Validation of the 2009 TNM Classification for Renal Cell Carcinoma: Comparison with the 2002 TNM Classification by Concordance Index.

Abstract

To assess the validity of the 2009 TNM classification for renal cell carcinoma (RCC) and compare its ability to predict survival relative to the 2002 classification.
We identified 1,691 patients who underwent radical nephrectomy or partial nephrectomy for unilateral, sporadic RCC between 1989 and 2007. Cancer-specific survival was estimated by the Kaplan-Meier method and was compared among groups by the log-rank test. Associations of the 2002 and 2009 TNM classifications with death from RCC were evaluated by Cox proportional hazards regression models. The predictive abilities of the two classifications were compared by using Harrell's concordance (c) index.
There were 234 deaths from RCC a mean of 38 months after nephrectomy. According to the 2002 primary tumor classification, 5-year cancer-specific survival was 97.6% in T1a, 92.0% in T1b, 83.3% in T2, 61.9% in T3a, 51.1% in T3b, 40.0% in T3c, and 33.6% in T4 (p for trend<0.001). According to the 2009 classification, 5-year cancer-specific survival was 83.2% in T2a, 83.8% in T2b, 62.6% in T3a, 41.1% in T3b, 50.0% in T3c, and 26.1% in T4 (p for trend<0.001). The c index for the 2002 primary tumor classification was 0.810 in the univariate analysis and increased to 0.906 in the multivariate analysis. The c index for the 2009 primary tumor classification was 0.808 in the univariate analysis and increased to 0.904 in the multivariate analysis.
Our data suggest that the predictive ability the 2009 TNM classification is not superior to that of the 2002 classification.

Full text

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Korean Journal of Urology
Ⓒ The Korean Urological Association, 2011
524
Korean J Urol 2011;52:524-530
www.kjurology.org
http://dx.doi.org/10.4111/kju.2011.52.8.524
Urological Oncology
Validation of the 2009 TNM Classification for Renal Cell Carcinoma:
Comparison with the 2002 TNM Classification by Concordance
Index
Chunwoo Lee, Dalsan You, Junsoo Park, In Gab Jeong, Cheryn Song, Jun Hyuk Hong,
Hanjong Ahn, Choung-Soo Kim
Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Purpose: To assess the validity of the 2009 TNM classification for renal cell carcinoma
(RCC) and compare its ability to predict survival relative to the 2002 classification.
Materials and Methods: We identified 1,691 patients who underwent radical neph-
rectomy or partial nephrectomy for unilateral, sporadic RCC between 1989 and 2007.
Cancer-specific survival was estimated by the Kaplan-Meier method and was compared
among groups by the log-rank test. Associations of the 2002 and 2009 TNM classi-
fications with death from RCC were evaluated by Cox proportional hazards regression
models. The predictive abilities of the two classifications were compared by using
Harrell’s concordance (c) index.
Results: There were 234 deaths from RCC a mean of 38 months after nephrectomy.
According to the 2002 primary tumor classification, 5-year cancer-specific survival was
97.6% in T1a, 92.0% in T1b, 83.3% in T2, 61.9% in T3a, 51.1% in T3b, 40.0% in T3c,
and 33.6% in T4 (p for trend＜0.001). According to the 2009 classification, 5-year can-
cer-specific survival was 83.2% in T2a, 83.8% in T2b, 62.6% in T3a, 41.1% in T3b, 50.0%
in T3c, and 26.1% in T4 (p for trend＜0.001). The c index for the 2002 primary tumor
classification was 0.810 in the univariate analysis and increased to 0.906 in the multi-
variate analysis. The c index for the 2009 primary tumor classification was 0.808 in
the univariate analysis and increased to 0.904 in the multivariate analysis.
Conclusions: Our data suggest that the predictive ability the 2009 TNM classification
is not superior to that of the 2002 classification.
