Low-grade Urothelial Carcinoma Research Articles

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.

Three‐dimensional cell groups with disordered nuclei and cellular discohesion (3DDD) are associated with high sensitivity and specificity for cystoscopic urine cytopathological diagnosis of low‐grade urothelial neoplasia

Cystoscopic urine obtained before the resection of low-grade urothelial carcinoma (LGUC), with adequate cytological sampling of the tumor, frequently revealed the presence of three-dimensional cell groups with disordered nuclei and cellular discohesion (3DDD). 936 cystoscopic urine specimens were categorized into five groups: Group 1 (80 specimens) with biopsy-proven LGUC within 6 months of cytologic examination, Group 2 (23 specimens) with biopsy proven LGUC within 6 to 36 months of cytologic examination, Group 3 (527 specimens) with a history of LGUC but no tumor for a period of greater than 3 years, Group 4 (300 specimens) with no association with LGUC, and Group 5 (6 specimens) with urinary lithiasis. Specimens with scant cellularity accounted for 20% of those in Group 1. For 3DDD in detecting LGUC in adequate cystoscopic urine, the sensitivity was 70%, specificity was 94%. Two- or three-dimensional cell groups with ordered nuclei and/or cellular non-discohesion were often seen in specimens from Groups 4 or 5. The 3DDD was present in a significant number of cases with concurrent negative cystoscopic findings but also positive LGUC in ensuing follow-up. In these cases, 3DDD with or without tumor identified at concurrent cystoscopy were found to be morphologically similar. Furthermore, the presence of 3DDD in 8% of Group 3 likely represents urothelial dysplasia that is not cystoscopically detectable. The high specificity and sensitivity of 3DDD is demonstrated. These findings are consistent with the decreased cell adhesion and disordered nuclear arrangement of low grade urothelial neoplasia.

Nephron-sparing surgery with autotransplantation for high-grade upper urinary tract urothelial carcinoma in a patient with solitary kidney

Instead of nephroureterectomy with bladder cuff excision, nephron-sparing surgery can be considered in selected patients with non-muscle invasive upper urinary tract urothelial carcinoma. The role of kidney-sparing surgery has been established for the management of low-grade urothelial carcinoma. We report a solitary kidney patient with high-grade renal pelvis urothelial carcinoma treated with nephron-sparing surgery by ex vivo tumor excision and autotransplantation. The results of the surgery were excellent.

Urothelial Tumors of the Urinary Bladder in Young Patients: A Clinicopathologic Study of 59 Cases

Urothelial tumors are rare in young patients. Because of their rarity, the natural history of the disease in young patients remains poorly understood. To understand the pathologic and clinical features of urothelial tumors of the urinary bladder in young patients. We identified 59 young patients with urothelial tumors of the urinary bladder treated at our institution and analyzed the tumors' pathologic features and the patients' clinical outcomes. All patients were 30 years or younger, with a mean age of 23.5 years (range, 4-30). Thirty-eight patients (64%) were male, and 21 (36%) were female. Most tumors were noninvasive, papillary urothelial tumors (49 of 59; 83%), including papillary urothelial neoplasms of low malignant potential (7 of 49; 14%), low-grade papillary urothelial carcinomas (38 of 49; 78%), and high-grade papillary urothelial carcinomas (4 of 49; 8%). Only a few (n=10) of the urothelial tumors were invasive, invading the lamina propria (n=5; 50%), muscularis propria (n=4; 40%), or perivesical soft tissue (n=1; 10%). Clinical follow-up information was available for 41 patients (69%), with a mean follow-up time of 77 months. Of 31 patients with noninvasive papillary urothelial tumors, only 1 patient (3%) later developed an invasive urothelial carcinoma and died of the disease, and 30 of these patients (97%) were alive at the end of follow-up, although 10 (32%) had local tumor recurrences. In the 10 patients with invasive urothelial carcinomas, 3 patients (30%) died of the disease and 5 others (50%) were alive with metastases (the other 2 [20%] were alive with no recurrence). Urothelial tumors in young patients are mostly noninvasive, papillary carcinomas and have an excellent prognosis; however, a small subset of patients may present with high-grade invasive urothelial carcinomas that result in poor clinical outcomes.

