Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2.

AIM: To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2. METHODS: The main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000mg/m(2) (days 1 and 8) plus either cisplatin (70mg/m(2)) or carboplatin (AUC=5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS). RESULTS: Among 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG-PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p=0.689), objective response rate (65.5% versus 53.2%, p=0.39), and median overall survival (15.7 versus 14.1 months, respectively, p=0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B. CONCLUSION: The unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.

[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.

Gene panel model predictive of outcome in patients with prostate cancer.

In men at high risk for prostate cancer, established clinical and pathological parameters provide only limited prognostic information. Here we analyzed a French cohort of 103 prostate cancer patients and developed a gene panel model predictive of outcome in this group of patients. The model comprised of a 15-gene TaqMan Low-Density Array (TLDA) card, with gene expressions compared to a standardized reference. The RQ value for each gene was calculated, and a scoring system was developed. Summing all the binary scores (0 or 1) corresponding to the 15 genes, a global score is obtained between 0 and 15. This global score can be compared to Gleason score (0 to 10) by recalculating it into a 0-10 scaled score. A scaled score ≥2 suggested that the patient is suffering from a prostate cancer, and a scaled score ≥7 flagged aggressive cancer. Statistical analyses demonstrated a strongly significant linear correlation (p=3.50E-08) between scaled score and Gleason score for this prostate cancer cohort (N=103). These results support the capacity of this designed 15 target gene TLDA card approach to predict outcome in prostate cancer, opening up a new avenue for personalized medicine through future independent replication and applications for rapid identification of aggressive prostate cancer phenotypes for early intervention.

Hybrid oncocytic/chromophobe renal cell tumours do not display genomic features of chromophobe renal cell carcinomas.

Hybrid oncocytic/chromophobe tumours (HOCT) are renal tumours recently described displaying histological features of both renal oncocytoma (RO) and chromophobe renal cell carcinoma (ChRCC), raising the question of their precise signification in the RO/ChRCC group. This study aimed to describe clinicopathological features of so called HOCT and to characterise their genomic profile. Five hundred and eighty-three tumours belonging to the ChRCC/RO group were retrospectively reviewed. Twelve tumours that could not be classified as RO or CHRC were considered as HOCT. Hale staining and cytokeratin 7 (CK7) immunostaining were performed. Genomic profile was established by array comparative genomic hybridisation (array-CGH) on frozen samples. Mean age at diagnosis was 70 years (range 46-83). No recurrence was observed (median follow-up: 18 months; range 9-72). Tumour size ranged from 1 to 11 cm. HOCT showed an admixture of RO- and ChRCC-like areas and/or "hybrid" cells with overlapping cytonuclear and/or histochemical features. Hale staining was apical in 50 to 100 % of cells, and CK7 was expressed in 10 to 100 % of cells. Genomic profile was balanced in seven cases or showed a limited number of random imbalances in five cases, as observed in RO. In no instances were observed the characteristic chromosome losses of ChRCC. These results suggest that so called HOCT are not true hybrid tumours and rather could represent a morphological variant of RO. From a diagnostic perspective, an array-CGH analysis could be performed in ambiguous ChRCC/RO cases to formally exclude the diagnosis of ChRCC.

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.

SMARCB1/INI1 inactivation in renal medullary carcinoma.

AIMS: Renal medullary carcinoma (RMC), a rare and highly aggressive tumour which occurs in patients with sickle-cell disease, shares many clinicopathological features with collecting duct carcinoma (CDC). The molecular mechanisms underlying RMC and CDC are mainly unknown, and there is ongoing debate about their status as distinct entities. Loss of expression of SMARCB1/INI1, a chromatin remodelling regulator and repressor of cyclin D1 transcription, has been reported recently in RMC. The aim of our study was to investigate if such loss of expression is specific for RMC. SMARCB1/INI1 genetic alterations and cyclin D1 expression were also studied. METHODS AND RESULTS: Using immunochemistry, neoplastic cells showed complete loss of SMARCB1/INI1 expression in all six cases of RMC but in only one of 22 cases of CDC. In two RMC cases investigated, comparative genomic hybridization demonstrated complete loss of one SMARCB1/INI1 allele, with no other genomic imbalances, and no mutations were found on the remaining allele. Cyclin D1 was expressed in all RMCs, suggesting that SMARCB1/INI1 inactivation may result in increased cyclin D1 transcription. CONCLUSIONS: The specific SMARCB1/INI1 inactivation observed in RMCs suggests that RMC and CDC are different entities.

