Noninvasive Papillary Urothelial Carcinoma Research Articles

Assessment of Two-Years Bladder Biopsy and Cystectomy Outcomes

Objective: To evaluate the outcome of bladder biopsy and resection evaluated in pathology department in 2014-2015. Material and methods: A total of 78 cases from 2014 to 2015 were included in this study. Reports of the cases were removed from the archive and the age, gender, diagnosis and prognostic parameters of the cases were recorded. The distribution of cases according to age and gender was evaluated. Results: 65 of the cases were male, 13 of the cases were female. The average age of cases is between 39 and 90. Twenty-one cases were cystitis and squamous metaplasia. The mean age of benign lesions is between 41 and 85. Five cases of dysplastic lesions were observed. The average age is 61.6 and all of them are male. 52 of the cases were malignant. 49 of the cases were male, 3 of the cases were female. 19 cases of non-invasive papillary urothelial carcinoma, 1 case of low malignant potential urothelial neoplasm, 2 of the prostate adenocarcinoma metastasis, 30 of invasive carcinoma. 20 of the cases were pT1, 9 of the cases were pT2, 1 of the case was pT4 and 19 of the cases were pTa. The mean age was 64.5. Invasive tumors are all male. The mean age was 74.6. Conclusion: In this study, tumors and non-tumoral lesions were seen spreading to a wide range of age in bladder. Benign and malignant lesions were observed in males. Benign lesions were more common in females than malignant lesions in females.

Noninvasive Papillary Basal-like Urothelial Carcinoma: A Subgroup of Urothelial Carcinomas With Immunohistochemical Features of Basal Urothelial Cells Associated With a High Rate of Recurrence and Progression.

We investigated the clinical and pathologic significance of a subgroup of noninvasive papillary urothelial carcinomas (UCs) expressing reactivity to urothelial basal cell markers. In total, 302 consecutive cases of noninvasive papillary UC were evaluated immunohistochemically with cytokeratin 5 (CK5)/CD44. Any UC that was reactive for greater than 25% thickness of the urothelium was designated as basal-like urothelial carcinoma (BUC); remaining UC cases were designated as non-BUC. The follow-up period was up to 3 years. Historical review of UC was extended for up to 3 retrospective years. Among 302 noninvasive UC, BUC was identified in 33 of 256 (12.9%) low-grade UC and 8 of 46 (17%) high-grade UC (P=0.041). Immunoreactivity for CD44 was similar to that of CK5, but displayed weaker and more diffuse staining. CK20 was reactive in 9 cases, primarily high-grade BUC. Other basal cell markers (34bE12, p63, bcl2, and EP4) were found to be neither sensitive nor specific in detecting UC with high CK5 expression. In comparison with non-BUC, BUC was associated with increased multifocality, larger tumor size, higher recurrence rate, and more frequent upgrading and stage progression. In the follow-up period of 3 years, distant metastasis occurred in 6 cases of which 5 were in the BUC subgroup. Our results showed that noninvasive papillary BUC represents a small subset associated with increased risk of tumor recurrence and progression. The aggressive behavior is likely associated with basal-like features of BUC, as seen in carcinomas with basal cell features in other body sites.

Enhancer of zeste homolog 2 (EZH2) expression in bladder cancer

BackgroundStudies evaluating enhancer of zeste homolog 2 (EZH2) expression and oncologic outcomes in bladder cancer have been discrepant. EZH2 expression in noninvasive bladder cancer is not well studied. We thus set out to address the discrepancy in previous reports, and to study expression of EZH2 in noninvasive bladder cancer and its associations, in a large cystectomy cohort. Materials and methodsEZH2 expression was evaluated in tissue microarray material (invasive and noninvasive cancer). Associations between EZH2 expression and oncologic outcomes, tumor stage, and disease type were determined. Receiver operating characteristic analysis was performed for EZH2 expression in the diagnosis of invasive carcinoma and flat carcinoma in situ (CIS) compared to benign urothelium. ResultsEZH2 expression was most common in CIS, followed by invasive carcinoma, noninvasive papillary urothelial carcinoma, and benign urothelium, in decreasing order (P<0.05 all comparisons, linear model). The receiver operating characteristic analysis demonstrated an area under the curve of 0.92 for CIS and 0.83 for invasive carcinoma, both compared to benign urothelium. At a cutoff of≥4, this corresponded to sensitivities of 89% and 73%, and specificities of 82% and 82%, for CIS and invasive carcinoma, respectively. The EZH2 expression was not associated with oncologic outcomes, including recurrence-free survival and death from bladder cancer. The EZH2 expression status (positive or negative) of noninvasive and invasive carcinomas taken from the same bladder correlated (P = 0.05, Fisher exact). ConclusionThat EZH2 status of noninvasive and invasive cancer correlated in individual patients suggests that EZH2 may be a marker of lineage. EZH2 may offer diagnostic utility, particularly in flat urothelial CIS vs. benign urothelium. The present study supports that EZH2 expression in bladder cancer is not predictive of oncologic outcome.