Constitutive β-Catenin Activation Induces Male-Specific Tumorigenesis in the Bladder Urothelium

The incidence for bladder urothelial carcinoma, a common malignancy of the urinary tract, is about three times higher in men than in women. Although this gender difference has been primarily attributed to differential exposures, it is likely that underlying biologic causes contribute to the gender inequality. In this study, we report a transgenic mouse bladder tumor model upon induction of constitutively activated β-catenin signaling in the adult urothelium. We showed that the histopathology of the tumors observed in our model closely resembled that of the human low-grade urothelial carcinoma. In addition, we provided evidence supporting the KRT5-positive;KRT7-negative (KRT5(+); KRT7(-)) basal cells as the putative cells-of-origin for β-catenin-induced luminal tumor. Intriguingly, the tumorigenesis in this model showed a marked difference between opposite sexes; 40% of males developed macroscopically detectable luminal tumors in 12 weeks, whereas only 3% of females developed tumors. We investigated the mechanisms underlying this sexual dimorphism in pathogenesis and showed that nuclear translocation of the androgen receptor (AR) in the urothelial cells is a critical mechanism contributing to tumor development in male mice. Finally, we carried out global gene profiling experiments and defined the molecular signature for the β-catenin-induced tumorigenesis in males. Altogether, we have established a model for investigating sexual dimorphism in urothelial carcinoma development, and implicated synergy between β-catenin signaling and androgen/AR signaling in carcinogenesis of the basal urothelial cells.

Urinary Bladder Cancer in Yemen

The aims of this study are to highlight the clinicopathological features of urinary bladder cancer in Yemen, and to describe the histological grading of urothelial neoplasms according to the World Health Organization and International Society of Urologic pathology (WHO/ISUP 1998) classification. This is a descriptive record-based study of 316 cases of bladder cancer diagnosed by two pathologists at the Department of pathology, Sana'a University from 1(st) January 2005 to 30(th) April 2009. The diagnoses were made on hematoxylin and eosin stained sections and categorized according to WHO/ISUP 1998 classification. Out of 316 urinary bladder cancers, 248 (78%) were urothelial neoplasms, 53 (17%) were squamous cell carcinoma, 7 (2%) were adenocarcinoma, and 3 (1%) were rhabdomyosarcoma. The remaining cases were metastatic carcinomas (n=3), small cell carcinoma (n=1), and non-Hodgkin's lymphoma (n=1). The urothelial neoplasms observed were carcinoma in situ 4 (2%), papilloma 7 (3%), papillary urothelial neoplasm of low malignant potential 26 (11%), papillary urothelial carcinoma of low grade 107 (43%), papillary urothelial carcinoma of high grade 18 (7%), and non-papillary urothelial carcinoma of high grade 85 (34%), with 60 years mean age for males and 58 years for females; along with a male to female ratio of 4:1. The peak incidence was observed in the 61-70 years age group. This study documents a high frequency of urothelial neoplasms, mostly papillary urothelial carcinoma of low grade and non-papillary urothelial carcinoma of high grade with male preponderance and peak incidence in 6(th) decade of age.