Key Words: Kidney neoplasms; Mortality; Neoplasm staging; Prognosis; Renal cell
carcinoma
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Article History:
received 26 May, 2011
accepted 16 June, 2011
Corresponding Author:
Choung-Soo Kim
Department of Urology, Asan Medical
Center, University of Ulsan College of
Medicine, 388-1, Pungnap 2-dong,
Songpa-gu, Seoul 138-736, Korea
TEL: +82-2-3010-3734
FAX: +82-2-477-8928
E-mail: cskim@amc.seoul.kr
INTRODUCTION
Accurate cancer staging systems are essential for planning
treatment, to estimate prognosis, to evaluate treatment re-
sults, to allow exchange of information among medical cen-
ters, and to investigate clinical trials for cancer [1].
Currently, the TNM classification, which defines local ex-
tension of the primary tumor (T), involvement of regional
lymph nodes (N), and presence of distant metastases (M),
is globally accepted for the staging of diverse solid tumors,
including renal cell carcinoma (RCC). The sixth edition of
the TNM classification of RCC, promulgated in 2002, has
been validated in single- and multi-institutional cohorts of
patients treated by surgery [2,3].
　The incidence of localized RCC has been increasing over
the past two decades, mainly because of a rise in the de-
tection of small renal masses [4]. As a result, many studies
have evaluated the prognostic significance of tumor size
and have proposed modifications of the TNM classification,
in particular with regard to the tumor size cutoffs for stage

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2009 TNM Classification of RCC
525
I and II disease [5]. Two recent studies proposed a sub-
classification of T2 patients into T2a and T2b subgroups
based on tumor size [6,7]. Moreover, locally advanced RCC
is a heterogeneous disease characterized by invasion of
various surrounding structures or extension through ve-
nous systems, and the subclassification thereof remains
controversial [5]. Accordingly, numerous proposals that
the 2002 TNM classification for RCC be updated have ap-
peared [8-15].
　On the basis of these recent studies, the Union Interna-
tionale Contre le Cancer (UICC) and the American Joint
Committee on Cancer (AJCC) updated the TNM classi-
fication of RCC in 2009. In this new classification system,
(i) T2 tumors are subdivided into two subgroups based on
a tumor size cutoff of 10 cm: as T2a if the tumor is 10 cm
or less and as T2b if the tumor is greater than 10 cm; (ii)
tumors with renal vein involvement are reclassified as T3a;
(iii) tumors with ipsilateral adrenal involvement are re-
classified as T4 if contiguous invasion and M1 if not con-
tiguous; and (iv) the lymph node classification is simplified
from N1 versus N2 to N1, regardless of number of positive
lymph nodes [16].
　Recently, an Italian group validated the new classi-
fication by using a multi-institutional cohort [17]. Another
two groups evaluated the prognostic impact of the 2009
TNM classification for T2 RCC [18] and RCC with venous
extension [19]. However, only one group has yet compared
the accuracies of the new and old systems with respect to
prediction of patient outcome [20]. In the present work, we
compared the predictive ability of the 2009 and 2002 TNM
classification by using a single-center cohort of patients
who underwent radical nephrectomy (RN) or partial neph-
rectomy (PN) for RCC.
MATERIALS AND METHODS
1. Patients
By review of the Nephrectomy Database of the Asan
Medical Center, we identified 1731 patients who under-
went RN or PN for RCC from 1989 to 2007. A total of 40 pa-
tients were excluded, 30 with bilateral RCC and 10 with
end-stage renal disease or von Hippel-Lindau disease. A to-
tal of 1691 patients underwent RN or PN for unilateral,
sporadic RCC in our analysis. The study protocol was ap-
proved by the Institutional Review Board of the Asan
Medical Center.
