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International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden 1 . In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence 2 . Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics., (© 2024. The Author(s).)

Hereditary Renal Cell Carcinomas (RCC) are caused by mutations in predisposing genes, the major ones including VHL, FLCN, FH and MET. However, many families with inherited RCC have no germline mutation in these genes. Using Whole Exome Sequencing on germline DNA from a family presenting three different histological renal tumors (an angiomyolipoma, a clear-cell RCC and an oncocytic papillary RCC), we identified a frameshift mutation in the Neighbor of BRCA1 gene 1 (NBR1), segregating with the tumors. NBR1 encodes a cargo receptor protein involved in autophagy. Genetic and functional analyses suggested a pathogenic impact of the mutation. Indeed, functional study performed in renal cell lines showed that the mutation alters NBR1 interactions with some of its partners (such as p62/SQSTM1), leading to a dominant negative effect. This results in an altered autophagic process and an increased proliferative capacity in renal cell lines. Our study suggests that NBR1 may be a new predisposing gene for RCC, however its characterization needs to be further investigated in order to confirm its role in renal carcinogenesis., Competing Interests: Declarations of Competing Interest none, (Copyright © 2021. Published by Elsevier Inc.)

Recent treatment developments for metastatic renal cell carcinoma offer combinations of immunotherapies or immunotherapy associated with tyrosine kinase inhibitors (TKI). There is currently no argument to choose one solution or another. Easy-to-use markers to assess longitudinal responses to TKI are necessary to determine when to switch to immunotherapies. These new markers will enable an earlier adaptation of therapeutic strategy in order to prevent tumor development, unnecessary toxicity and financial costs. This study evaluates the potential of ultrasound molecular imaging to track the response to sunitinib in a clear cell renal carcinoma model (ccRCC). We used a patient-derived xenograft model for this imaging study. Mice harboring human ccRCC were randomized for sunitinib treatment vs. control. The tumors were imaged at days 0, 7, 14 and 28 with ultrasound molecular imaging. Signal enhancement was quantified and compared between the two groups after injections of non-targeted microbubbles and microbubbles targeting VEGFR1 and FSHR. The tumor growth of the sunitinib group was significantly slower. There was a significantly lower expression of both VEGFR-1 and FSHR molecular ultrasound imaging signals in the sunitinib group at all times of treatment (Days 7, 14 and 28). These results confirm the study hypothesis. There was no significant difference between the 2 groups for the non-targeted microbubble ultrasound signal. This study demonstrated for the first time the potential of VEGFR1 and FSHR, by ultrasound-based molecular imaging, to follow-up the longitudinal response to sunitinib in ccRCC. These results should trigger developments for clinical applications.

