Papillary Urothelial Neoplasm Research Articles

226 Genomic alterations in urothelial carcinoma subgroups

Papillary urothelial neoplasms of the urinary bladder comprise a heterogeneous spectrum of ‘continuous’ lesions in which the assessment of an accurate histological grade and tumour stage is mandatory for the clinical management of patients. The 1998 World Health Organization/International Society of Urologic Pathologists (WHO/ISUP) consensus classification and the 1999 WHO classification proposed new malignancy grading schemes, mainly based on morphometric studies for the replacement of the 1973 WHO grading system. In accordance with these novel grading systems, two major categories of papillary urothelial neoplasms were distinguished: low-grade and high-grade papillary urothelial neoplasms. Concerning the specific subgroup of low-grade tumours, two other entities were defined: papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade papillary urothelial carcinomas (LGPUC). In long-term follow-up programmes, PUNLMP have demonstrated low recurrence rates and minimal risk for tumour progression in comparison with LGPUC. However, grade assessment is a subjective decision and, on occasion, the use of reproducible criteria by urological pathologists is difficult due to tumour heterogeneity and to the existence of a variable number of cases situated between consecutive groups. As a result, to determine a better correlation with clinicopathological patient outcome, other predictive markers are being investigated. Among these, the prognostic significance of classical clinicopathological, morphometric, cytometric, immunohistochemical and molecular markers have been widely reported. This review summarizes the prognostic importance of all these markers in the prediction of tumour recurrences and progression in low-grade papillary urothelial bladder neoplasms.

Prognostic Accuracy of Individual Uropathologists in Noninvasive Urinary Bladder Carcinoma: A Multicentre Study Comparing the 1973 and 2004 World Health Organisation Classifications

BackgroundGrading of noninvasive papillary urinary bladder carcinoma (PUC) is routinely performed in clinical oncologic practice; however, reports regarding diagnostic and prognostic accuracy are contradictory. ObjectiveTo compare the 1973 and 2004 World Health Organisation (WHO) classifications in terms of interobserver variability and prognostic implications. Design, setting, and participantsTwo hundred PUC were retrospectively reviewed by four independent expert genitourinary pathologists blinded with respect to patient identity and clinical outcome. Tumour grading was assigned according to the 1973 and 2004 WHO classifications. Surveying a mean postsurgical follow-up of 71.8 mo (range: 18–163 mo), clinical outcome in terms of recurrence-free and progression-free survival was recorded for all patients. InterventionAll of the patients underwent transurethral resection of the bladder. MeasurementsThe generalised κ (kappa statistic) for interobserver variability was calculated, and Kaplan-Meier analysis as well as univariate regression analysis were performed to evaluate prognostic implications in terms of recurrence and progression rates. Results and limitationsDuring the follow-up, a total of 84 (42%) patients experienced recurrence, whereas another 18 (9%) patients featured disease progression. Owing to the rare presence of papillary urothelial neoplasms of low malignant potential (PUNLMP) in our cohort (0–3.5%), the 2004 WHO classification approached a two-tier system (low and high grade), which showed less interobserver variability than the 1973 classification (κ: 0.30–0.52 vs 0–0.37, respectively). In comparing the power of both classifications to separate indolent from aggressive PUC, striking pathologist-dependent differences became apparent. ConclusionsBoth WHO classifications for grading of PUC suffer from substantial interobserver variability, with the 2004 WHO classification showing less interobserver variability. Stark differences in the prognostic power of the individual grading approaches were also found. These significant differences in the individual interpretation of the WHO grading schemes for noninvasive PUC highlight the necessity of better-defined criteria for conventional tumour grading; otherwise, the subdivision into prognostically different groups by conventional histomorphology might remain of limited value.

