Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.

[From new genetic and histological classifications to direct treatment]. / Carcinome urothélial : des classifications histologiques et moléculaires vers un traitement adéquat.

The most important criterion for optimal cancer treatment is a correct classification of the tumour. During the last three years, several very important progresses have been made with a better definition of urothelial carcinoma (UC), especially from a molecular point of view. We start having a global understanding of UC, although many details are still not completely understood.

Altered Expression of the Transcription Factor Forkhead Box A1 (FOXA1) Is Associated With Poor Prognosis in Urothelial Carcinoma of the Upper Urinary Tract.

OBJECTIVE: To determine the prognostic significance of Forkhead Box A1 (FOXA1) expression in patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). MATERIALS AND METHODS: A retrospective analysis of 566 patients undergoing RNU at seven academic medical centers was performed. Tissue microarrays were subjected to immunohistochemistry using a commercially available polyclonal FOXA1 antibody. Logistic regression determined the association of FOXA1 expression with pathologic features and survival outcomes. RESULTS: Three hundred twenty-two men and 244 women were included. The pathologic distribution of specimens included 53% muscle-invasive or greater (≥pT2), 74% high-grade, 16% with flat architecture, 13% with necrosis, 21% with lymphovascular invasion, 18% with concomitant carcinoma in situ, and 8% with positive lymph nodes. The median FOXA1 score was 5.0 (range: 0-8). Lower FOXA1 expression was significantly correlated with advanced pathologic stage (≥pT3) (P = .02), concomitant carcinoma in situ (P = .006), and renal pelvis (vs ureter) location (P < .0001). At a median follow-up of 27.0 months (range: 3-196), 139 patients (25%) experienced disease recurrence and 121 (21%) died from the disease. In a multivariate model, lower FOXA1 expression was independently associated with disease recurrence (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.05-1.62, P = .04), cancer-specific mortality (HR: 1.17, 95% CI: 1.03-1.92, P = .04), and all-cause mortality (HR: 1.08, 95% CI: 1.02-1.18, P = .05). CONCLUSION: Lower FOXA1 expression is associated with adverse pathologic features and inferior survival outcomes for UTUC patients undergoing RNU. These data indicate lower FOXA1 expression may be a marker of aggressive disease in UTUC.

Evaluation of the prognostic significance of altered mammalian target of rapamycin pathway biomarkers in upper tract urothelial carcinoma.

OBJECTIVE: To evaluate the prognostic value of altered mammalian target of rapamycin (mTOR) pathway biomarkers in upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: We performed a multi-institutional review of clinical and pathologic information on patients receiving extirpative surgery for UTUC from 1990 to 2008. Immunohistochemistry for phosphorylated-S6, mTOR, phosphorylated-mTOR, PI3K, phosphorylated-4EBP1, phosphorylated-AKT, PTEN, HIF-1a, raptor, and cyclin D was performed on tissue microarrays from radical nephroureterectomy (RNU) specimens. Prognostic markers were identified and the significance of altered markers was assessed with the Kaplan-Meier analysis and the Cox regression analysis. RESULTS: Six hundred twenty patients were included. Over a median follow-up of 27.3 months, 24.6% of patients recurred and 21.8% died of UTUC. On multivariate analysis, PI3K (odds ratio, 1.28; P = .001) and cyclin D (odds ratio, 3.45; P = .05) were significant predictors of clinical outcomes. Cumulative marker score was defined as low risk (no altered markers or 1 altered marker) or high risk (cyclin D and PI3K altered). Patients with high-risk marker score had a significantly higher proportion of high-grade disease (91% vs 71%; P <.001), non-organ-confined disease (61% vs 33%; P <.001), and lymphovascular invasion (35% vs 20%; P = .001). The Kaplan-Meier analysis demonstrated a significant difference in cancer-specific mortality (CSM) based on the risk groups. On Cox regression multivariate analysis for CSM incorporating non-organ-confined disease, grade, lymphovascular invasion, tumor architecture, and marker score, high-risk biomarker score was an independent predictor of CSM (hazard ratio, 1.5; 95% confidence interval, 1.04-2.3; P = .03). CONCLUSION: Alterations in mTOR pathway correlate with established adverse pathologic features and independently predict inferior oncologic outcomes. Incorporation of mTOR-based marker profiles may allow for enhanced patient counseling, risk stratification, and individualized treatment regimens.

Identification of pVHL as a novel substrate for Aurora-A in clear cell renal cell carcinoma (ccRCC).

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer and is often characterized by mutations or deletions of the Von Hippel Lindau (VHL) tumour suppressor gene. Aurora gene family members are implicated in proper mitotic progression and spindle checkpoint function and play a crucial role in cancer progression. In the present study, we assessed the expression of Aurora-A in a cohort of 30 ccRCC with fully characterized VHL status (wt/wt or mut/del) and Fuhrman grade. Aurora-A transcript and protein levels were significantly increased in high Fuhrman grade tumours and in VHLwt/wt tumours. These results suggest that Aurora-A and VHL interact in the ccRCC. We demonstrated that the two proteins interact in vivo and identified the Ser72 on the sequence of VHL as the unique site phosphorylated by Aurora-A.

Prognostic value of microvascular invasion in predicting the cancer specific survival and risk of metastatic disease in renal cell carcinoma: a multicenter investigation.

