Cheville, John C.

446 Background: Despite the development of prognostic algorithms based on clinico-pathologic features, the ability to identify aggressive forms of clear cell renal cell carcinoma (ccRCC) remains suboptimal. Topoisomerase IIA (TOP2a) is a biomarker of DNA replication and a target for antineoplastic agents. Herein, we evaluate the association of TOP2a expression in ccRCC tumors with pathologic features of aggressiveness and risk of cancer-specific death. Methods: We identified 947 patients who underwent nephrectomy to treat clinically localized ccRCC between January 16, 1990, and September 27, 2006. TOP2a expression was assessed using IHC and scored as number of positive cells per mm2. We evaluated TOP2a expression using a continuous variable and tertile categories. For associations with pathologic features, we employed Kruskal-Wallis tests and for associations with cancer-specific survival, we generated Cox proportional hazard regression models. Results: HigherTOP2a expression is associated with later stage, higher grade and higher Mayo SSIGN score (all p < 0.001). The risk of death from RCC increases with increasing TOP2a expression (p trend < 0.0001). Compared to patients in the lowest tertile, those patients with tumors in the highest tertile of TOP2a expression were at increased risk of RCC death (HR=2.31 95% CI 1.64-3.25; p < 0.0001). Interestingly, among those patients with low risk disease (SSIGN score 0-3; ~95% 10 year survival), those with high TOP2a were at increased risk of RCC death (HR=3.09 95% CI 1.29-7.40; p = 0.01). Conclusions: Higher TOP2a expression is associated with more aggressive pathologic features and increased risk of cancer-specific death among patients undergoing surgery for localized ccRCC. If confirmed, these data support further inquiry for TOP2a as a prognostic and predictive biomarker for ccRCC patients.

359 Background: Sarcomatoid renal cell carcinoma (RCC) is an aggressive form of RCC and is associated with a poor prognosis. Standard therapies tend to be less effective in this subset of patients. Methods: Using the Mayo Clinic Nephrectomy Registry, 206 patients with sarcomatoid RCC treated with partial or radical nephrectomy were identified. These patients were characterized based on extent of disease, treatment response and survival. Results: Of these 206, there was no evidence of distant metastases in 110 patients at the time of surgery and the estimated distant metastases-free survival at one year was 44%. The estimated cancer-specific survival rate at one and five years was 56% and 20%, respectively. Compared to patients with grade 4 RCC without sarcomatoid features, those with sarcomatoid RCC were more likely to develop distant metastases following surgery (hazard ratio 1.49). Considering those with metastatic sarcomatoid RCC, 96 patients had metastases at the time of surgery and 77 with no metastases at the time of surgery subsequently developed distant metastases (n=173). Of these, 156 died at a mean of 1.0 years from time of first evidence of distant metastases with a median cancer-specific survival of 0.6 years. Estimated cancer-specific survival rates from time of first metastases at one year and five years were 34% and 4%, respectively. The most common metastatic sites: lung (46%), bone (15%), liver (13%), non-regional lymph nodes (9%), and brain (5%). Patients who received targeted systemic therapy (10%) with either sunitinib (n=14), sorafenib (2) or pazopanib (1) for their first occurrence of distant metastases had an estimated cancer-specific survival rate at one year of 69%, compared to 30% for patients who did not. Median cancer-specific survival for those receiving targeted therapy as first-line was 2.2 years compared to 0.6 years for those patients who did not. Conclusions: Sarcomatoid RCC is an aggressive subtype of kidney cancer as evidenced by poor survival rates. The patients in this registry with metastatic sarcomatoid RCC who received targeted therapy as first-line treatment had improved cancer-specific survival rates.

