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ORIGINAL
New scoring system to create a prognostic criteria in colorectal
carcinoma based on serum elevation of C-reactive protein
and decrease in lymphocyte in peripheral blood
Tadahiro Nozoe, Mayuko Kono, Sosei Kuma, Eiji Tsujita, and Takefumi Ohga
Department of Surgery, Fukuoka Higashi Medical Center, Koga, Japan

Abstract : BACKGROUND. Both serum elevation of C-reactive protein (CRP) and reduction of lymphocyte in
the peripheral blood has been known as indicator for malignant potential of human tumors. METHODS. Whether
newly devised CLS (CRP/Lymphocyte Score), based on combined data of serum elevation of CRP and of lymphocyte percentage in the peripheral blood can be an indicator for progressive potential in colorectal carcinoma
was examined in 280 cases who had been surgically treated. RESULTS. Significant difference in survival wasobserved both between CLS 0 and 1 and between CLS 1 and 2, in both cases when analyzed among whole patients and patient who had been treated with curative resection. Multivariate analysis among patients whohad been treated with curative resection demonstrated that CLS (P < 0.0001), histologic type (P = 0.0003), andtumor stage (P = 0.039) were factors independently associated with worse prognosis of the patients. CONCLUSIONS. Newly devised criteria CLS could be an independent prognostic indicator in colorectal carcinoma andwould be utilized as a helpful information. J. Med. Invest. 66 : 264-268, August, 2019
Keywords : colorectal carcinoma, C-reactive protein, lymphocyte ratio, prognostic indicator

INTRODUCTION
Serum elevation of C-reactive protein has been known as anindicator for aggressiveness of the tumor and/or patients’ prognosis in malignant tumors of the digestive tracts such as gastriccarcinoma (1) and esophageal carcinoma (2) as well as colorectal
carcinoma (3, 4).
Decrease in lymphocyte in peripheral blood has been also
reported to be correlated with malignant potential in colorectal
carcinoma (5).
However, criteria based on the combined data of serum elevation of CRP and decrease in lymphocyte in peripheral blood inhuman tumors has not been presented.
In this study, we attempted to form a new scoring system todetermine outcome of the patients with colorectal carcinoma
based on combination of serum elevation of C-reactive protein
and decrease in lymphocyte in peripheral blood.

PATIENTS AND METHODSPatients, collection of blood samples, and measurement of C-reactive
protein (CRP) and lymphocyte percentage in peripheral blood. Two hundred and eighty patients, composed of 165 men and 115 women,with colorectal carcinoma, which had been treated by surgicalresection in our institute from 2004 to 2013, were enrolled inthis study.
This study was approved by the institutional ethic committeeof Fukuoka Higashi Medical Center.
Patients who have been suffering from other malignant
Received for publication November 7, 2018 ; accepted May 4, 2019.
Address correspondence and reprint requests to Tadahiro Nozoe,
MD, Department of Surgery, Fukuoka Higashi Medical Center, 1-1-1,Chidori, Koga, 811-3195, Japan and Fax : +81-92-943-8775.

tumors or other inflammatory diseases possibly causing theserum elevation of CRP were excluded from this study. Moreover
there was no patients who had been treated with neoadjuvant
therapy.
All blood samples to measure serum value of CRP were collected just before the operation. Patients who had the serum
concentration of more than 1.0 mg/dL, as applied in our seriesof investigations (1-3), were regarded to have a serum elevationof CRP. And among Japanese, the normal range of lymphocyte
percentage in peripheral blood has been described as 21.2-51.0%
in male and 21.3-50.2% in female in Kanai’s Manual of Clinical Laboratory Medicine widely utilized in most institution in
Japan. Then. lymphocyte percentage in the peripheral blood ofless than 20% were regarded to have a decrease in lymphocyte.
Pathologic investigation. Pathologic investigation was performed
using TNM classification of malignant tumors prescribed by theInternational Union Against Cancer (6).
Definition of CLS (CRP/Lymphocyte Score). Patients who had
both serum elevation of CRP and decrease in lymphocyte wereallocated a CLS of 2. Patients who had each one and neither wereallocated a CLS of 1 and 0, respectively (Table 1).
Follow-up of the Patients. The follow-up for patients was continued until their death and only patients who died of colorectal
carcinoma were included in the tumor-related deaths. The period

Table 1. Chart to calculate CLS
Serum elevation of C-reactive protein
Yes

NoYes

21No

10Decrease in lymphocytes
in peripheral blood

CLS, CRP/Lymphocyte Score

The Journal of Medical Investigation Vol. 66 2019

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The Journal of Medical Investigation Vol. 66 August 2019from the operation to the date of death was defined to be the survival time. The survival time ranged from one month to 8 years
and 6 months with a mean of 3 years and 6 months.
Statistical Analysis. All statistical analyses were performedusing StatView (SAS Institute Inc, Cary, NC). Chi-square
test and t test were used to compare the difference regarding
values in each CLS score. Survival curves were made by theKaplan-Meier method, and the Mantel-Cox test was used toanalyze the equality of the survival curves. Cox proportional
hazards model in a forward stepwise manner was used toperform a multivariate analysis to determine the independent
prognosticators. A P value of less than 0.05 was considered todemonstrate a significant difference.