Utility of ProEx C in the histologic evaluation of the neoplastic and nonneoplastic urothelial lesions

ProEx C is an antibody cocktail targeting the expression of topoisomerase IIα and minichromosome maintenance protein 2. ProEx C staining is being used mainly to assist in diagnoses of dysplasia in gynecological specimens. This study was designed to determine the utility of ProEx C in assessing the urothelial lesions. Sixty-four patient specimens were divided into 5 groups: group I, 22 benign; group II, 13 low-grade noninvasive papillary urothelial carcinoma; group III, 10 high-grade urothelial carcinoma in situ (flat lesion); and group IV, 19 high-grade noninvasive papillary and invasive urothelial carcinomas. ProEx C reactions were scored in basal, parabasal, intermediate, and superficial cell layers. A sample was recorded as positive when nuclear staining was seen in the cells of the intermediate and/or superficial layers. Of 22 cases in group I, 21 were negative for ProEx C with a specificity of 95%. Of 13 cases in group II, 11 had positive results with sensitivity of 85%. All cases in groups III and IV had positive staining pattern with ProEx C with a sensitivity of 100%. In this study, ProEx C stain had an overall 95% sensitivity and specificity with positive and negative predictive values of 98% and 91%, respectively, for detection of urothelial carcinoma. We conclude that ProEx C is effective in differentiating carcinoma in situ and benign urothelial lesions. It also resolves issues in low- versus high-grade papillary urothelial carcinomas. To our knowledge, this is the first publication on the diagnostic application of ProEx C in histopathology of the urothelial lesions.

Mixed low- and high-grade papillary urothelial carcinoma: histopathogenetic and clinical significance

There are two pathways of urothelial carcinogenesis: low-grade urothelial carcinoma (LGUC) with low rates of gene alterations and high-grade urothelial carcinoma (HGUC) with numerous gene alterations. HGUC often displays strong reactivity for cytokeratin 20 (CK20) and p16. Despite distinct molecular changes, urothelial carcinoma (UC) with both low- and high-grade features is not uncommon. We examined cases with patterns of mixed low- and high-grade UC (MLHGUC). Consecutive cases of UC at our institution were reviewed. There were 45 cases that showed a mixture of both LGUC and HGUC. IHC for CK5, CK20, CD44, p16, and Ki67 was performed. Areas of HGUC displayed strong and diffuse reactivity for p16, CK20, and Ki67 in 20-50% of the tumor, while LGUC areas had negative or focal reactivity for CK20 and Ki67 in 10-30%. There were two distinct cohorts of MLHGUC: patients with a history of LGUC (group A) and those without (group B). Group A patients (n = 8) had a history of LGUC for 1-10years. The tumor specimens weighed 1.5 ± 1.7g and had HGUC components of 25 ± 20% of the tissue. Superficial invasion was present in one case. All tumors had BCG treatment with one recurrence. In group B (n = 37), tumor specimens weighed 3 ± 3.9g and had HGUC components in 43 ± 21% of the tissue. Superficial invasion was present in five cases, and muscle invasion with lung metastasis occurred in one case. Four cases were refractory to BCG with an increased proportion of HGUC, and one case requiring cystectomy. Differences in size and proportion of HGUC between groups A and B MLHGUC were significant (P < 0.05), with group B presenting with a higher tumor burden and proportion of HGUC. MLHGUC is diagnostically challenging and is commonly assigned high grade since this determines prognosis. Group A MLHGUC likely develops as a result of progression from LGUC, whereas group B MLHGUC likely develops de novo, is associated with larger tumors, shows a higher proportion of HGUC, and follows a worse prognosis. Despite the similar histology of groups A and B, assignment to HGUC in a binary system may mask important prognostic information.

CEUS in the study of bladder, method, administration and evaluation, a technical note