Identification of CAD as an androgen receptor interactant and an early marker of prostate tumor recurrence.

Markers of prostate tumor recurrence after radical prostatectomy are lacking and highly demanded. The androgen receptor (AR) is a nuclear receptor that plays a pivotal role in normal and cancerous prostate tissue. AR interacts with a number of proteins modulating its stability, localization, and activity. To test the hypothesis that an increased expression of AR partners might foster tumor development, we immunopurified AR partners in human tumors xenografted into mice. One of the identified AR partners was the multifunctional enzyme carbamoyl-phosphate synthetase II, aspartate transcarbamylase, and dihydroorotase (CAD), which catalyzes the 3 initial steps of pyrimidine biosynthesis. We combined experiments in C4-2, LNCaP, 22RV1, and PC3 human prostate cell lines and analysis of frozen radical prostatectomy samples to study the CAD-AR interaction. We show here that in prostate tumor cells, CAD fosters AR translocation into the nucleus and stimulates its transcriptional activity. Notably, in radical prostatectomy specimens, CAD expression was not correlated with proliferation markers, but a higher CAD mRNA level was associated with local tumor extension (P=0.049) and cancer relapse (P=0.017). These results demonstrate an unsuspected function for a key metabolic enzyme and identify CAD as a potential predictive marker of cancer relapse.

A rare cause of hypertestosteronemia in a 68-year-old patient: a Leydig cell tumor due to a somatic GNAS (guanine nucleotide-binding protein, alpha-stimulating activity polypeptide 1)-activating mutation.

Leydig cell tumors of the testis are the most common type of non-germ cell testicular tumors. In adult patients, gynecomastia, oligozoospermia, erectile dysfunction, and other signs of feminization can be present, whereas testosterone levels are frequently in the normal range or slightly reduced. We describe a patient with a history of impaired sexual function, as well as progressive enlargement of the left testis, without gynecomastia. Hormonal evaluation demonstrated very high testosterone, estrogen, and pan-alpha-inhibin levels. Magnetic resonance imaging revealed the presence of left testicular hypertrophy without evidence of testicular mass. After left orchiectomy, histologic examination confirmed the diagnosis of Leydig cell tumor, and steroid hormone levels normalized. A heterozygous missense somatic gsp mutation (R201C) was found in tumoral tissue, whereas no mutation was found in the surrounding normal tissue or in leukocyte DNA. This case provides evidence that somatic activating gsp mutation in Leydig cells may result in tumor development, leading to overexpression of the inhibin alpha subunit and hyperactivity of the testosterone biosynthetic pathway.

Clear-cell papillary renal cell carcinoma: 24 cases of a distinct low-grade renal tumour and a comparative genomic hybridization array study of seven cases.

AIMS: To report clinicopathological and genomic characteristics of (ccpRCC), a rare, recently characterized renal tumour entity. METHODS AND RESULTS: Twenty-four renal tumours identified as ccpRCC were collected. Data from comparative genomic hybridization on microarrays (array-CGH) were obtained for seven of these. Most tumours (58%) occurred in the absence of renal disease. Mean patient age was 58.1 years. Tumours were small (mean size: 2.4 cm) and classified as pT1. Histological characteristics consisted of tubules and papillae lined by a single layer of small clear cells harbouring low-grade nuclei (Fuhrman grades 1 or 2). Architectural variations, with compact areas (41% of cases) and a micro- or macrocystic pattern (67% of cases) were observed frequently. Immunostaining demonstrated diffuse, strong expression of cytokeratin 7 and vimentin, whereas CD10, racemase, RCC antigen, translocation factor E3, TFE3 and translocation factor EB were consistently negative. In seven tumours, array-CGH detected no chromosomal imbalances. CONCLUSIONS: Clear-cell papillary renal cell carcinoma (ccpRCC) were differentiated from other renal neoplasms by a specific constellation of histopathological and immunohistochemical features, without characteristic genomic imbalances. Clinical, histopathological and genomic data suggested that these tumours have a low potential for malignancy.

