The Integration of Macroscopic Tumor Invasion of Adjacent Organs into TNM Staging System for Colorectal Cancer

Abstract

In addition to pathological TNM (pTNM) staging, the macroscopic staging (surgical TNM, sTNM) is another method used to stage and assess tumors, and it also potentially influences patient treatment guidelines. However, for the same patient, surgeons and pathologists might assess tumor depth differently. We aimed to evaluate the prognosis of patients who exhibit unconformity of intraoperative and postoperative results and propose a revised pT category (r-pT category) to predict survival in colorectal cancer.
In our study, 948 colorectal cancer patients were reviewed. We proposed a novel r-pT category in which surgical macroscopic T4b (sT4b) is incorporated into the pT category, namely, patients in the pT3 category with sT4b cancers are reclassified as being in the r-pT4a category; patients in the pT4a category with sT4b cancers are reclassified as being in the r-pT4b category. Cancer-specific survival according to the r-pT category was analyzed using Kaplan-Meier survival curves. A two-step multivariate analysis was used to determine correlations between the r-pT category and the prognosis. Harrell's C statistic was utilized to test the predictive capacity. There were significant prognostic differences among the r-pT subcategories. We substituted the r-pT category for the pT category in current TNM staging in a 2-step multivariate analysis. The Harrell's C statistical analysis results demonstrated that the r-pT category had superior predictive capacity compared to the pT category (Harrell' C: 0.668 vs. 0.636; P = 0.002).
Patients in the pT3 category with sT4b cancers, and patients in the pT4a category with sT4b cancers, are potentially under-staged, reclassification into higher categories could potentially benefit these patients. The results indicate that the r-pT category we proposed is potentially superior to the pT category in the assessment of prognosis for colorectal cancer.

Full text

The Integration of Macroscopic Tumor Invasion of
Adjacent Organs into TNM Staging System for Colorectal
Cancer
Ji-wang Liang
1.
, Peng Gao
1.
, Zhen-ning Wang
1
*, Yong-xi Song
1
, Ying-ying Xu
1
, Mei-xian Wang
2
,Yu-
lan Dong
2
, Hui-mian Xu
1
1Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, People’s Republic of China, 2Department of Tumor
Pathology and Surgical Oncology, First Hospital of China Medical University, Shenyang, People’s Republic of China
Abstract
Objective:
In addition to pathological TNM (pTNM) staging, the macroscopic staging (surgical TNM, sTNM) is another
method used to stage and assess tumors, and it also potentially influences patient treatment guidelines. However, for the
same patient, surgeons and pathologists might assess tumor depth differently. We aimed to evaluate the prognosis of
patients who exhibit unconformity of intraoperative and postoperative results and propose a revised pT category (r-pT
category) to predict survival in colorectal cancer.
Methods and Results:
In our study, 948 colorectal cancer patients were reviewed. We proposed a novel r-pT category in
which surgical macroscopic T4b (sT4b) is incorporated into the pT category, namely, patients in the pT3 category with sT4b
cancers are reclassified as being in the r-pT4a category; patients in the pT4a category with sT4b cancers are reclassified as
being in the r-pT4b category. Cancer-specific survival according to the r-pT category was analyzed using Kaplan-Meier
survival curves. A two-step multivariate analysis was used to determine correlations between the r-pT category and the
prognosis. Harrell’s C statistic was utilized to test the predictive capacity. There were significant prognostic differences
among the r-pT subcategories. We substituted the r-pT category for the pT category in current TNM staging in a 2-step
multivariate analysis. The Harrell’s C statistical analysis results demonstrated that the r-pT category had superior predictive
capacity compared to the pT category (Harrell’ C: 0.668 vs. 0.636; P = 0.002).
Conclusions:
Patients in the pT3 category with sT4b cancers, and patients in the pT4a category with sT4b cancers, are
potentially under-staged, reclassification into higher categories could potentially benefit these patients. The results indicate
that the r-pT category we proposed is potentially superior to the pT category in the assessment of prognosis for colorectal
cancer.