Contrast-enhanced ultrasound (CEUS) is the application of ultrasound contrast agents (UCAs) to traditional medical sonography. The development of UCAs allowed to overcome some of the limitations of conventional B-mode and Doppler ultrasound techniques and enabled the display of the parenchymal microvasculature. Purpose of this paper is to delineate the elements of a solid and science-based technique in the execution of urinary bladder CEUS. We describe the technical execution of urinary bladder CEUS and the use of perfusion softwares to perform contrast enhancement quantitative analysis with generation of time-intensity curves from regions of interest. During CEUS, normal bladder wall shows a wash-in time of 13s, a time to peak (TTP) >40s, a signal intensity (SI) <45% and a wash-out time >80s; Low-grade urothelial cell carcinoma (UCC) shows a wash-in time of 13s, a time to peak TTP >28s, a SI <45% and a wash-out time of 40s; High-grade UCC shows a wash-in time of 13s, a TTP >28s, a SI >50% and a wash-out time of 58s. CEUS is a useful tool for an accurate characterization of bladder UCC although it has some drawbacks. To avoid misunderstandings, a widely accepted classification and a standardized terminology about the most significant parameters of this application should be adopted in the immediate future.

Myeloid leukemia in a urine specimen: A case report and review of the literature

Urinary tract cytology has a long history of utilization for the diagnosis and follow-up of tumors involving the urothelial tract. As expected, the most common tumor encountered in exfoliative urine cytology is urothelial carcinoma. While the sensitivity of urinary tract cytology for the diagnosis of low-grade urothelial carcinomas is low, its sensitivity and accuracy for high grade urothelial carcinomas is much higher. However, nonurothelial malignancies, such as hematopoietic malignancies, can also be encountered in urine specimens. Leukemic cells in urine can be diagnosed readily by cytological examination in cases where more invasive procedures are difficult to perform. Additionally, cell block sections can be utilized to determine the immunocytochemical profile of the tumor cells to confirm the diagnosis. Herein we report a case of a 75-year-old man with a past medical history of acute myeloid leukemia (AML), who presented with congested heart failure and painless macroscopic hematuria. AML relapse was diagnosed. Cytological examination of the urine using a ThinPrep® smear, cytospin preparation, and immunohistochemical stains performed on the cell block sections were examined. Findings were consistent with leukemic cells of myeloid origin in the bladder washing specimen.

Holmium laser versus conventional transurethral resection of the bladder tumor

Background Transurethral resection of the bladder tumor (TURBT) remains the gold standard for non-muscle-invasive bladder cancer (NMIBC). Laser techniques have been widely used in urology. This analysis aimed to assess the safety and efficacy of holmium resection of the bladder tumor (HoLRBT) vs. TURBT. Methods A systemic search of MEDLINE, Embase, Web of Science, and The Cochrane Library as well as manual bibliography searches were performed to identify the relevant studies. The pooled estimates of operation time, obturator nerve reflex rate, bladder perforation rate, bladder irrigation rate, catheterization time, hospital stay, and one- and two-year recurrence free survivals were calculated. Results Five studies were enrolled into our meta-analysis. No significant difference was observed in the operation time between groups (weighted mean difference (WMD) 1.01, 95% confidential interval (95% CI) -3.52-5.54, P=0.66). The significant difference in the obturator nerve reflex (OR 0.05, 95% CI 0.01-0.04, P=0.004), bladder perforation (OR 0.14, 95% CI 0.03-0.61, P=0.009), bladder irrigation (OR 0.13, 95% CI 0.04-0.45, P=0.001), catheterization time (WMD -0.96, 95% CI -1.11 to -0.82, P &lt;0.00001), and hospital stay (WMD -1.46, 95% CI -1.65 to -1.27, P &lt;0.00001) showed advantages of HoLRBT over TURBT. The 2-year recurrence free survival rate favors the HoLRBT group (OR 1.46, 95% CI 1.02-2.11, P=0.04). Conclusions As a promising technique, HoLRBT is safe and efficient, and showed several advantages over TURBT. HoLRBT can be used as an alternative procedure for TURBT in terms of low-grade papillary urothelial carcinoma or low-grade early TNM-stage urothelial carcinoma.

Abstract 2174: Small molecule iInhibitors of PIM kinases as potential treatments for urothelial carcinomas.