Hereditary predispositions to adult kidney tumors involve around 5% of tumors and include a dozen of autosomal dominant syndromes. The most frequent tumors encountered in these setting are clear cell renal cell carcinomas, papillary renal cell carcinomas, chromophobe renal cell carcinomas and angiomyolipomas. Their detection is essential in order to adapt individual care and perform genetic screening of at-risk relatives, especially in the national french network PREDIR, labeled by the National Cancer Institute and dedicated to hereditary predispositions to kidney tumors. Targeted genetic analysis, which was guided in particular by the renal tumor subtype, has recently evolved into genetic analysis using panels of genes. Pathologist contribution's remains however central in the diagnosis of hereditary forms since we currently have immunohistochemical biomarkers that allow us to diagnose two specifically hereditary entities: hereditary leiomyomatosis and renal cell carcinoma associated-renal cell carcinoma, associated with a loss of fumarate hydratase and succinate dehydrogenase-deficient renal cell carcinoma associated with a loss of succinate deshydrogenase B expression. These diagnoses must however be confirmed by the identification of pathogenic germline variation in the corresponding genes. Improvement of kidney tumors characterization has also lead to identify new subtypes, expanding the algorithm of renal tumors associated with hereditary setting. Here we aim to review all subtypes of adult renal tumors encountered in predisposition syndromes., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome that is the main cause of inherited clear-cell renal cell carcinoma (ccRCC), which generally occurs in the form of multiple recurrent synchronized tumors. Affected patients are carriers of a germline mutation in the VHL tumor suppressor gene. Somatic mutations of this gene are also found in sporadic ccRCC and numerous pan-genomic studies have reported a dysregulation of microRNA (miRNA) expression in these sporadic tumors. In order to investigate the molecular mechanisms underlying the pathogenesis of VHL-associated ccRCC, particularly in the context of multiple tumors, the present study characterized the mRNA and miRNA transcriptome through an integrative analysis compared with sporadic renal tumors. In the present study, two series of ccRCC samples were used. The first set consisted of several samples from different tumors occurring in the same patient, for two independent patients affected with VHL disease. The second set consisted of 12 VHL-associated tumors and 22 sporadic ccRCC tumors compared with a pool of normal renal tissue. For each sample series, an expression analysis of miRNAs and mRNAs was conducted using microarrays. The results indicated that multiple tumors within the kidney of a patient with VHL disease featured a similar pattern of miRNA and gene expression. In addition, the expression levels of miRNA were able to distinguish VHL-associated tumors from sporadic ccRCC, and it was identified that 103 miRNAs and 2,474 genes were differentially expressed in the ccRCC series compared with in normal renal tissue. The majority of dysregulated genes were implicated in 'immunity' and 'metabolism' pathways. Taken together, these results allow a better understanding of the occurrence of ccRCC in patients with VHL disease, by providing insights into dysregulated miRNA and mRNA. In the set of patients with VHL disease, there were few differences in miRNA and mRNA expression, thus indicating a similar molecular evolution of these synchronous tumors and suggesting that the same molecular mechanisms underlie the pathogenesis of these hereditary tumors.

Hereditary leiomyomatosis and renal cell carcinoma syndrome is characterized by an increased risk of agressive renal cell carcinoma, often of type 2 papillary histology, and is caused by FH germline mutations. A prominent eosinophilic macronucleolus with a perinucleolar clear halo is distinctive of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma according to the 2012 ISUP and 2016 WHO kidney tumor classification. From an immunohistochemistry perspective, tumors are often FH-negative and S-(2-succino)-cysteine (2SC) positive. We performed a pathology review of 24 renal tumors in 23 FH mutation carriers, and compared them to 12 type 2 papillary renal cell carcinomas from FH wild-type patients. Prominent eosinophilic nucleoli with perinucleolar halos were present in almost all FH-deficient renal cell carcinomas (23/24). Unexpectedly, they were also present in 58% of type 2 papillary renal cell carcinomas from wild-type patients. Renal cell carcinoma in mutation carriers displayed a complex architecture with multiple patterns, typically papillary, tubulopapillary, and tubulocystic, but also sarcomatoid and rhabdoid. Such pattern diversity was not seen in non-carriers. FH/2SC immunohistochemistry was informative as all hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas were either FH- or 2SC+. For FH and 2SC immunohistochemistries taken separately, sensitivity of negative anti-FH immunohistochemistry was 87.5% and specificity was 100%. For positive anti-2SC immunohistochemistry, sensitivity, and specificity were 91.7% and 91.7%, respectively. All FH wild-type renal cell carcinoma were FH-positive, and all but one were 2SC-negative. In conclusion, multiplicity of architectural patterns, rhabdoid/sarcomatoid components and combined FH/2SC staining, but not prominent eosinophilic nucleoli with perinucleolar halos, differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma from type 2 papillary renal cell carcinoma with efficient FH gene. Our findings are crucial in identifying who should be referred to Cancer Genetics clinics for genetic counseling and testing.

