microRNA expression profile in a large series of bladder tumors: identification of a 3-miRNA signature associated with aggressiveness of muscle-invasive bladder cancer.

The aim of this study was to evaluate the expression levels of microRNAs (miRNAs) in bladder tumors in order to identify miRNAs involved in bladder carcinogenesis with potential prognostic implications. Expression levels of miRNAs were assessed by quantitative real-time RT-PCR in 11 human normal bladder and 166 bladder tumor samples (86 non-muscle-invasive bladder cancer (NMIBC) and 80 muscle-invasive bladder cancer (MIBC)). The expression level of 804 miRNAs was initially measured in a well-defined series of seven NMIBC, MIBC and normal bladder samples (screening set). The most strongly deregulated miRNAs in tumor samples compared to normal bladder tissue were then selected for RT-PCR validation in a well-characterized independent series of 152 bladder tumors (validation set), and in six bladder cancer cell lines. Expression levels of these miRNAs were tested for their association with clinical outcome. A robust group of 15 miRNAs was found to be significantly deregulated in bladder cancer. Except for two miRNAs, miR-146b and miR-9, which were specifically upregulated in MIBC, the majority of miRNAs (n = 13) were deregulated in the same way in the two types of bladder tumors, irrespective of pathological stage : three miRNAs were upregulated (miR-200b, miR-182 and miR-138) and the other 10 miRNAs were downregulated (miR-1, miR-133a, miR-133b, miR-145, miR-143, miR-204, miR-921, miR-1281, miR-199a and miR-199b). A 3-miRNA signature (miR-9, miR-182 and miR-200b) was found to be related to MIBC tumor aggressiveness and was associated with both recurrence-free and overall survival in univariate analysis with a trend to significance in the multivariate analysis (p = 0.05). Our results suggested a promising individual prognostic value of these new markers.

Surgery for bladder endometriosis: long-term results and concomitant management of associated posterior deep lesions.

BACKGROUND: Deep infiltrating endometriosis (DIE) is presented as a disease with high recurrence risk. Bladder DIE is the most frequent location in cases of urinary endometriosis. Surgical removal has been recommended for bladder DIE but long-term outcomes remains unevaluated. The objectives of this study are to evaluate the rate of recurrence after partial cystectomy for patients presenting with bladder DIE and to outline the surgical modalities for handling associated posterior DIE nodules. METHODS: Seventy-five consecutive patients with histologically proved bladder DIE were enrolled at a single tertiary academic center between June 1992 and December 2007. A partial cystectomy was performed for each patient. Complete surgical exeresis of all associated symptomatic DIE lesions was carried out during the same surgical procedure. Bladder DIE patients were classified into three groups: patients with isolated bladder DIE (Group A); patients with associated symptomatic posterior DIE (Group B); patients with associated asymptomatic posterior DIE (Group C). Bladder DIE recurrence was defined as a clinical reappearance of the disease or radiological evidence that mandated a new surgical procedure. We assessed pelvic pain symptoms pre- and post-operatively using a 10-cm visual analogue scale. RESULTS: In a series of 627 patients with DIE, we observed 75 patients (12%) with bladder DIE. With a 50.9 +/- 44.6 months mean follow-up after partial cystectomy no patient presented evidence of bladder DIE recurrence. Post-operatively, we observed a significant improvement with respect to pain symptoms, with only two patients (2.7%) developing major complications during follow-up. Among patients with non-operated associated asymptomatic posterior DIE lesions (n = 15), a second surgical procedure indicated for pain symptoms was necessary in only one patient (6.7%). CONCLUSIONS: For patients presenting with bladder DIE, no patients required further surgery for bladder recurrence after radical surgery consisting in partial cystectomy. Exeresis of associated posterior DIE nodules is indicated only when they are symptomatic.

Genomic expression and single-nucleotide polymorphism profiling discriminates chromophobe renal cell carcinoma and oncocytoma.

