Prognostic significance of inflammation-based prognostic scoring in patients with upper urinary tract urothelial carcinoma

ABSTRACT Objectives: To investigate whether Glasgow Prognostic Score has prognostic significance in patients with upper urinary urothelial carcinoma. Patients and methods: We retrospectively reviewed the clinical records of 74 patients with upper urinary urothelial carcinoma. We set the cut-off value for C-reactive protein as 1.0mg/dL, and 3.5mg/dL for albumin as Glasgow Prognostic Score. Their blood data including albumin and C-reactive protein for Glasgow Prognostic Score and cytokeratin 19 fragment 21-1 as a tumor marker were measured before starting treatment. The patients were stratified into three groups with Glasgow Prognostic Score: The Group-1, albumin ≥3.5g/dL and C-reactive protein < 1.0mg/dL; Group-2, albumin < 3.5g/dL or C-reactive protein ≥1.0mg/dL; Group-3, albumin < 3.5g/dL and C-reactive protein ≥1.0mg/dL. Results: The median follow-up for all patients was 26.9 months (range: 10.9-91.1 months), during which 37 (50%) patients died. There was a significant difference in the estimated survival rate among the 3 groups stratified by Glasgow Prognostic Score. The estimated survival rate in the Group-1 was significantly higher than those in Groups 2 and 3. In the univariate analysis C-reactive protein, serum cytokeratin 19 fragment 21-1 and Glasgow Prognostic Score were significant predictors of overall survival. On the multivariate analysis, serum cytokeratin 19 fragment 21-1 and Glasgow Prognostic Score were independently associated with shorter overall survival. Conclusion: Our review suggests Glasgow Prognostic Score may play as a prognostic predictor for upper urinary urothelial carcinoma.

Chorioallantoic urothelial tumor avatar. A clinical tool for phenotype-based therapy

Abstract In the muscle invasive bladder cancer (MIBC) standard of care treatment only patients presenting a major pathological tumor response are more likely to show the established modest 5% absolute survival benefit at 5 years after cisplatin-based neoadjuvant chemotherapy (NAC). To overcome the drawbacks of a blind NAC (i.e. late cystectomy with unnecessary NAC adverse events) with potential to survival improvements, preclinical models of urothelial carcinoma have arisen in this generation as a way to pre-determine drug resistance even before therapy is targeted. The implantation of tumor specimens in the chorioallantoic membrane (MCA) of the chicken embryo results in a high-efficiency graft, thus allowing large-scale studies of patient-derived "tumor avatar". This article discusses a novel approach that exploits cancer multidrug resistance to provide personalized phenotype-based therapy utilizing the MIBC NAC dilemma.

Low grade urothelial carcinoma mimicking basal cell hyperplasia and transitional metaplasia in needle prostate biopsy

ABSTRACT Purpose The vast majority of urothelial carcinomas infiltrating the bladder are consistent with high-grade tumors that can be easily recognized as malignant in needle prostatic biopsies. In contrast, the histological changes of low-grade urothelial carcinomas in this kind of biopsy have not been studied. Materials and Methods We describe the clinicopathologic features of two patients with low-grade bladder carcinomas infiltrating the prostate. They reported dysuria and hematuria. Both had a slight elevation of the prostate specific antigen and induration of the prostatic lobes. Needle biopsies were performed. At endoscopy bladder tumors were found in both cases. Results Both biopsies showed nests of basophilic cells and cells with perinuclear clearing and slight atypia infiltrating acini and small prostatic ducts. The stroma exhibited extensive desmoplasia and chronic inflammation. The original diagnosis was basal cell hyperplasia and transitional metaplasia. The bladder tumors also showed low-grade urothelial carcinoma. In one case, the neoplasm infiltrated the lamina propria, and in another, the muscle layer. In both, a transurethral resection was performed for obstructive urinary symptoms. The neoplasms were positive for high molecular weight keratin (34BetaE12) and thrombomodulin. No metastases were found in either of the patients, and one of them has survived for five years. Conclusions The diagnosis of low-grade urothelial carcinoma in prostate needle biopsies is difficult and may simulate benign prostate lesions including basal cell hyperplasia and urothelial metaplasia. It is crucial to recognize low-grade urothelial carcinoma in needle biopsies because only an early diagnosis and aggressive treatment can improve the prognosis for these patients.

