-cadherin and α, ß and γ-Catenin adhesion molecules and prognosis for upper urinary tract urothelial carcinomas.

INTRODUCTION: Cell adhesion molecules (CAM) are required for maintaining a normal epithelial phenotype, and abnormalities in CAM expression have been related to cancer progression, including bladder urothelial carcinomas. There is only one study that correlates E-cadherin and Α-, Β- and y-catenin expression with prognosis of upper tract urothelial carcinomas. Our aim is to study the pattern of immune expression of these CAMs in urothelial carcinomas from the renal pelvis and ureter in patients who have been treated surgically. Our goal is to correlate these expression levels and characteristics with well-known prognostic parameters for disease-free survival. MATERIALS AND METHODS: We evaluated specimens from 20 patients with urothelial carcinomas of the renal pelvis and ureter who were treated with nephroureterectomy or ureterectomy between June 1997 and January 2007. CAM expression was evaluated by immunohistochemistry in a tissue microarray and correlated with histopathological characteristics and patient outcomes after a mean follow-up of 55 months. RESULTS: We observed a relationship between E-cadherin expression and disease recurrence. Disease recurrence occurred in 87.5% of patients with strong E-cadherin expression. Only 50.0% of patients with moderate expression and 0% of patients with weak or no expression of E-cadherin had disease recurrence (p = 0.014). There was also a difference in disease-free survival. Patients with strong E-cadherin expression had a mean disease-free survival rate of 49.1 months, compared to 83.9 months for patients with moderate expression (p = 0.011). Additionally, an absence of Α-catenin expression was associated with tumors that were larger than 3 cm (p = 0.003). CONCLUSIONS: We demonstrated for the first time that immune expression of E-cadherin is related to tumor recurrence and disease-free survival rates, and the absence of Α-catenin expression is related to tumor size in upper tract urothelial carcinomas.

Primary mesenchymal chondrosarcoma of the kidney with synchronous implant and infiltrating urothelial carcinoma of the ureter.

Primary mesenchymal chondrosarcoma of the kidney is rare, and it shows distinct undifferentiated tumor cells and well differentiated cartilagenous components. Also assident infiltrating urothelial carcinoma of the ureter is an extremely rare cancer. We report a case of primary mesenchymal chondrosarcoma occurring in the left kidney with an ipsilateral and distinct distal ureteric implant, and a coexisting infiltrating urothelial carcinoma of the ureter in a 64-year-old man. Histopathological examination and immunohistochemical studuies showed the classic features of mesenchymal chondrosarcoma in kidney, as well as a few infiltrating urothelial in ureter. Multitarget fluorescence in situ hybridization (FISH) suggested that the development of the urothelial carcinoma in the ureter may be triggered or induced by the chondrosarcoma component. The patient died 2 month after left nephro-ureterectomy. This is the first reported case of a primary mesenchymal chondrosarcoma of the kidney with coexisting infiltrating urothelial carcinoma of the ureter. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1522835667751019.

Immune expression of E-cadherin and α, β and γ-Catenin adhesion molecules and prognosis for upper urinary tract urothelial carcinomas

INTRODUCTION: Cell adhesion molecules (CAM) are required for maintaining a normal epithelial phenotype, and abnormalities in CAM expression have been related to cancer progression, including bladder urothelial carcinomas. There is only one study that correlates E-cadherin and α-, β- and γ-catenin expression with prognosis of upper tract urothelial carcinomas. Our aim is to study the pattern of immune expression of these CAMs in urothelial carcinomas from the renal pelvis and ureter in patients who have been treated surgically. Our goal is to correlate these expression levels and characteristics with well-known prognostic parameters for disease-free survival. MATERIALS AND METHODS: We evaluated specimens from 20 patients with urothelial carcinomas of the renal pelvis and ureter who were treated with nephroureterectomy or ureterectomy between June 1997 and January 2007. CAM expression was evaluated by immunohistochemistry in a tissue microarray and correlated with histopathological characteristics and patient outcomes after a mean follow-up of 55 months. RESULTS: We observed a relationship between E-cadherin expression and disease recurrence. Disease recurrence occurred in 87.5% of patients with strong E-cadherin expression. Only 50.0% of patients with moderate expression and 0% of patients with weak or no expression of E-cadherin had disease recurrence (p = 0.014). There was also a difference in disease-free survival. Patients with strong E-cadherin expression had a mean disease-free survival rate of 49.1 months, compared to 83.9 months for patients with moderate expression (p = 0.011). Additionally, an absence of α-catenin expression was associated with tumors that were larger than 3 cm (p = 0.003). CONCLUSIONS: We demonstrated for the first time that immune expression of E-cadherin is related to tumor recurrence and disease-free survival rates, and the absence of α-catenin expression is related to tumor size in upper tract urothelial carcinomas.

