Low-grade oncocytic renal tumor (LOT): mutations in mTOR pathway genes and low expression of FOXI1.

Low-grade oncocytic renal tumor (LOT) is an emerging provisional entity, described as rare solid renal oncocytic/eosinophilic tumor sharing diffuse CK7 and negative CD117 immunoprofile. The links between LOT and other eosinophilic chromophobe like-renal cell carcinomas (RCC) are currently discussed. We sequenced tumoral DNA with a next generation sequencing panel for kidney cancer and carried out immunohistochemical analyses with CK7, CD117, SDHB, 4EBP1-P, S6K-P, and FOXI1 antibodies in a series of ten cases of LOT (9 females, 1 male; mean age at surgery: 66 years, 42.3 to 83.4) retrospectively diagnosed from a cohort of 272 tumors initially classified as chromophobe RCC (CHRCC). All LOT were single, without known hereditary predisposition, classified stage pT1 (70%), pT2 (20%) or pT3a (10%). Morphological features were similar to previous descriptions and clinical behavior was indolent for the six cases with available follow-up. We identified genetic variations in mTOR pathway related genes in 80% of cases, MTOR (7 cases) or TSC1 (1 case). Expression of FOXI1 was absent in all cases. In 9 LOT, 4EBP1-P and S6K-P were overexpressed, suggesting mTOR pathway activation.Our data highlights the major role of mTOR pathway in tumorigenesis of LOT mostly due to activating MTOR gene variations. Absence of FOXI1 expression is a strong argument to distinguish LOT from eosinophilic CHRCC and to bring them closer to other recently described FOXI1 negative eosinophilic-CHRCC like with MTOR/TSC mutations. Altogether, our data argue to consider LOT as a distinct entity with a favorable clinical outcome. However, in case of metastasis, an accurate diagnosis of LOT would be essential for the patient's management and could allow targeted therapy.

Clear Cell Papillary Renal Cell Carcinoma: A Recent Entity With Distinct Imaging Patterns.

OBJECTIVE. Clear cell papillary renal cell carcinoma (RCC), an entity with strikingly indolent behavior, recently was added to the World Health Organization classification of renal tumors and represents the fourth most common histologic type of renal cell carcinoma. This article aims to describe the imaging features of clear cell papillary RCC along with its clinical and pathologic characteristics. MATERIALS AND METHODS. This retrospective study consisted of 27 patients with 44 clear cell papillary RCC tumors. The inclusion criteria were a pathologically proven clear cell papillary RCC and the availability of preoperative imaging including at least CT or MRI. Two experienced radiologists performed the imaging analysis independently. RESULTS. Patients (mean age, 62 years old) presented with renal failure in 26% of cases, and four had a tumor-predisposing disease. Multiple clear cell papillary RCC tumors occurred in 5 of the 27 patients. Two imaging patterns were recognizable. Solid clear cell papillary RCC (n = 23, 52%) presented as heterogeneous tumors with minor cystic changes (74%) and rarely exhibited calcifications (10%). All solid tumors showed hyperintensity on T2-weighted images compared with renal cortex and maximal enhancement on corticomedullary phase with a delayed washout. Cystic clear cell papillary RCC (n = 21, 48%) were classified as Bosniak IV (57%), III (33%), or IIF (10%), with a predominant unilocular pattern (76%). Pathologic stage according to TNM classification was mostly pT1a and low grade on nucleolar grade. All patients were alive at the date of last follow-up after treatment with no metastasis or recurrence. CONCLUSION. Clear cell papillary RCC exhibits two imaging patterns including cystic and solid in almost equal proportion. Imaging characteristics of solid clear cell papillary RCC including high signal T2 intensity and early arterial enhancement are unexpectedly distinct from papillary RCC and very similar to clear cell RCC.

Integrative analysis of dysregulated microRNAs and mRNAs in multiple recurrent synchronized renal tumors from patients with von Hippel-Lindau disease.

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.

Paraganglioma of the bladder in a kidney transplant recipient: A case report.