Urothelial neoplasm of the bladder in childhood and adolescence: a rare disease

ABSTRACT Purpose: Bladder tumors are rare in children and adolescents. For this reason, the diagnosis is sometimes delayed in pediatric patients. We aimed to describe the diagnosis, treatment, and follow-up methods of bladder urothelial neoplasms in children and adolescents. Materials and Methods: We carried out a retrospective multicenter study involving patients who were treated between 2008 and 2014. Eleven patients aged younger than 18 years were enrolled in the study. In all the patients, a bladder tumor was diagnosed using ultrasonography and was treated through transurethral resection of the bladder (TURBT). Results: Nine of the 11 patients (82%) were admitted with gross hematuria. The average delay in diagnosis was 3 months (range, 0–16 months) until the ultrasonographic diagnosis was performed from the first episodes of macroscopic hematuria. A single exophytic tumor (1–4cm) was present in each patient. The pathology of all patients was reported as superficial urothelial neoplasm: two with papilloma, one with papillary urothelial neoplasm of low malignant potential (PUNLMP), four with low grade pTa, and four with low grade pT1. No recurrence was observed during regular cystoscopic and ultrasonographic follow-up. Conclusions: Regardless of the presence of hematuria, bladder tumors in children are usually not considered because urothelial carcinoma in this population is extremely rare, which causes a delay in diagnosis. Fortunately, the disease has a good prognosis and recurrences are infrequent. Cystoscopy may be unnecessary in the follow-up of children with bladder tumors. We believe that ultrasonography is sufficient in follow-up.

Cutaneous invasion from sarcomatoid urothelial carcinoma: clinical and dermatopathologic features

Abstract In Brazil, without considering the non-melanoma skin tumors, bladder cancer in men is the eighth most common, and the urothelial carcinoma or transitional cell carcinoma is the most common among these. Cutaneous metastases from urothelial neoplasms appear as single or multiple erythematous, infiltrated nodules or plaques, and like other cases of distant disease, it is indicative of poor prognosis. The invasive urothelial carcinoma is recognized for its ability to present divergent differentiation and morphological variants. The sarcomatoid urothelial carcinoma is a rare cancer that consists of two different components: one composed of epithelial tissue and the other with sarcomatoid features of mesenchymal origin. The authors describe a case of cutaneous metastasis of sarcomatoid urothelial carcinoma in a 63-year-old male patient.

Fibroblast Growth Factor Receptor 1 Overexpression Is Associated with Poor Survival in Patients with Resected Muscle Invasive Urothelial Carcinoma

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.

Sphingosine Kinase 1 urothelial expression is increased in patients with neurogenic detrusor overactivity

Objectives: To evaluate the expression of sphingosine kinase 1 (SPK1) in the bladder wall in patients with neurogenic lower urinary tract dysfunction and its association with clinical, urodynamic and pathological features. Materials and Methods: The expression of SPK1 was studied in bladder wall specimens obtained from cystectomy using immunohistochemistry in ten patients with spinal cord injury (n=8) or multiple sclerosis (n=2) with urodynamically proven neuropathic bladder dysfunction, and in controls (n=5). Inflammation and fibrosis were analysed with histological criteria and SPK1 expression was determined by individual immunohistochemical staining. Results: Significant increased SPK1 urothelial immunoreactivity was shown in patients compared to control group (p=0.03). By contrast, SPK1 immunoreactivity in patients was significantly decreased in the sub-urothelium, muscles and nerves, p=0.02; 0.01 and 0.003, respectively. Patients with neurogenic detrusor overactivity (NDO) had higher SPK1 urothelium expression than those without any DO (p=0.04). Conclusions: SPK1 is expressed in the human bladder wall, specifically the urothelium, in bladder specimens from patients with NDO. The role of SPK1 in the pathophysiology of NDO needs further elucidation.