Background: Clear cell renal cell carcinomas (ccRCC) frequently display a loss of function of the von Hippel-Lindau (VHL) gene., Objective: To elucidate the putative relationship between VHL mutation status and immune checkpoint ligand programmed death-ligand 1 (PD-L1) expression., Design, Setting, and Participants: A series of 32 renal tumors composed of 11 VHL tumor-associated and 21 sporadic RCCs were used to evaluate PD-L1 expression levels after sequencing of the three exons and exon-intron junctions of the VHL gene. The 786-O, A498, and RCC4 cell lines were used to investigate the mechanisms of PD-L1 regulation., Outcome Measurements and Statistical Analysis: Fisher's exact test was used for VHL mutation and Kruskal-Wallis test for PD-L1 expression. If no covariate accounted for the association of VHL and PD-L1, then a Kruskal-Wallis test was used; otherwise Cochran-Mantel-Haenzsel test was used. We also used the Fligner-Policello test to compare two medians when the distributions had different dispersions., Results and Limitations: We demonstrated that tumors from ccRCC patients with VHL biallelic inactivation (ie, loss of function) display a significant increase in PD-L1 expression compared with ccRCC tumors carrying one VHL wild-type allele. Using the inducible VHL 786-O-derived cell lines with varying hypoxia-inducible factor-2 alpha (HIF-2α) stabilization levels, we showed that PD-L1 expression levels positively correlate with VHL mutation and HIF-2α expression. Targeting HIF-2α decreased PD-L1, while HIF-2α overexpression increased PD-L1 mRNA and protein levels in ccRCC cells. Interestingly, chromatin immunoprecipitation and luciferase assays revealed a direct binding of HIF-2α to a transcriptionally active hypoxia-response element in the human PD-L1 proximal promoter in 786-O cells., Conclusions: Our work provides the first evidence that VHL mutations positively correlate with PD-L1 expression in ccRCC and may influence the response to ccRCC anti-PD-L1/PD-1 immunotherapy., Patient Summary: We investigated the relationship between von Hippel-Lindau mutations and programmed death-ligand 1 expression. We demonstrated that von Hippel-Lindau mutation status significantly correlated with programmed death-ligand 1 expression in clear cell renal cell carcinomas., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The behaviour of clear cell renal cell carcinoma (CCRCC) is highly unpredictable. Despite adequate initial surgery, 20 to 30 % of patients will develop local recurrence or metastasis during follow-up. Usual clinical and pathology parameters tend to classify most patients in an intermediate prognosis group, and molecular markers to determine prognosis more accurately are needed. A key feature of CCRCC is its abundant vascularization. Factors that upregulate angiogenesis, such as hypoxia and the presence of immune cells including macrophages, also modulate tumour proliferation and metastasis. We studied angiogenesis, as defined by nestin-positive capillaries, and tumour infiltration by macrophages especially in the good prognosis pT1 subgroup of CCRCC. We assessed whether these parameters are associated with metastatic extension and survival in CCRCC. The expression of HIF1α, CAIX, nestin, CD68 and CD163 was assessed by immunohistochemistry on a tissue microarray (TMA) containing tissue samples from 257 consecutive patients with sporadic CCRCC. Factors associated with progression-free (PFS) and overall survival (OS) were analysed. The presence of nestin-positive tumour vessels was independently associated with shorter PFS in the whole cohort and in the pT1 subgroup. The presence of tumour-infiltrating macrophages was independently associated with shorter OS in the whole cohort and in the pT1 subgroup. The presence of nestin-positive endothelial cells is associated with early relapse, especially in the pT1 subgroup and may help to select patients for antiangiogenic treatment. The presence of tumour-infiltrating M2-type macrophages is a strong predictor of short survival and may be used to adapt treatment strategy.