The pathology of urinary bladder lesions with an inverted growth pattern.

Inverted lesions in the urinary bladder have been the source of some difficulty in urological pathology. The two common ones are von Brunn's nests and cystitis cystic/cystitis glandularis, which are considered normal variants of urothelium. Apart from them, a number of other rare urothelial lesions with inverted growth pattern occur in the urinary bladder. Some of them are only reactive conditions, just as pseudocarcinomatous hyperplasia. Some are benign tumors, namely inverted papilloma. Whereas others are malignant neoplasms, including inverted papillary urothelial neoplasm of low malignant potential (PUNLMP), non-invasive inverted papillary urothelial carcinoma (low-grade and high-grade), and invasive urothelial carcinoma (inverted, nested and big nested variants). Because of the overlapping morphological features of all the inverted lesions mentioned above, even between high-grade invasive carcinoma and pseudocarcinomatous hyperplasia which are only a kind of reactive conditions, it is very important for the surgical pathologist to recognize and be familiar with these inverted lesions in urinary bladder. In this article, we review these spectrums of inverted lesions of the urinary bladder. Emphasis is placed on histogenesis, morphology, differential diagnosis of these lesions, and the pathologic grading of the non-invasive inverted neoplasms, such as inverted papilloma, inverted PUNLMP, non-invasive inverted papillary urothelial carcinoma with low-grade, and non-invasive inverted papillary urothelial carcinoma with high-grade.

Review of Medical Advisory Services by the Korean Society of Pathologists from 2003 to 2014.

Background:Since 2003, the Korean Society of Pathologists (KSP) has been officially providing medical advisory services (MAS). We reviewed the cases submitted to the KSP between 2003 and 2014.Methods:In total, 1,950 cases were submitted, most by private health insurance companies. The main purposes of the consultations were to clarify the initial diagnoses and to assign a proper disease classification code. We comprehensively reviewed 1,803 consultation cases with detailed information.Results:In spite of some fluctuations, the number of submitted cases has been significantly increasing over the 12 study years. The colon and rectum (40.3%), urinary bladder (14.2%), and stomach (6.9%) were the three most common tissues of origin. The most common diagnoses for each of the three tissues of origin were neuroendocrine tumor (50.7%), non-invasive papillary urothelial carcinoma (70.7%), and adenocarcinoma (36.2%). Regardless of the tissue of origin, neuroendocrine tumor of the digestive system was the most common diagnosis (419 of 1,803).Conclusions:In the current study, we found that pathologic consultations associated with private health insurance accounted for a large proportion of the MAS. Coding of the biologic behavior of diseases was the main issue of the consultations. In spite of the effort of the KSP to set proper guidelines for coding and classification of tumors, this review revealed that problems still exist and will continue to be an important issue.

Significance of a minor high-grade component in a low-grade noninvasive papillary urothelial carcinoma of bladder

To assess the clinicopathological features and prognostic significance of the presence of 5% or less high-grade component in otherwise low-grade noninvasive bladder urothelial carcinoma, referred to as mixed-grade (MG) urothelial carcinoma, we reviewed all archival cases with such diagnosis between 2005 and 2014. Clinicopathological and outcome parameters were compared to those in our previously reported low- and high-grade noninvasive bladder urothelial carcinoma cohorts (LGUC and HGUC, respectively). The study included 31 MG urothelial carcinomas. Mean patient age was 67.6 years, and mean follow-up was 39.7 months. Intravesical treatment was administered in 15 patients (48.4%). Recurrence occurred in 14 cases (45.2%): 10 as LGUC and 4 as HGUC; there was no stage progression. Mean time to progression was 9 months (5-17 months), and there was no death of disease. MG urothelial carcinoma stage progression and dead of disease rates were comparable to that of LGUC. MG urothelial carcinoma stage progression was significantly lower than that of HGUC, P = .002, using Pearson χ(2) test. MG urothelial carcinoma patients with no intravesical treatment had higher incidence rate of grade progression (25%) compared to LGUC patients (7.9%); however, the difference was not statistically significant. MG urothelial carcinoma had a prognosis closer to "pure" LGUC than "pure" HGUC. Untreated MG urothelial carcinoma may have a higher rate of grade progression than LGUC, although more data are needed before this issue can be definitively addressed. Until such data are available, it is reasonable to keep MG urothelial carcinoma as a distinct grade category with potential management implications.

Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer.

In addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical significance it may possess with regard to BC. The present study aimed to investigate the immunoreactivity of FGFR3 in primary urothelial bladder tumours, with regard to clinicopathological features and FGFR3 mutation status. Tissue microarrays were used to immunohistochemically analyse FGFR3 expression in 255 primary, unselected patients with BC. FGFR3 mutations were detected using SNaPshot analysis. Positive FGFR3 immunoreactivity was identified in 113/207 analysable cases (54.6%), and was significantly associated with FGFR3 mutation (P<0.001), low tumour stage (P<0.001), low histological grade (P<0.001) and a papillary growth pattern (P<0.001). Positive FGFR3 immunostaining (P=0.002) and FGFR3 mutation (P=0.002) were found to be significantly associated with increased disease-specific survival following univariate analysis, demonstrating a median follow-up period of 75 months. Using multivariate analyses, FGFR3 immunoreactivity was found not to be independent of classical pathological parameters. Immunohistochemical expression of FGFR3 is an early occurrence during the carcinogenesis of papillary non-invasive BC. The presence of FGFR3 immunoreactivity in non-invasive papillary urothelial carcinomas may be utilised as an indicator of tumours possessing low-grade features and good prognosis.

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.

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.

Immunohistochemical expression of p63, p53 in urinary bladder carcinoma

Urothelial carcinomas (UC) is of the most common cancers urinary bladder. The aim of the study is to assess the immunohistochemical staining differences between p63 and p53 according to the pathological stage and histological grade of the tumor in urinary bladder carcinomas. Totally 62 urinary bladder transurethral resection materials diagnosed with urothelial carcinoma in the pathology department of our hospital were included in the study. On pathological examination, cases were dichotomized as noninvasive and invasive, whereas noninvasive cases were dichotomized as low grade and high grade and invasive cases were dichotomized as pT1 and pT2. Subsequently, the cases were evaluated by means of p63 and p53 immunohistochemical staining. Statistical analyses were performed by SPSS program, and Chi-square and Fisher's exact tests. When pTa was evaluated in terms of p63 immunoreactivity, no statistically significant difference was observed between LGPUC and HGPUC, noninvasive papillary UC, regarding staining percentages ( P > 0.05), whereas statistically significant relation was observed for pT1 and pT2 regarding p63 staining percentages ( P < 0.05). For pTa, no statistically significant relation was observed between LGPUC and HGPUC, noninvasive papillary UC, in terms of p53 staining percentages ( P > 0.05). However, highly significant relationship was observed for pT1 and pT2 in terms of p53 staining percentages ( P < 0.01). No significant relationship was observed between the staining percentages of p53 and p63 ( P > 0.05). The role of p53 and p63 immunoreactivities in the differential diagnosis and prognosis of urinary bladder carcinomas according to the pathological stage and histological grade of the tumor will be understood better with the increasing number of long term investigations performed with large series at a molecular level.

Plasmacytoid variant of urothelial carcinoma: A report of a rare case

Plasmacytoid variant of urothelial bladder carcinoma is rare. We report a case with a detailed discussion of features that help characterize this variant. A 50-year-old man originally presented with gross hematuria. Resections at that time revealed a grade I-II superficial urothelial carcinoma. He did not return for follow-up until recently, three years later, when he presented with recurrent gross hematuria. An extensive tumor was identified on cystoscopy. Resection revealed a high-grade non-invasive papillary urothelial carcinoma. CT scan revealed a large urinary bladder solid mass with bilateral hydronephrosis. Metastatic workup was negative. The patient underwent a radical cystectomy with creation of ileal conduit. Final pathology revealed plasmacytoid variant of urothelial carcinoma with extensive vascular invasion and extension to the perivesical adipose tissue. We present a rare variant of urothelial carcinoma with comprehensive analysis of the morphological and immunophenotypic clues that characterize this variant.