Abstract The proto-oncogene PIM kinases (PIM-1, PIM-2, PIM-3) are serine/threonine kinases that have been shown to be involved in a number of signaling pathways important to cancer cells. PIM kinases act as downstream effectors as inhibitors of apoptosis and as positive regulators of G1-S phase progression through the cell cycle. PIM kinases are upregulated in multiple cancer indications, including lymphoma, leukemia, multiple myeloma, prostate, gastric, and head &amp; neck cancers. Overexpression of one or more PIM family members in patient tumors frequently correlates with poor prognosis. The aim of this investigation was to evaluate PIM expression in low- and high-grade urothelial carcinoma, and to assess for expression that may contribute to disease progression and serve as a potential site for targeted therapy. Seventy-two cases of urothelial carcinoma were included in this retrospective study of surgical biopsy and resection specimens from the University of Utah Department of Pathology (retrieved from 2008-2011). Tissue was stained with commercially available antibodies against PIM-1, PIM-2, and PIM-3. Cases were divided into three groups (invasive high grade urothelial carcinoma (n=49), non-invasive urothelial carcinoma/carcinoma in situ (n=16), and non-invasive low grade urothelial carcinoma (n=7)). Individual cases were then given a score (0-4) based upon a percentage of cells staining positive for each antibody (&amp;lt;5%=0; 5-25%=1; 26-50%=2; 51-75%=3; &amp;gt;75%=4). A score of 2 or greater was considered expressed. PIM-1, PIM-2 and PIM-3 expression was noted in 29% (2/7), 43% (3/7) and 86% (6/7) cases of non-invasive low-grade urothelial carcinoma; 44% (7/16), 50% (8/16), 44% (7/16) cases of non-invasive high-grade urothelial carcinoma; 10% (5/49), 27% (13/49), and 18% (9/49) cases of invasive high-grade urothelial carcinoma, respectively. These results suggest that expression of PIM-1, PIM-2 and PIM-3 is present in a significant percentage of urothelial carcinomas and may serve as a source for targeted PIM-kinase inhibition. We have developed PIM inhibitors exhibiting 4-10 fold improved potency against the PIM kinase family compared to our original PIM inhibitor SGI-1776. Our PIM inhibitors display sub-μM activity in pharmacodynamic marker modulation, proliferation and 2D colony formation assays using the UM-UC-3 bladder cancer cell line. These PIM kinase inhibitors also are potent inducers of apoptosis in T24, RT4, and UM-UC-3 bladder cancer cell lines. These compounds have favorable hERG and CYP inhibition profiles compared with SGI-1776, and demonstrate excellent oral bioavailability. In vivo xenograft studies using bladder cancer cell line models show that PIM kinase inhibition can reduce the tumor growth of these tumor models suggesting that PIM kinase inhibitors may be active in human urothelial carcinomas. Citation Format: Kent J. Carpenter, Rachel Brog, Christopher Moreno, Daniel J. Albertson, Jared J. Bearss, Ting Liu, Steven Warner, David J. Bearss. Small molecule iInhibitors of PIM kinases as potential treatments for urothelial carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2174. doi:10.1158/1538-7445.AM2013-2174