Citation: Liang J-w, Gao P, Wang Z-n, Song Y-x, Xu Y-y, et al. (2012) The Integration of Macroscopic Tumor Invasion of Adjacent Organs into TNM Staging System
for Colorectal Cancer. PLoS ONE 7(12): e52269. doi:10.1371/journal.pone.0052269
Editor: Connie J. Eaves, B.C. Cancer Agency, Canada
Received August 5, 2012; Accepted November 9, 2012; Published December 26, 2012
Copyright: ß2012 Liang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by National Science Foundation of China (30972879 and 81172370), the Program of Scientific and Technological Department
of Liaoning Province (2010225032) and the Program of Education Department of Liaoning Province (L2011137). The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: josieon826@yahoo.com.cn
.These authors contributed equally to this work.
Introduction
Colorectal cancer is the third most common malignancy in the
Western world, as well as the third leading cause of cancer-related
death worldwide [1]. In China, the incidence of colorectal cancer
is gradually increasing annually [2]. The International Union
Against Cancer (UICC)/American Joint Committee on Cancer
(AJCC) TNM staging system has been used for the staging of
colorectal cancer for many years. The TNM classification was
initially developed to predict prognosis and includes depth of
tumor invasion into or beyond the wall of the tumors, invasion of
or adherence to adjacent organs or structures (T), the number of
regional lymph nodes involved (N), and presence or absence of
distant metastasis (M) [3]. Since the mid-1980s, the TNM system
has become our global ‘‘language of cancer’’ [4]. In many research
studies, multiple clinicopathologic features are being investigated
to determine the relationship with patient survival [5–7]. It is well
accepted that T category is a significant or even independent
predictor of survival in colorectal cancer [8,9].
In clinical practice, there usually is another staging system called
surgical TNM (sTNM), which is applied to stage and assess the
cancer, and it potentially influences patient management guide-
lines [10,11,12]. The sTNM staging is also based on the tumors,
lymph nodes, and metastasis but is defined by surgeons according
to the intraoperative findings [10,12], in contrast to TNM staging,
which is performed by pathologists (pathologic TNM, pTNM). In
addition to providing information on the cancer, intraoperative
staging is utilized to allow for the selection of the optimal
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individualized surgical decision for the patient. It is commonly
accepted that accurate staging is not only a foundation for
deciding the most suitable subsequent therapy, but is also a critical
tool for assessment of survival. It is important to obtain accurate
intraoperative and postoperative staging, as these tools aid in the
evaluation of the optimal extent of tumor resection and offer useful
auxiliary treatment decisions. Nonetheless, in clinical practice, the
assessments might exhibit differences between surgical and
pathological stages of tumor depth [13,14,15]. Although some
researchers have analyzed the sources and consequences of this
phenomenon in patients with gastric cancer [12], the conse-
quences of overtreatment or undertreatment due to inconsistent
assessments have not been further investigated, as well as the
impact on patient postoperative outcome. Currently, few reports
have focused on this issue in a large sample of colorectal cancer
patients. It remains unclear whether or not the unconformity of
staging results influences the survival of patients with colorectal
cancer.
Thus, in this study we aimed to evaluate survival of colorectal
cancer patients with inconsistent assessments of tumor depth
between surgical and pathological staging. We also assessed the
feasibility of a new revised pT category (r-pT category), which
integrates the surgical T (sT) category with pathological T (pT)
category for prognostic assessment, and investigated whether it
exhibits any improvement in predictive capabilities.
Methods
Participants
Clinical information on all colorectal cancer patients who
underwent surgery at the Department of Surgical Oncology at the
First Hospital of China Medical University from April 1994 to
December 2007 was retrospectively collected and then reviewed
and analyzed. Patients with any of the following criteria were
excluded from this study: (i) patients who died in the immediate
postoperative period (within 30 days), (ii) patients with multiple
adenocarcinomas of colon and rectum, (iii) patients with synchro-
nous or metachronous tumors, (iv) patients with distant metastasis,
(v) patients who underwent neoadjuvant treatment, (vi) patients
with incomplete pathological data entries, and (vii) patients who
were lost to follow-up. After considering the above criteria, there
were 948 colorectal cancer patients in our study. The clinico-
pathologic data utilized included age, gender, date of surgery, date
of death (if applicable), cause of death, date of follow-up, location
of the primary tumor, tumor size, histologic grade, venous
invasion, lymphovascular invasion, depth of invasion, tumor
deposits, number of lymph nodes retrieved, and number of lymph
node metastases. The information was obtained through the
medical records for all patients. Tumors originating from cecum to
sigmoid colon were defined as colon cancer; tumors located in the
rectum or rectosigmoid junction were considered as rectal cancer
[16].
