Background Papillary renal cell carcinoma, accounting for 15% of renal cell carcinoma, is a heterogeneous disease consisting of different types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal cell carcinoma; no effective forms of therapy for advanced disease exist. Methods We performed comprehensive molecular characterization utilizing whole-exome sequencing, copy number, mRNA, microRNA, methylation and proteomic analyses of 161 primary papillary renal cell carcinomas. Results Type 1 and Type 2 papillary renal cell carcinomas were found to be different types of renal cancer characterized by specific genetic alterations, with Type 2 further classified into three individual subgroups based on molecular differences that influenced patient survival. MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene. Conclusions Type 1 and Type 2 papillary renal cell carcinomas are clinically and biologically distinct. Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis. Furthermore, Type 2 papillary renal cell carcinoma consists of at least 3 subtypes based upon molecular and phenotypic features.

Background Nephroureterectomy alone fails to adequately treat many patients with advanced upper tract urothelial carcinoma (UTUC). Perioperative platinum-based chemotherapy has been proposed but requires adequate renal function. Objective Our aim was to determine whether the ability to deliver platinum-based chemotherapy following nephroureterectomy is affected by postoperative changes in renal function. Design, settings, and participants We retrospectively reviewed data on 388 patients undergoing nephroureterectomy for UTUC between 1991 and 2009. Four institutions were included. Intervention All patients underwent nephroureterectomy. Measurements All patients had serum creatinine measured before and after surgery. The value closest to 3 mo after surgery was taken as the postoperative value (range: 2[en]52 wk). Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease study equation. EGFR values before and after surgery were compared using the paired t test. We chose an eGFR of 45 and 60 ml/min per 1.73 m2 as possible cut-offs for chemotherapy eligibility and compared eligibility before and after surgery using the chi-square test. Results and limitations Our cohort of 388 patients included 233 men (60%) with a median age of 70 yr. Mean eGFR decreased by 24% after surgery. Using a cut-off of 60 ml/min per 1.73 m2, 49% of patients were eligible for chemotherapy before surgery, but only 19% of patients remained eligible postoperatively. Using a cut-off of 45 ml/min per 1.73 m2, 80% of patients were eligible preoperatively, but only 55% remained eligible after surgery. This distribution persisted when we limited the analysis to patients with advanced pathologic stage (T3 or higher). Patients older than the median age of 70 yr were more likely to be ineligible for chemotherapy both pre- and postoperatively by either definition, and they were significantly more likely to have an eGFR <45 ml/min per 1.73 m2 postoperatively, regardless of their starting eGFR. This study is limited by its retrospective nature, and there was some variability in the timing of postoperative serum creatinine measurements. Conclusions EGFR is significantly diminished after nephroureterectomy, particularly in elderly patients. These changes in renal function likely affect eligibility for adjuvant cisplatin-based therapy. Accordingly, we suggest strong consideration of neoadjuvant regimens.

At almost 1 year followup stent failure due to extrinsic compression occurred in nearly half of treated patients. Analysis of data revealed a diagnosis of cancer, baseline mild renal insufficiency and metastatic disease requiring chemotherapy or radiation as predictors of stent failure. Managing extrinsic compression by retrograde stenting continues to be a practical but guarded decision and should be tailored to each patient.

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