BACKGROUND: Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are two distinct but closely related entities with strong morphologic and genetic similarities. While chRCC is a malignant tumor, oncocytoma is usually regarded as a benign entity. The overlapping characteristics are best explained by a common cellular origin, and the biologic differences between chRCC and oncocytoma are therefore of considerable interest in terms of carcinogenesis, diagnosis and clinical management. Previous studies have been relatively limited in terms of examining the differences between oncocytoma and chromophobe RCC. METHODS: Gene expression profiling using the Affymetrix HGU133Plus2 platform was applied on chRCC (n = 15) and oncocytoma specimens (n = 15). Supervised analysis was applied to identify a discriminatory gene signature, as well as differentially expressed genes. High throughput single-nucleotide polymorphism (SNP) genotyping was performed on independent samples (n = 14) using Affymetrix GeneChip Mapping 100 K arrays to assess correlation between expression and gene copy number. Immunohistochemical validation was performed in an independent set of tumors. RESULTS: A novel 14 probe-set signature was developed to classify the tumors internally with 93% accuracy, and this was successfully validated on an external data-set with 94% accuracy. Pathway analysis highlighted clinically relevant dysregulated pathways of c-erbB2 and mammalian target of rapamycin (mTOR) signaling in chRCC, but no significant differences in p-AKT or extracellular HER2 expression was identified on immunohistochemistry. Loss of chromosome 1p, reflected in both cytogenetic and expression analysis, is common to both entities, implying this may be an early event in histogenesis. Multiple regional areas of cytogenetic alterations and corresponding expression biases differentiating the two entities were identified. Parafibromin, aquaporin 6, and synaptogyrin 3 were novel immunohistochemical markers effectively discriminating the two pathologic entities. CONCLUSIONS: Gene expression profiles, high-throughput SNP genotyping, and pathway analysis effectively distinguish chRCC from oncocytoma. We have generated a novel transcript predictor that is able to discriminate between the two entities accurately, and which has been validated both in an internal and an independent data-set, implying generalizability. A cytogenetic alteration, loss of chromosome 1p, common to renal oncocytoma and chRCC has been identified, providing the opportunities for identifying novel tumor suppressor genes and we have identified a series of immunohistochemical markers that are clinically useful in discriminating chRCC and oncocytoma.

Loss of chromosomes 9 and 11 may be recurrent chromosome imbalances in juxtaglomerular cell tumors.

Juxtaglomerular cell tumor (JGCT), first described in 1967, is a rare tumor of the kidney that derived from specialized smooth muscle cells of the wall of the glomerular afferent arteriole. Less than 100 cases have been published, mainly as isolated case reports or small series. JGCTs are considered benign, but the clinical follow-up is short in most reported cases. Only 1 metastatic case has been reported to date, raising the question of tumors of uncertain malignant potential rather than clearly benign neoplasms. Genomic features have been studied in only 2 cases that showed gain of chromosome 10 as well as loss of chromosomes 9, 11q, and X. The present work studied the genomic characteristics of 2 additional cases of JGCT by comparative genomic hybridization. Similarly to the 2 previously reported cases, these 2 tumors showed loss of chromosomes 9 and 11, suggesting recurrent chromosomal imbalances. In addition, 1 case showed gain and loss of entire chromosomes, similar to a previous case studied by karyotyping. Such an aneuploid karyotype may reflect a potential for malignancy as previously reported. Thus, JGCT might be better considered as a tumor of uncertain malignant potential and then necessitates a prolonged follow-up. Future clinicopathologic and genomic studies of large retrospective and prospective series may help to better understand the biology of this fascinating entity.

[Use of a portfolio during the second cycle of medical studies in a urology department]. / Utilisation du portfolio au cours du deuxième cycle des etudes médicales dans un service d'urologie.

OBJECTIVE: To introduce the use of a portfolio (PF) as a learning and evaluation tool for hospital medical students in a urology department. METHODS: In the course of 6 consecutive 3-month sessions, 36 medical students each constituted a PF. After having chosen a urological topic, each student identified his/her learning needs and constructed a PF by collecting various types of information (books, medical articles, internet, orals, ...) with the aid of a tutor. The PF had to be established in the form of a series of questions asked by the student followed by answers provided by the information collected. The PF was scored (out of 20) and contributed to validation of the session. Students completed a satisfaction questionnaire. RESULTS: All students were validated (mean score: 14.2/20). Results of the satisfaction questionnaire showed that, although no student had previously performed a PF, 27/30 expressed the desire to establish a PF for another training attachment. This questionnaire also showed that the PF helps to improve theoretical knowledge (30/36), the needs in relation to professional practice (17/36), the ability to select data (34/36), and is a good self-learning tool (36/36). The major difficulty encountered by students concerned sorting of data (26/36) and written formulation of questions and answers (35/36). CONCLUSION: The PF appears to be a good learning and evaluation tool that can be used in surgical training attachments. It guides students in their personal study and highlights the quality of their reasoning.