Classification Methods
During the surgical procedure for colorectal cancer, the tumor
of each patient was examined, and the final macroscopic depth of
invasion was confirmed by all of the surgeons present during the
operation after tumor exploration was complete [17]. In order to
ensure the integrity of the tumor specimen, surgeons did not cut
open the tumor to determine sT staging. The pathologists
subsequently evaluated the postoperative tumor staging. Selecting
the postoperative therapeutic option and evaluating the prognosis
of patients were still based on the pT staging.Macroscopic
assessment of tumor depth during surgery named sT staging was
performed as follows: sT1 lesions were diagnosed when the lesion
felt normal, and the assessment combined with preoperative
auxiliary examination; sT2 lesions were diagnosed when the lesion
felt mobile on the muscle layer of the colorectal wall; sT3 lesions
were diagnosed when tumor did not invade through the serosa,
and the lesion felt nodular on the serosal layer of the colorectal
wall; sT4a lesions when serosal involvement were visible and sT4b
lesions were directly invaded, or was adherent to other organs or
structures [12].
Pathological Procedures
All specimens were fixed in formalin, embedded in paraffin, and
stained with hematoxylin and eosin. The sections of tumor were
examined by two independent pathologists and confirmed by
a third pathologist to arrive at the final diagnosis. Disagreements
regarding the diagnosis were resolved by consensus on subsequent
review of the slides, with all three pathologists present [18].
Follow Up
Postoperative follow-up was completed for the entire study
population in November 2008. The median and mean follow-up
periods were 39.0 months and 50.5 months (range: 1.1–167.1
months), respectively.
Ethics Statement
The study was approved by the Research Ethics Committee of
China Medical University, China. Written informed consent was
obtained from all patients prior to participation in this study.
Statistical Analysis
Continuous data are presented as mean 6standard deviation
(SD). Cancer-specific survival was analyzed using Kaplan-Meier
survival curves, and comparisons were made using the log-rank
test. For the purpose of our study, we proposed a novel category, r-
pT, in which sT4b was included in the pT category, patient
survival was then assessed and compared according to staging
using the r-pT category. Multivariate analysis was performed using
Cox’s proportional hazards model. Two-step multivariate analyses
were applied to identify which category (the pT category in
current TNM staging, and the r-pT category) had the greater
potential to predict patient survival. The predictive value was also
evaluated using Harrell’s C statistic: a higher C statistic indicates
a more desirable model for predicting outcome [19,20]. Statistical
analyses and graphics were performed using PASW Statistics 18.0
software (SPSS, Inc., Somers, NY, USA) and STATA MP ver.10
(StataCorp LP, College Station, TX) statistical software. A value of
P,0.05 was considered to be statistically significant.
Results
Clinicopathological characteristics of 948 colorectal cancer
patients are listed in Table 1. In our study, there were 551
(58.1%) males and 397 females (41.9%; ratio 1.4:1) with a median
age of 62.00 years (range 20–88 years). Among these patients, 475
patients (50.1%) suffered colon tumors and 473 patients (49.9%)
suffered rectum tumors. Patients were classified according to the
following sT category and the pT category in current TNM
staging: 13 (1.37%) patients, 61 (6.43%) patients, 124 (13.08%)
patients, 527 (55.59%) patients, and 223 (23.52%) patients were
sT1, sT2, sT3, sT4a and sT4b, respectively; 12 (1.27%) patients,
164 (17.30%) patients, 651 (68.67%) patients, 99 (10.44%)
patients, and 22 (2.32%) patients were pT1, pT2, pT3, pT4a
and pT4b, respectively. Univariate analysis identified the sT
category (P,0.001) and the pT category in the seventh edition of
Macroscopic Tumor Invasion of Adjacent Organs
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TNM staging (P,0.001) were significantly correlated with
prognosis (Table 1).
The 5-year survival rates for all patients stratified according to
sT category were calculated for each group. The 5-year survival
rate for patients with sT4b cancer was significantly lower
compared to sT3 cancer patients (53.5% vs. 68.1%; P =0.002),
and also lower compared to sT4a cancers (53.5% vs. 74.9%;
P,0.001), however, sT3 and sT4a cancers had similar 5-year
survival rates (68.1% vs. 74.9%; P = 0.404) (Table 1, Figure 1A).
When prognosis was compared, there were significant differences
among pT subcategories (Figure 1B).
For patients in each pT category, prognosis was compared
according to the sT category, and no significant differences were
found among sT1, sT2, sT3, and sT4a in pT3 category, as well as
in pT4a category (P.0.05). As shown in Figure 2, for patients in
pT3 category, there was a significant prognostic difference
between sT1-4a and sT4b cancers (P,0.001) (Figure 2A), and
for patients in pT4a category, there was a significant prognostic
difference between sT1-4a and sT4b cancers (P = 0.001)
(Figure 2B). Therefore, marked prognostic heterogeneity was
demonstrated in the pT3 and pT4a categories.
We then integrated sT4b with the pT category and reclassified
patients in the pT3 and pT4a categories. We compared the
prognosis, and no significant differences were found between pT3/
sT4b and pT4a/sT1-4a (P =0.599), as well as pT4a/sT4b and
pT4b (P = 0.351), which suggests that the heterogeneity disap-
peared among these groups (Figure 3A). Therefore, we in-
corporated pT3/sT4b into pT4a/sT1-4a, as well as pT4a/sT4b
into pT4b. We then compared survival curves, and found
significant differences among the different categories (Figure 3B).
Based on these results, we proposed a novel category, r-pT, in
which patients categorized as pT3 with sT4b were incorporated
into the category pT4a (r-pT4a), and patients categorized as pT4a
with sT4b were incorporated into the category pT4b (r-pT4b).
To further elucidate the correlation between r-pT category and
prognosis, two-step multivariate analyses was used. In the step one
multivariate analysis, pN category, lymphovascular invasion, sT
category, pT category and tumor deposits were confirmed to be
independent prognostic factors (P = 0.001 for lymphovascular
invasion, P = 0.041 for sT category, P,0.001 for all the others,
Table 3). Interestingly, in the step two multivariate analysis, in
which the r-pT category was also considered together with the
factors of the step one multivariate analysis, pN category,
lymphovascular invasion and tumor deposits remained significant
(P = 0.002 for lymphovascular invasion, P,0.001 for all others,
Table 3). In the step two multivariate analysis, the pT category lost
its significance and was substituted by the r-pT category.
The r-pT and pT categories were measured by Harrell’s C
statistic to determine which exhibited a superior predictive
capacity. Our findings demonstrated that the r-pT category
(Harrell’s C = 0.668; 95% CI:0.635–0.702) was superior to the pT
category in current TNM staging (Harrell’s C = 0.636; 95%
CI:0.604–0.667) (P = 0.002).
Discussion
The UICC/AJCC TNM staging system, although controver-
sial, is considered the most powerful and reliable predictor of
prognosis for colorectal cancer globally. Presently, it is generally
accepted that the depth of tumor invasion in the TNM staging
system is an important prognostic factor. In particular, pT4 as
a complex subgroup is strongly correlated with adverse events
[21]. In the new era of comprehensive diagnostic modalities, the
importance of surgical staging in standard cancer management has
been well established [11]. In many clinical settings, defining the
patient prognosis and subsequent therapeutic management is
potentially difficult in the absence of appropriate surgical staging
[11]. For example, in a report by Gajra et al, they emphasized that
surgical staging of cancer impacts the prognosis of non-small-cell
Table 1. Clinicopathologic features of 948 patients with
colorectal cancers.
n
a
5-YSR
b
(%) P value
Gender 0.620
Male 551 68.6
Female 397 72.3
Age 0.110
#60 433 73.3
.60 515 67.1
Tumor location 0.599
Colon 475 71.4
Rectum 473 69.0
Size 0.662
#5.0 cm 543 71.2
.5.0 cm 405 69.2
Venous invasion ,0.001
Positive 9 16.7
Negative 939 70.8
Lymphovascular invasion ,0.001
Positive 58 43.0
Negative 890 72.0
Histologic grade 0.001
Well 435 75.5
Moderate 435 66.3
Poor 78 57.3
Tumor deposits ,0.001
Positive 135 36.9
Negative 813 75.5
pT category ,0.001
pT1 12 100.0
pT2 164 83.4
pT3 651 71.7
pT4a 99 47.5
pT4b 22 35.8
sT category ,0.001
sT1 13 100.0
sT2 61 77.5
sT3 124 68.1
sT4a 527 74.9
sT4b 223 53.5
pN category ,0.001
pN0 561 84.4
pN1 271 58.7
pN2 116 25.2
n
a
: Number of patients.
5-YSR
b
: 5-year accumulative survival rate.
doi:10.1371/journal.pone.0052269.t001
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lung cancer [22]. In addition, the relationship between intrao-
perative and postoperative staging is of potentially great impor-
tance [11]. For cases in which accurate macroscopic and
pathologic assessments were obtained, it is possible to provide
a much more reasonable estimate of prognosis. However, in
clinical practice, intraoperative and postoperative assessments of T
category frequently have unconformity due to lots of reasons,
resulting in inadequate tumor staging and posing an obstacle to
standardized treatment management. The unconformity of gastric
cancer staged by pT and sT staging has been previously reported
in numerous studies [12,13]. In this study, we present a retrospec-
tive single-center analysis of 948 Chinese patients with colorectal
cancer. There were 755 patients with inconsistent staging results in
our study, and our findings demonstrated a noticeable tendency in
which surgeons stage tumors in a low category to a higher category
during the surgical procedure compared to the pathological
staging (Table 2).
In several previous studies concerning gastric cancer, some
researchers only explained the possible reasons of this unconfor-
mity, but the patients’ prognostic outcomes that were influenced
by the unconformity were not further investigated [12,13]. Until
now, the data regarding colorectal cancer and this issue has been
limited. In our study, using univariate analysis, we found that the
sT category was an important independent prognostic factor.
Simultaneously, the cancer-specific survival rates of patients
stratified by sT category were compared among the different pT
groups. We found that there was a significant difference between
sT1-4a and sT4b in pT3 cancers (P,0.001), as well as in pT4a
cancers (P = 0.001). Our findings indicated that there was
prognostic heterogeneity in these groups. Taken together, our
findings indicated that there are potential shortcomings in the
current pT category for staging patients when their surgical and
pathological results are inconsistent, and sT4b cancers should not
Figure 1. Comparison of survival curves among the patients according to the sT and pT category. A, Survival curves of patients with
different sT categories. B, Survival curves of patients with different pT categories.
doi:10.1371/journal.pone.0052269.g001
Figure 2. Comparison of survival curves of the patients stratified by pT and sT category. A, For patients in pT3 category, there was
prognostic difference between sT4a and sT4b cancer (P,0.001). B, For patients in pT4a category, there was prognostic difference between sT4a and
sT4b cancer (P = 0.001).
doi:10.1371/journal.pone.0052269.g002
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be neglected when colorectal tumors were classified according to
the pT category.
We compared the 5-year survival curves of the patients
categorized as having pT3 and pT4 cancers. We found that there
were no significant prognostic differences between pT3/sT4b and
pT4a/sT1-4a, as well as pT4a/sT4b and pT4b. These loss of
differences indicated that pT3/sT4b cancers might more homo-
geneous with pT4a/sT1-4a cancers, as well as pT4a/sT4b with
pT4b cancers. This suggested that subclassification of pT3/sT4b
and pT4a/sT1-4a cancers into one group is warranted, as well as
pT4a/sT4b and pT4b cancers should be subclassified into one
group. We compared survival curves, and found significant
differences among the different categories. Based on above results,
we proposed a novel r-pT category: patients in pT3 with sT4b
cancers were categorized as r-pT4a, and patients in pT4a with
sT4b cancers were categorized as r-pT4b. And then, we tested this
novel r-pT category in our study. When comparing the prognostic
power of the r-pT category to that of the present pT category, 2-
step multivariate analysis was utilized. In the step 1 multivariate
analysis, the pT category was identified as an independent
prognostic factor, as well as the sT category. However, when the
step 2 multivariate analysis was applied, the pT category and sT
category lost significance and were substituted by the r-pT
category. This result suggests that the r-pT category had superior
prognostic value compared to the pT category. In addition, we
used Harrell’s C statistic to further elucidate whether the r-pT
category was superior to pT category in terms of predictive
capacity, and the results demonstrated that the r-pT category stage
exhibited a stronger predictive power. Both statistic methods
confirmed that the novel r-pT category was more accurate than
the pT category in prognostic assessment.
It is commonly accepted that intraoperative assessment of tumor
depth is often difficult. Nonetheless, sT4b, a category that
represents tumors that directly invade other organs, is much
easier for surgeons to distinguish and identify compared to other
subgroups during surgery. Based on these considerations, this
novel category which incorporated the sT4b category into the pT
category was simple to perform in clinical settings.
We acknowledge that there are several limitations in this study.
Our study is based on the retrospective analysis of a mono-
institutional clinicopathological database of 948 Chinese colorectal
cancer patients. Certainly, our conclusions are constrained by the
usual limitations of retrospective analysis from a single institution.
Whether our results can be applied to other institutions remains to
be demonstrated. We look forward to performing studies with
a larger sample size, as well as international multicentric studies in
patients with colorectal cancer in the near future and authenticat-
ing the accuracy in a large population-based collective of patients.
According to the results generated in our study, we suggest that
macroscopic tumor invasion of adjacent organs should be taken
into account for prognosis of patients with colorectal cancer.
When patients are categorized as pT3 with sT4b, they could be
reclassified as r-pT4a, and when patients are categorized as pT4a
with sT4b, they could be reclassified as r-pT4b. This novel r-pT
category that we proposed could be applied to predict the patient
prognosis and is also potentially superior to the seventh edition of
the T category for assessment of the prognostic power in colorectal
cancer.
Figure 3. Survival curves of patients with colorectal cancers according to the r-pT category. A, Survival curves of patients grouped by pT
categories when patients in pT3 and pT4a were stratified by sT categories. There were no significant differences between pT3/sT4b and pT4a/sT1-4a
(P = 0.599), as well as pT4a/sT4b and pT4b (P= 0.351). B, Survival curves of patients stratified by r-pT category, there were significant differences
among the patients.
doi:10.1371/journal.pone.0052269.g003
Table 2. Comparison and kappa statistics between the sT
and pT categories patients.
sT n
a
sT1 sT2 sT3 sT4a sT4b
pTsT15610012
pT2 6 32 36 69 21 164
pT3 2 20 76 396 157 651
pT4a 0 3 11 60 25 99
pT4b00022022
n
a
13 61 124 527 224 949
n
a
: Number of patients.
doi:10.1371/journal.pone.0052269.t002
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Author Contributions
Conceived and designed the experiments: JWL PG ZNW. Performed the
experiments: JWL PG MXW YLD. Analyzed the data: PG. Contributed
reagents/materials/analysis tools: PG YXS YYX HMX. Wrote the paper:
JWL PG YXS.
References
1. Ostadi MA, Harnish JL, Stegienko S, Urbach DR (2007) Factors affecting the
number of lymph nodes retrieved in colorectal cancer specimens. Surg Endosc
21: 2142–2146.
2. Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. (2008) Cancer Statistics, 2008.
CA Cancer J Clin 58: 71–96.
3. Sobin LH, Gospodarowicz MK, Wittekind CH (2009) UICC TNM classifica-
tion on malignant tumours. 7th edition.
4. Greene FL, Sobin LH (2009) A worldwide approach to the TNM staging system:
collaborative efforts of the AJCC and UICC. J Surg Oncol 99: 269–272.
5. Tong LL, Gao P, Wang ZN, Song YX, Xu YY, et al. (2011) Can lymph node
ratio take the place of pN categories in the UICC/AJCC TNM classification
system for colorectal cancer? Ann Surg Oncol 18: 2453–2460.
6. Nagtegaal ID, Quirke P (2007) Colorectal tumour deposits in the mesorectum
and pericolon: a critical review. Histopathology 51: 141–149.
7. Tong LL, Gao P, Wang ZN, Yue ZY, Song YX, et al. (2011) Is pT2
subclassification feasible to predict outcome in colorectal cancer ? Ann Surg
Oncol 18: 1389–1396.
8. Hemminki K, Santi I, Weires M, Thomsen H, Sundquist J, et al. (2010) Tumor
location and patient characteristics of colon and rectal adenocarcinomas in
relation to survival and TNM classes. BMC Cancer 10: 688.