Renal transplantation has been associated with a significantly increased risk of developing cancer, including bladder neoplasia, with urothelial carcinoma being the most frequent type of bladder cancer. Bladder paraganglioma, also referred to as extra-adrenal pheochromocytoma, is a rare but severe condition that may cause a severe hypertensive crisis during handling and mobilization of the tumor. We herein present the case of a 67-year-old kidney transplant recipient with a bladder polyp consistent with paraganglioma of the bladder. During bladder polyp resection, the patient developed severe hypertension, which resolved with appropriate treatment. The histological analysis of the resected bladder polyp was consistent with extra-adrenal pheochromocytoma, or paraganglioma, and the patient finally underwent partial cystectomy, with no reported postoperative recurrence. To the best of our knowledge, this is the first report of a case of paraganglioma of the bladder in a kidney tranplant recipient. Total or partial bladder cystectomy is considered to be an effective treatment for this type of bladder tumor. Screening for mutations of the succinate dehydrogenase subunit B gene may also be recommended.

Increased risk of solid renal tumors in lithium-treated patients.

Cystic kidney diseases and toxic interstitial nephritis may be complicated by renal tumors. Long-term lithium intake is associated with tubulointerstitial nephritis and renal cysts but to date such an association with tumors has not been determined. We evaluated this in a retrospective study to determine whether lithium-treated patients were at higher risk of renal tumors compared with lithium-free patients with chronic kidney disease (CKD), and to the general population. Over a 16-year period, 14 of 170 lithium-treated patients had renal tumors, including seven malignant and seven benign tumors. The mean duration of lithium exposure at diagnosis was 21.4 years. The renal cancers included three clear-cell and two papillary renal cell carcinomas, one hybrid tumor with chromophobe and oncocytoma characteristics, and one clear-cell carcinoma with leiomyomatous stroma. The benign tumors included four oncocytomas, one mixed epithelial and stromal tumor, and two angiomyolipomas. The percentage of renal tumors, particularly cancers and oncocytomas, was significantly higher in lithium-treated patients compared with 340 gender-, age-, and estimated glomerular filtration rate (eGFR)-matched lithium-free patients. Additionally, the Standardized Incidence Ratio of renal cancer was significantly higher in lithium-treated patients compared with the general population: 7.51 (95% confidence interval (CI) (1.51-21.95)) and 13.69 (95% CI (3.68-35.06)) in men and women, respectively. Thus, there is an increased risk of renal tumors in lithium-treated patients.

Expression and characterization of androgen receptor coregulators, SRC-2 and HBO1, during human testis ontogenesis and in androgen signaling deficient patients.

Androgen receptor (AR) is essential for testicular physiology and spermatogenesis. SRC-2 and HBO1 are two AR coregulators yet their expression and roles in human testis are unknown. For the first time, we studied by immunohistochemistry and RT-PCR, the expression and distribution of these two coregulators during human testicular ontogenesis, in patients with altered AR signaling (Androgen insensitivity syndrome, AIS) and evaluated the functional impact of SRC-2 and HBO1 on AR signaling in a Sertoli cell context. SRC-2 was present in Sertoli cells at all developmental stages. HBO1 was barely or focally detected in the fetal testis yet its expression, in Sertoli and germ cells, drastically increased postnatally from early infancy to adulthood. In transient co-transfection studies we showed that SRC-2 induced, while HBO1 inhibited AR-mediated transactivation of reporter constructs in murine Sertoli SMAT1 cells. HBO1, but not SRC-2, expression was reduced in testes of patients with AIS compared to normal testes.

Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression.

BACKGROUND: Germline mutations in the folliculin (FLCN) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack FLCN mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied. METHODS: BHDS individuals were identified symptomatically and FLCN mutations were confirmed by DNA sequencing. Comparative gene expression profiling analyses were carried out on renal tumors isolated from individuals afflicted with BHDS and a panel of sporadic renal tumors of different subtypes using discriminate and clustering approaches. qRT-PCR was used to confirm selected results of the gene expression analyses. We further analyzed differentially expressed genes using gene set enrichment analysis and pathway analysis approaches. Pathway analysis results were confirmed by generation of independent pathway signatures and application to additional datasets. RESULTS: Renal tumors isolated from individuals with BHDS showed distinct gene expression and cytogenetic characteristics from sporadic renal oncocytoma and chromophobe RCC. The most prominent molecular feature of BHDS-derived kidney tumors was high expression of mitochondria-and oxidative phosphorylation (OXPHOS)-associated genes. This mitochondria expression phenotype was associated with deregulation of the PGC-1α-TFAM signaling axis. Loss of FLCN expression across various tumor types is also associated with increased nuclear mitochondrial gene expression. CONCLUSIONS: Our results support a genetic distinction between BHDS-associated tumors and other renal neoplasias. In addition, deregulation of the PGC-1α-TFAM signaling axis is most pronounced in renal tumors that harbor FLCN mutations and in tumors from other organs that have relatively low expression of FLCN. These results are consistent with the recently discovered interaction between FLCN and AMPK and support a model in which FLCN is a regulator of mitochondrial function.