2. Evaluation
Staging work-up at the time of diagnosis included chest
X-ray, computed tomography (CT) of the abdomen and pel-
vis, and a bone scan. Based on signs and symptoms, some
patients underwent CT of the chest or brain imaging. RN
and PN were performed by using standard techniques. If
an enlarged lymph node (greater than 1 cm in the longest
dimension) was evident on the preoperative CT scan, we
always performed regional lymphadenectomy. Sampling
biopsies were performed in patients with disease of T3 or
higher. Pathologic stage was reclassified according to the
2002 and 2009 TNM classifications. All patients were rec-
ommended to undergo radiological evaluation, including
chest X-ray, CT of the abdomen and pelvis, and bone scan,
every 6 months for 2 years and yearly thereafter. Diagnosis
of disease recurrence was based on radiological findings
and was confirmed by biopsy if needed. The mean follow-up
duration was 60 months (median 51; range, 1-238 month).
3. Statistical analysis
Quantitative data are expressed as means and medians
with ranges. Cancer-specific survival (CSS) was calculated
from the time of surgery to death from RCC. Follow-up du-
ration was calculated from the time of surgery to the date
of death or last follow-up. Cause of death was determined
from medical records, from death certificates, or by contact-
ing the family. Patients who were alive or died from causes
other than RCC were censored at the date of last contact
or death. Kaplan-Meier survival curves were used to esti-
mate CSS and were compared by using log-rank tests.
Estimated CSS rates are expressed as percentages with
standard errors (SEs). Associations of disease stages based
on the 2002 and 2009 TNM classifications with death from
RCC were evaluated by using Cox proportional hazards re-
gression models. Each correlation between CSS and dis-
ease stage is expressed as a hazard ratio (HR) with 95% con-
fidence interval (CI). The predictive abilities of the two clas-
sifications were evaluated by using Harrell’s concordance
index (c index) [21]. A c index value of 1.0 indicates that the
model perfectly separates patients with different out-
comes, and a value of 0.5 indicates that the model yields
data no better than would be obtained by chance alone. All
statistical tests were two-sided, with a p＜0.05 considered
significant. Data were analyzed by using the SAS software
package (SAS Institute, Cary, NC, USA).
RESULTS
Of the 1,691 evaluated cases, 465 patients (27.5%) were fe-
males and 1,226 (72.5%) were males. Mean age was 54.3
years, with a range of 10 to 87 years. There were 1,365
(80.7%) clear cell RCCs, and the Fuhrman nuclear grade
distribution was as follows: grade 1, n=82 (4.8%); grade 2,
n=842 (49.8%); grade 3, n=629 (37.2%); grade 4, n=118
(7.0%); and unmentioned, n=20 (1.2%).
　Table 1 summarizes the distribution of the 1,691 pa-
tients according to the two TNM systems. The 2009 TNM
system subdivided the 211 T2 patients into 144 T2a pa-
tients and 67 T2b patients, and the numbers of patients in
the T3a, T3b, and T4 classifications also differed compared
with the numbers seen with use of the older system.
　At the last follow-up, 326 patients had died, including
234 who succumbed to RCC at a mean time of 38 months
after nephrectomy (median 26; range, 2-176 months). The
mean follow-up time of the 1,366 patients who were still
alive at the last follow-up was 64 months (median 57; range,
1-238 months). Estimated 5- and 10-year CSS rates for the

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Lee et al
FIG. 1. Cancer-specific survival according to the 2002 (A) and 2009 (B) primary tumor classifications.
TABLE 1. TNM distributions of enrolled renal cell carcinoma
patients
2002 TNM
system
No. of
patients (%)
2009 TNM
system
No. of
patients (%)
Primary tumor classification
T1a
T1b
T2
T3a
T3b
T3c
T4
Lymph node classification
Nx＋N0
N1
N2
Metastasis classification
M0
M1
766 (45.3)
420 (24.8)
211 (12.5)
143 (8.5)
124 (7.3)
10 (0.6)
17 (1.0)
T1a
T1b
T2a
T2b
T3a
T3b
T3c
T4
766 (45.3)
420 (24.8)
144 (8.5)
67 (4.0)
217 (12.8)
38 (2.2)
8 (0.5)
31 (1.8)
1,623 (96.0)
23 (1.4)
45 (2.7)
Nx＋N0
N1
1,623 (96.0)
68 (4.0)
1,549 (91.6)
142 (8.4)
M0
M1
1,548 (91.5)
143 (8.5)
FIG. 2. Cancer-specific survival according to the 2002 lymph
node classification.
entire cohort were 86.3±1.0% and 79.2±1.7%, respectively.