Strength of molecular cytogenetic analyses for adjusting the diagnosis of renal cell carcinomas with both clear cells and papillary features: a study of three cases.

Histological features are usually sufficient for providing an accurate diagnosis of renal cell carcinomas (RCC). However, the morphological appearance might sometimes be misleading. For instance, RCC with papillary areas and extensive clear cell changes may be difficult to classify either as clear cell renal carcinoma or as papillary renal cell carcinoma (pRCC). We used the combination of immunohistochemistry, conventional cytogenetics, fluorescence in situ hybridization (FISH), bacterial artificial chromosomes comparative genomic hybridization arrays and high-density single nucleotides polymorphism arrays (SNP arrays) to characterize three cases of RCC showing a predominant cytology of cells with clear cytoplasm and variable amounts of papillary areas. In accordance with the 2004 World Health Organization (WHO) classification, we initially assessed the diagnosis of clear cell RCC for one of the cases and unclassified RCC for the two remaining cases. However, because of a strong immunohistochemical labeling for alpha-methylacyl-CoA racemase, as well as the presence of a gain of chromosomes 7 and 17, we concluded that two of these tumors were actually pRCC. As for the third case, because of the presence of both pCCR and ccCCR molecular cytogenetic aberrations, including gains of chromosomes 7 and 17, loss of chromosome Y and whole chromosome 3 loss of heterozyosity (isodisomy), the final diagnosis was hybrid tumor cc-pRCC, so-called "unclassified RCC" according to the WHO classification. Our observations demonstrate the necessity to use immunohistochemical and cytogenetic tools in all cases of RCC showing unusual features. The combination of FISH and SNP arrays is prevailing for characterizing cases with hybrid features.

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.

Activation of the PI3K/AKT pathway induces urothelial carcinoma of the renal pelvis: identification in human tumors and confirmation in animal models.

Urothelial carcinoma of the renal pelvis is a deadly disease with an unclear tumorigenic mechanism. We conducted gene expression profiling on a set of human tumors of this type and identified a phosphatidylinositol 3-kinase (PI3K)/AKT activation expression signature in 76.9% (n = 13) of our samples. Sequence analysis found both activating mutations of PIK3CA (13.6%, n = 22) and loss of heterozygosity at the PTEN locus (25%, n = 8). In contrast, none of the other subtypes of kidney neoplasms (e.g., clear-cell renal cell carcinoma) harbored PIK3CA mutations (n = 87; P < 0.001). Immunohistochemical analysis of urothelial carcinoma samples found loss of PTEN protein expression (36.4%, n = 11) and elevation of phosphorylated mammalian target of rapamycin (mTOR; 63.6%, n = 11). To confirm the role of the PI3K/AKT pathway in urothelial carcinoma, we generated mice containing biallelic inactivation of Pten in the urogenital epithelia. These mice developed typical renal pelvic urothelial carcinomas, with an incidence of 57.1% in mice older than 1 year. Laser capture microdissection followed by PCR confirmed the deletion of Pten exons 4 and 5 in the animal tumor cells. Immunohistochemical analyses showed increased phospho-mTOR and phospho-S6K levels in the animal tumors. Renal lymph node metastases were found in 15.8% of the animals with urothelial carcinoma. In conclusion, we identified and confirmed an important role for the PI3K/AKT pathway in the development of urothelial carcinoma and suggested that inhibitors of this pathway (e.g., mTOR inhibitor) may serve as effective therapeutic agents.

Hybrid tumour 'oncocytoma-chromophobe renal cell carcinoma' of the kidney: a report of seven sporadic cases.