Use of portfolios as a learning and assessment tool in a surgical practical session of urology during undergraduate medical training.

We chose to introduce a portfolio as a learning and assessment tool in a practical training session of urological surgery for undergraduate medical students. Our primary objectives were to develop the students' self reflexive ability in front of complex medical cases and to teach them how to identify their learning needs in a short period of time, on a specific topic. Students completed, during their training session, a portfolio on a urological topic under the constant supervision of a tutor. The students were evaluated on their portfolio's presentation with a 20-point grade grid known in advance. Even in a surgical training session, a portfolio can be a useful learning and assessment tool. It clearly encourages self-reflection and pre-professional practice.

[Theoretical, practical, and assessment modalities of urology teaching during the second cycle of medical training in France]. / Modalités théoriques, pratiques et docimologiques de l'enseignement de l'urologie au cours du deuxième cycle des études médicales en france.

INTRODUCTION: To comply with current legislation, French medical schools organize theoretical speciality teaching for medical students in speciality poles or in global modules. The objective of this study was to assess the theoretical, practical and assessment modalities of Urology teaching based on a survey. METHODS: In January 2004, a four-part questionnaire was sent to all urology teachers in 45 French universities. These 4 parts concerned: modalities of theoretical teaching, modalities of practical teaching, assessment modalities, evaluation of teaching, each evaluated by several questions. RESULTS: The response rate was 64.4% (29/45). Twelve medical schools chose teaching by speciality poles and 15 chose modular teaching. CCAs (Senior Registrars) played a greater role in modular teaching than in speciality pole teaching (75% and 53.3% of medical schools). Among the 12 medical schools with a speciality pole organization, 7 provided integrated teaching. An average of 23% of students of any one year receive Urology teaching during their training. Most medical schools conduct evaluation of theoretical (82.7%) and practical teaching (65.5%). CONCLUSION: Speciality teaching can be performed according to a polar or modular organization. A modular organization would be theoretically more appropriate to achieve the objective of a global approach to medicine, but artificial grouping of diseases can sometimes complicate speciality teaching in a speciality as diverse as Urology.

Confrontation of immunohistochemistry and fluorescent in situ hybridization for the assessment of HER-2/ neu (c-erbb-2) status in urothelial carcinoma.

Specific treatments targeted toward oncogenes expressed in cancer cells are currently under development. Patients with urothelial carcinomas showing HER-2/ neu (human epidermal growth factor receptor 2) overexpression are candidates for such a specific treatment (trastuzumab). However, to be effective, this therapeutic approach requires an extremely reliable evaluation of HER-2/ neu status in tumors. In order to assess the status of expression of this gene and to optimize its assessment, we analyzed a series of 64 primary urothelial carcinomas using immunohistochemistry (IHC) with the CB11 monoclonal antibody coupled with fluorescent in situ hybridization (FISH) in 21 cases. Strong HER-2/ neu overexpression was detected using IHC in 15 of the 64 (23%) cases analyzed, and this rate rose to 33% for patients with metastases. HER-2/ neu overexpression, as revealed using IHC, is strongly associated (95%) with gene amplification assessed using FISH. Patients with urothelial carcinomas overexpressing HER-2/ neu using IHC are potential candidates for targeted chemotherapy.

[Diet and prostate cancer: from prevention to treatment]. / Alimentation et cancer de la prostate: de la prévention au traitement.

Prostate cancer, the most frequent cancer in men over the age of 50, appears to be associated with certain nutritional risk factors. The role of these factors is revealed by epidemiological data (variation of prostate cancer incidence according to various regions of the world, modification of these incidences in relation to migratory flows of certain populations) and eating habit studies. These findings are the basis for a number of studies designed to determine the ideal diet to prevent and, if possible, contribute to the treatment of prostate cancer. The fat intake, the type of fat, the absorption of vitamins, trace elements, antioxidants (beta-carotene, lycopene), phyto-oestrogens, including soybean or plant mixtures such as PC-SPES, may all constitute nutritional factors involved in prostatic carcinogenesis. However, although a review of the literature shows that some populations appear to be more effectively protected than others by their cultural consumption of particular substances, the link with efficacy, in terms of prevention, of a diet based on this substance administered to another population has yet to be demonstrated. Although the ideal diet is unknown at the present time, some of these ingredients appear to be good candidates, such as unsaturated fats, soybean proteins, carotenoids, lycopene and vitamin E.

[Pre-pubic abscess of unknown cause]. / Un abcès pré-pubien de cause indéterminée.