As rapidly developing patient-derived xenografts (PDX) could represent potential sources of cancer stem cells (CSC), we selected and characterized non-cultured PDX cell suspensions from four different renal carcinomas (RCC). Only the cell suspensions from the serial xenografts (PDX-1 and PDX-2) of an undifferentiated RCC (RCC-41) adapted to the selective CSC medium. The cell suspension derived from the original tumor specimen (RCC-41-P-0) did not adapt to the selective medium and strongly expressed CSC-like markers (CD133 and CD105) together with the non-CSC tumor marker E-cadherin. In comparison, PDX-1 and PDX-2 cells exhibited evolution in their phenotype since PDX-1 cells were CD133high/CD105-/Ecadlow and PDX-2 cells were CD133low/CD105-/Ecad-. Both PDX subsets expressed additional stem cell markers (CD146/CD29/OCT4/NANOG/Nestin) but still contained non-CSC tumor cells. Therefore, using different cell sorting strategies, we characterized 3 different putative CSC subsets (RCC-41-PDX-1/CD132+, RCC-41-PDX-2/CD133-/EpCAMlow and RCC-41-PDX-2/CD133+/EpCAMbright). In addition, transcriptomic analysis showed that RCC-41-PDX-2/CD133- over-expressed the pluripotency gene ERBB4, while RCC-41-PDX-2/CD133+ over-expressed several tumor suppressor genes. These three CSC subsets displayed ALDH activity, formed serial spheroids and developed serial tumors in SCID mice, although RCC-41-PDX-1/CD132+ and RCC-41-PDX-2/CD133+ displayed less efficiently the above CSC properties. RCC-41-PDX-1/CD132+ tumors showed vessels of human origin with CSC displaying peri-vascular distribution. By contrast, RCC-41-PDX-2 originated tumors exhibiting only vessels of mouse origin without CSC peri-vascular distribution.Altogether, our results indicate that PDX murine microenvironment promotes a continuous redesign of CSC phenotype, unmasking CSC subsets potentially present in a single RCC or generating ex novo different CSC-like subsets.

Background: Many cases of familial renal cell carcinoma (RCC) remain unexplained by mutations in the known predisposing genes or shared environmental factors. There are therefore additional, still unidentified genes involved in familial RCC. PBRM1 is a tumour suppressor gene and somatic mutations are found in 30-45% of sporadic clear cell (cc) RCC., Methods: We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene., Results: A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) was found in one patient. The patient's mother, his sister and one niece also had ccRCC. The mutation co-segregated with the disease as the three affected relatives were carriers, while an unaffected sister was not, according with autosomal-dominant transmission. Somatic studies supported these findings, as we observed both loss of heterozygosity for the mutation and loss of protein expression in renal tumours., Conclusions: We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. International studies are necessary to estimate the contribution of PBRM1 to RCC susceptibility, estimate penetrance and then integrate the gene into routine clinical practice., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Clear cell renal cell carcinomas (RCC) frequently display inactivation of von Hippel-Lindau (VHL) gene leading to increased level of hypoxia-inducible factors (HIF). In this study, we investigated the potential role of HIF2α in regulating RCC susceptibility to natural killer (NK) cell-mediated killing. We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared with the VHL-corrected cell line (WT7). This resistance was found to require HIF2α stabilization. On the basis of global gene expression profiling and chromatin immunoprecipitation assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF2α and that targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Mechanistically, HIF2α in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NK-mediated killing through the activation of autophagy in target cells by NK-derived signal. Interestingly, both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Our data provide insight into the link between HIF2α, the ITPR1-related pathway, and natural immunity and strongly suggest a role for the HIF2α/ITPR1 axis in regulating RCC cell survival., (©2014 American Association for Cancer Research.)

Background: The Birt-Hogg-Dubé syndrome is a rare cancer susceptibility syndrome characterised by renal tumours, lung cysts and pneumothoraces, and fibrofolliculomas. It is caused by dominantly inherited mutations in FLCN. Our objective was to report renal tumour characteristics in a large series of patients with the Birt-Hogg-Dubé syndrome., Methods: We studied French Birt-Hogg-Dubé patients with a history of renal tumour., Results: We included 33 patients with 21 distinct germline FLCN mutations. Median age at diagnosis of first renal tumour was 46, and age varied from 20 to 83. Twenty cases had one renal tumour, the remainder had two or more tumours. Most cases (23/33, 70%) had oncocytoma or renal cell carcinoma of the chromophobe or hybrid chromophobe-oncocytoma type, three had clear cell carcinoma (9%), and the other seven had carcinoma of papillary, undifferentiated or undetermined histology. Four cases had metastatic disease, although none died of it., Conclusions: Age at renal tumour diagnosis was highly variable, highlighting the need for regular surveillance from young adulthood to old age. Most cases had tumour types classically associated with Birt-Hogg-Dubé, i.e. oncocytoma or renal cell carcinoma of the chromophobe or hybrid type. Nevertheless, 9% had clear cell renal cell carcinoma. Geneticists, urologists and oncologists should therefore be alert to the possibility of Birt-Hogg-Dubé in patients with renal cell carcinoma of clear cell histology, especially if there are associated manifestations. Finally, the behaviour of metastatic carcinoma seemed more indolent than in sporadic renal cancers.