A Case Report of an Inverted Papilloma of the Prostatic Urethra and a Synchronous Low-Grade Papillary Carcinoma of the Bladder

Inverted urothelial papilloma is a rare benign tumour and represents one of the urothelial lesions with inverted morphology. Accurate diagnosis and differentiation from other inverted lesions is important because its proper clinical management and expected clinical outcomes are distinctly different. Here we describe a case of a large inverted urothelial papilloma of the prostatic urethra and a synchronous non-invasive low-grade papillary urothelial carcinoma of the bladder in a 60-year-old man. We focus on the differential diagnosis of inverted urothelial papilloma.

Hematuria in sickle cell trait: the importance of ruling out occult cancer

Dear Editor, Sickle cell trait is characterized by a heterozygous inheritance of the sickle hemoglobin gene. Unlike sickle cell disease, sickle cell trait is commonly viewed as a benign process in asymptomatic patients [1]. However, a growing number of case reports and observational studies reveal that complications do occur in these individuals [2]. Both microscopic and gross hematuria are the most common complication [3]. About 50% of these cases have been attributed to renal papillary necrosis [4]. Despite this association, the diagnostic workup for cases of hematuria should always include a urine analysis, urine culture, urine cytology, computed tomography (CT) with and without contrast, and cystoscopy with ureteroscopy if necessary. This report aims to highlight the importance of careful diagnostic workup in patients with sickle cell trait presenting with hematuria. A 49-year-old African–American male with sickle cell trait presented with a history of intermittent, sharp left flank pain, and gross hematuria throughout micturition. Aside from hematuria, all other studies including a noncontrast abdomen/pelvis CT scan were unremarkable. His condition was initially attributed to a kidney stone due to spontaneous resolution. However, these episodes recurred with passage of dark red tissue 3 weeks later. A repeat CT was ordered, this time with contrast, along with cystoscopy. Both studies were again negative despite persistence of his symptoms. Given his long history of sickle cell trait and a negative workup, his hematuria was attributed to papillary necrosis. However, his flank pain progressively worsened with continued passage of necrotic tissue, unrelieved by hydration and urine alkalization. He was referred to the hematology clinic where repeat studies were obtained given the severity and increased frequency of his symptoms. An abdomen/pelvis CT revealed a filling defect in the upper collecting system of the left kidney (Fig. 1), suspicious for malignancy, along with multiple subcentimeter periaortic lymph nodes. A retrograde pyelogram confirmed these findings. Ureteroscopy and biopsy demonstrated a high-grade, non-invasive papillary urothelial carcinoma involving the renal pelvis, extending into the left proximal ureter. A metastatic workup including cystoscopy was unremarkable aside from previously noted lymphadenopathy. Laparoscopic left nephroureterectomy was performed with no further evidence of cancer. Two months later, multiple bladder lesions, biopsy-proven as “drop metastases”, were found on cystoscopy and treated with fulguration. He was treated with intravesical mitomycin C and a 6-week course of Bacille Calmette-Guerin (BCG). Since that time, his adenopathy has been stable and he has had only one recurrence at the bladder dome that was treated with fulguration. Intravesical BCG will be continued for another 6 weeks with frequent monitoring for recurrence. B. S. Gill (*) School of Medicine, The George Washington University, 922 24th Street NW, Apt 421, Washington, DC 20037, USA e-mail: bsgill@gwmail.gwu.edu

Papillary Urothelial Carcinoma of the Bladder With Exuberant Pseudosarcomatous Stromal Reaction Following Radiation Therapy

An 82-year-old man, with 6-year history of radical prostatectomy followed by radiotherapy performed for prostatic carcinoma, underwent transurethral resection of a papillary tumor of the bladder lateral walls. Histologically, the lesion displays 2 distinct components: epithelial and stromal. The epithelial component was composed of a noninvasive papillary urothelial carcinoma, predominantly low grade and focally high grade. The stromal component exhibited extensive myxoid changes with increased cellularity but lacking cellular atypia and mitoses. The epithelial component was immunoreactive for pan-cytokeratins and negative for smooth muscle actin (SMA) and vimentin. The stromal component exhibited focal positivity for pan-cytokeratins and SMA, and diffuse immunoreactivity for vimentin. The ki67 reached 70% in the epithelial component and 20% in the stromal component. Papillary intraurothelial carcinoma following radiotherapy may be associated with pseudosarcomatous stromal proliferation. The clinical history and the lack of cellular atypia and mitoses point toward the correct diagnosis.