Ureterectomy in the treatment of urothelial carcinoma of the distal ureter

IntroductionSegmental ureterectomy with preservation of the kidney is a treatment option for the low grade urothelial carcinoma (LG-UC) in distal ureter that is not a candidate for endoscopic resection. Laparoscopic distal ureterectomy (LDU) with ureteral reimplantation is common in benign conditions (stenosis, iatrogenic lesion, endometriosis). However, it has been hardly described in malignant ureteral condition. The literature is reviewed in this regard and the surgical technique is described. Material and methodsThe experience regarding two cases of LDU due to low grade urothelial carcinoma in distal ureter is presented. In both, previous bladder transurethral resection (RTU) was performed. The urinary cytology was negative and the imaging studies identified urinary obstruction and distal ureter filling defect. One of the patients had a background of T1G3 bladder cancer and suffered renal failure. In both, the ureter was ligated early. Segmental ureterectomy was performed using a combined endoscopic and laparoscopic procedure with ureteral desinsertion in one case. In the other, it was exclusively laparoscopic. Both were done with 4 trocars. Ureteral reimplantation was conducted with continuous hermetic suture and without tension. In one case with background of high grade bladder tumor, pelvic lymphadenectomy was also performed. ResultsOperating time was 180 and 240min, respectively, with estimated bleeding of 100 and 250ml. Hospitalization time was 6 and 4 days. The only post-operatory complication was paralytic ileum (Clavien I) in the first case. With a 20 and 12 month follow-up, there is no evidence of recurrence or dilatation. In the patient with renal failure, creatinine clearance improved. ConclusionsThe LDU with ureteral reimplantation is a complex technique. However, it represents a feasible and effective alternative for the treatment of LG-UC in distal ureter, as long as the oncological and reconstructive principles are respected.

Nephrogenic Adenoma

Nephrogenic adenoma of the urinary bladder, where they present most frequently, are typically confined to the lamina propria but can on occasion focally involve the superficial muscularis propria. Less commonly, nephrogenic adenoma involves the renal pelvis and ureter where again they almost always only involve the lamina propria. We identified 3 consult cases in which tubules of nephrogenic adenoma extensively involved the muscularis propria and focally infiltrated the perinephric adipose tissue, for which the contributing pathologists considered the diagnosis of adenocarcinoma. In 1 case, that of a 71-year-old man, the lesion was associated with a hemorrhagic renal cyst (3.0 cm) and a spontaneous retroperitoneal bleed (6.0 cm) of unknown origin. In the second case, that of a 73-year-old woman, 2 foci (2.2, 1.6 cm) were present in the renal pelvis. They developed after biopsy of a low-grade noninvasive papillary urothelial carcinoma in the same site complicated by perforation. The third case was that of a 20-year-old woman with ureteropelvic junction obstruction and severe hydronephrosis associated with renal calculi. In all cases, the lesions were positive for CK7 and PAX8. These 3 cases report the novel finding that nephrogenic adenoma can occasionally have a deep infiltrative pattern into perinephric adipose tissue, possibly as a result of either biopsy-associated perforation or extensive disruption due to hemorrhage or mechanical obstruction. Awareness of this worrisome infiltration pattern, although rare, can prevent a misdiagnosis of an infiltrating carcinoma.

Short telomeres and chromosome instability prior to histologic malignant progression and cytogenetic aneuploidy in papillary urothelial neoplasms

PurposeEvaluation of the relationships existing among 3 histologic types of urothelial tumors, chromosomal instability, and telomere length. Patients and methodsWe examined 37 consecutive cases of papillary urothelial neoplasm, from which 26 (70.3%) were suitable for karyotype analysis, comprising 7 papillary urothelial neoplasms of low malignant potential (PUNLMPs), 10 low-grade papillary urothelial carcinomas (PUCs), and 9 high-grade PUCs. We performed karyotype and anaphase bridge analyses, and measured telomere lengths by quantitative fluorescence in situ hybridization. ResultsPUNLMPs were always diploid and had anaphase bridges. Low-grade PUCs showed diploidy (n = 2), hypoploidy (n = 4) and polyploidy (n = 4), and high-grade PUCs showed diploidy (n = 1) and polyploidy (n = 8); both had anaphase bridges. The incidence of anaphase bridges did not differ significantly between PUNLMPs and high-grade PUCs (P = 0.105). The telomere lengths of PUNLMP, low-grade PUC, and high-grade PUC, expressed as mean telomere fluorescence units (TFU)±SD, were 7906±3197, 4893±1567, and 3299±1406, respectively. The differences among the 3 groups were significant. However, 42.9% of the PUNLMPs had shorter telomeres than the mean value for low-grade PUCs, and 30.0% of the low-grade PUCs had shorter telomeres than those for high-grade PUCs. There was an inverse correlation between telomere length and the incidence of anaphase bridges. ConclusionsPUNLMP appears to progress to low-grade PUC and high-grade PUC in association with telomere shortening and chromosomal instability. Our data suggest that critically shortened telomeres cause chromosomal instability during progression of papillary urothelial neoplasms.