Expression of stathmin in localized upper urinary tract urothelial carcinoma: correlations with prognosis.

OBJECTIVES: To investigate the expression of stathmin in upper urinary tract (UUT) urothelial carcinoma (UC) in human tissues and to determine whether the level of stathmin expression was correlated with prognosis because overexpression of stathmin has been observed in various malignancies. METHODS: We first analyzed stathmin mRNA level in 5 UUT-UC paired fresh specimens (tumor and nontumoral urothelium) by RT-PCR. Besides, a total of 58 patients with localized UUT-UC (pT1-3N0M0) treated by nephroureterectomy were enrolled. The stathmin expression in UUT-UC specimens was analyzed by immunohistochemical (IHC) staining. Stathmin IHC score was defined as the proportion of positive staining tumor cells from each patient's specimen. The stathmin IHC score > or = 0.5 was defined as strong (+) immunoreactivity and < 0.5 as weak (-) immunoreactivity. RESULTS: Significant differences in stathmin mRNA between UUT-UC and paired normal urothelium were noted in 5 of the patients. Of the 58 UUT-UC specimens, stathmin immunoreactivity (strong [+] vs weak [-]) was significantly associated with pT stage (P = .006) as well as with recurrence-free and cancer-specific survival. In multivariate analysis, stathmin IHC score was a significant predictor for both recurrence-free survival (hazard rates: 22.4; P = .001) and cancer-specific survival (hazard rates: 39.8; P = .0012). CONCLUSIONS: The stathmin immunostaining is a novel prognosticator for patients with localized UUT-UC stathmin may be a help identify such patients with poor outcomes to benefit from receiving close follow-up and early adjuvant therapy.

Identification of immunohistochemical factors that predict the synchronous or metachronous development of bladder tumors in patients with upper urinary tract tumors.

OBJECTIVE: To identify markers that predict the synchronous or metachronous development of bladder cancer in patients with upper urinary tract (UUT) tumors. MATERIALS AND METHODS: Between March 2001 and December 2005, we identified 38 consecutive patients who had been histologically diagnosed as having transitional cell carcinoma in the renal pelvis and ureter. These patients were divided into 2 groups (n = 19 per group): group 1 patients with metachronous or synchronous bladder cancer, and group 2 patients with UUT tumors only. We analyzed the differences between the 2 groups with respect to the expression of various biomarkers (p53, Rb, Ki-67, PTEN, and bcl-2) and in terms of clinical parameters. RESULTS: The 2 groups differed significantly in terms of multiplicity (p = 0.029), papillary configuration (p = 0.001), the presence of lymphovascular emboli (p = 0.019), and Ki-67 overexpression (p = 0.029) in UUT tumors. Multivariate analysis revealed that Ki-67 overexpression in UUT tumor tissues significantly predicts bladder cancer development (HR 6.440; 95% CI 1.121-37.014; log rank p = 0.037). CONCLUSION: Ki-67 overexpression in UUT tumor tissues was found to be an independent predictor of the development of bladder cancer in UUT tumor patients.

Multicentric transitional cell carcinoma of the vagina and the ureter.

Primary transitional cell carcinoma (TCC) of the vagina represents an extremely rare neoplasm and is associated with multicentric TCC of the urinary tract in all described cases. A case of multicentric TCC of the vagina and the left ureter in a 73-year-old woman is reported. Immunohistochemical analysis of cytokeratin expression was performed. Immunohistochemistry proved to play an important role in the differential diagnosis of vaginal TCC, supported the morphological diagnosis of TCC, and largely excluded the diagnosis of vaginal papillary carcinoma with transitional features as a morphological variant of squamous cell carcinoma. Subsequent urological examination revealed multicentric TCC of the left ureter. During the follow up, the metastases of the vaginal TCC into the regional inguinal lymph nodes were diagnosed, suggesting that indolent clinical course is not a rule in this type of tumor.

Neoplasms of the upper urinary tract: a review with focus on urothelial carcinoma of the pelvicalyceal system and aspects related to its diagnosis and reporting.