Evolution on experimental animal model for upper urothelium carcinogenesis

No optimal, well designed and reproducible animal model for upper urothelial carcinogenesis exists. This study characterized the histopathological features on top of immunolocalization of alpha-dystroglycans (alpha-DG) and matrix metalloproteinase (MMP-9) and cell turn-over in the upper urinary tract using a novel experimental model. Seventy-five female Fischer 344 rats were divided into three groups: the control group received a 0.30-ml dose of 0.9% physiological saline; the MNU group (chemical carcinogen N-methyl-N-nitrosourea) received 0.30 ml of MNU; and the MNU-citrate group received 0.30 ml of MNU plus sodium citrate, every one intravesically every other week for a total of 4 doses. After 15 weeks, bladder, ureters and renal pelvis were collected for morphological and molecular analysis. Associated management with MNU and sodium citrate was able to lead to 100% of both urinary bladder and upper urinary tract tumors, being the high-grade noninvasive papillary urothelial carcinoma the most frequent lesion. The upper urothelium showed reduced alpha-DG and increased MMP-9 and Ki-67 immunoreactivities in the MNU-citrate group in relation to the other groups. MNU group presented no upper urothelium tumor and 100% bladder tumor. This is a relevant evolution on experimental animal model for upper urinary tract carcinogenesis field. MMP-dependent disruption of the DG complex plays an important role in urothelial tumor carcinogenesis and showed the model applicability and significance. MNU-citrate model could contribute to a better understanding of human upper urothelial cancer development as well as to its local treatment strategies in a near future.

Small Endoscopic Biopsies of the Ureter and Renal Pelvis

Technical advances in endoscopic equipment have led to increased ureteroscopic biopsies of the upper urinary tract, resulting in limited biopsy material. We retrospectively reviewed 76 consecutive mid-upper ureter and renal pelvis biopsies submitted for consultation from January 2004 to January 2009, where follow-up was obtainable. There were 49 (64.5%) males and 27 (35.5%) females. Thirty-nine (51.3%) of the biopsies were from the ureter with the remaining 37 (48.7%) from the renal pelvis. The mean age was 70 years for males and 71 for females (range: 24 to 89). At consultation, the most common diagnoses were benign urothelium (n=25, 32.9%); atypical (n=17, 22.4%); low-grade noninvasive papillary urothelial carcinoma (n=10, 13.2%); and high-grade noninvasive papillary urothelial carcinoma (n=8, 10.5%). In cases where a definitive diagnosis could not be reached on expert review, it was mainly because of the limited size of the biopsy, absence of papillary fronds, crush artifact, and distorted architecture. There were 7 major discrepancies between the outside and second opinion diagnosis, where all of the cases were initially diagnosed as an urothelial neoplasm, yet was non-neoplastic upon review. Strips of urothelium without well-developed fibrovascular cores, polypoid ureteritis/pyelitis, and reactive urothelium mimicked urothelial neoplasms. In 5 of these 7 cases, there was no gross lesion suspicious of a tumor present according to the urologist. Overall, 33 of the 44 (75%) cases with a mass noted by the urologist or by radiography was found to have a neoplasm at follow-up. Conversely, 24 of the 32 (75%) cases without a grossly suspected tumor had no neoplasm at follow-up. The association between the histologic presence of a neoplasm at follow-up and the presence of a clinically suspected tumor was highly significant (P<0.0001). Pathologists need to recognize that in almost 1 of the 4 renal pelvic/ureteral biopsies a definitive diagnosis cannot be made because of the inadequate tissue. Caution must be exercised in the evaluation of these limited specimens, especially in the absence of a clinically suspected tumor.