OBJECTIVES: To determine whether renal hybrid tumours (HT) appear as a specific clinical and radiological entity, as HT are characterized by the association of both oncocytes and chromophobe cells within the same tumour, and have been described in patients with oncocytosis and Birt-Hogg-Dube syndrome. PATIENTS AND METHODS: We reviewed the medical charts of 67 patients who had a partial or radical nephrectomy in our institution for renal oncocytoma (RO, 24), chromophobe renal cell carcinoma (CRCC, 36) and HT (seven), from January 2006 to October 2007. We report the clinical, radiological and pathological characteristics of the seven cases of HT. RESULTS: The mean (range) age of the patients was 56 (41-68) year. None of the seven patients had any suspicion of RO, based on computed tomography (CT). Two patients had a history of kidney cancer. Five patients had partial and two a radical nephrectomy. The mean (range) maximum tumour diameter was 5.5 (1.8-9) cm. Two tumours were pT1a, two were pT1b and three were pT2. Pathological analysis showed RO-like and CRCC-like cells intermixed (six patients) or distinct (one). After a median (range) follow-up of 20 (8-25) months, none of the patients had any evidence of disease recurrence. CONCLUSIONS: In a large series of patients with sporadic RO and CRCC, 10% of the tumours had hybrid morphological features, as described in oncocytosis and Birt-Hogg-Dube syndrome. We were unable to identify any specific clinical characteristic. Most importantly, none of these HT showed any of the radiological characteristics of RO.

Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 31 cases of a distinctive rare subtype of renal cell carcinoma.

A distinctive tumor described under the terms Bellini duct carcinoma and low-grade collecting duct carcinoma has been referred to by us and others as tubulocystic carcinoma. This renal cell carcinoma subtype is not recognized in the World Health Organization 2004 classification. Herein, we present a detailed study of 31 cases to further characterize this rare subtype of renal cell carcinoma. The tumor occurred in adults (mean age, 54 years) with a strong male predominance (7:1). Grossly, the tumors ranged from 0.7 to 17 cm, and exhibited a spongy or "bubble wrap" appearance reflecting the microscopic presence of variably sized cystically dilated tubules lined by a single layer of epithelium. The lining varied with a cuboidal, flat, and hobnail cell appearance, and the neoplastic cells had abundant eosinophilic cytoplasm and enlarged nuclei with prominent nucleoli. The cysts were closely spaced with an intervening variably fibrotic stroma. Immunohistochemistry and ultrastructural examination showed features of proximal convoluted tubules (Pax 2 immunoreactivity and short microvilli with brush border organization) and distal nephron (kidney-specific cadherin immunoreactivity and cytoplasmic interdigitation). Gene expression profiling showed that tubulocystic carcinoma displayed a unique molecular signature. Twenty-four tumors were stage pT1, 4 stage pT2, and 3 stage pT3. Disease progression (median follow-up of 56 months) occurred in 3 patients; 1 with local recurrence, and 2 with distant metastasis to bone and liver. In light of the distinctive clinicopathologic features and a low but definite metastatic potential, this unique subtype of renal cell carcinoma deserves formal recognition in the contemporary classification of renal neoplasms.

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.

[Non clear cell renal cell carcinoma. 2008 update in renal tumor pathology]. / Les tumeurs du rein qui ne sont pas des carcinomes à cellules claires. Etat des lieux en 2008.

Non clear cell renal cell carcinomas represent almost 20% of all renal neoplasms. Their classification is continuously being adjusted according to new cytogenetic and molecular data. Since molecular techniques are expensive, diagnosis still relies on morphological and immuno-histochemical criteria detailed hereby. Papillary renal cell carcinomas are the most important group and its classification is more and more complex. It encompasses low-grade papillary carcinomas (type 1 papillary renal cell carcinoma, oncocytic papillary renal cell carcinoma) and high-grade papillary carcinomas (type 2 papillary renal cell carcinoma, juvenile papillary carcinoma corresponding to renal carcinoma associated with Xp11.2 translocations and unclassified carcinomas). Mucinous tubular and spindle cell carcinoma and tubulocystic carcinoma are new entities, actually considered by some authors as low-grade papillary carcinomas. The so-called carcinoma of collecting ducts of Bellini and renal medullary carcinoma should be considered as intrarenal urothelial carcinoma or as high-grade papillary or unclassified carcinoma. Sarcomatoid carcinoma derives from morphological progression of any type of renal cell carcinoma. The group of oncocytomas/chromophobe renal cell carcinomas can be considered as a spectrum from benign (oncocytoma) to malignant neoplasm (chromophobe renal cell carcinoma). They are sometimes encountered in oncocytomatosis or familial Birt-Hogg-Dubbe syndrome in which tumoral cells may have hybrid features. Angiomyolipoma is usually a benign mesenchymatous neoplasm, that can be sporadic or familial (tuberous sclerosis). In the latter situation, some cases of epithelioid angiomyolipoma (potentially malignant) have been described. Renal epithelial and stromal tumors (REST) is a new concept gathering two benign mixed mesenchymal and epithelial tumors: cystic nephroma and mixed epithelial and stromal tumors (MEST).