PURPOSE: While microvascular invasion is an accepted risk factor in various cancers, its prognostic role in renal cell carcinoma is still unclear. Therefore, a large multicenter study examining the experience of 5 international institutions was performed to evaluate the prognostic value of microvascular invasion in the occurrence of metastases and cancer specific survival. MATERIALS AND METHODS: A total of 2,596 patients (475 with microvascular invasion and 2,121 without microvascular invasion) having up to 212 (median 22.4) months of followup were compared for differences in clinicopathological features, occurrence of metastases and cancer specific survival. RESULTS: Patients with microvascular invasion presented with higher age (p = 0.001) and a worse Eastern Cooperative Oncology Group performance status (p <0.0001). Microvascular invasion was associated with larger tumor diameter (p <0.0001), higher Fuhrman grade (p <0.0001), more advanced pT stage (p <0.0001), and the presence of lymph node and distant metastases (p <0.0001). In particular, in nonmetastatic cases worse survival was associated with microvascular invasion (p <0.0001, HR 2.38). Univariate analysis demonstrated a strong correlation between microvascular invasion and cancer specific survival (p <0.0001). However, after controlling for gender, Eastern Cooperative Oncology Group performance status, Fuhrman grade and TNM stage statistical significance was lost. Of interest, low stage tumors with microvascular invasion were strongly correlated with the occurrence of metastases (p <0.0001). CONCLUSIONS: Microvascular invasion occurs in nearly 1 of 5 patients with renal cell carcinoma, is tightly correlated with adverse clinicopathological features and is an independent predictor of metastatic spread including in those presenting with low stage tumors.

Susceptibility of human testis to human immunodeficiency virus-1 infection in situ and in vitro.

Semen represents the main vector for human immunodeficiency virus (HIV) dissemination worldwide and has been shown to harbor replication-competent virus despite otherwise effective highly active anti-retroviral therapy, which achieves undetectable viral load in plasma. Despite this, the origin of seminal HIV particles remains unclear, as does the question of whether the male genital tract organs contribute virus to semen. Here we investigated the presence of HIV receptors within the human testis using immunohistochemistry and quantitative real-time polymerase chain reaction. We also analyzed the infectivity of a dual tropic HIV-1 strain in an organotypic culture, as well as the impact of viral exposure on testosterone production. Our study establishes that CXCR4+, CCR5+, CD4+, and DC-SIGN+ cells are present within the interstitial tissue of human testis and that these molecules persist throughout our organotypic culture. Our data also reveal that the human testis is permissive to HIV-1 and supports productive infection, leaving testosterone production apparently unaffected. Infected cells appeared to be testicular macrophages located within the interstitial tissue. That the testis itself represents a potential source of virus in semen could play a role in preventing viral eradication from semen because this organ constitutes a pharmacological sanctuary for many current antiretrovirals.

[Correlation between the mode of presentation of renal tumors and patient survival]. / Corrélation entre le mode de présentation des tumeurs du rein et la survie des patients.

OBJECTIVES: To establish a symptom score and to test its prognostic value in comparison with the usual histological prognostic criteria. MATERIAL AND METHODS: 388 renal tumours were classified into three symptomatic grades according to the circumstances of discovery: S1: incidental discovery, S2; patient presenting with haematuria or low back pain, S3: patient presenting with alteration of general state or symptomatic metastasis. The following prognostic criteria were studied: age, gender, tumour volume, symptom score, ECOG (0 vs 1 or more), stage (TNM 1997), Fuhrman grade, venous and adrenal invasion. Survival rates were compared by the Kaplan-Meier method (Log rank test). Multivariate analysis was performed according to the Cox model. RESULTS: Tumours were classified as T1, T2, T3, T4 in 140 (36.1%), 73 (18.80%), 162 (41.8%) and 13 (3.4%) cases, respectively. 31 tumours were graded as G1 (8%), 167 as G2 (43%), 152 as G3 (39.2%) and 38 as G4 (9.8%), 143 tumours were classified as S1 (36.9%), 159 as S2 (41%) and 86 as S3 (22.10%). 45 patients were N+ (11.6%) and 54 were M+ (13.9%), The mean follow-up was 73 months. The significant parameters on univariate analysis were: ECOG, symptom score, TNM stage, grade, venous and adrenal invasion and tumour volume (p < 0.001), while symptom score, TNM stage and Fuhrman grade were significant on multivariate analysis (p < 0.001). CONCLUSION: The symptom score is an independent prognostic factor in the same way as tumour stage and grade. This score could be used in a mathematical algorithm predictive of survival of patients with renal cancer.

[Renal cell carcinoma before the age of 40: prognostic factors]. / Le carcinome à cellules claires du rein avant 40 ans: facteurs pronostiques.

OBJECTIVE: To study the prognostic value of tumour diameter, TNM stage, Führman's nuclear grade and CD44 adhesion molecule expression in renal cell carcinoma (RCC) before the age of 40 years. MATERIAL AND METHODS: Nineteen patients under the age of 40 (12 males and 7 females; mean age 30.8 years), undergoing total nephrectomy for RCC were included in this study. Tumour diameter, TNM 1997 stage, and Führman's nuclear grade were defined for each tumour. Standard CD44 adhesion molecule (CD44H) expression was evaluated semiquantitatively by immunohistochemistry on each tumour. The prognostic value of the various variables was determined by Mann-Whitney and Chi-square tests and survival analysis was performed by the Kaplan-Meier method. RESULTS: Six patients (31.5%) died from their cancer with a mean follow-up of 81.4 months. Mean tumour diameter was 9 +/- 4.5 cm. Tumours were Führman I/II in 4 cases, Führman III/IV in 15 cases, T1/T2 in 14 cases and T3/T4 in 5 cases. CD44H expression was high (> or = 20%) in 9 cases (47.3%). The prognostic factors identified in this study were: tumour stage (p = 0.01), grade (p = 0.04), venous extension (p = 0.001) and CD44H overexpression (p = 0.003). CONCLUSION: Prognostic factors of renal cancer in patients under the age of 40 years do not appear to be different from those of older patients. The prognostic factors identified in this study must be validated by multicentre studies based on larger populations.