Prognostic markers in low-grade papillary urothelial neoplasms of the urinary bladder: an update

Papillary urothelial neoplasms of the urinary bladder comprise a heterogeneous spectrum of ‘continuous’ lesions in which the assessment of an accurate histological grade and tumour stage is mandatory for the clinical management of patients. The 1998 World Health Organization/International Society of Urologic Pathologists (WHO/ISUP) consensus classification and the 1999 WHO classification proposed new malignancy grading schemes, mainly based on morphometric studies for the replacement of the 1973 WHO grading system. In accordance with these novel grading systems, two major categories of papillary urothelial neoplasms were distinguished: low-grade and high-grade papillary urothelial neoplasms. Concerning the specific subgroup of low-grade tumours, two other entities were defined: papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade papillary urothelial carcinomas (LGPUC). In long-term follow-up programmes, PUNLMP have demonstrated low recurrence rates and minimal risk for tumour progression in comparison with LGPUC. However, grade assessment is a subjective decision and, on occasion, the use of reproducible criteria by urological pathologists is difficult due to tumour heterogeneity and to the existence of a variable number of cases situated between consecutive groups. As a result, to determine a better correlation with clinicopathological patient outcome, other predictive markers are being investigated. Among these, the prognostic significance of classical clinicopathological, morphometric, cytometric, immunohistochemical and molecular markers have been widely reported. This review summarizes the prognostic importance of all these markers in the prediction of tumour recurrences and progression in low-grade papillary urothelial bladder neoplasms.

Concomitant carcinoid tumor and papillary urothelial neoplasm of low malignant potential in a patient with Crohnʼs disease: a case report

Patients with a long-term history of inflammatory bowel diseases show an increased risk of developing colorectal cancers. In the case of Crohn's disease, such an increased risk is also associated with other malignant tumors. The report presents a very rare case of a concomitant carcinoid tumor and papillary urothelial neoplasm of low malignant potential in a 35-year-old patient with diagnosed Crohn's disease complicated by an enterovesical fistula. The carcinoid tumor and papillary urothelial neoplasm of low malignant potential were diagnosed by postoperative histopathology. In patients with Crohn's disease, concomitant occurrence of various malignancies may be observed even earlier in life.

Immunohistochemical Evaluation of Global DNA Methylation and Histone Acetylation in Papillary Urothelial Neoplasm of Low Malignant Potential

A preceding study has shown that karyometry detected subvisual differences in chromatin organization status between non-recurrent and recurrent papillary urothelial neoplasm of low malignant potential (PUNLMP). The status of chromatin organization depends on epigenetic events, such as DNA methylation and histone acetylation. The aim of this study is to explore global DNA methylation and global histone acetylation in non-recurrent and recurrent PUNLMP. 5-methylcytosine (5MeC) and acetylated histone H3 lysine 9 (AcH3K9) were investigated by immunohistochemistry (IHC) in 20 PUNLMP cases (10 non-recurrent and 10 recurrent), in 5 cases of normal urothelium (NU) and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). For global DNA methylation, the mean percentage of positive nuclei in the cells adjacent to the stroma increased from NU (79%) through non-recurrent and recurrent PUNLMP (86% and 93%, respectively) to UC (97%). The percentages of positive nuclei in the intermediate cell layers and in the superficial cells in the four groups were similar to those adjacent to the stroma. The proportion of nuclei with weak-to-moderate intensity was far greater than that of those strongly stained and increased steadily from NU to UC. For global histone acetylation, the mean percentage of positive nuclei was highest in non-recurrent PUNLMP (i.e. 90%) and lowest in recurrent PUNLMP (i.e. 81%). In NU and UC the mean percentages of positive nuclei were 84% and 86%, respectively. The percentage of positive nuclei decreased from the cell layer adjacent to the stroma to the superficial cell layer. The proportion of nuclei with weak-to-moderate intensity was slightly greater than that of those strongly stained. In comparison with global DNA methylation, the proportion of strongly stained nuclei was much higher. In conclusion, there are differences in global DNA methylation and histone acetylation patterns between non-recurrent and recurrent PUNLMP. Further studies are needed to elucidate the complex interplay between chromatin structure, its modifications and recurrence of PUNLMP.