The authors report a case of prepubic abscess in a young man presenting with pain. Surgical exploration revealed a group A Streptococcus abscess. The cause of this abscess was not determined.

[Study of intermittent endocrine therapy in patients presenting with biologic recurrence after radical prostatectomy or radiotherapy]. / Etude de l'hormonothérapie intermittente chez les patients présentant une récidive biologique après prostatectomie radicale ou radiothérapie.

INTRODUCTION: Study of the efficacy of intermittent endocrine therapy after failure of local treatment. MATERIAL AND METHODS: 74 patients were treated for biochemical recurrence after radical prostatectomy (n = 30), radiotherapy (n = 28) or radical prostatectomy followed by radiotherapy (n = 16). Treatment (63 patients were treated by antiandrogens alone, 8 by LHRH analogue and 3 by complete androgen suppression) was continued for 6 months after obtaining undetectable PSA levels for patients after radical prostatectomy (and restarted when PSA > 4 ng/ml) or a PSA nadir < 4 ng/ml for the other patients (and restarted for PSA > 10 ng/ml). RESULTS: The duration of periods without treatment represented 50% of the total treatment cycle. With a mean follow-up of 43.8 months, the overall 5-year biochemical progression-free survival rate was 54.6%. On multivariate analysis, factors predictive of biochemical progression were age less than 70 years (p = 0.05), Gleason score greater than or equal to 8 (p = 0.038) and the presence of lymph node metastases (p = 0.05). CONCLUSION: Intermittent endocrine therapy is a treatment option for patients with recurrence after local treatment. Candidates for intermittent endocrine therapy must be over the age of 70, with localized adenocarcinoma and a Gleason score less than or equal to 7.

[Should we systematically screen for Lynch syndrome in patients with upper urinary tract carcinoma?]. / Tumeurs du haut appareil urinaire et syndrome de Lynch : doit-on proposer un dépistage systématique ?

OBJECTIVE: The data describing the urologic extracolonic cancers associated with Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]) are variable. The aim of our study was to establish the frequency of mutations in mismatch repair (MMR) genes in patients with upper urinary tract transitional cell carcinoma (UUT-TCC) and to evaluate the clinical benefits of a systematic screening. METHODS: Specimen blocks were obtained from 146 patients treated for UUT-TCC in our center. Clinicopathological characteristics and survival data of patients were collected (median follow-up = 42.5 months). Immunohistochemistry was performed by tissue microarray (TMA), in order to detect mutations in mismatch repair genes. Results obtained after TMA analysis were confirmed at a molecular level by microsatellite instability (MSI) analysis. RESULTS: Mutations in mismatch repair genes were detected in seven patients (4.8%) at immunohistochemistry screening, and confirmed by MSI analysis for five of them (3.4%). Clinicopathological characteristics and survival data did not differ significantly in patients with instability compared with patients without. After a median follow-up of 42.5 months, none of them experienced a new HNPCC manifestation. CONCLUSION: The frequency of mutations in mismatch repair genes in UUT-TCC was very low, with a good accuracy of immunohistochemistry. Systematic screening should not be proposed in daily practice.

Severe ureteral endometriosis: the intrinsic type is not so rare after complete surgical exeresis of deep endometriotic lesions.

OBJECTIVE: To evaluate the rate of intrinsic ureteral endometriosis in patients presenting with severe ureteral endometriosis. DESIGN: Observational study between June 1992 and December 2007. SETTING: University tertiary referral center. PATIENT(S): Twenty-nine patients presenting deeply infiltrating endometriosis (DIE) with severe ureteral endometriosis. Severe ureteral endometriosis was defined as DIE lesions causing significant obstruction to the urinary flow with ureteral stenosis. INTERVENTION(S): Complete surgical exeresis of DIE lesions. MAIN OUTCOME MEASURE(S): Pre- and peroperative evaluation associated with histologic analysis. Intrinsic ureteral endometriosis was defined as presence of DIE lesions infiltrating the ureteral muscularis. RESULT(S): In a series of 627 patients with histologic proved DIE, we observed 29 (4.6%) patients with severe ureteral endometriosis. Ureteral lesions (n = 34) were right sided in 7 (24.1%) patients, left sided in 17 (58.6%) patients, and bilateral in 5 (17.3%) patients. Eleven (37.9%) patients presented intrinsic lesions. Out of the 34 ureteral lesions 13 (38.2%) were intrinsic. In cases of radical ureteral surgery (n = 21 patients; n = 24 ureteral lesions) intrinsic ureteral DIE was observed in 52.4% (11 cases) of the patients and in 54.2% (13 cases) of the ureteral lesions. CONCLUSION(S): The prevalence of intrinsic ureteral endometriosis is underestimated. This result must be taken into account when specifying the surgical modalities for patients presenting with severe ureteral endometriosis.