Generation of Monoclonal Antibody Targeting Fibroblast Growth Factor Receptor 3

Fibroblast growth factor receptor 3 (FGFR3) is a member of the FGFR family of receptor tyrosine kinases, whose function has been implicated in diverse biological processes, including cell proliferation, differentiation, survival, and tumorigenesis. Deregulation of FGFR3 signaling has been implicated with human pathologies, including cancer. Activating mutations in FGFR3 gene are frequently detected in bladder cancer, multiple myeloma, and noninvasive papillary urothelial cell carcinomas, while the overexpression of the receptor is observed in thyroid lymphoma and bladder cancer. The main aim of this study was to generate hybridoma clones producing antibody that could specifically recognize FGFR3/S249C mutant, but not the wild-type FGFR. To achieve this, we used for immunization bacterially expressed fragment of FGFR3 corresponding to loops II-III of the extracellular domain (GST-His/FGFR3/S249C-LII-III), which possesses oncogenic mutation at Ser249 detected in at least 50% of bladder cancers. Primary ELISA screening allowed us to isolate several hybridoma clones that showed specificity towards FGFR3/S249C, but not FGFR3wt protein. Unfortunately, these clones were not stable during single-cell cloning and expansion and lost the ability to recognize specifically FGFR3/S249C. However, this study allowed us to generate several monoclonal antibodies specific towards both FGFR3wt and FGFR3/S249C recombinant proteins. Produced hybridomas secreted MAbs that were specific in Western blotting towards bacterially expressed FGFR3wt and FGFR3/S249C, as well as the full-length receptors ectopically expressed in Sf21 and HEK293 cells. Moreover, transiently expressed wild-type and oncogenic forms of FGFR were efficiently immunoprecipitated with selected antibodies from the lysates of infected Sf21 and transiently transfected HEK293. In summary, generated antibodies should be useful as tools for examining the expression pattern and biological functions of FGFR3 in normal and pathological cells and tissues.

Association between atherosclerosis and urothelial tumors of the renal pelvis

An association between the prevalence of general and local atherosclerosis and various types of cancer has previously been reported. The present study therefore aimed to morphometrically compare atherosclerotic changes in kidneys with urothelial carcinomas of the renal pelvis and tumor-negative renal tissue. The intima-to-media ratio (IMR), which is the most sensitive marker for the degree of atherosclerosis, was evaluated in arteries (n = 492) of non-invasive papillary urothelial carcinoma (n = 128), invasive urothelial carcinoma (n = 168) and tumor-negative renal specimens (n = 196). IMR was significantly higher and more often exceeded 1 in invasive and non-invasive urothelial carcinomas than in tumor-negative specimens. Furthermore, in invasive urothelial carcinomas IMR was significantly higher in immediately peritumorous arteries than in more distant arteries. Moreover, IMR correlated weakly with age and renal parenchymal inflammation but not with peritumorous inflammation, coronary heart disease (CHD) or gender. Local atherosclerosis was more pronounced in tumor-positive than in tumor-negative renal specimens. IMR > 1 was significantly associated with urothelial tumors and the overall odds of having a urothelial tumor were significantly greater for patients with an IMR > 1 than for patients with an IMR < or = 1, supporting the view that patients with local atherosclerotic lesions are at elevated risk for urothelial carcinoma of the renal pelvis.

Survivin as a Useful Adjunct Marker for the Grading of Papillary Urothelial Carcinoma

Distinguishing low-grade and high-grade noninvasive papillary urothelial carcinoma based on morphologic criteria can be challenging and adjunct markers are highly desirable. Survivin, presumably an antiapoptotic protein, was previously proposed as a prognostic marker for urothelial carcinoma. To assess interobserver variability by 2004 World Health Organization classification and the value of survivin and Ki-67 as potential markers for grading noninvasive papillary urothelial carcinoma. Fifty-one bladder biopsies were graded blindly by 5 experienced general surgical pathologists. The protein and messenger RNA expression of survivin and Ki-67 was evaluated by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction using paraffin-embedded tissue. The immunohistochemistry result was quantitatively analyzed using a computer-based color deconvolution module. The diagnostic agreement among 5 pathologists was fair to poor, with 32% of the cases graded differently by at least 2 raters. All cases were divided into 3 groups: consensus low-grade, consensus high-grade, and indeterminate. The percentage of urothelial cells with positive survivin nuclear staining (survivin score) was significantly higher in the high-grade than in the low-grade group (P < .001). Survivin score outperformed Ki-67 in separating the high-grade group from the low-grade group and showed a significantly higher predictive accuracy for high-grade recurrence than the histologic grade. The disagreement of grading for the indeterminate group could be resolved by their survivin scores in most cases. Survivin messenger RNA level correlated well with survivin score by immunohistochemistry but was not a more discriminating marker. Significant interobserver variability exists in grading low-grade versus high-grade papillary urothelial carcinoma. Survivin immunohistochemical staining can be a useful adjunct tool for the grading of challenging cases.

Survivin as a useful adjunct marker for the grading of papillary urothelial carcinoma.

Abstract Context.—Distinguishing low-grade and high-grade noninvasive papillary urothelial carcinoma based on morphologic criteria can be challenging and adjunct markers are highly desirable. Survi...