Relationship of Ki67, TP53, MDM-2 and BCL-2 expressions with WHO 1973 and WHO/ISUP grades, tumor category and overall patient survival in urothelial tumors of the bladder

Using the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) (2004 WHO), 1999 WHO/ISUP, and 1973 WHO classifications, we examined Ki67, BCL-2, TP53, and MDM-2 expressions in invasive and noninvasive urothelial neoplasias of the bladder of 72 patients, and compared the results regarding tumor category and grade with clinical outcome to determine the clinicopathological relevance of these classifications. Ki67 and TP53 expressions were correlated with tumor grades of the 1973 WHO classification, and they also distinguished “papillary urothelial neoplasm with low malignant potential” from other WHO/ISUP grades ( p<0.05). No difference was observed for Ki67 and TP53 expressions between the other WHO/ISUP grades ( p>0.05). Neither tumor grade nor tumor category correlated with MDM-2 or BCL-2 expressions ( p>0.05). WHO/ISUP classifications are obviously not superior to the 1973 WHO classification for grading urothelial neoplasia of the bladder. However, if the “papillary urothelial neoplasm with low malignant potential” is distinguished from grade 1 tumors of the 1973 WHO classification, more precise prognostic information may be obtained.

Expression of RNA-binding protein IMP3 (KOC) in benign urothelium and urothelial tumors

RNA-binding protein IMP3 is a KH-domain-containing protein and a member of the insulin-like growth factor messenger RNA-binding protein family. It is identical to K-homology protein overexpressed in cancer that was identified through screening for genes differentially expressed between benign pancreatic tissue and pancreatic cancer. Several studies have shown that IMP3 is associated with aggressive and advanced tumors in various organs. We studied the expression of IMP3 in benign urothelium and urothelial tumors by immunohistochemistry. The expression pattern of IMP3 was further compared with that of p53 and p16. Our study shows that IMP3 is generally not expressed in benign urothelium or low-grade urothelial tumors including urothelial dysplasia, papillary urothelial neoplasm of low malignant potential, and low-grade papillary urothelial carcinoma. The expression of IMP3 is significantly increased in high-grade urothelial tumors including high-grade papillary urothelial carcinoma, urothelial carcinoma in situ, and invasive urothelial carcinoma. Expression of IMP3 in urothelial tumors parallels the accumulation of nuclear p53, although there is not always a one to one correlation. In contrast, expression of p16 in the different groups of urothelial tumors is more variable. Urothelial carcinomas with invasion of muscularis propria appear to express IMP3 more frequently than lower-stage tumors. These findings suggest that IMP3 may be involved in the progression of urothelial tumors from low grade to high grade in both papillary and flat lesions. Immunohistochemical detection of the combined expression of IMP3 and p53 is useful in the diagnosis of high-grade urothelial tumors, particularly in small, superficial materials.

Loss of heterozygosity at 9q32–33 (DBC1 locus) in primary non‐invasive papillary urothelial neoplasm of low malignant potential and low‐grade urothelial carcinoma of the bladder and their associated normal urothelium