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.

Objectives: To study the prevalence and the characteristics of renal cell carcinoma (RCC) in patients with autosomal dominant polycystic kidney disease (ADPKD) in our series., Methods: We reviewed retrospectively all the nephrectomies performed in our department between 1982 and 2003 in patients with ADPKD and chronic renal failure., Results: Seventy-nine patients (42 males and 37 females) with ADPKD and chronic renal failure underwent 89 nephrectomies; in 10 of 79, both kidneys were removed but not simultaneously. Mean age was 50.4 years (range, 32-69 years). Of 79 patients, 50 had end-stage renal disease (ESRD) and were on hemodialysis or had received a transplant for >1 year. On histologic examination, 11 of 89 kidneys were diagnosed with carcinomas. There was 1 patient with bilateral tumor (tubulopapillary Ca) and 3 kidneys (27.3%) with multifocal tumors. Regarding the histologic type, there were 7 of 12 (58.3%) clear cell carcinomas and the remaining 5 (41.7%) were tubulopapillary carcinomas., Conclusions: The prevalence of RCC was higher in patients with ADPKD and ESRD, with >1 year on dialysis or renal transplantation undergoing nephrectomy according the protocol. It would be 2 to 3 times more frequent than RCC in patients with ESRD alone. The clinician should maintain a high alert of suspicion for RCC in such patients.

We report clinicopathologic features of a large series of renal translocation carcinomas from a multicentric study. Diagnosis was performed by cytogenetic examination of fresh material and/or by immunochemistry with antibodies directed against the C-terminal part of transcription factor E3 (TFE3) and native transcription factor EB (TFEB) proteins. Clinical data, follow-up, and histologic features were assessed. Antibodies against CK7, CD10, vimentin, epithelial membrane antigen, AE1-AE3, E-cadherin, alpha-methylacyl-coenzyme A racemase, melan A, and HMB45 were tested on tissue microarrays. Whole-genome microarray expression profiling was performed on 4 tumors. Twenty-nine cases were diagnosed as TFE3 and 2 as TFEB renal translocation carcinomas, including 13 males and 18 females, mean age 24.6 years. Two patients had a previous history of chemotherapy and 1 had a history of renal failure. Mean size of the tumor was 6.9 cm. Thirteen cases were > or = pT3 stage. Twelve cases were N+ or M+. Mean follow-up was 29.5 months. Three patients presented metastases and 5 have died. Mixed papillary and nested patterns with clear and/or eosinophilic cells represented the most consistent histologic appearance, with common foci of calcifications regardless of the type of translocation. Using a 30 mn incubation at room temperature, TFE3 immunostainings were positive in only 82% of our TFE3 translocation carcinomas. Both TFE3 and TFEB renal translocation carcinomas expressed CD10 and alpha-methylacyl-coenzyme A racemase in all cases. An expression of E-cadherin was observed in two-third of cases. Cytokeratins were expressed in less than one-third of cases. Melanocytic markers were expressed at least weakly in all cases except two. Unsupervised clustering on the basis of the gene expression profiling indicated a distinct subgroup of tumors. TRIM 63 glutathione S-transferase A1 and alanyl aminopeptidase are the main differentially expressed genes for this group of tumors. Our results suggest that these differentially expressed genes may serve as novel diagnostic or prognostic markers.

