Papillary Transitional Cell Carcinoma Research Articles

Demographic and prognostic factors in papillary transitional cell carcinoma: An analysis of the National Cancer Database.

541 Background: Transitional cell carcinomas account for the majority of bladder cancers, with the papillary subtype comprising most of these cases. The role of race in bladder cancers has been investigated in the past, but there have been no studies that collectively investigated the role of different demographic factors in survival and mortality in papillary transitional cell carcinoma (PTCC). This study analyzes the effects of demographic factors on overall mortality (OM) in patients with PTCC. Methods: A retrospective cohort analysis was conducted using National Cancer Database data from 2004-2019, including 12,300 patients with histologically confirmed PTCC (ICD-O-3=8130). Sex, race (Black, White, and Other), insurance status, and median household income quartile (based on 2016-2020 American Community Survey data) were examined. Kaplan-Meier curves were used to calculate 2, 5, and 10 year survival (2-5-10 YS). Multivariable Cox regression was used to calculate hazard ratios (HR) to identify independent prognostic factors. Statistical significance was set at α=0.05. Results: Females had higher 2-5-10 YS and decreased OM compared to males (HR=0.85, P<.001). White patient survival was higher at 2 years compared to Black patients, but Black patient survival was higher at 5 and 10 years. There was no significant difference in OM between Black and White patients (HR=1.07, P=0.260). Patients of other races had higher 2-5-10 YS and decreased OM compared to White (HR=0.85, P=0.023) and Black patients (HR=0.80, P=0.011). Patients on Medicaid had lower 2-5-10 YS and increased OM compared to patients on private insurance (HR=1.19, P=0.036). Patients on Medicaid had higher 2-5-10 YS than patients on Medicare, but no significant difference in OM (HR=0.87, P=0.091). Patients on private insurance (HR=0.70, P<.001) and Medicare (HR=0.73, P=0.003) had decreased OM compared to uninsured patients. Patients in the fourth income quartile had decreased OM compared to patients in the first (HR=0.82, P<.001), second (HR=0.87, P<.001), and third quartiles (HR=0.90, P=0.003). Conclusions: Male sex, uninsured status, and lower income were associated with increased OM. Black patients and White patients had increased OM compared to patients of other races. Future research should investigate the reasons for these disparities and how to minimize them. [Table: see text]

The Potent Anti-Tumor Effects of Rhodiola Drinking Are Associated with the Inhibition of the mTOR Pathway and Modification of Tumor Metabolism in the UPII-Mutant Ha-Ras Model.

Background: SHR-5 has been used as an "adaptogen" for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the underlying mechanisms of action. Methods: UPII-mutant Ha-ras bladder-cancer-transgenic mice, that developed low-grade and noninvasive papillary transitional urothelial cell carcinoma, were fed with 1.25 and 6.25 mg/mL SHR-5 in drinking water for 6 months. The survival of the mice, obstructive uropathy, tumor burden and morphology, and proliferation were evaluated by pathological, molecular, metabolic, and statistical analyses. Results: Approximately 95% or more of the male UPII-mutant Ha-ras mice that drank SHR-5 daily survived over 6 months of age, while only 33.3% of those mice that drank normal water survived over 6 months of age (p < 0.0001); SHR-5 drinking exposure also reduced tumor-bearing bladder weight and urinary tract obstruction and inhibited mTOR signaling in neoplastic tissues. Global metabolic analysis revealed that SHR-5 resulted in increased phenolic metabolites and decreased CoA, a critical metabolic cofactor for lipid metabolism. Conclusions: Our findings highlight the potential of SHR-5 as an anti-aging agent for bladder cancer prevention through reshaping tumor metabolism via the inhibition of the mTOR signaling. Global metabolomics profiling provides a unique and efficient tool for studying the mechanisms of complex herb extracts' action.