Tumour recurrence has a major impact on patients with non-invasive papillary urothelial tumours of the bladder. To explore the role of DBC1 (deleted in bladder cancer 1 locus), a candidate tumour suppressor gene located at 9q32-33, as prognostic marker we have performed loss of heterozygosity (LOH) testing in 49 patients with primary papillary urothelial tumours and associated normal urothelium. Data from the 38 tumours and 11 specimens of normal urothelium that were informative in the LOH study (D9S195 marker) showed that LOH in urothelium (45.4%) but not in non-invasive tumours (60.5%) was associated with tumour recurrence (p = 0.026) but not to grade or progression. Also, tumours whose normal urothelium had LOH were larger (p = 0.020) and showed cyclin D1 over-expression (p = 0.032). Non-significant increased expression of p53, p21Waf1, apoptotic index and tumour proliferation, and decreased expression of p27Kip1 or cyclin D3 also characterized tumours whose normal urothelium had LOH. The expression of these G1-S modulators, apoptotic index and tumour proliferation was more heterogeneous in papillary urothelial tumours, irrespective of having retained heterozygosity or LOH. Also, Bax expression decreased in papillary urothelial tumours having LOH (p = 0.0473), but Bcl-2 was unrelated to LOH status. In addition, FGFR3 protein expression decreased in LOH tumours (p = 0.036) and in those having LOH in their normal urothelium (p = 0.022). FGFR3 immunohistochemical expression was validated by western blot in selected cases. The survival analysis selected LOH in normal urothelium as a marker of disease-free survival (log-rank 5.32, p = 0.021), progression-free survival (log-rank 3.97, p = 0.046) and overall survival (log-rank 4.26, p = 0.038); LOH in tumours was significant in progression-free survival (log-rank 3.83, p = 0.042). It is concluded that LOH at the DBC1 locus in normal urothelium seems to be relevant in the prognosis of non-invasive papillary tumours of the bladder via selecting cases with increased proliferation, frequent alterations of the G1-S phase modulators, and decreased FGFR3 protein expression.

Polypoid/Papillary Cystitis: A Series of 41 Cases Misdiagnosed as Papillary Urothelial Neoplasia

Polypoid cystitis and its more chronic phase papillary cystitis, which results as a reaction to injury to the bladder mucosa, is a benign lesion mimicking various papillary urothelial neoplasms. Analogous lesions occur throughout the urothelial tract and are referred to as polypoid urethritis, polypoid ureteritis, and polypoid pyelititis when present in the urethra, ureter, and renal pelvis, respectively. For simplicity, these lesions in different sites and papillary cystitis will typically be referred to as polypoid cystitis in this manuscript. A search of the consultation files from our institution from January 2000 to July 2007 was performed. Of 155 cases diagnosed as polypoid cystitis, we identified 41 cases that were diagnosed as papillary urothelial neoplasms by contributing pathologists and only sent to us, typically at the request of the urologist after the case had be signed out. For cases where information was available, clinical symptoms included bladder obstruction (n=7), gross hematuria (n=6), colovesicular fistula (n=4), follow-up status posttreatment of bladder and ureter carcinoma (n=4), bladder/urethral stones (n=2), benign prostate hyperplasia (n=2), follow-up after radiation for prostate cancer (n=2), long-standing urinary stents (n=2), and voiding dysfunction (n=1). Original diagnoses included noninvasive low grade papillary urothelial carcinoma (n=23), noninvasive high grade papillary urothelial carcinoma (n=6), papillary urothelial neoplasm of low malignant potential (n=5), papilloma (n=3), urothelial neoplasia (n=2), carcinoma in situ (n=1), and squamous carcinoma (n=1). The mean age at diagnosis was 63 years (range, 19 to 93 y; median 63 y). Male to female ratio was 3.1 to 1. Clinical symptoms varied with the most common manifestations, including gross hematuria, bladder/urethral stones, history of prostate cancer treated with radiation, follow-up after bladder/ureter carcinoma treatment, long-term urinary stents, and colovesicular fistulas. At cystoscopy, lesions were variably described as polypoid, trabeculations, bullous polyps, and diffuse erythema and edema. The locations of polypoid cystitis were bladder (n=34), ureteral orifice (n=2), urethra (n=2), renal pelvis (n=2), and undesignated (n=1). Architecturally, 31 cases had isolated papillary fronds with in 1 case branching papillary structures. The base of the papillary stalks were characterized as both broad and narrow (n=24), only broad (n=9), and only narrow (n=3). The overlying urothelium of polypoid cystitis was diffusely and focally thickened in 8 cases and 5 cases, respectively. Umbrella cells were identified in 32 cases. Acute and chronic inflammation was present in 28 cases, moderate in 15, and mild in 13 cases. Eleven cases showed chronic inflammation, mild in 10, and moderate in 1 case. Reactive urothelial atypia was noted in 26 cases with mitotic figures present in 22 cases, frequent in 3 and rare in 19 cases. Stroma edema was seen in 32 cases with fibrosis within the polypoid stalks seen in 16 cases. The key to correctly diagnosing polypoid/papillary cystitis is to recognize at low magnification the reactive nature of the process with an inflamed background that is edematous or densely fibrous with predominantly simple, non-branching, broad-based fronds of relatively normal thickness urothelium, and not focus at higher power on the exceptional frond that may more closely resemble a urothelial neoplasm either architecturally or cytologically. In cases where the diagnosis of papillary neoplasia is not straightforward and there is a question of polypoid cystitis, pathologists should seek clinical history that might suggest a reactive process. Because the urologist can more often better recognize the inflammatory nature of the lesion than the pathologist, the pathologist should hesitate diagnosing urothelial neoplasia when the cystoscopic impression is that of an inflammatory lesion.