[Evaluation of p63 and p504s markers for the diagnosis of prostate cancer]. / Evaluation des marqueurs p63 et p504s dans le diagnostic du cancer de prostate.

Prostate cancer with 60,000 new cases a year is a public health problem which requires adapted and effective responses. The era of PSA screening dramatically increased the number of prostate biopsies that pathologists have to screen and consequently the number of difficult cases requiring analysis. Immunohistochemistry with anti-AMACR/p504s is useful for detecting prostate cancer in the full range of prostate specimens encountered in needle biopsies. In particular, studies to date with AMACR/p504s clearly demonstrate the ability of this marker to support a diagnosis of malignancy in prostate needle biopsies, combined with negative staining for a basal cell marker, such as p63. This study conducted by the Prostate Committee of the French Association of quality assurance in pathological anatomy and cytology (AFAQAP), reports the evaluation of the current practices with available anti-p63 and -p504s antibodies. The results of this investigation show a correct evaluation of the immunostaining procedure. Overall, from the 39/56 structures tested, the value of the test was positive in 85%. The best results were obtained after antigenic restoration with TRIS-EDTA pH 9, p504s (13H4, 1/200) and p63 (A4A, 1/100).

[Juxtaglomerular cell tumors: report of two cases with genomic analysis]. / Tumeur à rénine du rein : à propos de deux cas, avec analyse génomique.

Juxtaglomerular-cell tumor (JGCT), first described in 1967, is a rare tumor of the kidney that derives from specialized smooth-muscle cells of the wall of the glomerular afferent arteriole. Less than 100 cases have been published, mainly as single-case reports or small series. JGCTs are considered benign, but the clinical follow-up has been short in most reported cases. Only one 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 two cases that showed gains on chromosome 10 as well as deletions on chromosomes 9, 11q and X. The present work studied the genomic characteristics of two additional cases of JGCT by CGH. Similarly to the two previously reported cases, these two tumors showed losses on chromosomes 9 and 11, suggesting recurrent chromosomal imbalances. In addition, one case showed gains and losses 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 consequently requiring 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.

Somatic pairing of chromosome 19 in renal oncocytoma is associated with deregulated EGLN2-mediated [corrected] oxygen-sensing response.

Chromosomal abnormalities, such as structural and numerical abnormalities, are a common occurrence in cancer. The close association of homologous chromosomes during interphase, a phenomenon termed somatic chromosome pairing, has been observed in cancerous cells, but the functional consequences of somatic pairing have not been established. Gene expression profiling studies revealed that somatic pairing of chromosome 19 is a recurrent chromosomal abnormality in renal oncocytoma, a neoplasia of the adult kidney. Somatic pairing was associated with significant disruption of gene expression within the paired regions and resulted in the deregulation of the prolyl-hydroxylase EGLN2 [corrected] a key protein that regulates the oxygen-dependent degradation of hypoxia-inducible factor (HIF). Overexpression of EGLN2 [corrected] in renal oncocytoma increased ubiquitin-mediated destruction of HIF and concomitantly suppressed the expression of several HIF-target genes, including the pro-death BNIP3L gene. The transcriptional changes that are associated with somatic pairing of chromosome 19 mimic the transcriptional changes that occur following DNA amplification. Therefore, in addition to numerical and structural chromosomal abnormalities, alterations in chromosomal spatial dynamics should be considered as genomic events that are associated with tumorigenesis. The identification of EGLN2 as a significantly deregulated gene that maps within the paired chromosome region directly implicates defects in the oxygen-sensing network to the biology of renal oncocytoma.