Cystic Renal Cell Carcinoma: A Report on Outcomes of Surgery and Active Surveillance in Patients Retrospectively Identified on Pretreatment Imaging.

PURPOSE: We evaluated the outcomes of surgical intervention and active surveillance in patients diagnosed with cystic renal cell carcinoma at our hypothesized radiological cutoff of greater than 50% cystic. MATERIALS AND METHODS: We identified all 430 patients with a pathologically confirmed cystic renal mass that fit our criteria from 2000 to 2015. The 292 patients with a lack of computerized tomography, tumors less than 50% cystic on imaging, multifocal tumors and prior renal cell carcinoma were excluded from study. Patients were stratified into benign or malignant subgroups, and radiological, clinicopathological and oncologic features were determined. Univariate and multivariate associations between clinicoradiological parameters in each group were analyzed. We similarly reviewed the records of a separate cohort of patients treated with active surveillance for cystic renal cell carcinoma. RESULTS: Of the 138 identified cases of cystic renal cell carcinoma 102 (73.9%) were renal cell carcinoma and 36 (26.1%) were benign masses. Of the tumors 77.5% were Fuhrman grade 1-2, 83.4% were stage pT2 or less and 65.9% showed clear cell histology. On univariate analysis male gender, a solid component and increasing Bosniak classification were significant for malignancy. In a separate cohort we identified 38 patients on active surveillance. The growth rate was 1.0 mm per year overall and 2.3 mm per year for the solid component. At a median followup of more than 4 years in all cohorts there was no evidence of recurrence or metastasis of cystic renal cell carcinoma. CONCLUSIONS: Patients with unifocal cystic renal cell carcinoma evaluated using a standardized radiological threshold of greater than 50% cystic had an excellent prognosis on active surveillance and after surgical resection.

The association of renal cell carcinoma with gastrointestinal stromal tumors.

BACKGROUND AND OBJECTIVES: Prior small studies have reported a possible association between renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs). In the largest known series, our objective was to describe the prevalence of RCC among patients with GISTs over 26 years at Memorial Sloan Kettering Cancer Center (MSKCC). METHODS: We retrospectively reviewed MSKCC's prospectively maintained sarcoma and RCC databases and identified all patients with both RCC and GIST between 1980 and 2016. Demographic and clinicopathological characteristics were obtained. RESULTS: A total of 9/405 (2.2%) GIST patients were identified with RCC, with a mean follow-up of 9.2 (range 3.8-28.4) years. Five out of nine (55.6%) patients had RCC and GIST diagnosis within 6 months of each other. Mean RCC tumor size was 3.0 (range 1.8-8) cm and 8/9 (88.9%) patients were RCC stage 1. A total of 4/9 (44.4%) patients had papillary RCC (pRCC) histology, 5/9 (55.6%) had additional alternative malignancies, and 4/9 (44.4%) had primary small bowel GIST. CONCLUSIONS: Our series suggests a possible association of RCC with GISTs. In addition, we found a high frequency of pRCC histology, alternative malignancies, and small bowel GISTs in co-occurring RCC-GIST patients. Further investigation to identify genetic mutations, in this population, would assist in surveillance and treatment.

Secondary pelvic congestion syndrome: description and radiographic diagnosis.

INTRODUCTION: Pelvic congestion syndrome (PCS) is a complex condition of the pelvic venous system leading to nonspecific pelvic pain that was initially described in females alone. The underlying abnormalities, though diverse, all result in increased pressure in the left gonadal vein which is transmitted retrograde into the pelvic venous system. Our primary aim was to describe our findings of secondary PCS as a distinct entity from primary PCS in that it has an identifiable vascular etiology and is gender nonspecific. We also aimed to assess the adequacy of late-arterial phase CT urography (CTU) as the initial imaging modality in diagnosing and evaluating secondary PCS. MATERIALS AND METHODS: We retrospectively reviewed 59 patients with PCS, 36 males and 23 females ages 24 to 63, from 2000-2011. To maximize opacification, CTU images were taken in the late-arterial phase with a 35-50 second delay after contrast administration. RESULTS: Review of our cases revealed multiple etiologies for PCS, including: Nutcracker syndrome (19 cases), cirrhosis (17), retroaortic left renal vein (11), tumor thrombosis of the IVC (5), portal vein thrombosis (4), renal cell carcinoma with left renal vein thrombosis (2), and left kidney AVF (1). The most common symptom was unexplained chronic pelvic pain. The patients in our series had clearly identifiable vascular flow abnormalities leading to the development of PCS, and were therefore diagnosed as having secondary PCS. All cases were easily identified utilizing CTU to visualize and measure dilation of the left gonadal vein and pelvic varices. This modality also proved valuable in the identification and management of the various underlying causes of secondary PCS. CONCLUSION: Secondary PCS is distinct from primary PCS in that it arises from clearly identifiable vascular flow abnormalities and occurs in both males and females. The diverse set of underlying etiologies, as well as the resulting congested varices, can be reliably and adequately visualized using CTU as the initial imaging modality.