Large-scale real-time reverse transcription-PCR approach of angiogenic pathways in human transitional cell carcinoma of the bladder: identification of VEGFA as a major independent prognostic marker.

BACKGROUND: Actors of the angiogenesis pathways are targets for the new promising targeted therapies already used in several malignancies. In bladder cancer, antiangiogenic molecules could also add to already existing treatment options. OBJECTIVE: To evaluate the involvement of angiogenesis pathways in bladder carcinogenesis and identify new molecular markers having a clinical implication. DESIGN, SETTING, AND PARTICIPANTS: Expression levels of 40 genes involved in angiogenesis were assessed by quantitative real time RT-PCR in 157 urothelial tumour bladder samples obtained from patients who underwent transurethral bladder resection or radical cystectomy between 2001 and 2005. Pathologic tumour staging showed: 73 non-muscle-invasive bladder tumours (30 low-grade pTa, 14 high-grade pTa, and 29 high-grade pT1), and 84 muscle-invasive tumours (> or = pT2), all of high grade. RT-PCR results were associated with a survival analysis. RESULTS AND LIMITATIONS: VEGFA, MET, CXCR4, and IL8 were significantly overexpressed in tumour samples as compared to normal bladder tissue. VEGFA overexpressions were found in 89% of non-muscle-invasive and 66% of muscle-invasive tumour samples. In univariate analysis, for invasive tumours, VEGFA overexpression was associated with a poorer outcome in both overall and disease-free survival (p=0.011 and 0.026 respectively) at a 13-mo median follow-up. Multivariate analysis retained T stage, N status, and VEGFA overexpression as independent prognostic factors in both overall and disease-free survival (p=0.02 and p=0.04, respectively, for VEGFA). CONCLUSIONS: This study shows that, in bladder cancer, VEGFA status could be used as a prognostic factor at the individual level. VEGFA overexpression could guide a rationalized use of the costly antiangiogenic therapies which could therefore become part of the treatment options in bladder cancer.

Predictive factors for progression in patients with clinical stage T1a prostate cancer in the PSA era.

OBJECTIVE: In the literature, most data regarding the outcome of patients with clinical stage T1a prostate cancer were established before the prostate-specific antigen (PSA) era. The aim of our study was to determine the predictive factors of progression in patients with T1a prostate cancer diagnosed in the PSA era. METHODS: Consecutive patients (n=144) with newly diagnosed T1a prostate cancer (tumor involving < or =5% of the resected prostatic tissue) were included. None of them was treated before evidence of tumor progression confirmed by prostate needle biopsies. The associations between tumor characteristics and time to cancer progression were assessed using Cox regression analysis. RESULTS: With a mean follow-up of 5.1 yr, 30 patients (21%) experienced cancer progression. Five adverse parameters were significantly associated with cancer progression: preoperative PSA> or =10 ng/ml, postoperative PSA> or =2 ng/ml, prostate weight > or =60 g, weight of resected tissue > or =40 g, and Gleason score> or =6. The 5-yr progression rate was 12% if fewer than two of these parameters were present, whereas it was 47% if two or more parameters were present (p<0.001). CONCLUSION: In the PSA era the risk of progression associated with T1a prostate cancer can be predicted using five criteria, and two groups of patients can be defined. The patients at low risk of progression may be good candidates for surveillance. In those with a high risk of progression, a more aggressive treatment should be discussed.

Identification of risk factors for voiding dysfunction following TVT placement.

