[Show abstract][Hide abstract] ABSTRACT: Objective
Few studies of renal cell cancer with tumor thrombus have evaluated the risk of recurrence after attempted curative surgery. The objective of this study was to determine predictors of postsurgical recurrence for non-metastatic patients with RCC and venous thrombus.Methods
Records from consecutive non-metastatic RCC patients with tumor thrombus treated surgically from 2000 to 2012 at three centers were reviewed. Univariable and multivariable analysis was used to evaluate the association of risk factors for post-surgical recurrence.ResultsA total of 465 non-metastatic patients were identified including patients with thrombus present in: renal vein 257 (55.3%), infrahepatic IVC 144 (31.0%), and suprahepatic IVC 64 (13.8%). Median follow-up was 28.3 months (IQR 12.2-56.4) with metastatic RCC developing in 188 (40.5%) patients.Independent predictors of recurrence included: BMI ≤20 (HR 2.66; 95% CI 1.29-5.49), low pre-operative hemoglobin (HR 1.54; 95% CI 1.07-2.20), perinephric fat invasion (HR 1.51; 95% CI 1.09-2.10), IVC thrombus height (HR 2.64; 95% CI 1.47-4.74), tumor diameter (HR 1.04 95% CI 1.00-1.09), nuclear grade (HR 1.56 95% CI 1.12-2.15), and non-clear cell histology (2.13; 1.30-3.50).Independently predictive variables were used to create a recurrence model for 3 risk groups based on 0, 1-2, or >2 risk factors respectively. Five-year RFS was significantly different in favorable risk (79.1%) compared to intermediate risk (55.1%) or high risk (22.1%) patients, p<0.0001.Conclusions
Seven risk factors for recurrence are identified for patients with non-metastatic RCC with thrombus, which can be used to select patients who may benefit from increased surveillance or adjuvant therapy clinical trials.This article is protected by copyright. All rights reserved.
BJU International 08/2015; DOI:10.1111/bju.13268 · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Management of patients with metastatic renal cell carcinoma is challenging and continues to be delivered in a multidisciplinary context. Even with the advent of systemic targeted therapy, complete remission with these new agents is rare using systemic therapy alone. Surgical resection of the primary tumor and metastatic deposits continues to play an important role in managing patients with metastatic renal cell carcinoma when aiming for complete remissions. To date, despite the lack of level 1 evidence, metastasectomy appears to prolong survival and achieve long-term cure in carefully selected patients. This review examines current evidence for the role of metastasectomy in renal cell carcinoma.
Studies continue to consistently support a benefit of complete metastasectomy for overall and cancer-specific survival at most sites for resection, with the exception of brain and bone, which tend to perform for symptomatic relief and palliation. Metastasectomy has not yet been examined in a randomized setting. The debate of survival benefit because of selection bias of patients or differences in tumor biology is relevant and has yet to be resolved in the literature. Clearly, careful patient selection remains paramount in optimizing survival benefit from metastasectomy.
Patients with isolated surgically resectable metastatic disease, with long disease-free intervals, and with good performance status are likely to benefit the most from metastasectomy.
Current opinion in urology 06/2015; DOI:10.1097/MOU.0000000000000196 · 2.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rhabdoid histology in clear-cell renal cell carcinoma is associated with a poor prognosis. The prognosis of patients with clear-cell renal cell carcinoma may also be influenced by molecular alterations. The aim of this study was to evaluate the association between histologic features and salient molecular changes in rhabdoid clear-cell renal cell carcinoma. We macrodissected the rhabdoid and clear-cell epithelioid components from 12 cases of rhabdoid clear-cell renal cell carcinoma. We assessed cancer-related mutations from eight cases using a clinical next-generation exome-sequencing platform. The transcriptome of rhabdoid clear-cell renal cell carcinoma (n=8) and non-rhabdoid clear-cell renal cell carcinoma (n=37) was assessed by RNA-seq and gene expression microarray. VHL (63%) showed identical mutations in all regions from the same tumor. BAP1 (38%) and PBRM1 (13%) mutations were identified in the rhabdoid but not in the epithelioid component and were mutually exclusive in 3/3 cases and 1 case, respectively. SETD2 (63%) mutations were discordant between different histologic regions in 2/5 cases, with mutations called only in the epithelioid and rhabdoid components, respectively. The transcriptome of rhabdoid clear-cell renal cell carcinoma was distinct from advanced-stage and high-grade clear-cell renal cell carcinoma. The diverse histologic components of rhabdoid clear-cell renal cell carcinoma, however, showed a similar transcriptomic program, including a similar prognostic gene expression signature. Rhabdoid clear-cell renal cell carcinoma is transcriptomically distinct and shows a high rate of SETD2 and BAP1 mutations and a low rate of PBRM1 mutations. Driver mutations in clear-cell renal cell carcinoma are often discordant across different morphologic regions, whereas the gene expression program is relatively stable. Molecular profiling of clear-cell renal cell carcinoma may improve by assessing for gene expression and sampling tumor foci from different histologic regions.Modern Pathology advance online publication, 26 June 2015; doi:10.1038/modpathol.2015.68.