Pad count is a poor measure of the severity of urinary incontinence.

PURPOSE: We analyzed the correlation between pad use, as determined by objective pad count, and the severity of urinary incontinence, as measured by pad weight. MATERIALS AND METHODS: We performed a retrospective study of consecutive incontinent patients who wore pads on a daily basis and were instructed to complete a 24-hour pad test. They were told to use the usual pads, change them as usual and place each in a separate plastic bag the day before the scheduled appointment. All pads were weighed and total urine loss was calculated by subtracting dry pad weight from wet pad weight, assuming that a 1 gm weight increase was equivalent to 1 ml of urine loss. The number of pads was correlated to pad weight using the Spearman rank correlation coefficient due to the nonparametric nature of the data. RESULTS: The 116 patients included 51 men 39 to 89 years old (mean age 66) and 65 women 27 to 95 years old (mean age 72). When comparing the number of pads used to the gm of urine lost, the Spearman ρ was 0.26 (p=0.005) in the total cohort, and 0.40 and 0.26 (each p<0.05) in males and females, respectively. CONCLUSIONS: There was little correlation between the number of pads used and the severity of urinary incontinence (r=0.26). These data suggest that pad count should not be used as an objective measure of incontinence severity. Instead, pad weight on a 24-hour pad test should be used.

Characterization and Impact of TERT Promoter Region Mutations on Clinical Outcome in Renal Cell Carcinoma.

BACKGROUND: Mutations in the promoter region of the TERT gene have been detected in a variety of cancers. These mutations can potentially lead to unlimited cell divisions and result in poor clinical prognosis. OBJECTIVE: To determine the role and relevance of TERT promoter region mutations in both clear cell (ccRCC) and non-clear cell (nccRCC) renal cell carcinoma using ultra-deep and whole-genome sequencing methods on primary tumor samples. DESIGN, SETTING, AND PARTICIPANTS: DNA from 281 kidney tumors (147 ccRCC and 134 nccRCC) was sequenced between 2013 and 2015, and clinical outcomes for these patients from a single institution were retrospectively analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Differences in patient characteristics and mutational status were tested using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Survival times were estimated using the Kaplan-Meier method and differences were tested using the log-rank test. RESULTS AND LIMITATIONS: TERT mutations occurred in 12.2% of ccRCC and 10.4% of nccRCC cases. In >80% of the cases, mutations were located at C228T and were found to co-occur only rarely with other relevant RCC driver genes. The median follow-up among survivors overall was 2.5 yr (range 0.1-18.3). TERT promoter mutations were significantly associated with cancer-specific survival in ccRCC (hazard ratio 2.68, 95% confidence interval 1.19-6.01; p=0.013). In nccRCC, TERT mutations were significantly associated with larger tumors and metastatic development. Assessment of further relevant clinical associations was precluded in the nccRCC group by the heterogeneous and small sample size. CONCLUSIONS: Our data suggests that TERT mutational status reflects a distinct pathogenesis with an aggressive disease course in RCC. Stratifying patients with this unique tumorigenesis that leads to poor clinical outcomes could be a putative target for novel therapeutics. PATIENT SUMMARY: We show a previously unrecognized frequency of TERT promoter mutations in both clear cell and non-clear cell renal cell carcinoma. TERT promoter mutations were associated with some worse outcomes in patients with clear cell renal cell carcinoma.

Characterizing recurrent and lethal small renal masses in clear cell renal cell carcinoma using recurrent somatic mutations.

INTRODUCTION: Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. METHODS: We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas (n = 110), University of Tokyo (n = 37), The International Cancer Genome Consortium (n = 31), and from our own institutional prospective database (n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations. RESULTS: In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033. CONCLUSIONS: We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed.

Plasma Glycosaminoglycans as Diagnostic and Prognostic Biomarkers in Surgically Treated Renal Cell Carcinoma.