Paraplegia after epidural anaesthesia

A 59-year-old woman presented with 6-week history of recurrent haematuria. Her medical history was unremarkable apart from a 22-pack-year smoking history and hypothyroidism. There was no history of alcohol or...

Detection of MicroRNAs in Archival Cytology Urine Smears

MicroRNAs’ dysregulation and profiling have been demonstrated to be clinically relevant in urothelial carcinoma (UC). Urine cytology is commonly used as the mainstay non-invasive test for secondary prevention and follow-up of UC patients. Ancillary tools are needed to support cytopathologists in the diagnosis of low-grade UC. The feasibility and reliability of microRNAs profiling by qRT-PCR analysis (miR-145 and miR-205) in archival routine urine cytology smears (affected by fixation/staining [Papanicolau] and room temperature storage) was tested in a series of 15 non-neoplastic and 10 UC urine specimens. Only samples with >5,000 urothelial cells and with <50% of inflammatory cells/red blood cells clusters were considered. Overall, a satisfactory amount of total RNA was obtained from all the considered samples (mean 1.27±1.43 µg, range 0.06–4.60 µg). Twenty nanograms of total RNA have been calculated to be the minimal total RNA concentration for reliable and reproducible miRNAs expression profiling analysis of archival cytological smears (slope = -3.4084; R-squared = 0.99; efficiency = 1.94). miR-145 and miR-205 were significantly downregulated in UC samples in comparison to non-tumor controls. These findings demonstrate that urine archival cytology smears are suitable for obtaining high-quality RNA to be used in microRNAs expression profiling. Further studies should investigate if miRNAs profiling can be successfully translated into clinical practice as diagnostic or prognostic markers.

Low-grade micropapillary urothelial carcinoma: Does it exist? A SEER analysis of management and outcomes.

315 Background: Micropapillary Urothelial Bladder Carcinoma (MPBC) is a rare aggressive variant histology of bladder cancer. Management of non-muscle invasive (NMI) MPBC is controversial, as bladder sparing strategies routinely used when managing TCC have resulted in worse outcomes. In order to better understand its behavior, we reviewed all MPBC pts in the SEER database and compared them with TCC pts. Methods: Data was collected from SEER 17. Age, sex, race, grade, stage, treatment, and cause of death were collected. Kaplan-Meier (KM) and Cox proportional hazards (CPH) models were performed. Results: From 2001-2008, 120 pts with MPBC were identified, 0.1% of all bladder cancer. Mean age was 70.3 yrs, 76.7% were male, and 90.8% were Caucasian. No difference in age, sex, or race was detected between MPBC and TCC pts. MPBC presented with more high grade (HG) disease (86.1% vs. 38.7%, p&lt;0.0001) and with higher stage (40.8% NMI vs. 90.4% NMI, p &lt; 0.0001). KM analysis demonstrated that NMI MPBC had significantly worse overall survival (OS) than NMI TCC (not controlling for grade, p&lt;0.0001). Low grade (LG) NMI MPBC pts had worse OS and cancer specific survival (CSS) as compared to LG TCC pts (p=0.0037, p&lt;0.0001 respectively), and did no better than HG NMI MPBC pts. No difference was detected between HG NMI MPBC and HG NMI TCC pts. A CPH model controlling for stage, grade, treatment, age, race, and sex detected no significant survival difference in MPBC vs. TCC (HR 1.04, p=0.7966). For NMI MPBC (n=49), only 4 pts underwent definitive therapy (2 had cystectomy and 2 received EBRT). During the median follow-up period of 31 months, no cancer specific deaths occurred in this group of pts. However, in those not receiving definitive therapy (n=45), 7 cancer specific deaths occurred (15.6%). Conclusions: MPBC is a rare variant with high stage and grade presentation. Controlling for stage and grade, no difference could be detected in survival between MPBC and TCC. However, LG NMI MPBC behaved similarly to both HG MPBC and HG TCC in regards to survival outcomes. We propose that all MPBC (regardless of grade) be managed as HG disease, and that strong consideration for definitive therapy should be given even in the setting of NMI disease.