494 Background: Renal cell carcinoma (RCC) with rhabdoid differentiation is thought to portend a poor prognosis, similar to RCC with sarcomatoid differentiation. Both rhabdoid and sarcomatoid differentiation are classified as grade 4 RCC based on the most recent International Society of Urological Pathology (ISUP) grading system. We sought to determine the prognostic value of rhabdoid differentiation in comparison to RCC with sarcomatoid differentiation, grade 4 RCC without rhabdoid or sarcomatoid differentiation, and grade 3 RCC. Methods: Using the Mayo Clinic Nephrectomy Registry, we identified 406 patients with ISUP grade 4 RCC and 1,758 patients with grade 3 RCC. A urologic pathologist reviewed all specimens to determine the presence of both rhabdoid and sarcomatoid differentiation. Associations of clinical and pathologic features with death from RCC were evaluated using Cox models. Results: Among the 406 grade 4 RCC tumors, 111 (27%) had rhabdoid differentiation and 189 (47%) had sarcomatoid differentiation, although only 28 (7%) demonstrated both rhabdoid and sarcomatoid differentiation. In multivariable analysis of grade 4 RCC tumors, the presence of rhabdoid differentiation was not associated with death from RCC (HR 0.95, p=0.75); in contrast, sarcomatoid differentiation was significantly associated with death from RCC (HR 1.63, p<0.001). Patients with RCC with rhabdoid differentiation were significantly more likely to die of RCC than patients with grade 3 RCC (HR 2.45, p<0.001) and grade 3 RCC with necrosis (HR 1.62; p<0.001). Conclusions: This study confirms that RCC with rhabdoid differentiation is appropriately classified as grade 4. However, unlike sarcomatoid differentiation, the presence of rhabdoid differentiation in grade 4 RCC is not associated with an increased risk of death from RCC. Therefore, rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC.

447 Background: Components of the peripheral blood counts (PBC) are associated with poor prognosis in patients diagnosed with non-metastatic clear cell renal cell carcinoma (ccRCC). Related to this, higher tumor expression of programmed death ligand one (PDL1) is also associated with poor ccRCC prognosis. Herein, we utilize a large cohort of patients undergoing nephrectomy for localized ccRCC to evaluate the association of PBC with tumor expression of PDL1. Secondarily, we examine the association of PBC and relapse free survival (RFS) after adjusting for age and PDL1 expression. Methods: Through chart review, we obtained PBC values at time of nephrectomy for patients enrolled in the Mayo Clinic Renal Registry from 1990-2009 who were treated for localized (M0) ccRCC including the following: hemoglobin (HGB), white blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute eosinophil count (AEC), absolute monocyte count (AMC), and platelets (PLT). We determined tumor PDL1 expression as a continuous variable (% of positive PDL1 tumor cells) using the 5H1 antibody on archived tissues. We analyzed the correlation of PBC values with PDL1 expression as a continuous variable using a linear estimate. To evaluate the association of PBC values with RFS after adjusting for PDL1 expression, we employed multivariate Cox regression models. Results: A total of 706 ccRCC patients had available PDL1 expression and PBC. PDL1 expression was inversely associated with HGB (linear estimate of -0.02, p<0.001) and positively associated with platelets (linear estimate 1.73, p<0.001) whereas there was no association with PDL1 with WBC, ANC, AEC, or AMC. After adjusting for age and PDL1 expression, a higher HGB (HR=0.87, p<0.001), higher ALC (HR 0.68, p=0.003), and higher AEC (HR 0.12, p=0.002) were all associated with improved relapse free survival. Conversely, higher PLT was associated with decreased RFS (HR 1.002, p<0.001). Conclusions: PDL1 expression is associated with decreased HGB and increased PLT at the time of nephrectomy. After adjusting for PDL1 expression and age, higher HGB, ALC, and AEC are associated with improved RFS, while higher platelets are associated with decreased RFS.

420 Background: Cytoreductive nephrectomy (CN) has been associated with significant morbidity, but there is little data identifying patients at increased risk. We evaluated the association of clinicopathologic features with early post-operative complications and prolonged length of stay (pLOS) among CN patients. Methods: We identified 294 patients treated with radical nephrectomy for M1 renal cell carcinoma between 1990 and 2009 at the Mayo Clinic. All complications within 30 days of surgery were reported using standardized methodology according to the Clavien classification. Associations with the presence of any early complication and pLOS (defined as ≥8 days, the top 25th percentile) were evaluated using logistic regression models. Results: Thirty-five (12%) patients experienced at least one early complication and 15 (5%) patients experienced at least one Clavien grade ≥3 early complication. The median LOS was 6 days (IQR 5-7), and 68 (23%) patients had a pLOS. On univariate analysis, liver metastases, symptomatic presentation, intraoperative transfusion, and pathologic nodal stage were significantly associated with both early complications and pLOS (Table). Two multivariate models were constructed. In Model 1 (limited to pre-operative features), only liver metastases (p<0.01) were associated with early complications while liver metastases (p=0.01) and open approach (p=0.02) were associated with pLOS. In Model 2 (all variables included), liver metastases (p=0.01), intraoperative transfusion (p<0.01), and high nuclear grade (p<0.01) were associated with early complications while intraoperative transfusion (p<0.01) and positive nodes (p=0.05) were associated with pLOS. Conclusions: CN was associated with a low incidence of early post-operative complications, particularly Clavien ≥3 complications. Presence of liver metastases and intraoperative transfusion were independently associated with increased risk of both complications and pLOS. [Table: see text]