Prognosis of male lung cancer patients with urinary cancer: a study from a national population-based analysis

Lung cancer accounts for the most cancer-related deaths in the world. Our previous study suggested the improved survival of lung cancer patients, mainly female patients, with subsequent metachronous primary breast cancer. However, whether the survival advantages of the two primaries are associated with patients’ sex and the specific breast cancer is unclear. Whether male lung cancer patients with another primary may encounter the same survival advantage as female patients is also uncertain. The uncertainty hinders these patients from the potential benefit of lung cancer clinical trial. A total of 343 male lung adenocarcinoma patients with subsequent bladder papillary transitional cell carcinoma (LCBC), 1539 lung adenocarcinoma patients with prior bladder papillary transitional cell carcinoma (BCLC), 1181 lung adenocarcinoma patients with subsequent prostate adenocarcinoma (LCPC), 7426 lung adenocarcinoma patients with prior prostate adenocarcinoma (PCLC), and patients with single bladder/prostate/lung (SLC) cancer were identified from the Surveillance, Epidemiology, and End Results. Patients were classified into simultaneous two primary cancer (sTPC), metachronous two primary cancer 1 (mTPC1), or mTPC2 groups when interval time between two cancers was within 6 months, between 7 and 60 months, or over 60 months, respectively. Propensity matching score program was executed to match the two primary cancers with single primary. Cox regression and competing risk regression were performed to identify confounders associated with all-cause and cancer-specific survival, respectively. The major cancer-related and non-cancer-related death in the two primaries were lung cancer and heart disease, respectively. Median overall survival times since lung primary of LCBC and SLC were 97 and 17 months, respectively, and incidence of all-cause and cancer-specific death in LCBC since lung malignancy was significantly lower (Coef. − 1.24, 95% CI − 1.49 to 0.99; SHR 0.42, 95% CI 0.33–0.53). Among the categorized groups, prognosis values of sTPC and mTPC2 groups were not statically different from that of the matched single lung cancer, whereas increased overall survival time and decreased incidence of all-cause and cancer-specific death relative to the matched patients were observed in mTPC1 group (H.R 0.28, 95% CI 0.19–0.41; SHR 0.33, 95% CI 0.23–0.47). Similar prognosis of LCPC relative to SLC was also observed. Furthermore, a generally improved survival relative to SLC was observed in PCLC (median survival times of PCLC and SLC were 17 and 12 months, respectively; Coef. − 0.32, 95% CI − 0.43 to 0.22; SHR 0.77, 95% CI 0.69–0.85), whereas prognosis of BCLC was similar to the matched ones. These results hinted that survival of lung cancer patients might vary with prior cancer history. Further analysis among groups with the two primaries suggested that advanced bladder cancer was not associated with prognosis of patients with LCBC and BCLC. On the contrary, advanced prostate cancer was associated with all-cause and cancer-specific death in patients with PCLC but not in patients with LCPC. Compared with patients with single lung cancer, male lung cancer patients with subsequent bladder/prostate primary over 6 months experienced generally improved survival. These results were similar to our previous study regarding female lung cancer patients with another breast primary. On the contrary, male lung cancer patients with prior primary malignancy encountered varied prognosis: improved survival relative to single lung primary was observed in lung cancer with prior prostate cancer, whereas prognosis of lung cancer with prior bladder cancer was not different. Therefore, great attention was required to characterize prognosis of lung cancer patients with another primary in advance, which was essential to eliminate the potential bias when these patients were included into the clinical trials.

Prostate cancer nomenclature at diagnosis can affect treatment decisions.

Prostate cancer nomenclature at diagnosis can affect treatment decisions.

High-grade intradiverticulum bladder tumor: A case report.