OBJECTIVE: To determine preoperative risk factors of postoperative voiding dysfunction after tension-free vaginal tape (TVT) procedure. METHODS: In 2004, 100 patients with genuine stress urinary incontinence underwent surgery by the TVT procedure. Preoperative and postoperative urodynamic study was performed for each patient. Postoperatively, patients' perception of result and quality of life were assessed on two validated scales, namely, Mesure du Handicap Urinaire (MHU) and Ditrovie. Voiding dysfunction was defined by a postoperative peak flow rate of <15 ml/s at 3 mo. Clinical and urodynamic parameters were compared and analysed. RESULTS: At 3 mo, 20 patients (20%) showed evidence of voiding dysfunction despite the absence of clinical symptoms in 14 of them (70%). Multivariate analysis showed that age (p<0.038) and preoperative peak flow rate (p<0.001) were independent risk factors for voiding dysfunction. Parity, menopausal status, body mass index, and maximal urethral closure pressure were not statistically related to the risk of voiding dysfunction. CONCLUSIONS: This study confirms the existence of an important rate of postoperative voiding dysfunction, mostly asymptomatic, and identifies age and preoperative maximal peak flow rate as independent preoperative risk factors. Identification of voiding dysfunction in patients may lead to better follow-up and early detection of late potential complications of suburethral procedures.

Survival analysis of 130 patients with papillary renal cell carcinoma: prognostic utility of type 1 and type 2 subclassification.

OBJECTIVES: To evaluate the prognostic significance of subtyping papillary renal cell carcinoma (PRCC) into type 1 and type 2 tumors. METHODS: From 1995 to 2004, 1358 patients underwent surgery for renal cell carcinoma, of whom 130 had PRCC alone on the specimen. The tumor characteristics, including their subtype, were analyzed; small basophilic cells and large eosinophilic cells were defined type 1 and type 2 tumors, respectively. Survival analyses were performed retrospectively. RESULTS: Of the 130 patients (110 men and 20 women, mean age 60.6 +/- 15.3 years) with PRCC, 102 underwent radical nephrectomy (78.4%) and 28 underwent partial nephrectomy (21.6%). The median tumor size was 4.5 cm (range 0.5 to 21). The comparison of the 68 (52.3%) type 1 PRCCs and 62 (47.7%) type 2 PRCCs revealed that type 2 tumors were associated with a greater stage and grade and microvascular invasion significantly (P <0.001) more often. The median follow-up was 48 months (range 2 to 111). Of the 130 patients, 22 died of cancer-specific causes, 5 (7%) with type 1 and 17 (27%) with type 2 tumors (P = 0.002). The overall and disease-free survival rate was 89% and 92% in type 1 tumors and 55% and 44% in type 2 tumors, respectively. Univariate analysis identified tumor type, stage (P <0.001), grade (P <0.001), microvascular invasion (P <0.001), an absence of foam cells (P <0.001), the presence of sarcomatoid cells (P = 0.001), and tumor necrosis (P = 0.007) as prognostic factors. Multivariate analysis retained tumor type (P = 0.034) and TNM stage (P <0.001). CONCLUSIONS: The results of our study have shown that histologic subtyping of PRCC allows for the identification of an independent prognostic factor.

Gene expression profiling of ERBB receptors and ligands in human transitional cell carcinoma of the bladder.

PURPOSE: The ErbB driven growth pathway has been implicated in most human epithelial malignancies. Therefore, its blockade is a promising therapeutic strategy and several candidate drugs are currently undergoing clinical trials. Paradoxically little is known of the expression pattern or clinical significance of the 4 ErbB receptors and their 11 ligands in TCC of the bladder. MATERIALS AND METHODS: To obtain further insight into the molecular pathogenesis of TCC we used quantitative real-time reverse transcriptase-polymerase chain reaction assay to quantify mRNA expression of the 4 ERBB and their 11 known ligand genes, including recently described EPGN/epigen, in 73 tumor samples. RESULTS: The level of mRNA of 4 ligand genes (EGF, NRG1, NRG2 and NRG3) was extremely low, that is detectable but not quantifiable. Six genes were over expressed (ERBB2, TGFA, HB-EGF, AREG, EREG and EPGN), 3 were under expressed (ERBB1, ERBB4 and NRG4) and 2 were over or under expressed (ERBB3 and BTC). ERBB2 and AREG expression differed between early stage tumors (pTa grade 1) and normal samples. The most marked differences in expression were ERBB3, EREG and NRG4 between superficial and muscle invasive tumors (p = 0.0069, 0.00007 and 0.0000001, respectively), and TGFA and NRG4 between low and high grade superficial tumors, and between pT1 or greater and pTa tumors. CONCLUSIONS: This study shows the involvement of the ERBB family and ligand genes in TCC. Most receptor and ligand genes are deregulated at different stages of carcinogenesis, implying that they should be studied simultaneously. Quantitative real-time reverse transcriptase-polymerase chain reaction could be used to determine ErbB signaling pathway status in individuals with a view to tailored therapy.