　According to the 2002 primary tumor classification, the
5-year CSS rates were estimated as 97.6±0.7% for T1a pa-
tients, 92.0±1.5% for T1b, 83.3±2.7% for T2, 61.9±4.6% for
T3a, 51.1±5.1% for T3b, 40.0±15.5% for T3c, and 33.6±
11.8% for T4 (p for trend＜0.001) (Fig. 1A). According to the
2009 classification, the 5-year CSS rates were estimated
as 83.2±3.2% for T2a patients, 83.8±5.0% for T2b, 62.6±
3.7% for T3a, 41.1±8.8% for T3b, 50.0±17.7% for T3c, and
26.1±8.4% for T4 (p for trend＜0.001) (Fig. 1B). In a subset
of 211 patients with T2 disease, the CSS values of patients
with T2a and T2b RCC did not differ significantly (p=
0.945). Considering only the 198 patients with N0/NxM0
RCC, the difference between these two classifications was
not statistically significant (p=0.986). The pairwise surviv-
al differences among other T stages were statistically sig-
nificant with the exception of those observed between T3b
and T3c diseases (pairwise p=0.759) and between T3c and
T4 diseases (pairwise p=0.569).
　According to the 2002 lymph node classification, the
5-year CSS rates were estimated as 93.7±1.0% for Nx pa-
tients, 84.1±1.5% for N0, 33.2±10.1% for N1, and 29.7±
7.8% for N2 (p＜0.001) (Fig. 2). However, in a subset of 68
patients with regional lymph node metastases, the CSS
values of patients with N1 and N2 classification were not
significantly different (p=0.728).
　Table 2 and 3 show the results of the univariate and mul-
tivariate analyses of the 2002 and 2009 primary tumor clas-
sifications with respect to prediction of CSS, respectively.
The c index for the 2002 primary tumor classification was
0.810 (95% CI: 0.782-0.839) in the univariate analysis and
increased to 0.906 (95% CI: 0.886-0.925) after adjustment
for regional lymph node involvement, distant metastases,
cell type, and grade by multivariate analysis. The c index
for the 2009 primary tumor classification was 0.808 (95%
CI: 0.779-0.837) in the univariate analysis and increased
to 0.904 (95% CI: 0.884-0.923) in the multivariate analysis.

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2009 TNM Classification of RCC
527
TABLE 2. Univariate and multivariate cox regression analyses of the abilities of the 2002 primary tumor classifications to predict
cancer-specific survival
Classification
Univariate analyses
HR (95% CI)
p-value
Multivariate analyses
HR (95% CI)
p-value
2002 primary tumor classification
　T1a
　T1b
　T2
　T3a
　T3b
　T3c
　T4
2002 lymph node classification
　Nx＋N0
　N1
　N2
2002 metastasis classification
　M0
　M1
c index
4.10 (2.30-7.31)
8.02 (4.51-14.27)
19.24 (11.02-33.59)
27.86 (16.04-48.38)
57.21 (22.32-146.63)
50.11 (24.43-102.77)
NA
NA
0.810 (0.782-0.839)
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
3.37 (1.89-6.01)
4.77 (2.65-8.57)
9.32 (5.24-16.61)
9.73 (5.43-17.45)
17.64 (6.58-47.34)
11.23 (5.16-24.48)
2.46 (1.42-4.28)
1.46 (0.95-2.23)
12.79 (9.38-17.43)
0.906 (0.886-0.925)
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
0.001
0.083
＜0.001
HR: hazard ratio, CI: confidence interval, NA: not applicable
TABLE 3. Univariate and multivariate cox regression analyses of the abilities of the 2009 primary tumor classifications to predict
cancer-specific survival
Classification
Univariate analyses
HR (95% CI)
p-value
Multivariate analyses
HR (95% CI)
p-value
2009 primary tumor classification
　T1a
　T1b
　T2a
　T2b
　T3a
　T3b
　T3c
　T4
2009 lymph node classification
　Nx＋N0
　N1
2009 metastasis classification
　M0
　M1
c index
4.11 (2.31-7.33)
8.01 (4.38-14.65)
7.97 (3.70-17.19)
19.08 (11.17-32.61)
37.38 (19.73-70.80)
45.24 (15.10-135.58)
60.74 (32.55-113.34)
NA
NA
0.808 (0.779-0.837)
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
3.39 (1.90-6.05)