Introduction and importanceBladder diverticula are mucosal outpunching of the bladder without a muscle layer. It could be detected incidentally or by giving symptoms of its complications.Case presentationA 59-year-old male patient presented with painless gross hematuria. A primary tumor arising in a bladder diverticulum was detected with computed tomography. Partial cystectomy with para-aortic lymph node dissection was performed. The pathology report showed high-grade papillary transitional cell carcinoma (PT3). Unfortunately, the patient died of an acute cardiac event and sepsis after one month postoperative.Clinical discussionOnce patient had a bladder diverticulum, we should expect the patient to have complications. One of that is intradiverticulum bladder malignancy. Imaging studies such computed tomography with contrast should be performed to confirm the diagnosis. Surgical interventions play a major role in the treatment. Most patients present with late, so the survival rate is poor in general.ConclusionIntradiverticulum bladder tumors are a major challenge in urological practice and need multiple investigations to be detected. These types of bladder tumors have high mortality rate.

Chemopreventive Potential of Myrtenal against Nitrosamine-Initiated, Radiation-Promoted Rat Bladder Carcinogenesis

The present study was undertaken to evaluate the chemopreventive activity of myrtenal, a natural monoterpene, against bladder carcinoma in rats induced with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) and promoted with γ-ionizing radiation (γ-IRR) as well as to assess the involvement of inflammation, apoptosis and oxidative damage in tumor development. Histopathological examination of rat bladder revealed the presence of noninvasive papillary transitional cell carcinoma (Grade 2) in sections from BBN group indicating the credibility of the applied carcinogenesis model. Myrtenal treatment caused improvement in urinary bladder mucosa with cells more likely in Grade 1. Administration of myrtenal to BBN-treated rats exhibited downregulation in the expressions of COX-2, NF-kB and STAT-3 associated with suppression of inflammatory cytokines levels of TNF-α and IL-6 as well as biomarkers of oxidative damage (MDA & NO). In addition, myrtenal treatment caused a significant increase in caspase-3 activity and Bax/Bcl-2 ratio. Data obtained suggested that the anti-inflammatory effect and the induction of apoptosis contributed largely to the beneficial antitumor effects of myrtenal in rats with BBN/γ-IRR-induced bladder carcinoma. Present findings, in addition to benefits described in other pathologies, indicated myrtenal as a potential adjuvant natural compound for the prevention of tumor progression of bladder cancer.

The role of surgery on the primary tumor site in bladder cancer with distant metastasis: significance of histology type and metastatic pattern.

Due to the limited data and research on bladder cancer with distant metastasis, the role of surgery on the primary tumor site in metastatic bladder cancer has been controversial. The aim of this study was to investigate the impact of surgery on patients with metastatic bladder cancer and to identify any factors correlated with the treatment efficacy. Using the Surveillance, Epidemiology and End Results dataset, we performed a large population‐based retrospective study. We classified patents with distant metastasis into subgroups according to their histology type and metastatic pattern. Propensity score matching (PSM) was used to balance clinical variables bias in a 1:3 ratio. A total of 2470 patients with distant metastasis were identified from 2010 to 2016. After PSM, the study eventually included 1068 patients in the surgery group and 356 patients in the non‐surgery group. The histologic types, the number of metastatic sites, liver metastasis, surgery, and chemotherapy were significant prognostic variables for patients with distant metastasis before and after PSM. In terms of histologic types, the survival of patients with transitional cell papillary carcinoma, transitional cell non‐papillary carcinoma and adenocarcinoma can be improved by surgery alone, while the survival of patients with squamous cell carcinoma can be improved only by combining chemotherapy and surgery. In terms of the number of metastatic sites, surgery alone was an independent prognostic factor in patients with 1 or 2 metastatic sites. In terms of the specificity of metastatic organs, surgery affected overall survival for patients with bone metastasis only, liver metastasis only and lung metastasis only, but for distant lymph nodes metastasis only. It may be helpful to classify patients with bladder cancer and distant metastasis into different groups by integrating variables including histology types and metastatic patterns to choose appropriate treatment strategies.