The Characteristics of Recurrent Upper Tract Urothelial Carcinoma after Radical Nephroureterectomy without Bladder Cuff Excision

PURPOSE: To investigate oncological outcomes based on bladder cuff excision (BCE) during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) and to provide clinical evidence of tumor recurrence in patients without BCE. MATERIALS AND METHODS: We retrospectively collected data of 372 consecutive patients who underwent RNU at our institution from May 1989 through October 2010. After excluding some data, we reviewed 336 patients for the analysis. RESULTS: Of the patients who underwent RNU with BCE (n=279, 83.0%) and without BCE (n=57, 17.0%), patients without BCE had poorer cancer-specific and overall survival rates. Among 57 patients without BCE, 35 (61.4%) experienced tumor recurrence. Recurrence at the remnant ureter resulted in poor oncological outcomes compared to those in patients with bladder recurrence, but better outcomes were observed compared to recurrence at other sites. No significant predictors for tumor recurrence at the remnant ureter were identified. In patients without BCE, pathological T stage [hazard ratio (HR), 5.73] and lymphovascular invasion (HR, 3.65) were independent predictors of cancer-specific survival, whereas age (HR, 1.04), pathological T stage (HR, 5.11), and positive tumor margin (HR, 6.50) were independent predictors of overall survival. CONCLUSION: Patients without BCE had poorer overall and cancer-specific survival after RNU than those with BCE. Most of these patients experienced tumor recurrence at the remnant ureter and other sites. Patients with non-organ confined UTUC after RNU without BCE may be considered for adjuvant chemotherapy with careful follow-up.

Preoperative Underweight Patients with Upper Tract Urothelial Carcinoma Survive Less after Radical Nephroureterectomy

The prognostic impact of body mass index (BMI) in patients with upper tract urothelial carcinoma (UTUC) is an ongoing debate. Our study aimed to investigate the prognostic role of BMI in patients treated with radical nephroureterectomy (RNU) for UTUC from a multi-institutional Korean collaboration. We retrospectively reviewed data from 440 patients who underwent RNU for UTUC at four institutions in Korea. To avoid biasing the survival estimates, patients who had previous or concomitant muscle-invasive bladder tumors were excluded. BMI was categorized into approximate quartiles with the lowest quartile assigned to the reference group. Kaplan-Meier and multivariate Cox regression analyses were performed to assess the influence of BMI on survival. The lower quartile BMI group showed significantly increased overall mortality (OM) and cancer specific mortality (CSM) compared to the 25%-50% quartiles and upper quartile BMI groups. Kaplan-Meier estimates showed similar results. Based on multivariate Cox regression analysis, preoperative BMI as a continuous variable was an independent predictor for OM and CSM. In conclusion, preoperative underweight patients with UTUC in Korea survive less after RNU. Preoperative BMI may provide additional prognostic information to establish risk factors.

P70S6K and Elf4E Dual Inhibition Is Essential to Control Bladder Tumor Growth and Progression in Orthotopic Mouse Non-muscle Invasive Bladder Tumor Model

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.

P70S6K and Elf4E Dual Inhibition Is Essential to Control Bladder Tumor Growth and Progression in Orthotopic Mouse Non-muscle Invasive Bladder Tumor Model

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.

Evaluation of the metabolism of glycosaminoglycans in patients with interstitial cystis

Introduction: Painful bladder syndrome/interstitial cystitis (PBS/IC) pathogenesis is not fully known, but evidence shows that glycosaminoglycans (GAG) of bladder urothelium can participate in its genesis. The loss of these compounds facilitates the contact of urine compounds with deeper portions of bladder wall triggering an inflammatory process. We investigated GAG in urine and tissue of PBS/IC and pure stress urinary incontinence (SUI) patients to better understand its metabolism. Materials and Methods: Tissue and urine of 11 patients with PBS/IC according to NIDDK criteria were compared to 11 SUI patients. Tissue samples were analyzed by histological, immunohistochemistry and immunofluorescence methods. Statistical analysis were performed using t Student test and Anova, considering significant when p < 0.05. Results: PBS/IC patients had lower concentration of GAG in urine when compared to SUI (respectively 0.45 ± 0.11 x 0.62 ± 0.13 mg/mg creatinine, p < 0.05). However, there was no reduction of the content of GAG in the urothelium of both groups. Immunofluorescence showed that PBS/IC patients had a stronger staining of TGF-beta, decorin (a proteoglycan of chondroitin/dermatan sulfate), fibronectin and hyaluronic acid. Conclusion: the results suggest that GAG may be related to the ongoing process of inflammation and remodeling of the dysfunctional urothelium that is present in the PBS/IC. .