4.55 (2.46-8.42)
5.08 (2.34-11.02)
9.38 (5.38-16.35)
8.77 (4.45-17.25)
28.09 (9.28-85.08)
14.17 (7.10-28.29)
1.65 (1.14-2.40)
12.45 (9.13-16.99)
0.904 (0.884-0.923)
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
＜0.001
0.009
＜0.001
HR: hazard ratio, CI: confidence interval, NA: not applicable
DISCUSSION
Until the 1990s, Robson’s modification of Flocks and
Kadesky’s system, which emphasized outcomes in patients
with locally advanced RCC by focusing on the extent of tu-
mor spread, was accepted as the standard staging system.
With the rising incidence of localized RCC over the past two
decades [4], the TNM classification has become more wide-
ly accepted in clinical practice, and many investigators
have assessed the predictive ability of the system, resulting
in its continuous refinement [5].
　Following the introduction of the 2002 TNM classi-
fication, large retrospective cohort studies have suggested
subdivision of T2 disease on the basis of tumor size [6,7],
and the National Cancer Data Base findings were con-
firmed regarding impact of size of T2 disease on CSS [16].
In addition, several independent studies suggested that T3
RCC should be subdivided, because ipsilateral adrenal in-
volvement was associated with poorer survival than was
T3a RCC with fat invasion [8-10]. Other studies showed
that the survival rates of patients with renal vein thrombo-
sis were better than those of patients with subdiaphra-

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Lee et al
gmatic vena caval thrombosis [11-13]. These led to further
subclassification of T2 RCC in 2009 into T2a and T2b with
a 10-cm cutoff, and the criteria for T3 and T4 classifications
were modified [16].
　The 2002 TNM classification of RCC has been validated
by various institutions [2,3], but the 2009 TNM classi-
fication has not yet been widely explored. A multi-institu-
tional Italian study found that the 2009 TNM classification
was a powerful independent predictor of CSS, but that
some primary tumor classifications afforded overlapping
prognoses, and some included patients with heterogeneous
outcomes [17]. However, the cited study had the limi-
tations of heterogeneity of multi-institutional data and a
lack of comparison with the 2002 classification. This moti-
vated us to perform our current work, which compares the
2002 and 2009 TNM classification of RCC with the use of
a large, single institutional cohort.
　Our results indicate that the 2009 primary tumor classi-
fication performed well in stratification of patients with lo-
cally advanced RCC on the basis of CSS. The 2009 primary
tumor classification was statistically significantly asso-
ciated with death from RCC with a stepwise increase in risk
ratios from T3a to T4, which were approximately 19 for T3a,
37 for T3b, 45 for T3c, and 61 for T4 in the univariate
analysis. Although the pairwise survival differences be-
tween T3c and the adjacent primary tumor classification
did not show statistical significance owing to the small
sample size, the difference between T3b and T4 approached
statistical significance (pairwise p=0.095). In a multi-in-
stitutional Italian study, Novara et al also reported similar
CSS between patients with T3c and T4 RCC [17]. Similarly,
from a large, single institutional cohort, Kim et al reported
no significant survival difference between T3b and T3c dis-
eases [20]. However, in a multi-institutional study includ-
ing 585 patients with inferior vena cava involvement or
higher, Martínez-Salamanca et al found tumor thrombus
level was an independent predictor of CSS even after ad-
justment for tumor size, grade, regional lymph node in-
volvement, distant metastases, and fat invasion [19].