Unique genomic and neoepitope landscapes across tumors: a study across time, tissues, and space within a single lynch syndrome patient

Lynch syndrome (LS) arises in patients with pathogenic germline variants in DNA mismatch repair genes. LS is the most common inherited cancer predisposition condition and confers an elevated lifetime risk of multiple cancers notably colorectal and endometrial carcinomas. A distinguishing feature of LS associated tumors is accumulation of variants targeting microsatellite repeats and the potential for high tumor specific neoepitope levels. Recurrent somatic variants targeting a small subset of genes have been identified in tumors with microsatellite instability. Notably these include frameshifts that can activate immune responses and provide vaccine targets to affect the lifetime cancer risk associated with LS. However the presence and persistence of targeted neoepitopes across multiple tumors in single LS patients has not been rigorously studied. Here we profiled the genomic landscapes of five distinct treatment naïve tumors, a papillary transitional cell renal cell carcinoma, a duodenal carcinoma, two metachronous colorectal carcinomas, and multi-regional sampling in a triple-negative breast tumor, arising in a LS patient over 10 years. Our analyses suggest each tumor evolves a unique complement of variants and that vaccines based on potential neoepitopes from one tissue may not be effective across all tumors that can arise during the lifetime of LS patients.

Thrombomodulin Expression in Bladder Cancer Tissue and Its Association with Prognosis and Patient Survival.

BackgroundDecreased expression of thrombomodulin (TM) in bladder cancer tissue has been shown to be associated with cell proliferation, increased malignancy and a poor prognosis. The aim of this study was to investigate the immunoexpression of TM in bladder tissue cores by immunohistochemistry (IHC) and the relationship between TM score and patient survival for the following pathologies: transitional cell papillary carcinoma (TCPC), transitional cell carcinoma (non-papillary) (TCC), squamous cell carcinoma (SCC), adenocarcinoma, and sarcoma. TM immunoexpression was also evaluated in normal adjacent bladder tissue cores.MethodsTM immunoexpression was assessed in n=185 formalin-fixed paraffin-embedded (FFPE) bladder tissue cores from n=98 patients by IHC. Tissue cores included TCPC (n=29), TCC (n=85), SCC (n=21), adenocarcinoma (n=12), sarcoma (n=4), and normal tissue cores (n=34).ResultsTM immunoexpression scores are stronger in TCPC, TCC and SCC bladder cancer tissue cores with respect to adenocarcinoma and sarcoma (mean TM immunoexpression scores: 3.04, 2.57, 2.55, 1.55 and 1.19, respectively) (Kruskal–Wallis p<0.001). TM immunoexpression scores significantly decreased in bladder cancer tissue cores across both stage (p<0.001) and grade (p<0.001) (Kruskal–Wallis). Survival data were available for n=45 bladder cancer patients (mean follow-up of 34 months). Applying a TM immunoexpression cut-off score of 3.0 demonstrated that patients with bladder cancer who had a TM immunoexpression score <3.0 had lower survival rates (median survival 23.5 months). In contrast, patients with TM immunoexpression scores ≥3.0 had longer survival rates (median survival 40 months) (log-rank; p=0.045).ConclusionTM immunoexpression in bladder cancer tissue may be a clinically relevant predictor of tumor progression and survival. Low expression of TM in bladder cancer biopsies or in recurrent bladder cancer may be indicative of a poor prognosis. TM immunoexpression could be used to guide clinical decision making.

Transitional cell carcinoma of the renal pelvis masquerading as renal tuberculosis

We report a case of transitional cell carcinoma of the right renal pelvis mimicking the signs, symptoms and radiological findings of renal tuberculosis (TB). She had been diagnosed initially for urinary tract infection and radiological diagnosis initially was more towards renal TB and urine cytology and cultures were normal. Specific investigations for tuberculosis all showed negative results. But as neoplasia could not be ruled out by ureterorenoscopy due to presence of multiple ureteric strictures, decision was taken for an exploratory surgery. During surgery it was found that there was a tumour in the upper pole of kidney involving the renal pelvis and was found to be papillary transitional cell carcinoma on histopathological examination.