La ureterectomía distal laparoscópica en el tratamiento del carcinoma urotelial del uréter distal

IntroductionSegmental ureterectomy with preservation of the kidney is a treatment option for the low grade urothelial carcinoma (LG-UC) in distal ureter that is not a candidate for endoscopic resection. Laparoscopic distal ureterectomy (LDU) with ureteral reimplantation is common in benign conditions (stenosis, iatrogenic lesion, endometriosis). However, it has been hardly described in malignant ureteral condition. The literature is reviewed in this regards and the surgical technique described. Material and methodsThe experience regarding two cases of LDU due to low grade urothelial carcinoma in distal ureter is presented. In both, previous bladder transurethral resection (RTU) was performed. The urinary cytology was negative and the imaging studies identified urinary obstruction and distal ureter filling defect. One of the patients had a background of T1G3 bladder cancer and suffered renal failure. In both, the ureter was ligated early. Segmental ureterectomy was performed using a combined endoscopic and laparoscopic procedure with ureteral desinsertion in one case. In the other, it was exclusively laparoscopic. Both were done with 4 trocars. Ureteral reimplantation was conducted with continuous hermetic suture and without tension. In one case with background of high grade bladder tumor, pelvic lymphadenectomy was also performed. ResultsOperating time was 180 and 240min, respectively, with estimated bleeding of 100 and 250ml. Hospitalization time was 6 and 4 days. The only post-operatory complication was paralytic ileum (Clavien I) in the first case. With a 20 and 12 month follow-up, there is no evidence of recurrence or dilatation. In the patient with renal failure, creatinine clearance improved. ConclusionsThe LDU with ureteral reimplantation is a complex technique. However, it represents a feasible and effective alternative for the treatment of LG-UC in distal ureter, as long as the oncological and reconstructive principles are respected.

TRAIL and osteoprotegerin (OPG) expression in bladder urothelial carcinoma: correlation with clinicopathological parameters and prognosis

To investigate the expression of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) in bladder urothelial carcinomas (UCs) and assess possible interrelations with other regulators of TRAIL induced apoptosis (p65/NF-κB, p-ERK1/2, p-AKT) and FGFR3, as well as to elucidate their potential involvement in bladder tumourigenesis and determine their potential prognostic utility. Paraffin embedded transurethral resection tissue from 128 patients with UC was immunostained for TRAIL and OPG as well as for p65/NF-κB, p-ERK1/2, p-AKT and FGFR3. TRAIL and OPG were coexpressed in 96.6% of cases and positively interrelated. OPG expression was significantly different among histological grades, being higher in low-grade UCs and was inversely correlated with the presence of lymphovascular invasion (LVI). TRAIL also displayed an inverse relationship with histological grade, T-category and LVI. Both OPG and TRAIL expression were positively correlated with FGFR3 expression, the former relationship being marginal. Moreover, increased TRAIL expression was marginally correlated with lower NF-κB/p65 nuclear expression. Increased OPG expression adversely affected survival both in univariate and multivariate analysis. OPG and TRAIL are frequently expressed and coexpressed in UCs, supporting the involvement of OPG in the resistance to TRAIL-driven apoptosis. Inhibition of NF-κB activation may also play a similar role, although less important. OPG emerged as an independent prognostic marker of adverse significance.