Anorectal Epstein-Barr virus infection mimicking Hodgkin lymphoma in an immunocompetent man.

Anorectal Hodgkin lymphoma (HL) is rare, mainly described in human immunodeficiency virus (HIV) patients with exceptional cases reported in immunocompetents. We report the case of a middle age HIV male, presenting with intestinal occlusion. Rectosigmoidoscopy showed multiple anorectal nodular and ulceronecrotic masses. The biopsy specimens revealed a diffuse polymorphous inflammatory infiltrate in the lamina propria, associated with CD30, CD20, CD3, CD15, and ALK1 scattered large Hodgkin and/or Reed Sternberg -like cells stained by LMP1 antibody and EBER. A diagnosis of EBV-associated atypical lymphoproliferative disease mimicking HL was made. These lesions remained stable for 2 years without treatment then disappeared leaving a mucosal scar. A later control biopsy showed a condylomatous lesion, without lymphoid lesion, suggesting a sexually acquired infection. Eight years later, the complete resolution of the lesion without any treatment is a strong argument against a malignant lymphoid process and raises doubts as to the reality of isolated anorectal HL in immunocompetent participants.

Prognostic significance of new immunohistochemical markers in refractory classical Hodgkin lymphoma: a study of 59 cases.

Although most classical Hodgkin lymphoma patients are cured, a significant minority fail after primary therapy and may die as result of their disease. To date, there is no consensus on biological markers that add value to usual parameters (which comprise the International Prognostic Score) used at diagnosis to predict outcome. We evaluated 59 patients (18 with primary refractory or early relapse disease and 41 responders) for bcl2, Ki67, CD20, TiA1 and c-kit expression by semi-quantitative immunohistochemical study and correlated the results with the response to treatment.The results showed that expression of bcl2 and CD20 in Hodgkin and Reed Sternberg cells, and expression of TiA1 in micro-environmental lymphocytes, and c-kit positive mast cells in microenvironment, were independent prognostic markers. These novel cHL markers could be used in association with clinical parameters to identify newly diagnosed patients with favorable or unfavorable prognosis and to better tailor treatment for different risk groups.

Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature.

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.

[Diagnosis of renal metanephric adenoma: relevance of immunohistochemistry and biopsy]. / Diagnostic d'adénome métanéphrique rénal: Intérêt de l'immunohistochimie et apport de la biopsie.

Most renal tumors of the adult are carcinomas. Their treatment is surgical, consisting of limited excision or nephrectomy. In some instances, biopsy of the tumor can be performed in order to adapt treatment. We report the case of a 45 year-old woman presenting with renal tumor. A biopsy of the mass showed a metanephric adenoma. No surgical excision was performed because of the benignity of this tumor. Here we develop the interest of immunohistochemistry for differential diagnosis of metanephric adenoma and other "basophilic small cell tumors" of the kidney. We also put the stress on the growing role of biopsy of renal tumor allowing optimal treatment.

Dramatic clinical efficacy of cladribine in Rosai-Dorfman disease and evolution of the cytokine profile: towards a new therapeutic approach.

Rosai-Dorfman disease (RDD) is a rare disorder, often benign but with possible life-threatening prognosis. In most cases, specific treatment is not necessary; when required, the management of RDD is not codified to date, and various chemotherapies have been shown to be ineffective. Here, we report a patient with RDD who presented a dramatic and sustained response with cladribine. Analysis of the cytokine profile evolution shows a clear correlation between serum levels of TNF-alpha and IL-6 and disease activity. Our findings show the promising efficacy of cladribine and suggest that therapies targeting specifically cytokines might be useful in some cases of active RDD.

Renal cell carcinoma with an Xp11.2 translocation in a 16-year-old girl: a case report with cytological features.