Transitional Cell Carcinoma arising in Ovarian Cystic Teratoma: A Rare Case Report

Mature cystic teratoma (MCT) is one of the commonest germ cell neoplasms of the ovary, but only 1–2% gets transformed into a malignant neoplasm. Amongst these, squamous cell carcinoma and adenocarcinoma are most commonly documented in the literature. The development of transitional cell carcinoma is exceptionally uncommon, and only eight cases have been reported in the literature till date as per our knowledge. Here, we report a case of transitional cell carcinoma arising in a dermoid cyst of right ovary in a 48-year-old woman who presented with history of abdominal mass since 3–4 months. Grossly, the ovary was cystic. Microscopically, the cyst wall revealed classic features of MCT and papillary fronds at one place showing features of papillary transitional cell carcinoma (TCC). IHC showed positivity for CK7 and CK20 and negativity for WT-1. When TCC is found as a component of MCT, the origin of the carcinoma should be evaluated.

NEPHRECTOMY BY PAPILAR CARCINOMA OF TRANSITIONAL CELLS (UROTELIAL) HIGH GRADE NOT INVASIVE CASE STUDY

Cancer is one of the main causes of morbidity and mortality worldwide, it is produced by the transformation of normal cells into tumor cells in a multiple stages process that can progress to a precancerous lesion to a malignant tumor that can spread through the blood and lymphatic system causing metastasis. The incidence of kidney cancer seems to be increasing, in adults, it begins in the kidneys and can spread to the entire urinary tract that surrounds distant organs or places, renal cell carcinoma is the most common type of kidney cancer and represents approximately 90 percent of cancers tumors.&#x0D; The present study evidences the case of a patient who comes to medical services when the problem shows symptoms.&#x0D; Objective - To describe the renal cancer case of a patient with papillary transitional cell carcinoma who was operated to remove a kidney tumor in order to prevent it from triggering in severe states.&#x0D; Method - The literature on cancer and cancer patients has been reviewed, in the urinary system the data of a case that generated kidney tumor surgery performed in a 63-year-old female patient has been reviewed.&#x0D; Result - High-grade, non-invasive papillary transitional cell carcinoma (UROTELIAL) can occur, in patients altering the quality of life of people, if it is detected and treated in time complications can be avoided&#x0D; Conclusion - It is essential to identify the risk factors and possible causes that can trigger this type of pathology, the information collected is expected to be useful to professionals and to contribute as an alert to detect health problems in patients early.

Imaging of Unusual Renal Tumors.

Renal masses are a wide entity and a common finding in clinical practice. Detection of these masses has increased in the last years, yet mortality rates have slightly decreased. According to the World Health Organization classification, there are 8 types, 51 subtypes, and a lot more subsequent subclassifications of renal tumors. Histopathological analysis should always be assessed for final diagnosis of theses tumors. However, imaging can be an important diagnostic guidance. The most common diagnoses of renal tumor are clear cell carcinoma, papillary renal cell carcinoma, angiomyolipoma, and transitional cell carcinoma. Nonetheless, a considerable variety of particular tumors can arise from the kidney, challenging the expertise of radiologists and urologists on this subject. The awareness of these unusual entities is vital for professionals working at a complex medical facility with greater volume of patients. We hereby present uncommon renal tumors and its pathological and radiological features.

Utility of Exfoliative Cytology of Voided Urine in Comparison with Ultrasonogram and Cystoscopy Findings in the Diagnosis of Urothelial Cancers