513 Background: Chromophobe renal cell carcinoma (chRCC) is the third most common histologic subtype of kidney cancer. While most of these tumors have an indolent behavior, 7% of patients with chRCC develop metastases, with no currently available standard of care. The Cancer Genome Atlas characterized chRCC, highlighting pathognomonic single copy chromosomal losses of 1, 2, 6, 10, 13 and 17, as well as a minimal mutation burden distinguishing it from all other cancer types. However, only 15% of the analyzed patients had advanced disease. We analyzed metastatic chRCC to further characterize these tumors and elucidate mechanisms leading to aggressive disease using a variety of next generation and whole genome sequencing. Methods: Our cohort of metastatic chRCC consisted of 40 patients with available clinical and pathologic data. Whole genome sequencing (WGS) was performed on 6 patients (4 primary tumors and 2 metastases), 42 additional samples from 33 patients were analyzed using targeted next-generation sequencing (MSK-IMPACT). Notably, we were able to collect and analyze matched primary and metastatic tumors from 7 patients. As control cohort 27 non-metastatic chRCC tumors were sequenced with MSK-IMPACT. Copy number patterns were computed with OncoSNP seq and FACETS. Results: The most commonly mutated genes in the aggressive chRCC tumors were TP53 and PTEN (WGS: TP53 67 %, PTEN 33%; MSK-IMPACT: TP53 61%, PTEN 27%). No other genes were mutated frequently. Primary tumor samples of chRCC did show the typical pattern of chromosomal losses in 1, 2, 6, 10, 13 and 17. Interestingly, these canonical losses could not be detected in the metastases even when accounting for tumor purity. Conclusions: TP53 and PTEN mutations are highly enriched in both primary and metastatic tumors of aggressive chRCC compared to the non-aggressive tumors and likely play a critical role in disease progression. More intriguingly, the observation of differential copy numbers in matched primary and metastatic tumors suggest whole genome or whole chromosome events in these samples. We are currently employing different bioinformatic and cytogenetic platforms to validate our novel hypothesis of chromosomal events as driver for metastatic development in chRCC.

Split cord malformation (SCM) is a rare abnormality of notochord development. The majority of cases occur in the thoracolumbar region, with more than 30 cases of cervical SCM reported. The clinical impact of SCMs involving the cervical cord is therefore largely unknown. In addition, the concomitant finding of brainstem involvement is presumably incompatible with life in the majority of patients, resulting in a paucity of data regarding this clinical scenario. In this paper the authors present the first case, to their knowledge, of an incomplete cervical SCM involving the brainstem and discuss its clinical impact, diagnosis, and management.

Objectives To evaluate the prognostic significance of urinary collecting system invasion ( UCSI ) in a large series of patients with clear‐cell renal cell carcinoma ( RCC ). Materials and Methods Patients with clear‐cell RCC treated with nephrectomy between 2001 and 2010 were reviewed from a prospectively maintained registry. One urological pathologist re‐reviewed all slides. Cancer‐specific survival was estimated using the Kaplan–Meier method, and associations of UCSI with death from RCC were evaluated using Cox models. Results Of the 859 patients with clear‐cell RCC , 58 (6.8%) had UCSI . At last follow‐up, 310 patients had died from RCC at a median of 1.8 years after surgery. The median follow‐up for patients alive at last follow‐up was 8.2 years. The estimated cancer‐specific survival at 10 years after surgery for patients with UCSI was 17%, compared with 60% for patients without UCSI ( P < 0.001). In a multivariable model, UCSI remained independently associated with an increased risk of death from RCC (hazard ratio 1.5; P = 0.018). Further, among patients with pT 3 RCC , those with USCI had survival outcomes similar to those of patients with pT 4 RCC. Conclusions Collecting system invasion is associated with poor prognosis among patients with clear‐cell RCC . If validated, consideration should be given to including UCSI in future staging systems.