　However, we found no significant difference in the CSS
of patients with T2a and T2b disease, and we observed that
the subclassification of T2 disease by using the 2009 pri-
mary tumor classification did not afford superior pre-
dictive ability than that offered by the 2002 classification
(0.808 vs. 0.810). Our observation that the CSS values of
T2a and T2b RCC patients did not differ may be partly at-
tributable to our relatively small sample size. Our study
cohort included only 211 patients with T2 RCC and was
thus statistically underpowered to detect survival differ-
ences between patients with T2a and T2b disease. In a sin-
gle-institutional study of 544 patients with T2 RCC, Frank
et al reported that patients with tumors 10 cm or greater
in diameter were more likely to die of RCC than were pa-
tients with tumors less than 10 cm in diameter, after ad-
justment for regional lymph node involvement and distant
metastasis [6]. Recently, from the same institutional co-
hort including more patients, Kim et al reconfirmed the ad-
verse prognosis for T2b tumors compared with T2a and
found modestly superior predictive ability of the new TNM
classification compared with the 2002 TNM classification
[20]. In an international multicenter study of 706 patients
with T2 RCC, Klatte et al found a significant association
of tumor size with CSS (HR 1.11, p＜0.001) and suggested
that a tumor diameter size cutoff of 11 cm was appropriate
[7]. The results from a multi-institutional Italian study
supported a subdivision of T2 tumors by 10 cm [17].
However, a recent multi-institutional German study of 579
patients with T2 RCC revealed no significant difference in
CSS between T2a and T2b patients (p=0.38). Even so, pre-
vious reports found that tumor size was significantly asso-
ciated with CSS when size was modeled as a continuous
variable in patients with localized RCC [22] and also in pa-
tients with locally advanced RCC [23,24]. Thus, it may be
that any cutoff is significantly associated with CSS if the
sample size is sufficiently large.
　The 2002 lymph node classification considers the abso-
lute number of metastatic lymph nodes (Nx, no regional
lymph nodes resected; N0, no nodes with metastasis; N1,
metastasis in a single regional lymph node; N2, metastasis
in more than one regional lymph node), assuming that at
least eight lymph nodes are examined. However, several
studies found no significant difference in the survival of N1
and N2 patients [14,15], and the 2009 lymph node classi-
fication thus integrated N1 and N2 into a single stage, des-
ignated N1 [16]. In the present study, we found no sig-
nificant difference in the CSS of patients with N1 or N2
disease. Thus, amalgamation of node-positive RCC may
improve the predictive ability of the 2009 TNM classi-
fication when adjusted for regional lymph node involve-
ment.
　The present study had several limitations. The major
problem is that we used a retrospective design and did not
include pathologic review, and thus our results may be vul-
nerable to confounding errors and bias. Second, with a tre-
mendous increase in stage I tumors, the proportions of T2b,
T3b, T3c, and T4 disease were rather low. Thus, our study
may not have had sufficient statistical power to detect sur-
vival differences among groups of patients with these clas-
sifications of disease. Finally, most of our patients who ex-
perienced recurrence did not have access to targeted thera-
pies for RCC because they were treated before the develop-
ment of these relatively new agents.
　Primary tumor size has long been a key component of the
primary tumor classification for localized RCC. In the de-
velopment of the 1997 classification, the only modifications
of the 1987 classification were the selection of optimal tu-
mor size cutoff points to distinguish T1 and T2 disease.
However, the tumor size was still an independent prog-
nostic factor in integrated prognostic systems, including
tumor stage [25,26]. The 2002 and 2009 TNM classi-
fications were modified to select optimal tumor size cutoffs
for classification of T1 and T2 disease.
　In general, TNM classifications must be modified over
time to improve prognostic ability and to keep pace with the