Carcinoma of the urinary bladder affects men more often than women and occurs in patients over the age of 50 years. Transitional cell carcinoma (TCC) comprises about 90% of all primary tumor of urinary bladder. In this study a total of 57 cases were taken. The aim of the study was to establish diagnostic role of voided urine cytology, ultrasonography and cystoscopy in urothelial cancers. Out of 57 cases, cytological diagnosis was positive in 53 cases (93%) and negative in 4 cases (7%). There were no atypical or suspicious cases. Of the total cases, cytology was negative only in 7% cases. Among 42 invasive carcinomas 14 (33%) grade III invasive flat carcinoma, one (2%) invasive papillary adenocarcinoma and two (5%) invasive squamous cell carcinoma, each of them gave 100% positive cytology. Of the remaining 25 (60%) invasive papillary TCC, 21 were in grade II and 4 were in grade III. They gave 90% and 100% positive cytologic results. Ultrasonogram of urinary bladder gave 95% (approx.) positive results and out of 57 cases, 3 cases failed to give positive results in ultrasonogram (USG) of the urinary tract. Cystoscopy detected tumor mass in 98% cases and it gave false negative result in 2% cases. Fifty-two tumors had a diameter ranging 1.1- 6 cm. Single lesions were seen in 40 cases, double lesion in one case and multiple in 13 cases. The probability of later invasive carcinomas nearly tripled in-patients with multiple lesions on presentation (13.6%) compared with those who presented with a single lesion (4.6%). Consistent with previously published data, this study showed the highest diagnostic accuracy with high-grade tumors and lowest with low-grade tumors. So in a proper clinical setting, non-invasive technique like voided urine cytology and ultrasonography could be done as a first line cost effective method in the diagnosis of urothelial cancers.TAJ 2017; 30(2): 39-46

The epidemiological and histological trend of bladder cancer in Iran.

Bladder cancer is the ninth common cancer in the world, the third common cancer among men in the Arabic and Western Asian countries, and the second in some regions of Iran (a country in the Middle East). There was no study on the epidemiological and histological trend of bladder cancer in Iran. This study aimed to the epidemiological and histological trend of bladder cancer in Iran. In this study, data were extracted from annual cancer registry reports of Iranian Ministry of Health between 2003 and 2008. Standardized incidence rates were calculated using the world standard population and incidence rate was calculated by age groups, sex, and histological type. Data on epidemiologic trend and histology were analyzed using Joinpoint software package. A total of 23,291 cases were reported. Almost 17.70% (4127 cases) were women and 82.30% (19,170 cases) men. The sex ratio (male to female) was 4.65. Joinpoint analysis showed the significant increased trend of age-standardized incidence rate (ASIR) for both sexes. The annual percentage change of standardized incidence rate was 11.5 (confidence interval [CI]: 9.0-14.0) in women and 10.8 (CI: 8.0-13.6) in men. Two histological types of transitional cell carcinoma (TCC), not otherwise specified and papillary TCC included 43.89% and 49.86% of all cancer cases, respectively. According to this study the trend of ASIR of bladder cancer in Iran is rising, so it is necessary to conduct further researches in future to provide accurate information on the cancer and investigate related risk factors and implement prevention programs in Iran.

INTRA-VESICAL BCG INDUCED GRANULOMATOUS HEPATITIS AND DISSEMINATED KOCH’S: OUR EXPERIENCE

Bacille Calmette-Guerin (BCG) vaccine, developed by Calmette and Guerin at Institute Pasteur (Lille, France), is a live-attenuated Mycobacterium bovis strain. There are many therapeutic uses of the species have been described, Intravesical BCG has been established as an effective treatment of superficial bladder cancer. A 66-year old gentleman with newly diagnosed superficial high-grade papillary transitional cell carcinoma involving lamina propria (T1) of the bladder underwent 3 cycles of intravesical BCG. First 2 cycles were uneventful and tolerated well. After 3rd BCG cycle, patient developed granulomatous hepatitis with disseminated Koch's. BCG-induced sepsis after intra-vesical instillation for bladder cancer is a rare complication. Pathophysiology remains largely unknown, but BCG’s low virulence suggests that immunological hypersensitivity reaction probably plays a role. There have been no prospective studies to evaluate the optimal treatment for BCG infection. Keywords: Bacille Calmette-Guerin (BCG), Mycobacterium bovis strain, granulomatous hepatitis.