We report a case of a 16-year-old girl with a left renal tumor discovered by her family practitioner. On physical examination the patient had a painless abdominal mass, located in the upper medium portion of the abdomen on the left side with a voussure of the abdominal wall. Ultrasound and abdominal pelvic CAT scan revealed a large heterogeneous mass with calcifications in the inferior portion of the left kidney. We made touch-imprint cytological preparations of the biopsy fragments, obtained under ultrasound guidance. Cytological analysis revealed highly cellular smears with malignant cells arranged in large clusters or rarely isolated, sometimes surrounding hyaline nodules with numerous psammoma bodies. After May-Grünwald-Giemsa staining, cells displayed moderately irregular nuclei with an abundant and pale basophilic cytoplasm with well-defined borders and a finely granular texture. The diagnosis of a special type of renal cell carcinoma was suspected, and was then confirmed after examination of the biopsy sample and the corresponding surgical specimen. The histomorphologic features were those of a renal cell carcinoma associated with an Xp11.2 translocation. Immunohistochemistry revealed this translocation by showing nuclear positivity in tumor cells for an antibody raised against the TFE3 protein. The clinical outcome was marked several months later by metastases in lymph nodes, bone, lung, and adrenal gland as well as a local recurrence.

Intravascular lymphoma associated with haemophagocytic syndrome: a very rare entity in western countries.

Intravascular lymphoma (IVL) is a rare and aggressive disorder, characterised by frequent cutaneous and neurological involvement and medullary infiltration. In rare cases particularly in Asia, IVL can be associated with haemophagocytic syndrome (IVL-HS). Here, we report the case of a 61-year-old Caucasian female who presented with IVL-HS. Bone marrow biopsy showed haemophagocytic features and medullary localisation of a diffuse large B-cell lymphoma. Liver biopsy showed exclusive sinusoidal infiltration by large B cells. Treatment by polychemotherapy associated with rituximab induced a rapid complete remission. Unfortunately, death occurred as a consequence of septic shock. Early recognition of IVL-HS by performing bone marrow biopsy is critical to start rapidly appropriate treatment. The role of rituximab in the management of IVL-HS remains to be established.

[Tumors of the kidneys: new entities]. / Tumeurs du rein: les nouvelles entités.

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.

Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas.

Mutations in one copy of the hepatocyte nuclear factors (HNF) 1alpha and 1beta homeodomain containing transcription factors predispose the carrier to maturity-onset diabetes of the young (MODY) types 3 and 5, respectively. Moreover, previous identification of biallelic inactivation of HNF1alpha in hepatocellular adenoma identified its tumor suppressor function in hepatocarcinogenesis. The seminal observation of an ovarian carcinoma in a MODY5 patient who subsequently developed a chromophobe renal cell carcinoma, prompted us to screen for HNF1beta and HNF1alpha inactivation in a series of 20 ovarian and 35 renal neoplasms. Biallelic HNF1beta inactivation was found in two of 12 chromophobe renal carcinomas by association of a germline mutation and a somatic gene deletion. In these cases, the expression of PKHD1 (polycystic kidney and hepatic disease 1) and UMOD (Uromodulin), two genes regulated by HNF1beta, was turned off. Interestingly, in two of 13 clear cell renal carcinomas, we found a monoallelic germline mutation of HNF1alpha with no associated suppression of target mRNA expression. In normal and tumor renal tissues, we showed the existence of a network of transcription factors differentially regulated in tumor subtypes. We identified two related clusters of co-regulated genes associating HNF1beta, PKHD1 and UMOD in the first group and HNF1alpha, HNF4alpha, FABP1 and UGT2B7 in the second group. Finally, these results suggest that germline mutations of HNF1beta and HNF1alpha may predispose to renal tumors. Furthermore, we suggest that HNF1beta functions as a tumor suppressor gene in chromophobe renal cell carcinogenesis through a PKHD1 expression control.

Cystic kidney disease, chromophobe renal cell carcinoma and TCF2 (HNF1 beta) mutations.

BACKGROUND: The proband, a 33-year-old woman, presented with renal cysts, mild renal failure and a renal tumor. One of the proband's two sons had hyperechogenic kidneys and the other had renal cortical microcysts. Her 71-year-old mother had mild renal failure and small renal cysts. INVESTIGATIONS: Ultrasonography, blood and urine analysis, MRI, CT scan, and genetic investigations focusing on the transcription factor 2 (TCF2) gene which encodes hepatocyte nuclear factor 1 beta. DIAGNOSIS: The proband was diagnosed with cystic kidney disease and chromophobe renal cell carcinoma, characterized by a 46delC germline mutation of TCF2 and a complete somatic deletion of TCF2 in the renal tumor. The germline TCF2 mutation was also present in the proband's sons and mother. Pancreas atrophy was detected in the proband and her mother. MANAGEMENT: Tumorectomy followed by radical nephrectomy of the left kidney 4 years later. Lisinopril (5 mg/day) and lifelong follow-up. The patient's sons will be regularly screened for progressive renal disease, diabetes mellitus and chromophobe renal cell carcinoma.