BACKGROUND: Plasma glycosaminoglycan (GAG) measurements, when aggregated into diagnostic scores, accurately distinguish metastatic clear-cell renal cell carcinoma (RCC) from healthy samples and correlate with prognosis. However, it is unknown if GAG scores can detect RCC in earlier stages or if they correlate with prognosis after surgery. OBJECTIVE: To explore the sensitivity and specificity of plasma GAGs for detection of early-stage RCC and prediction of recurrence and death after RCC surgery. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective case-control study consisting of a consecutive series of 175 RCC patients surgically treated between May 2011 and February 2014 and 19 healthy controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Plasma GAGs in preoperative and postoperative RCC and healthy samples were measured using capillary electrophoresis with laser-induced fluorescence in a single blinded laboratory. A discovery set was first analyzed to update the historical GAG score. The sensitivity of the new GAG score for RCC detection versus healthy subjects was validated using the remaining samples. The correlation of the new GAG score to histopathologic variables, overall survival, and recurrence-free survival was evaluated using nonparametric and log-rank tests and multivariable Cox regression analyses. RESULTS AND LIMITATIONS: The RCC cohort included 94 stage I, 58 stage II-III, and 22 stage IV cases. In the first discovery set (n=67), the new GAG score distinguished RCC from healthy samples with an area under the receiver operating characteristic curve (AUC) of 0.999. In the validation set (n=108), the GAG score achieved an AUC of 0.991, with 93.5% sensitivity. GAG scores were elevated in RCC compared to healthy samples, irrespective of and uncorrelated to stage, grade, histology, age, or gender. The total chondroitin sulfate concentration was an independent prognostic factor for both overall and recurrence-free survival (hazard ratios 1.51 and 1.25) with high concordance when combined with variables available at pathologic diagnosis (C-index 0.926 and 0.849) or preoperatively (C-index 0.846 and 0.736). Limitations of the study include its retrospective nature and moderate variability in GAG laboratory measurements. CONCLUSIONS: Plasma GAGs are highly sensitive diagnostic and prognostic biomarkers in surgically treated RCC independent of stage, grade, or histology. Prospective validation studies on GAG scores for early detection, prediction, and surveillance for RCC recurrence are thus warranted. PATIENT SUMMARY: In this study, we examined if a new molecular blood test can detect renal cell carcinoma in the early stages and predict if the cancer might relapse after surgery. The trial is registered on ClinicalTrial.gov as NCT03471897.

Comparison of Postradical Cystectomy Ileus Rates Using GIA-80 Versus GIA-60 Intestinal Stapler Device.

OBJECTIVE: To assess the impact on recovery of bowel function using an 80 mm versus 60 mm gastrointestinal anastomosis (GIA) stapler following radical cystectomy and urinary diversion (RC/UD) for bladder cancer. METHODS: We identified 696 patients using a prospectively maintained RC/UD database from January 2006 to November 2010. Two nonrandomized consecutive cohorts were compared. Patients between January 2006- and December 2007 (n = 180) were treated using a 60 mm GIA stapler, and 331 patients between January 2008 and December 2010 were subject to an 80 mm GIA stapler. All patients were treated on the same standardized postoperative recovery pathway. After accounting for baseline patient and perioperative characteristics, using a multivariable logistic regression model, we directly compared rates of postoperative ileus using a standardized definition. RESULTS: Of 511 evaluable patients, ileus was observed in 32% (57/180) for 60 mm GIA versus 33% (110/331) for the 80 mm GIA. Preoperative renal function, age, gender, body mass index, and type of diversion were comparable between cohorts. On multivariate analysis, stapler size was not significantly associated with the development of ileus (GIA-60 vs GIA-80: OR 1.11; 95% CI 0.75, 1.66; P = .6). Positive fluid balance was associated with an increased risk (P = .019) and female sex a decreased risk (P = .008) of developing ileus compared to patients with negative fluid balance. CONCLUSION: The size of the intestinal bowel anastomosis (GIA 80 mm vs 60 mm) does not independently impact the time to bowel recovery following RC/UD.

Comparative Genomic Profiling of Matched Primary and Metastatic Tumors in Renal Cell Carcinoma.

BACKGROUND: Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. OBJECTIVE: To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. DESIGN, SETTING, AND PARTICIPANTS: Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture-based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S-Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites. RESULTS AND LIMITATIONS: Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2. We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p=0.088). CONCLUSIONS: Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation. PATIENT SUMMARY: In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.

Prognostic value of lymph node yield during nephroureterectomy for upper tract urothelial carcinoma.

INTRODUCTION: Lymph node dissection (LND) performed during radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) remains controversial and difficult to evaluate. The aim of this study was to investigate whether removal of more lymph nodes during RNU is safe and improves oncologic outcomes. METHODS: We evaluated 422 patients who underwent RNU with concomitant LND for upper tract urothelial carcinoma between 1976 and 2015, assessing for an association between total nodes removed, recurrence-free survival, and cancer-specific survival using Cox proportional hazards models. We also investigated the relationship between nodal yield and perioperative metrics and intersurgeon variability using linear regression. RESULTS: In our cohort of 442 patients, 239 developed recurrences and 94 patients died of disease. Median follow-up among survivors was 3.7 years (interquartile range: 1.2, 7.4). The median nodal yield was 9 (interquartile range: 4, 16). Among patients with node-positive disease (pN1), we observed a significant improvement in recurrence-free survival (hazard ratio = 0.84 per 5 nodes removed, P = 0.039) and a nonsignificant improvement in cancer-specific survival with an increase in the nodal yield (hazard ratio = 0.90 per 5 nodes removed, P = 0.2). There was no evidence of an association between node yield and operative time, estimated blood loss, or 30-day complications on multivariable analysis. There was significant heterogeneity among surgeons regarding the extent of LND (P<0.0001). CONCLUSIONS: We found that a more extensive node dissection may improve oncologic outcomes in a subset of high-risk patients without significantly increasing operative time or serious complications. Additionally, we identified considerable intersurgeon heterogeneity regarding the extent of LND furthering the notion of surgeon variability as a nonstandardized factor.