Lower Pelvicalyceal Transitional Cell Carcinoma of Right Kidney Mimicking a Peripelvic Cyst on Renal Ultrasound

Transitional cell carcinoma of the kidney is an ominous condition, compared with benign renal cysts. The diagnosis is usually made by pathological examination of the specimen. The pelvicalyceal hypoechoic lesion on ultrasound combined with hematuria, flank pain and urine atypical transitional cells should raise the suspicion of possible malignancy. The differentiation between hemorrhagic or infected benign cysts and malignant hypoechoic lesions of the kidney on the renal ultrasound is a diagnostic challenge. We presented a male patient diagnosed with urine cytology, renal ultrasound, enhanced multidetector computerized tomography, ureterocystoscopic biopsy, and then surgical intervention. Case report and literature review. This 73-year-old gentleman presented to Taipei City Hospital, Zhongxiao Branch with right flank soreness and hematuria on August 12, 2016. Urine cytology revealed the presence of atypical transitional cells. The renal ultrasound revealed a hypoechoic lesion at B mode examination and hypovascular lesion at color Doppler examination (Fig 1a and Fig 1b). Enhanced multidetector computerized tomography showed bilateral renal cysts, chronic cystitis, enlargement of prostate gland and 2 filling defects in the lower pelvicalyceal areas (Fig 2a and 2b). The pathological findings of preoperative ureterocystoscopic biopsy showed low differentiated papillary transitional cell carcinoma of the lower pelvicalyceal system of right kidney (Fig 3), which arranged in papillary structure with mild to moderate nuclear atypia and showed no stromal invasion in this specimen. We highlighted that pelvicalyceal hypoechoic lesions combined with hematuria, flan pain and urine atypical transitional cells should be evaluated further for possible malignancy.

ETS-1 oncoprotein expression is decreased in aggressive papillary transitional cell carcinoma of the urinary bladder: An immunohistochemical study

IntroductionETS-1 proto-oncogene is a transcription factor that plays multiple roles in the process of oncogenesis and helps in the process of tumor invasion. ETS-1 oncoprotein correlation with high grade and invasive tumors is controversial; as it is found to be upregulated with some tumors and down regulated with others. Expression of ETS-1 in urinary bladder carcinoma (UBC) and its correlation with tumor differentiation and invasiveness are still under-investigated. So far, there is no reliable prognostic marker has been proved for detection of the tumor progression and recurrence. ObjectivesTo analyze the correlation between ETS-1 oncoprotein immunohistochemical expression and the different stages and grades of the primary papillary transitional cell carcinoma of the urinary bladder. Patients and methodsThis is a retrospective cross sectional study that included archival material from 150 cancer cases and 24 control biopsies. ResultsThere was a decreased ETS-1 oncoprotein expression with increasing stage and grade of the tumor with a highly significant statistical correlation (P=0.001). With the quantitative assessment of the immunohistochemical results and using ROC (receiver operating characteristics) curve, cut-off values were found, that were associated with high grade and muscle invasive tumors (≤30% and ≤20%, respectively). ConclusionETS-1 oncoprotein is down regulated with high grade and highly invasive urinary bladder papillary transitional cell carcinomas. This oncoprotein may be used as an independent prognostic marker to predict the aggressive papillary transitional carcinomas with high invasive potential. More studies are needed to confirm our results.

Ovarian Brenner Tumors Revisited: Do We Have Space for Malignant Tumorsvand Methanol

Summary We present a case of a 75-year-old female who underwent a total abdominal hysterectomy with bilateral salpingooophorectomy for an ovarian tumor. Hematoxylin-eosin- stained slides from tumor specimen revealed 1) focci of benign Brenner tumor; 2) mucinous cysts and 3) intracystic papillary projections resembling low-grade papillary transitional cell carcinoma (Grade 1-2) with squamous differentiation and comedo-type necrosis; 4) focal areas resembling noninvasive papillary transitional cell carcinoma Grade 3. Immunohistochemical investigation with a panel of antibodies (p63, p53, Ki-67, Wilms Tumor 1 - WT1, pi 6) was initiated. Areas resembling urothelial carcinoma showed diffuse nuclear positive reaction for p63 and wild-type expression of p53. Ki-67-nuclear positivity varied from less than 5% up to 30% in areas resembling high-grade urothelial carcinoma. WT1 expression was not seen. Weak but still exceeding background staining was observed in predominantly cytoplasmic fashion with few scattered positive nuclei in transitional cell nest of the benign component. No reactivity, however, was seen within the proliferative component. The histopathological diagnosis was a borderline/atypical proliferative Brenner tumor. The patient has been regularly followed up and is at present disease-free 5 years after diagnosis. In this paper, the authors describe the morphological characteristics of Brenner tumors and address some debatable issues in the light of recent immunohistochemical and molecular studies.

Abstract 617: Canine transitional cell carcinoma of the bladder expresses activated BRAF, but is not sensitive to vemurafenib

Abstract Transitional cell carcinoma (TCC) is the most common bladder cancer in humans and their canine companions. Canine TCCs are usually papillary infiltrative TCCs of intermediate to high grade. Genetic defects identified in human TCCs aid in the diagnosis and therapy of human bladder cancer. We utilized whole exome sequencing to screen canine TCCs for gene mutations that contribute to pathogenesis. Genomic DNA was isolated from 11 canine TCCs, 3 matched normal tissue samples, and 2 canine TCC cell lines. Whole exome capture was conducted using the Canine Agilent Sure-select in-solution capture system, and captured fragments were sequenced using an Illumina HiSeq2000 platform. The sequences were mapped to the CanFam3.1 canine reference genome and somatic mutations were identified using Freebayes. Somatic mutations were characterized and compared to the Cancer Gene Census (COSMIC). Nonsense, missense, and insertion/deletion mutations were identified in 126 genes shown to be drivers or repressors in human cancer. Missense mutations were further screened using SIFT to identify alterations deleterious to protein function. The genes exhibiting in/dels, nonsense, or missense mutations with SIFT scores &amp;lt; 0.45 in at least 2 sites or 2 samples were: BRAF, RPL5, RANBP2, EWSR1, NONO, PTPRB, LYL1, JAK1, MSH2, PER1, PIM1, and WRN. In fact, an activating BRAF V to E mutation was identified in 5 of the tumors and both cell lines. The RPL5 and RANBP2 mutations were also hotspot mutations identified in 5 and 3 of the samples, respectively. Mutations were confirmed using Sanger sequencing of amplified genomic DNA. Interestingly, deleterious RANBP2 mutations were only observed in non-BRAF mutant samples. Drug sensitivity assays using the BRAF V600E targeting drug, Vemurafenib, were conducted in the BRAF mutant canine cell lines as well as the BRAF mutant human A375 melanoma cell line. As previously described, the IC50 for the sensitive A375 line was approximately 100 nM, while each of the BRAF mutant canine lines had an IC50 value ≥ 10 μM. Reverse transcriptase PCR was used to amplify the coding sequence for BRAF from the Bliley canine TCC cell line. The amplified transcript (2125 bp) was sequenced, confirming the heterozygous expression of the V548 to E mutant form of BRAF in this cell line. The sequence also indicated that the predicted expressed protein (AA 10 - 715 of XP_013975364.1, corresponding to predicted exons 1 through 20 of XM_014119889.1) exhibited 99% homology to human BRAF AA53 - 763 (NP_004324.2). BRAF protein expression in these cell lines was confirmed by Western blot analysis. Thus, insensitivity to Vemurafenib is not due to differences in canine BRAF, reduced expression, or alternative splicing of the expressed transcript as previously observed in some Vemurafenib resistant human melanomas. These data indicate that although constitutively active BRAF is expressed in canine TCC, other factors may contribute to pathogenesis. Citation Format: Belen Hernandez, Kathryn Cronise, James C. Costello, Rodney Page, Susan Lana, Kenneth L. Jones, Dawn L. Duval. Canine transitional cell carcinoma of the bladder expresses activated BRAF, but is not sensitive to vemurafenib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 617.