Ureterectomía radical distal por cáncer urotelial y reconstrucción ureteral asistida por robot / Radical distal ureterectomy secondary to an urotelial cancer and ureteral reconstruction robot-assisted: case report

Objective: To report a case of distal ureterectomy with robotic-assisted laparoscopic reimplantation using a Boari flap technique. Material and Methods: We report a 55 year old man with a diagnosis of distal ureteral urothelial carcinoma without multifocality. Results: A radical distal ureterectomy and robotic-assisted laparoscopic vesicoureteral reimplantation using a Boari flap technique was performed with the da Vinci S-HD surgical system. The operative time was 210 minutes, the estimated blood loss was 200 mL. The hospital stay was 48 hours, without perioperative complications. The histopathological study showed a high grade non-muscle invasive urothelial carcinoma of the distal ureter (pT1NxMx) with negative margins. Conclusions: The distal radical ureterectomy with Boari replacement is feasible and more precise with robotic assistance. Its oncological role must be demostrated with a larger number of cases.

Objetivo: Comunicar un caso de tumor ureteral distal tratado con ureterectomía radical y neoimplante vesicoureteral con técnica de Flap Boari asistida por robot. Material y Métodos: Paciente hombre de 55 años, con diagnóstico de carcinoma urotelial de uréter distal sin compromiso multifocal. Resultados: Se realizó ureterectomía distal radical y neoimplante vesicoureteral con Flap Boari asistido por Robot da Vinci S-HD. El tiempo operatorio fue de 210 minutos, con un sangrado estimado de 200 ml. La estadía hospitalaria fue de 48 horas, sin complicaciones perioperatorias. El estudio histológico mostró un carcinoma urotelial de alto grado con infiltración de la lámina propia (pT1NxMx) y márgenes quirúrgicos negativos. Conclusiones: La ureterectomía radical distal con reconstrucción tipo Boari es técnicamente factible y más precisa con la asistencia robótica. Su rol oncológico requiere de validación con mayor número de casos.

A case of a sporadic malignant peripheral nerve sheath tumor of the urinary bladder with concomitant in situ urothelial carcinoma treated by transuretheral resection.

Malignant peripheral nerve sheath tumor (MPNST) of the urinary bladder is a very rare clinical entity. The association of such a tumor with urothelial carcinoma is even more unusual. Differential diagnosis between coexisting two distinct primary tumors and carcinosarcoma of the urinary bladder is very important as both the treatment and prognosis vary widely. Herein, we report a case of an MPNST with a concomitant in situ urothelial carcinoma in a 53-year-old man. To our knowledge, this is the first documented case of MPNST of the bladder that is treated by transuretheral resection which is in contrast with the previous reports that used cystectomy.

Utility of p63 immunohistochemical stain in differentiating urothelial carcinomas from adenocarcinomas of prostate.

Background: Prostatic adenocarcinoma and urothelial carcinoma of the urinary bladder are common cancers in men. High grade forms of these tumors may present ambiguous morphologic features that do not permit a definite diagnosis. This distinction between the two tumors has significant staging and therapeutic implications. Hence, an accurate diagnosis is essential for optimal patient care. p63 is a new marker which can be used in this context. It is expressed in most of the urothelial carcinomas and negative in majority of prostatic adenocarcinomas. Aim: To compare the expression of p63 in urothelial carcinomas and adenocarcinomas of prostate. Materials and Methods: Comparative cross--sectional study was carried out at a tertiary cancer hospital from 15 June 2006 to 15 December 2006. Immunohistochemical stain p63 was performed on 50 cases of urothelial carcinoma and 50 prostatic adenocarcinomas. Patients' name, age, histology numbers, grade of tumor, and expression of p63 were recorded. p63 expression was seen in 44 of 50 urothelial carcinomas (88%). None of the prostatic adenocarcinomas expressed p63. The ages of patients with prostatic adenocarcinoma ranged from 49 to 86 years with a median age of 71 years and 41 to 83 years for urothelial carcinomas with a median age of 60.5 years. Conclusion: p63 can be used as a reliable marker to distinguish prostatic adenocarcinomas from urothelial carcinomas in difficult cases in conjunction with other markers like PSA.