Diagnostic algorithm for papillary urothelial tumors in the urinary bladder

Papillary urothelial neoplasms with deceptively bland cytology cannot be easily classified. We aimed to design a new algorithm that could differentiate between these neoplasms based on a scoring system. We proposed a new scoring system that enables to reproducibly diagnose non-invasive papillary urothelial tumors. In this system, each lesion was given individual scores from 0 to 3 for mitosis and cellular thickness, from 0 to 2 for cellular atypia, and an additional score for papillary fusion. These scores were combined to form a summed score allowing the tumors to be ranked as follows: 0–1 = UP, 2–4 = low malignant potential (LMP), 5–7 = low-grade transitional cell carcinoma (TCC), and 8–9 = high-grade TCC. In addition to the scoring system, ancillary studies of MIB and p53 indexes with CK20 expression pattern analyses were compared together with clinical parameters. The MIB index was strongly correlated with disease progression. Four of the 22 LMP patients (18.2%) had late recurrences, two of these four (9.1%) had progression to low-grade carcinoma. The MIB index for LMP patients was strongly associated with recurrence (recurrence vs. non-recurrence, 16.5 vs. 8.1, p < 0.001). The proposed scoring system could enhance the reproducibility to distinguish papillary urothelial neoplasms.

P16 ink4 immunoreactivity is a reliable marker for urothelial carcinoma in situ

Morphological discrimination of urothelial carcinoma (UC) in situ, a precursor of high-grade invasive carcinoma, from severe reactive atypia is essential, but can be challenging at times. Mutations of the cell cycle regulatory gene INK4a (located at 9p21) that encodes p16(INK4) are one of the critical early events in carcinogenesis of UC. The purpose of this study was to investigate p16(INK4) expression in different urothelial lesions and assess its possible utility in distinguishing reactive versus neoplastic changes. Immunoreactivity of p16(INK4) was investigated using paraffin sections from 8 different sample groups (n = 80), including organ donor bladders with normal and/or reactive urothelium; bladder biopsies with reactive atypia; isolated carcinoma in situ; high-grade UC with concurrent carcinoma in situ; low-grade papillary urothelial neoplasms; high-grade stage T1 UC; and high-grade stage T2-T4 UC without concomitant carcinoma in situ. A composite staining score was calculated (Sigma% positive cells x intensity) for each case. Fluorescence in situ hybridization analysis was performed in selected cases. A uniform and weak cytoplasmic p16(INK4) expression was observed in normal urothelium and urothelium with reactive atypia from organ donors. Bladder biopsies with reactive atypia showed lower scores and loss of p16(INK4) expression in 38% of cases. Strong p16(INK4) staining was found in 100% of carcinoma in situ with no loss of p16(INK4) expression. The strong p16(INK4) immunoreactivity in foci of carcinoma in situ clearly demarcated the neoplastic cells from adjacent nonneoplastic cells, which showed either normal or focal loss of p16(INK4) staining. Fluorescence in situ hybridization study revealed abundant deletion of chromosome 9p21 or polysomy of chromosome 9 in malignant cells of carcinoma in situ. Increased p16(INK4) expression was also seen in most high-grade invasive UC with concurrent carcinoma in situ, but the intensity of p16(INK4) staining did not correlate with the cancer grade or stage. We conclude that the 16(INK4) immunoreactivity seems to be most useful in distinguishing carcinoma in situ from severe reactive atypia. Alterations of 9p21/chromosome 9 detected by fluorescence in situ hybridization can also be used for diagnostic confirmation and prognostic prediction.

