Two patient specimens evaluated by DIA were not adequate for VA, leaving a total of 310 patients for our current study. At last follow-up, 177 patients had died, including 97 patients who died from RCC at a mean of 3.5 years after nephrectomy (median, 2.2; range, 0-13). Among the 133 patients who were still alive at last follow-up, the mean duration of follow-up was 11.1 years (median, 11.3; range, 0-15). Cancer-specific survival rates (SE, number still at risk) at 1, 5, and 10 years after nephrectomy were 90.6% (1.7%, 262), 73.9% (2.6%, 192), and 67.7% (2.9%, 129), respectively.
The average survivin expression by DIA was 2.3% (median, 1.0%; minimum, 0.01%; maximum, 35.8%). There were 95 (30.7%) patients with tumors that were classified as having high survivin expression (≥2%) using this method. The average survivin expression by VA was 16.2 positive tumor cells per square millimeter (median, 9.1; minimum, 0; maximum, 138.8). One hundred five (33.9%) patients had high survivin expression (≥15 survivin-positive tumor cells per square millimeter) by VA (). However, the patients classified as having high survivin expression by DIA were not necessarily the same patients with high expression by VA. There were 188 (60.7%) patients with low expression by both methods and 78 (25.1%) classified as having high expression by both methods. Conversely, there were 17 (5.5%) with high expression by DIA but low expression by VA and 27 (8.7%) with low expression by DIA but high expression by VA. Of interest, when we compared the 85.8% of cases with concordant results to the 14.2% with discordant results, we did not detect any statistically significant differences with respect to any of our clinical or pathologic covariates. The κ statistic for the comparison of low and high survivin tumor expression between the 2 methods was .68, indicating evidence of a “substantial” level of agreement. In addition, when we analyzed survivin expression as a continuously scaled variable, the intraclass correlation coefficient was 0.70, again indicating substantial agreement between the DIA and VA methods.
Representative photomicrographs of ccRCC showing low (A) and high (B) levels of survivin expression as determined by VA using light microscopy. Original magnification, × 400.
provides a comparison of clinical and pathologic features between those patients classified as having low and high survivin
expression by VA. Similar to our previously published data using DIA to evaluate survivin
], high expression was significantly associated with several adverse pathologic features. Specifically, patients with tumors that had ≥15 survivin
-positive cells per square millimeter were more likely to be symptomatic at presentation and have larger tumors that were more likely to extend into the renal vein, be of advanced stage and grade, and contain areas of necrosis and sarcomatoid differentiation compared with patients whose tumors showed low levels of survivin
Comparison of clinical and pathologic features by VA of survivin expression for 310 patients with ccRCC
In a univariate setting, each increase of 10 survivin-positive tumor cells per square millimeter was associated with a 37% increase in the risk of death from RCC (risk ratio = 1.37; 95% CI, 1.28-1.46; P < .001). Patients classified as having high survivin tumor expression by VA were nearly 5 times more likely to die from RCC compared with patients with low survivin tumor expression (risk ratio = 4.73; 95% CI, 3.13-7.13; P < .001; ). Visualization of the survival experience of these 2 groups confirmed the poorer survival for patients with high survivin tumor expression and showed that this difference was apparent early in the follow-up period (, P < .001). Cancer-specific survival rates (SE, number still at risk) at 1, 5, and 10 years after nephrectomy were 77.2% (4.2%, 74), 45.8% (5.2%, 37), and 41.8% (5.3%, 22), respectively, for patients with tumors that had ≥15 survivin-positive cells per square millimeter compared with 97.5% (1.1%, 188), 87.7% (2.4%, 155), and 80.4% (3.0%, 107), respectively, for patients with tumors containing <15 survivin-positive cells per square millimeter.
Association of survivin tumor expression (high versus low) with death from RCC for 310 patients with ccRCC
Fig. 3 Association of survivin expression by VA with death from RCC for 310 patients with ccRCC (risk ratio = 4.73; 95% CI, 3.13-7.13; P < .001). Cancer-specific survival rates (SE, number still at risk) at 1, 5, and 10 years after nephrectomy were 77.2% (more ...)
The associations of survivin expression (high versus low) by both DIA and VA with death from RCC after multivariate adjustment are summarized in . Although the associations of survivin expression with death from RCC were attenuated after multivariate adjustment, high survivin expression by either method was still significantly associated with patient outcome after adjusting individually for ECOG performance status, the 2002 TNM stage groupings, tumor size, nuclear grade, and presence of necrosis (). Moreover, patients with high survivin tumor expression by VA were more than twice as likely to die from RCC compared with patients with low survivin tumor expression even after adjusting for the UISS scoring system (risk ratio = 2.82; 95% CI, 1.76-4.52; P = .004; ) and the SSIGN score (risk ratio = 2.01; 95% CI, 1.26-3.22; P = .004; ). Finally, based on c index values obtained from univariate and multivariate analysis, the ability of survivin expression to predict death from RCC was nearly identical whether the expression was determined by DIA or by VA ().