Objectives: To evaluate the risks of local recurrence and repeat surgery after nephron-sparing surgery (NSS) in von Hippel-Lindau (VHL) disease to propose a therapeutic strategy to patients., Methods: A total of 21 patients with VHL disease and renal tumors were followed up from February 1987 to August 2005. Surgical resection of all tumors was chosen when the largest tumor exceeded a diameter of 30 mm., Results: Of the 21 patients, 18 underwent surgery at a mean age of 38.5 years (range 24 to 69). The median follow-up of the series was 100 months. Of the 17 patients treated by NSS, 8 developed a recurrence. The mean time to local recurrence was 53 +/- 38.8 months (range 10 to 115), and the recurrence tumors grew at a stable mean rate of 0.34 +/- 0.32 cm/yr (range 0.1 to 1.08). Repeat NSS was performed on the same kidney in 2 cases and eight recurrences were kept under surveillance. The disease-specific survival rate was 93.8% at 10 years. The local recurrence rate was 45.6% at 5 years and 83.7% at 10 years. The overall repeat surgery rate was 23.1% at 5 years and 63.4% at 10 years. No metastasis or chronic renal insufficiency was observed in patients undergoing NSS only., Conclusions: Five years after NSS, the risk of developing new tumors in the same kidney and the overall risk of repeat surgery was about 50% and 25%, respectively. However, the strategy of elective NSS and close surveillance preserved renal function without increasing the risk of metastasis.

Mucinous tubular and spindle cell carcinomas are low-grade renal epithelial neoplasms, which were first recognized as a specific entity in the World Health Organization 2004 classification. Forty-five documented cases have been reported. We present 15 additional cases that were incidentally discovered in ten women and five men, with a mean age of 53 years. The tumor is characteristically made up of large eosinophilic regular spindle cells separated by a myxoid stroma with intercellular alcian-blue-positive clear droplets. In peripheral areas, elongated tubules and papillae covered by cubic cells are found. Until this entity had been defined, pathologists used to classify these tumors as variants of solid papillary carcinomas with compressed and elongated papillae, metanephric adenomas, and sarcomatoid carcinomas. In the literature, cytogenetic data indicate various chromosomal losses and gains, but no loss of 3p or trisomy 7 and/or trisomy 17. In two cases, we demonstrate chromosomal loss involving chromosomes 1, 4, 6, 11, 8, 13, 14, 15, 18, and 22. In our 15 cases, immunohistochemistry favored a distal tubule origin (EMA(+), AE1/AE3(+), CK7(+), CK19(+), E-cadherin(+), AMACR(+), and CD10(-)). Prognosis was favorable in our cases, while in the literature, two metastatic cases were reported. Further investigations are required to determine the frequency and true prognosis of these tumors, which are easily identifiable morphologically.

Since 1998 new entities have surfaced in renal tumor classification and have been included in the WHO 2004 classification. In this article, we will discuss the following entities: multilocular clear cell renal carcinoma, Xp11 translocation carcinoma, low grade mucinous tubular carcinoma, epithelioid angiomyolipoma, benign mixed epithelial and stromal tumor. We will investigate new concepts of hybrid oncocytoma and chromophobe renal cell carcinoma and the syndrome of Birt-Hogg-Dube which is associated to kidney tumors. At least, we will touch on new elements in the Bellini carcinoma definition.

Von Hippel-Lindau (VHL) disease is characterized by multiple tumors in specific target organs. The tumors at different sites share distinct morphologic and genetic characteristics but their cell of origin is unknown. We show that VHL disease-associated renal clear cell carcinomas (RCC) consistently coexpress erythropoietin (Epo) and Epo receptor (EpoR). In addition, coexpression of Epo and EpoR is detected in many renal cysts, providing further evidence that renal cysts are potential precursors for RCC. In conjunction with VHL gene deficiency, coexpression of Epo and EpoR in renal cysts and tumors may reflect a developmental arrest in immature mesenchymal cells. Such arrest may lead to autocrine stimulation, cell proliferation, and renal tumor development, similar to tumorigenesis of VHL disease-associated hemangioblastomas.

The authors report the case of a 57-year-old woman operated in 1992 for meningeal haemangiopericytoma. Nine years later, this patient was operated for a liver tumour and then a renal tumour, which were both diagnosed as haemangiopericytoma and therefore corresponded to metastases of the primary tumour. The presence of a renal tumour in a patient previously operated for meningeal haemangiopericytoma should raise the suspicion of renal metastasis. Localized metastases can be treated by surgical resection. The possibility of late recurrence justifies annual thoraco-abdominal CT scan and bone scan for more than ten years.