Modern Pathology 06/2015; DOI:10.1038/modpathol.2015.68 · 6.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
To evaluate how many patients could have undergone PN instead of RN before and after neoadjuvant axitinib therapy, as assessed by 5 independent urologic oncologists, and to study the variability of inter-observer agreement.Patients and Methods
Pre- and post systemic treatment CT scans from 22 patients with ccRCC in a phase II neoadjuvant axitinib trial were reviewed by 5 independent urologic oncologists. RENAL score and Kappa statistics were calculated.ResultsMedian RENAL score changed from 11 pre-treatment to 10 post-treatment, p=0.0017. Five tumors with moderate-complexity pre-treatment remained moderate-complexity post-treatment. Of 17 tumors with high-complexity pre-treatment, 3 became moderate-complexity post-treatment. Overall kappa statistic was 0.611. Moderate-complexity kappa was 0.611 vs. high-complexity kappa of 0.428. Pre-treatment kappa was 0.550 vs. post-treatment of 0.609. After treatment with axitinib, all 5 reviewers agreed that only 5 patients required RN (instead of 8 pre-treatment) and that 10 patients could now undergo PN (instead of 3 pre-treatment). The odds of PN feasibility were 22.8-times higher after treatment with axitinib.Conclusions
There is considerable variability in inter-observer agreement on the feasibility of PN in patients treated with neoadjuvant targeted therapy. Although more patients were candidates for PN after neoadjuvant therapy, it remains difficult to identify these patients a priori.This article is protected by copyright. All rights reserved.
BJU International 06/2015; DOI:10.1111/bju.13188 · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PurposeMetastases to the kidney are a rare entity, historically described in autopsy studies. The primary aim of this study was to describe the presentation, treatment, and outcomes of patients with metastatic tumors to the kidney treated at a tertiary referral center.Patients and Methods
We retrospectively identified 151 patients diagnosed with a primary non-renal malignancy with renal metastasis. Clinical, radiographic and pathologic characteristics were assessed. Overall survival (OS) was calculated using Kaplan-Meier methods.ResultsMedian patient age was 56.7 years. The most common presenting symptoms were flank pain (30%), hematuria (16%) and weight loss (12%). Most primary cancers were carcinomas (80.8%). The most common primary tumor sites were lung (43.7%), colorectal (10.6%), ENT (6%), breast (5.3%), soft tissue (5.3%), and thyroid (5.3%). Renal metastases were typically solitary (77.5%). Concordance between radiologist and clinician imaging assessment was 54.0%. Three ablations and 48 nephrectomies were performed. For non-surgical patients, renal metastasis diagnosis was made with FNA or biopsy. Median OS from primary tumor diagnosis was 3.08 years and median OS from time of metastatic diagnosis was 1.13 years. For patients treated with surgery, median OS from primary tumor diagnosis was 4.81 years, and OS from metastatic diagnosis was 2.24 years.Conclusions
Metastases to the kidney are a rare entity. Survival appears to be longer in patients who are candidates for, and are treated with surgery. Surgical intervention in carefully selected patients with oligometastatic disease and good performance status should be considered. A multi-disciplinary approach with input from urologists, oncologists, radiologists, and pathologists is needed to achieve the most optimal outcomes for this specific patient population.This article is protected by copyright. All rights reserved.
BJU International 06/2015; DOI:10.1111/bju.13194 · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sarcomatoid transformation, wherein an epithelioid carcinomatous tumour component coexists with a sarcomatoid histology, is a predictor of poor prognosis in clear cell renal cell carcinoma (ccRCC). Our understanding of sarcomatoid change has been hindered by the lack of molecular examination. Thus, we sought to characterize molecularly the biphasic epithelioid and sarcomatoid components of sarcomatoid ccRCC and compare them to non-sarcomatoid ccRCC. We examined the transcriptome of the epithelioid and sarcomatoid components of advanced stage sarcomatoid ccRCC (n=43) and non-sarcomatoid ccRCC (n=37) from independent discovery and validation cohorts using the cDNA microarray and RNA-seq platforms. We analyzed DNA copy number profiles, generated using SNP arrays, from patients with sarcomatoid ccRCC (n=10) and advanced non-sarcomatoid ccRCC (n=155). The epithelioid and sarcomatoid components of sarcomatoid ccRCC had similar gene expression and DNA copy number signatures that were, however, distinct from those of high-grade, high-stage non-sarcomatoid ccRCC. Prognostic ccRCC gene expression profiles were shared by the biphasic components of sarcomatoid ccRCC and the sarcomatoid component showed a partial epithelial-to-mesenchymal transition signature. Our genome-scale microarray-based transcript data were validated in an independent set of sarcomatoid and non-sarcomatoid ccRCCs using RNA-seq. Sarcomatoid ccRCC is molecularly distinct from non-sarcomatoid ccRCC, with its genetic programming largely shared by its biphasic morphological components. These data explain why a low percentage of sarcomatoid histology augurs a poor prognosis; suggest the need to modify the pathological grading system; and introduce the potential for candidate biomarkers to detect sarcomatoid change preoperatively without specifically sampling the S component. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant (P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (Pmeta-analysis = 9.15 × 10-4, Pheterogeneity = 0.427). Strong correlation indicated that rs1063355 was a cis-expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman's rank r = -0.59, p = 5.61 × 10-6). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC.