The validity of predicting prognosis by the number of lymph node metastases in node-positive colon cancer

doi:10.4236/ojgas.2013.34036

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Open Journal of Gastroenterology, 2013, 3, 217-222 OJGas

doi:10.4236/ojgas.2013.34036 Published Online August 2013 (http://www.scirp.org/journal/ojgas/)

The validity of predicting prognosis by the number of

lymph node metastases in node-positive colon cancer*

Kiichi Sugimoto, Masaya Kawai, Kazuhiro Takehara, Yoshihiko Tashiro, Shinya Munakata,

Kiichi Nagayasu, Koichiro Niwa, Shun Ishiyama, Hiromitsu Komiyama, Makoto Takahashi,

Yutaka Kojima, Michitoshi Goto, Yuichi Tomiki, Kazuhiro Sakamoto

Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University, Tokyo, Japan

Email: [email protected]

Received 22 May 2013; revised 22 June 2013; accepted 15 July 2013

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background: We examined the possibility of predict-

ing prognosis by the number of lymph node metasta-

ses. Methods: Two hundred and forty-nine patients

with lymph node metastases who underwent curative

surgery for colon cancer were enrolled in this study.

We calculated cancer-specific survival according to

the number of lymph node metastases. Results: There

was a tendency toward better rates of cancer-specific

survivals among the patients with 1 LNM, compared

with those with 2 LNM (p = 0.07). When comparing

cancer-specific survival between the patients with 1, 2

- 3 and 4 or more lymph node metastases, cancer-

specific survival was well stratified (p < 0.0001). With

regard to stage classification, in the Japanese classi-

fication, there was a significant difference in cancer-

specific survival between Stages IIIa and IIIb (p <

0.0001). On the other hand, in the TNM classification,

cancer-specific survivals in Stages IIIA, IIIB and IIIC

were stratified into three groups with significant dif-

ferences (IIIA vs. IIIB; p = 0.007, IIIB vs. IIIC; p <

0.0001). Conclusion: It appeared to be valid to strat-

ify cancer-specific survival into three groups, i.e., the

patients with 1, 2 and 3 and 4 or more lymph node

metastases. This study was in favor of the TNM clas-

sification in which N category is classified by the

number of lymph node metastases.

Keywords: Colon Cancer; Lymph Node Metastasis;

Stage Classification; TNM Classification; Prognostic

Factors

1. INTRODUCTION

Colorectal cancer is a major cause of cancer death in the

United States and Japan, and its incidence is rapidly

increasing in Japan [1,2]. Several prognostic factors have

been evaluated in colorectal cancer [3-7]. Nodal involve-

ment is accepted as one of the important prognostic fac-

tors in colorectal cancer [8-10] and postoperative adju-

vant chemotherapy is recommended for node-positive

colorectal cancer [11,12]. In the United States the num-

ber of lymph node metastases (LNM) is regarded as an

important prognostic factor in node-positive colorectal

cancer and stage classification by the number of LNM

has been adopted in the TNM classification of malignant

tumors, 7th Edition [13]. In Japan, stage classification by

the distribution of LNM has been modified to that by the

number of LNM in order to also integrate with the TNM

classification in the Japanese classification of colorectal

carcinoma 2nd English Edition [14]. However, there have

been few reports regarding the validity of predicting

prognosis by the number of LNM in node-positive colon

cancer in Japan. We retrospectively examined the possi-

bility of predicting prognosis by the number of LNM and

considered the validity of stage classification in TNM

classification and Japanese classification.

2. METHODS

2.1. Patient Selection

Two hundred and forty-nine patients with LNM who

underwent curative surgery for colon cancer at our

department between January 1992 and December 2004

were enrolled in this study. We retrospectively reviewed

the database and medical records. All patients were

followed for 5 years after the operation. Cases with

multiple primary cancer, preoperative adjuvant therapy

and 11 or fewer dissected lymph nodes, and cases that

died because of non cancer-related causes were ex-

cluded from this study. The median observation period

*Conflict of interest statement: Authors have no conflict of interest.

Published Online August 2013 in SciRes. http://www.scirp.org/journal/ojgas

K. Sugimoto et al. / Open Journal of Gastroenterology 3 (2013) 217-222

218

was 8.6 years (range: 0.2 - 14.6 yeras).

2.2. Clinicopathological Analysis

We first calculated cancer-specific survival according to

the number of LNM in order to examine whether or not

stratification of the prognosis by the number of LNM is

appropriate. Secondly, clinicopathological factors, such

as age, gender (male/female), location (proximal/distal),

invasion depth (TNM classification: T1-T3/T4), differ-

entiation (well differentiated adenocarcinoma/others),

lymphatic invasion (none-mild/moderate-severe), venous

invasion (none-mild/moderate-severe), preoperative serum

CEA, the number of dissected lymph nodes, the number

of LNM and survival data were analyzed to determine

prognostic factors related to cancer-specific survival.

Finally, we considered the differences between the TNM

classification and the Japanese classification.

2.3. Pathological Examination

All specimens were examined in the following manner:

After resection of the primary tumor, the excised speci-

men was opened on the antimesenteric side by the sur-

geon. The surgeon identified the lymph nodes, isolated

them, and recorded both their number and distribution.

After formalin fixation, the specimens and lymph nodes

were examined by the pathologist.

2.4. Follow-Up Program

All patients were followed for 5 years after the opera-

tion. During the first 3 years, patients were followed

every 3 months with clinical assessment and measure-

ment of serum carcinoembryonic antigen, and every 3 - 6

months with chest X-ray and abdominal ultrasonography

or computed tomography. For the remaining 2 years, all

tests were performed every 6 months. Colonoscopy was

performed 1 year after the operation and every 2 years

for the next 4 years.

2.5. Statistical Analysis

Discrete variables were compared using Fisher’s exact

probability test and continuous variables were compared

using the Mann-Whitney U-test. Clinicopathological fac-

tors, for which there was a significant difference in the

univariate analysis, were used as covariables for the mul-

tivariate analysis. For the multivariate analysis, the Cox

proportional-hazard model was used with the Hazard

ratio as a measure of association by applying a stepwise

procedure. The survival rate was calculated using the

Kaplan-Meier method and univariate analyses were per-

formed using the log-rank test. Data were statistically

analyzed using JMP 9.0.2 software (SAS Institute Inc.,

Cary, NC, USA). Differences were considered statisti-

cally significant at p < 0.05. Values are expressed as

median (min. - max.).

3. RESULTS

3.1. The Stratification of Cancer-Specific

Survival According to the Number of Lymph

Node Metastases

Cancer-specific survival according to the number of

LNM is shown in Figure 1. Cancer-specific survival of

the patients with 5 or 7 LNM was better than those with

4 or 6 LNM. With the exception of those cases, cancer-

specific survival was worse as the number of LNM in-

creased. When comparing cancer-specific survival ac-

cording to the number of LNM, there was a tendency

toward better rates of cancer-specific survivals among

the patients with 1 LNM, compared with those with 2

LNM (p = 0.07) (Table 1). There were no significant dif-

ferences in cancer-specific survival between the patients

with 3 or more LNM. Next, we examined whether or not

stratification of the cancer-specific survival according to

the number of LNM was possible. When dividing the

number of LNM into groups (i.e., 2/3≤, 2 - 3/4≤, 2 - 4/5≤,

etc.), except for the patients with one LNM, among

whom cancer-specific survival was better, there were sig-

nificant differences in cancer-specific survival between

groups (i.e., 2 - 3/4≤, 2 - 4/5≤, 2 - 5/6≤) (p = 0.007,

Figure 1. Cancer-specific survival according to number of

lymph node metastases.

K. Sugimoto et al. / Open Journal of Gastroenterology 3 (2013) 217-222 219

p = 0.03, p = 0.02, respectively) (Table 2). Among them,

the p-value was lowest in comparison of the cancer-spe-

cific survival between the patients with 2 - 3 and 4 or

more LNM. Therefore, when comparing cancer-specific

survival between the patients with 1, 2 - 3 and 4 or

more LNM, cancer-specific survival was well stratified

(p < 0.0001) (Figure 2).

3.2. Prognostic Factors for 5-Year Survival

There were 76 patients (30.5%) in the non-survivor

group. In univariate analysis of the non-survivor group

compared with the 5-year survivor group, there were

significantly more patients with invasion depth (T4) (p =

0.0001), lymphatic invasion (moderate-severe) (p =

0.003), venous invasion (moderate-severe) (p = 0.0002)

and the number of LNM (p < 0.0001) (Table 3). With

respect to the other clinicopathological factors, there

were no significant differences between the two groups.

According to the multivariate analysis using these clini-

copathological factors, invasion depth (T4) (p = 0.004,

Odds ratio = 2.43), venous invasion (moderate-severe) (p

= 0.04, Odds ratio = 1.98) and the number of LNM (p =

0.0007, Odds ratio = 1.19) were significant independent

Figure 2. Stratification of the cancer-specific survival accord-

ing to the number of lymph node metastases.

Table 1. Differences in cancer-specific survival according to

number of lymph node metastases.

No. of lymph

node metastases No. of

patients 5-year cancer

specific survival (%) p-value

1 111 87.4

2 42 71.4

3 28 67.9

4 19 47.4

5 9 55.6

6 9 44.4

≥7 31 51.6

Total 249

Table 2. Stratification of the cancer-specific survival according

to the number of lymph node metastases except for the patients

with one lymph node metastasis.

No. of lymph node

metastases No. of

patients 5-year cancer-specific

survival (%) p-value

2 42 71.4

≥3 96 55.2

0.05

2 - 3 70 70.0

≥4 68 50.0

0.007

2 - 4 89 65.2

≥5 49 51.0

0.03

2 - 5 98 64.3

≥6 40 50.0

0.02

2 - 6 107 62.6

≥7 31 51.6

0.07

Table 3. Prognostic factors for 5-year cancer-specific survival

in univariate analysis.

Clinico-

pathological

factor Category 5-year

survivor group

(n = 173)

Non-survivor

group

(n = 76) p-value

Age 64 (30 - 90) 66.5 (44 - 89)0.08

Male 95 44

Gender

Female 78 32

0.68

Proximal66 26

Location

Distal 107 50

0.57

T1 - T3 122 33

Invasion depth

T4 51 43

0.0001

Well diff.

adenoca. 79 27

Differentiation

Others 94 49

0.16

None-mild68 15

Lymphatic

invasion Moderate

severe 173 61

0.003

None - mild113 30

Venous

invasion Moderate

severe 60 46

0.0002

Preoperative

serum CEA

(μg/dl)

3.8

(0.6 - 1034)

6.8

(1.1 - 44.6)0.09

No. of dissected

lymph nodes 19

(3 - 74)

(6 - 108) 0.21

No. of

lymphnode

metastases

(1 = 17)

(1 - 19) <0.0001

Present 138 56

Postoperative

adjuvant

chemotherapy Absent 35 20

0.32

0.07

0.69

0.16

0.70

0.50

0.80

K. Sugimoto et al. / Open Journal of Gastroenterology 3 (2013) 217-222

220

prognostic factors (Table 4).

3.3. Comparisons between the TNM

Classification and the Japanese

Classification Systems

Each of the classification systems is shown in Figure 3.

In the Japanese classification, N1 is defined as metastasis

in 1 to 3 pericolic/perirectal or intermediate lymph nodes;

N2 is defined as metastasis in 4 to more pericolic/peri-

rectal or intermediate lymph nodes, and N3 is defined as

metastasis in the main or lateral lymph nodes. Moreover,

N1 is defined as Stage IIIa, and N2 and N3 are defined as

Stage IIIb independent of invasion depth. On the other

hand, in the TNM classification, N1a is defined as meta-

stasis in one regional lymph node; N1b is defined as

metastasis in 2 - 3 regional lymph nodes; N2a is defined

as metastasis in 4 - 6 regional lymph nodes, and N2b is

defined as metastasis in 7 or more regional lymph nodes.

Moreover, by combining these N categories with inva-

sion depth, the patients with LNM are further divided

into three groups, i.e., IIIA, IIIB and IIIC. Cancer-spe-

cific survival in each N category is shown in Figure 4

and survival for each stage classification is presented in

Figure 5. With respect to the classifications by N cate-

gory, in the Japanese classification, cancer-specific sur-

Figure 3. Comparisons between the TNM classification and the

Japanese classification systems. (a) Japanese classification of

Coloretal Carcinoma. 2nd English Edition; (b) TNM classifica-

tion of Malignant Tumours, 7th Editon.

Table 4. Prognostic factors for 5-year cancer-specific survival

in multivariate analysis.

Clinicopathological

factors p-valueOdds ratio 95% confidence

interval

Invasion depth (T4) 0.004 2.43 1.33 - 4.43

Lymphatic invasion

(moderate - severe) 0.37 1.40 0.67 - 2.95

Venous invasion

(moderate - severe) 0.04 1.98 1.03 - 3.80

No. of lymph node

metastases 0.0007 1.19 1.07 - 1.31

Figure 4. Cancer-specific survival in each N category. (a) Ja-

panese classification of Coloretal Carcinoma. 2nd English Edi-

tion; (b) TNM classification of Malignant Tumours, 7th Editon.

Figure 5. Cancer-specific survival for each stage classification.

(a) Japanese classification of Coloretal Carcinoma, 2nd English

Edition; (b) TNM classification of Malignant Tumours, 7th

Edition.

vival in N1 was significantly better than that in N2 or N3

(p < 0.0001). However, cancer-specific survival in N2

was nearly equal to that in N3 and there was no sig-

nificant difference between N2 and N3 (p = 0.79). On the

other hand, in the TNM classification, cancer-specific

survival in N1a was significantly better than that in N1b

(p = 0.02), and that in N1b was significantly better than

that in N2a (p = 0.02). However, there was no significant

difference in cancer-specific survival between N2a and

N2b (p = 0.76). With regard to stage classification, in the

Japanese classification, there was a significant difference

in cancer-specific survival between Stages IIIa and IIIb

(p < 0.0001). On the other hand, in the TNM classi-

fication, cancer-specific survival in Stages IIIA, IIIB and

IIIC were stratified into three groups with significant

differences (IIIA vs. IIIB; p = 0.007, IIIB vs. IIIC; p <

0.0001). The 5-year cancer-specific survival in Stage

IIIA was 96.4%, and was considered to be extremely

good.

K. Sugimoto et al. / Open Journal of Gastroenterology 3 (2013) 217-222 221

4. DISCUSSION

LNM is an important determinant of prognosis in pa-

tients with colorectal cancer, as acknowledged in both

the Japanese and TNM classification systems. In the

TNM classification, the N category is classified by the

number of LNM. The validity of the stage classification,

which consists of the number of LNM and invasion

depth, was confirmed by inspection of a database of

more than 100,000 colorectal cancer patients [15]. How-

ever, because this inspection was based on surgical out-

comes in the United States, it was not clear whether or

not the stage classification would be useful in Japan.

Moreover, in the Japanese classification, the conven-

tional classification by the distribution of LNM was mo-

dified to take into account the number of LNM, in order

to integrate with TNM classification. Therefore, we in-

vestigated the validity of predicting prognosis based on

the number of LNM in node-positive colon cancer.

In this study, cancer-specific survival decreased as the

number of LNM increased. There was a tendency toward

better rates of cancer-specific survivals among the pa-

tients with 1 LNM, compared with those with 2 LNM.

This was consistent between classification systems, in

that the 1 LNM would be classified into N1a in TNM

classification and reflected that the prognoses among the

patients with 1 LNM were good. Because the prognoses

of the patients with 1 LNM were good, we examined the

stratification of cancer-specific survival according to the

number of LNM among the patients with 2 or more

LNM. Consequently, the stratification of cancer-specific

survival between two groups, i.e., the patients with of 2

and 3 LNM and those with 4 or more was the most ideal

for stage classification. This result was consistent with

the TNM classification, in which the patients with 4 or

more LNM were classified into N2. Therefore, it appears

to be valid that cancer-specific survival should be stra-

tified into three groups, i.e., the patients with 1 LNM,

those with 2 and 3 and those with 4 or more. On the

other hand, cancer-specific survival among the patients

with 7 or more LNM was better than those with 4 or 6. It

would appear that sufficient investigation on the patients

with 4 or 5 or 6 LNM was not possible, due to the small

number of such patients; this would appear to be a limi-

tation of conducting this type of investigation in a single

institution.

Based upon the multivariate analysis, invasion depth

(T4), venous invasion and the number of LNM were

significant, independent prognostic factors. Some authors

have reported that the number of LNM was an indepen-

dent prognostic factor in multivariate analysis [16-18].

Invasion depth and the number of LNM were also inde-

pendent prognostic factors in this study. Therefore, this

result was consistent in that the stage classifications, i.e.,

the Japanese classification and the TNM classification,

consider invasion depth and the number of LNM.

In comparison of the Japanese and TNM classification

systems, the TNM classification appears to be more com-

plicated than the Japanese classification. The reason is

because the grades of invasion depth and the number of

LNM are subdivided in the TNM classification. Conse-

quently, there are many substages and the intervals be-

tween cancer-specific survival in each stage are becom-

ing narrower. Because overlaps and inversions are often

recognized in cancer-specific survival, predictions of

prognosis that are indicated by each stage are vague [19].

On the other hand, the patients in T1-T2N1 and T1N2a

are classified into Stage IIIA in the TNM classification,

and the patients in Stage IIIA have a good prognosis

[12,20]. In other words, these patients with a good prog-

nosis can be distinguished from the patients in Stage III

who have a poor prognosis by using the TNM classifica-

tion. When considering the indication and protocol of

postoperative adjuvant chemotherapy in Stage III, it ap-

pears necessary to distinguish the patients in Stage IIIA

from those in Stage III. In this study, the 5-year cancer-

specific survival was 96.4% and was extremely good. On

the other hand, the stage classification by using the num-

ber of LNM was introduced in order to integrate with the

TNM classification when revising the Japanese classifi-

cation. However, the concept of distribution of LNM was

left in category N3 of the Japanese classification. In

other words, metastasis in the main or lateral lymph

nodes is defined as N3 regardless of the number of LNM.

This is because N category in the Japanese classification

is designed to indicate the extent of lymph node dis-

section during the operation, as well as predictions of

prognosis. Therefore, in this point the Japanese classifi-

cation is quite distinct from the TNM classification. In

this study, there was no significant difference between

category N2 and N3, and this study was in favor of the

TNM classification in which the N category is classified

by the number of LNM. However, there were only

eighteen patients in N3 in this study and further research

is needed to evaluate this properly. Indeed, Kobayashi et

al. [21] reported that the distribution and the number of

LNM represented an important index of prognosis in pa-

tients with colon cancer. In this study, those data were

examined in a single institute, and only a small number

of patients were enrolled in this study. Therefore, further

investigation using a greater sample population through-

out Japan will be necessary.

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