Histological classification and stage of newly diagnosed bladder cancer in a population-based study from the Northeastern United States

There are limited data on the distribution of bladder cancers in the general population, classified by World Health Organization (WHO)/International Society of Urological Pathology (ISUP) criteria. This study evaluated the classification and stage of bladder cancers as part of a population-based epidemiological study of bladder cancer in the Northeastern United States. All New Hampshire residents with bladder cancer newly diagnosed from 1998 to 2000 were identified through the state cancer registry. All slides were reviewed by a single pathologist. Tumors were classified by two sets of standard criteria. The retrieval rate for cases was over 90%. Of 342 cases reviewed, 15 were excluded for technical reasons or because malignancy was not definitively diagnosed. According to WHO/ISUP criteria, 25.7% of tumors were papillary urothelial neoplasms of low malignant potential (PUNLMP), 34.3% low-grade papillary carcinomas, 22.6% high-grade papillary carcinomas, 10.1% non-papillary urothelial carcinomas and 5.5% carcinoma in situ. By WHO (1973) criteria, 52.5% of tumors were grade 1, 21.4% grade 2 and 26.1% grade 3. Two-thirds of all tumors were stage Ta, 20.8% stage T1 and 7.6% stage >or=T2. 100% of PUNLMPs were non-invasive, 6.3% of low-grade carcinomas were invasive and 64.9% of high-grade carcinomas were invasive. Compared to clinic or hospital referral-based series, this study documents a higher percentage of non-invasive tumors and a lower percentage of muscle-invasive tumors. There was also a higher percentage of PUNLMP tumors and fewer high-grade papillary carcinomas than in other series. These results may more accurately reflect prevalence data for bladder cancer grade and stage, although geographic variability may exist.

Strong immunohistochemical expression of fibroblast growth factor receptor 3, superficial staining pattern of cytokeratin 20, and low proliferative activity define those papillary urothelial neoplasms of low malignant potential that do not recur

Papillary urothelial neoplasm of low malignant potential (PUNLMP) is a clinically significant lesion because recurrence occurs in approximately 35% of patients. To date, it is not possible to identify those cases that will recur based on conventional histopathologic assessment. The objective of the current study was to evaluate immunohistochemically tissue expression of fibroblast growth factor receptor 3 (FGFR3), cytokeratin 20 (CK20), and MIB-1 in nonrecurrent and recurrent PUNLMP. FGFR3, CK20, and MIB-1 were investigated by immunohistochemistry (IHC) in 80 PUNLMP cases (41 nonrecurrent and 39 recurrent), in 4 cases of normal urothelium (NU), and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). Statistics included discriminant analysis. NU demonstrated a weak to moderate FRFG3 staining intensity, a superficial pattern of CK20 staining, and low proliferative activity. UC was found to have FGFR3 staining similar to NU, an abnormal CK20 expression, and high proliferative activity. The nonrecurrent PUNLMP group demonstrated strong FGFR3 intensity in 80.5% of the cases (vs 56.4% of the recurrent cases), a superficial CK20 staining pattern in 53.7% of the cases (vs 28.2% of the recurrent cases), and a percentage of MIB-1-positive nuclei below the median value of all the PUNLMP cases in 61% of the cases (35.9% in the recurrent cases). The differences were statistically significant. Discriminant analysis based on these 3 features demonstrated that 67.5% of cross-validated grouped PUNLMP cases were correctly allocated, with 73.2% of the nonrecurrent and 61.5% of the nonrecurrent cases being correctly classified. The specificity and sensitivity were 73.1% and 61.5%, respectively. Strong immunohistochemical expression of FGFR3, a superficial staining pattern of CK20, and a low proliferative activity define those papillary urothelial neoplasms of low malignant potential that do not recur.