Primary renal adenosquamous carcinoma

A case of renal adenosquamous carcinoma is presented. The fact that the urothelium has no glandular or squamous structures makes the pathogenesis of this tumor unique. The process is assumed to begin with urothelial metaplasia resulting from chronic irritation leading to dysplasia and subsequently squamous and glandular differentiation

Paniculitis mesentérica: ¿predictor de una neoplasia? / Mesenteric panniculitis: predictor of a neoplasm

Introduction: Mesenteric panniculitis is a rare disorder characterized by chronic, non-specific inflammation involving the adipose tissue of the bowel mesentery of unknown aetiology. It has been associated with different processes, including digestive and urothelial malignancies. Case report: A 44-years-old man carne to the Emergency Department complaining of mesogastric pain for the last 24 hours. CT sean showed an increased density of the mesenteric adipoid tissue. Mesenteric paniculitis was diagnosed and antibiotic treatment was instaured. The patient recovered uneventfully. Two months later the patient was diagnosed of an infiltrating urothelial carcinoma. Conclusions: Mesenteric panniculitis may be associated with malignancies and other pathologies. It is advisable to perform tests to dismiss the coexistence of these disorders. In those cases, in which associated diseases could not be demonstrated, a frequent follow-up would be advisable to achieve an early diagnosis if these appear.

Introducción: La paniculitis mesentérica es un trastorno poco frecuente caracterizado por inflamación crónica inespecífica del tejido adiposo del mesenterio intestinal de etiología desconocida. Se ha relacionado con diversas patologías, entre ellas neoplasias digestivas y uroteliales. Caso clínico: Varón de 44 años que acude a Urgencias por un dolor mesogástrico de 24 horas de evolución. En la TC abdominal se objetivó un aumento de densidad de la grasa de la raíz del mesenterio. Se diagnosticó de paniculitis mesentérica y se trató mediante antibioterapia. A los 2 meses el paciente es diagnosticado de un carcinoma urotelial infiltrante. Discusión: La paniculitis mesentérica puede estar relacionada con neoplasias y otras patologías. Es conveniente realizar pruebas para descartar la coexistencia de alguna de las enfermedades asociadas. En aquellos casos en los que no se demuestre, sería recomendable un seguimiento periódico.

The Utility of Fluorescence In Situ Hybridization for Detection of Bladder Urothelial Carcinoma in Routine Clinical Practice

To evaluate the ability of fluorescence in situ hybridization (FISH) in detecting bladder urothelial carcinoma (BUC), FISH and cytology were compared for the evaluation of 308 consecutive urine samples from patients suspected of having BUC. All patients underwent cystoscopy for identification of bladder lesions. The FISH results were compared with the cytology assessment. In all, 122 patients had confirmed BUC. Among them, 68 (55.7%) were FISH-positive, while only 33 (27%) were positive on cytology. According to disease stage (superficial vs. invasive) and grade (low vs. high), the sensitivities of FISH were also significantly higher than those of cytology in all categories. Moreover, in 36 patients who had no visible tumor with flat, erythematous mucosa (suspicious lesion), FISH was more sensitive than cytology for the detection of BUC (83.3% vs. 33.3%, P=0.002). The FISH was negative in 168 (90.3%) of 186 patients with no histological evidence of BUC or negative cystoscopy findings. The sensitivity of FISH for detecting BUC was superior to that of cytology, regardless of tumor stage and grade. FISH is a significant additional and complementary method for detection of BUC in patients who have suspicious lesions on cystoscopy.