9. Goldstein NS, Turner JR (2000) Pericolonic tumour deposits in patients with
T3N+M0 colon adenocarcinomas: markers of reduced disease free survival and
intra-abdominal metastases and their implications for TNM classification.
Cancer 88: 2228–2238.
10. Harisi R, Schaff Z, Flautner L, Winternitz T, Jaray B, et al. (2008) Evaluation
and comparison of the clinical, surgical and pathological TNM staging of
colorectal cancer. Hepatogastroenterology 55: 66–72.
11. Markman M (2003) Surgical staging of cancer: impact on prognosis and
potential for bias in clinical trials. Curr Onco Rep 5: 437–438.
12. Madden MV, Price SK, Learmonth GM, Dent DM (1987) Surgical staging of
gastric carcinoma: sources and consequences of error. Br J Surg 74: 119–121.
13. Xu HM, Chen JQ, Wang SB, Qi CL, Shan JX (1995) Prediction of the staging
and biological behavior from the serosal change in gastric cancer. J China
Medical University 24: 352–355.
14. Chen YG, Liu YL, Jiang SX, Wang XS (2011) Adhesion pattern and prognosis
studies of T4N0M0 colorectal cancer following en bloc multivisceral resection:
evaluation of T4 subclassification. Cell Biochem Biophys 59: 1–6.
15. Compton CC, Greene FL (2 004) The staging of colorectal cancer: 2004 and
beyond. CA Cancer J Clin 54: 295–308.
16. Chok KS, Law WL (2007) Prognostic factors affecting survival and recurrence of
patients with pT1 and pT2 colorectal cancer. World J Surg 31: 1485–1490.
17. Chen JQ, Qi CL, Wang SB, Shan JX, Zhang WF, et al. (1986) The serosal types
of gastric cancer and its biologic significance. J China Medical University 15:
347–350.
18. Sun Z, Zhu GL, Lu C, Guo PT, Huang BJ, et al. (2009) A novel subclas sification
of pT2 gastric cancers according to the depth of muscularis propria invasion:
superficial muscularis propria versus deep muscularis propria/subserosa. Ann
Surg 249: 768–775.
19. Harrell FE Jr, Lee KL, Mark DB (1996) Multivariable prognostic models: issues
in developing models, evaluating assumptions and adequacy, and measuring and
reducing errors. Stat Med 15: 361–387.
20. Harrell FE Jr, Lee KL, Califf RM, Pryor DB, Rosati RA (1984) Regression
modelling strategies for improved prognostic prediction. Stat Med 3: 143–152.
21. Tong LL, Gao P, Wang ZN, Song YX, Xu YY, et al. (2012) Is the 7th edition of
the UICC/AJCC TNM staging system reasonable for patients with tumor
deposits in colorectal cancer? Ann Surg 225: 208–213.
22. Gajra A, Newman N, Gamble GP, Kohman LJ, Graziano SL (2003) Effect of
number of lymph nodes sampled on outcome in patients with stage I non-small-
cell lung cancer. J Clin Oncol 21: 1029–1034.
Table 3. Two-step multivariate analysis of the prognostic factors for 948 patients.
Relative Risk 95% Confidence Interval
P
value*
Step 1
{
sT category 1.232 1.009–1.504 0.041
pT category 1.693 1.393–2.059 ,0.001
pN category 2.303 1.923–2.759 ,0.001
Tumor deposits 1.821 1.347–2.463 ,0.001
Lymphovascular invasion 1.927 1.288–2.885 0.001
Step 2
{
pN category 2.283 1.906–2.735 ,0.001
Lymphovascular invasion 1.902 1.270–2.849 0.002
Tumor deposits 1.833 1.354–2.480 ,0.001
r-pT category 1.846 1.566–2.176 ,0.001
*Pvalues were made by Cox’s proportional hazards model.
{
Step 1, with consideration of all significantly important prognostic factors in univariate analysis, except for the r-pT category.
{
Step 2, with consideration of all significantly important prognostic factors in univariate analysis, including the r-pT category.
doi:10.1371/journal.pone.0052269.t003
Macroscopic Tumor Invasion of Adjacent Organs
PLOS ONE | www.plosone.org 6 December 2012 | Volume 7 | Issue 12 | e52269