Overexpression of p27kip1 in urinary bladder urothelial carcinoma

Cyclins and cyclin-dependent kinase (CDK) complexes have important regulatory roles during cell cycle progression and can be used as prognostic markers in various kinds of malignant tumors. This study investigated the expression of proliferative cell nuclear antigen (PCNA), p53, Rb, p27(kip1), and cyclin D1 by immunostains in bladder tumors, especially urothelial papilloma, papillary urothelial neoplasm of low malignant potential, and low and high grade urothelial carcinoma, to see if their expression is associated with classification or grading of the urinary bladder urothelial carcinoma. Nuclear expression of PCNA, p53, Rb, p27(kip1), and cyclin D1 was determined immunohistochemically in a series of 89 urinary bladder tumor specimens, including 13 papilloma, 15 urothelial neoplasm of low malignant potential, 17 low grade urothelial carcinoma, and 44 high grade urothelial carcinoma. The results of immunoreactivity were analyzed with respect to the associations with tumor grade. Eighty-two percent (38/45) of the p27(kip1) positive tumors were urothelial carcinoma, and the percentage of the p27(kip1) positivity was higher with increasing grade of the urothelial carcinoma (P = 0.011). A tendency of higher percentage of positive p53 immunoreactivity was noted in the urothelial carcinoma (P = 0.053). There was no significant difference in cyclinD1, Rb and PCNA expression between benign, low malignant potential and urothelial carcinoma. We first noted an overexpression of p27(kip1) in urinary bladder urothelial carcinoma. The result indicates that some urothelial carcinomas may tolerate this inhibitor of cell cycle progression.

Survival Following the Diagnosis of Noninvasive Bladder Cancer: WHO/International Society of Urological Pathology Versus WHO Classification Systems

The WHO/International Society of Urological Pathology classification of bladder cancer, introduced in 1998, differs from the traditional 1973 WHO classification. Few studies have reported survival data based on the WHO/International Society of Urological Pathology classification and none has demonstrated clear superiority compared to the 1973 WHO system. In a large, nonselected population of patients with bladder cancer we rated all incident tumors using each system and compared long-term patient survival. New Hampshire residents with bladder cancer diagnosed between 1994 and 2000 were identified through the State Cancer Registry. Slides were retrieved from more than 90% of cases and reviewed by a single pathologist. Tumors were classified according to WHO and WHO/International Society of Urological Pathology criteria. Overall patient survival was determined for the cohort of 504 patients after an average of 7 years using a national mortality database. For both grading systems there was a gradient of progressively lower survival times from the lowest grade to the highest grade tumors. Hazard ratios and 95% confidence intervals for the WHO/International Society of Urological Pathology system were 1.9 (1.0-3.4) for low grade papillary urothelial carcinoma and 3.0 (1.5-6.0) for high grade papillary urothelial carcinoma, compared to papillary urothelial neoplasms of low malignant potential. For the WHO (1973) system compared to grade 1 tumors the hazard ratio for grade 2 tumors was 1.8 (1.1-3.1) and for grade 3 was 2.4 (1.2-4.7). Advantages of the WHO/International Society of Urological Pathology bladder tumor classification include more detailed diagnostic criteria, the ability to define a lesion with minimal malignant potential and the ability to identify a larger group of patients needing closer surveillance. However, we found that the WHO/International Society of Urological Pathology tumor categories did not detect a clear overall survival advantage compared to the WHO (1973) classification system.