Tumors of the renal pelvis account for approximately 7% to 8% of all renal malignancies, greater than 90% of these are of urothelial (transitional cell) origin. These tumors more typically occur in the sixth to eight decade with a slight male preponderance. Varying risk factors for urothelial carcinomas of the upper tract are recognized including environmental and occupational hazards, chemotherapeutic exposure, and previous history of urinary bladder or ureteral carcinomas. Tumor multifocality is frequent and additional tumors may arise in the ureter, bladder, or on the contralateral side. The histopathologic nuances presented by urothelial carcinoma in this region are generally similar to those in the urinary bladder. Though the World Health Organization 2004/International Society of Urological Pathology system used in the bladder is customarily also employed for grading of urothelial tumors of this region, its prognostic significance at this site is not entirely clear as most tumors are treated with nephroureterectomy irrespective of the grade of the tumor. Histologic grade may be an independent prognostic factor in papillary pT1 tumors; however, most pT2 and higher stage tumors tend to be nonpapillary and of higher grade. Despite advances in treatment modalities with sophisticated endoscopic techniques, tumor stage remains the most important prognostic factor. There are several confounding issues related to staging such as the variable presence and thickness of subepithelial connective tissue and muscularis in the renal calyces, renal pelvis, and the ureter; intratubular pagetoid cancer spread (pTis vs. pT3); and assessing invasion in papillary neoplasms with endophytic or inverted growth. Careful gross examination with adequate sampling and understanding the microanatomy of the pelvicalyceal wall are crucial for accurate stage assignment. Poor fixation of large friable tumors and processing artifacts may compound difficulties in accurate staging. This review focuses on urothelial carcinoma of the upper tract highlighting issues related to its diagnosis, staging, and reporting.

Correlation of COX-2 expression in stromal cells with high stage, high grade, and poor prognosis in urothelial carcinoma of upper urinary tracts.

OBJECTIVES: To investigate COX-2 expression in carcinoma and stromal cells in patients with urothelial carcinoma of upper urinary tracts (UCUUT) and determine whether expression patterns are associated with clinical characteristics and survival. METHODS: We performed immunohistochemistry for COX-2 on paraffin-embedded tumors of UCUUT specimens from 79 patients. We evaluated the level of expression in carcinoma cells, presence of stromal cell expression, and infiltration of inflammatory cells. RESULTS: We observed strong and moderate expression of COX-2 in carcinoma cells in 19 (24.1%) and 46 (58.2%) cases, respectively. In 36 (45.6%) cases COX-2 expression was present in stromal cells. The level of COX-2 expression in carcinoma cells was not correlated with pathological stage (P = 0.22) or grade (P = 0.45). COX-2 expression in stromal cells was correlated with high stage (P <0.0001) and high grade (P <0.0001). The patient's survival was reduced if the tumor revealed strong or moderate expression of COX-2 in carcinoma cells (P = 0.03), the presence of COX-2 expression in stromal cells (P <0.0001), and infiltrating inflammatory cells (P = 0.0001), by log-rank test. Prognosis was poor if the tumor was positive for both COX-2 expression in stromal cells and inflammatory cell infiltrate (P <0.0001). CONCLUSIONS: COX-2 expression in stromal cells shows greater correlation with high stage and high grade than COX-2 expression in carcinoma cells. Stromal COX-2 expression may be used as a marker of invasiveness and poor prognosis for patients with UCUUT.

Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers.

PURPOSE: The programmed death-1 (PD-1)/B7-H1 (also called PD-L1) pathway negatively regulates T cell activation and has been suggested to play an important role in regulating antitumor host immunity. To investigate the clinical significance of B7-H1 expression to the tumor grade and postoperative prognosis of patients with urothelial cancer, we analyzed the relationship between B7-H1 expression and various clinicopathological features and postoperative prognosis. EXPERIMENTAL DESIGN: Sixty-five urothelial cancer cases were examined. B7-H1 expression in tumors and the numbers and phenotypes of tumor-infiltrating lymphocytes were evaluated by immunohistochemistry and flow cytometry. RESULTS: A substantial expression of B7-H1 was observed in all urothelial cancers investigated. Tumor specimens from patients with higher WHO grade or primary tumor classifications showed significantly higher percentages of tumor-associated B7-H1. Tumor-associated B7-H1 expression was significantly associated with a high frequency of postoperative recurrence and poor survival rate. Furthermore, multivariate analysis indicated that tumor-associated B7-H1 was more significant prognostic factor than WHO grade. CONCLUSIONS: Our results demonstrate that the aberrant expression of B7-H1 in urothelial cancer is associated with aggressive tumors, suggesting a regulatory role of tumor-associated B7-H1 in antitumor immunity. Therefore, the manipulation of tumor-associated B7-H1 may become a beneficial target for immunotherapy in human urothelial cancer.