Low Frequency of Molecular Changes and Tumor Recurrence in Inverted Papillomas of the Urinary Tract

Inverted papilloma (IP) of the urinary tract can be difficult to distinguish from noninvasive urothelial carcinoma with prominent inverted growth pattern (invNIUC). Ancillary markers may help to resolve such cases and clarify the reported malignant potential of some IPs. Eighty-nine urothelial lesions initially diagnosed as IP were reviewed by 4 experienced urologic pathologists and studied immunohistochemically (Ki67, p53, CK20, MSH2, MLH1, and MSH6). Mutations of the FGFR3 gene, deletions (loss of heterozygosity) of 9p, 9q, and 17p, microsatellite instability, and elevated microsatellite instability at selected tetranucleotides were also analyzed. Considerable interobserver variability in histopathologic diagnoses was noticed. Only 62 (69.7%) initial diagnoses were confirmed by the review pathologists whereas 23 tumors (25.8%) were redefined as invNIUC. Molecular analyses revealed infrequent alterations in IPs, including microsatellite instability (1.8%), elevated microsatellite instability at selected tetranucleotides (13.2%), FGFR3 mutations (9.8%), 9p deletions (3.9%), 9q deletions (13.2%), 17p deletions (5.1%), nuclear p53 accumulation (18.9%), and aberrant immunostaining for MSH2 (5.8%), MLH1 (11.8%), and MSH6 (3.8%). IP and invNIUC differed in FGFR3 mutations and Ki-67 labeling index (P<0.001 each), and 9q loss of heterozygosity (P=0.03). There were fewer recurrences in IP (5.4%) compared with invNIUC (40.9%; P<0.0001). IP is a benign lesion that lacks specific genetic alterations found in exophytic noninvasive papillary urothelial tumors. These lesions could be reactive in nature, perhaps secondary to chronic inflammation or a neoplastic process that lack specific genetic alterations. Nevertheless given the clinical and molecular data of this study a conservative clinical approach is appropriate.

Aggressive Behavior of Low-Grade Ta Papillary Urothelial Bladder Neoplasm in a 17-Year-Old Patient

Bladder tumors rarely occur in the first two decades of life, and, in contrast to the cases in adults, 97% of transitional cell carcinomas of the bladder in childhood are low grade, superficial, and of good prognosis, with a progression rate of only 2% to 4%. This report presents a case of low-grade bladder cancer in a 17-year-old patient which behaved quite aggressively. The most striking features of this case included the histopathologic findings and rapid disease progression, despite treatment with agents known for their efficacy against tumors of epithelial and mesenchymal origin.

Papillary urothelial neoplasm of low malignant potential in a pediatric renal transplant recipient (PUNLMP): A case report

Papillary urothelial neoplasm of low malignant potential in a pediatric renal transplant recipient (PUNLMP): A case report

Poorly Differentiated Adenocarcinomas of Prostate Versus High-Grade Urothelial Carcinoma of the Bladder: A Diagnostic Dilemma With Immunohistochemical Evaluation of 2 Cases

The differential diagnosis between carcinoma of the urinary bladder and adenocarcinoma of the prostate can be difficult, especially in the poorly differentiated forms infiltrating the neighboring organs. In this article, the authors report 2 cases that pose a diagnostic dilemma to the pathologist. The first is an infiltration of the bladder by a poorly differentiated adenocarcinoma of the prostate, which was clinically suspected as a papillary urothelial neoplasm. The second is a collision tumor composed of prostatic adenocarcinoma and urothelial carcinoma observed on a core needle biopsy of the prostate. In both cases, a large panel of immunohistochemical markers were used and demonstrated positivity for prostate-specific antigen and alpha methyl racemase in the prostatic carcinomas and immunoreactivity for CK7, CK20, Ag 34betaE12, and p53 in the urothelial carcinoma. The differentiating histological and immunohistochemical findings are discussed.

Histologic analysis of bladder cancer: A new mouse model

Background: The progression of Papillary Urothelial Neoplasm of Low Malignant Potential and Urothelial Carcinoma In Situ into bladder cancer is currently not well understood. Design: We developed a...