RESULTS
Correlation of the CLS with clinicopathologic features wasshown in Table 2. Significant difference was observed regarding
depth of tumor (P = 0.003), stage of the tumor (P = 0.0053), andsimilarly, the rate of curative resection (P = 0.021).
The survival of CLS 1 patients with 5-year survival rate of
73.3% was significantly more unfavorable than that of CLS
0 patients with 5-year survival rate of 90.8% (P = 0.003). Prognosis of CLS 2 patients with 5-year survival rate of 43.2% wassignificantly worse than that of TRHRS 1 patients (P = 0.015,Fig. 1).
An analysis restricted to patients who had been treated with

Table 2. Relationship Between CLS and Patients’ Clinicopathologic Characteristics
CLS 0(n = 178)

CLS 1
(n = 63)

CLS 2(n = 39)

P-valueMale

105 (59.0)

Female73 (41.0)

33 (52.4)

27 (69.2)

0.243

30 (47.6)

12 (30.8)

69.6 ± 11.7

70.8 ± 10.9

71.0 ± 9.2

0.477

Colon

122 (68.5)

46 (73.0)

33 (84.6)

0.126

Rectum56 (31.5)

17 (27.0)

6 (15.4)

T1, 2

62 (34.8)

12 (19.0)

4 (10.3)

T3, 4

114 (65.2)

51 (81.0)

35 (89.7)

Well

58 (32.6)

15 (23.8)

10 (25.6)

Moderately

109 (61.2)

41 (65.1)

26 (66.7)

Poorly11 ( 6.2)

7 (11.1)

3 ( 7.7)

No

103 (57.9)

39 (61.9)

18 (46.2)

Yes

75 (42.1)

24 (38.1)

21 (53.8)

No

105 (59.0)

39 (61.9)

17 (43.6)

Yes

73 (41.0)

24 (38.1)

22 (56.4)

Sex

Age
Location of tumor

Depth of tumor
0.0005

Histology*
0.127

Nodal metastasis
0.083

Lymphatic invasion
0.153

Venous invasionNo

133 (74.7)

50 (79.4)

28 (71.8)

Yes

45 (25.3)

13 (20.6)

11 (28.2)

I

57 (32.0)

12 (19.1)

2 ( 5.2)

II

45 (25.3)

21 (33.3)

14 (35.9)

III

67 (37.6)

25 (39.7)

16 (41.0)IV

9 ( 5.1)

5 ( 7.9)

7 (17.9)169 (94.9)

58 (92.1)

32 (82.1)

9 ( 5.1)

5 ( 7.9)

7 (17.9)

0.654

Tumor stage
0.0053Curability for resection
Curative
Non-curative

0.021

CLS, CRP/Lymphocyte Score
Values in the parenthesis are the percentages.
*Well, well differentiated adenocarcinoma ; Moderately, moderately differentiated adenocarcinoma ; Poorly,pooyly differentiated adenocarcinoma;T. Nozoe, et al. CLS in colorectal carcinoma

266

curative resection was additionally done (Table 3). A significant
difference was observed regarding depth of tumor (P = 0.003)
and stage of the tumor (P = 0.013).
The survival of CLS 1 patients with 5-year survival rate of
75.3% was significantly more unfavorable than that of CLS 0 patients with 5-year survival rate of 93.6% (P = 0.002). Prognosisof CLS 2 patients with 5-year survival rate of 45.2% was significantly worse than that of CLS 1 patients (P = 0.030, Fig. 2).
In univariate analysis among patients who had been treatedwith curative resection, CLS (P < 0.0001), lymphatic invasion(P = 0.0005), venous invasion (P = 0.038), histologic type (P <0.0001) and tumor stage (P = 0.0004) were factors possibly todetermine patients’ prognosis. Multivariate analysis including
all these factors demonstrated that CLS (P < 0.0001) as well as
histologic type (P = 0.0003) and tumor stage (P = 0.039) werefound to be factors independently associated with worse prognosis of the patients (Table 4).
Fig. 1. CLS and survival curves among whole patients.

Significant difference was observed between survival of CLS 0 and 1patients (P = 0.030) and between survival of CLS 1 and 2 patients (P= 0.015).

Table 3. Relationship Between CLS and Clinicopathologic Characteristics of Patients Treated with Curative Resection

CLS 0(n = 169)

CLS 1(n = 58)

CLS 2(n = 32)

P-value

103 (60.9)

31 (53.4)

21 (65.6)

0.468

SexMaleFemale

66 (39.1)

27 (46.6)

11 (34.4)

70.0 ± 11.8

70.5 ± 11.2

72.0 ± 8.1

0.204

Colon

119 (70.4)

43 (74.1)

27 (84.4)

0.258

Rectum50 (29.6)

15 (25.9)

5 (15.6)

T1, 2

62 (36.7)

12 (20.7)

4 (12.5)

T3, 4

107 (63.3)

46 (79.3)

28 (87.5)

Well

56 (33.1)

15 (25.9)9 (28.1)

Moderately

103 (61.0)

37 (63.8)

20 (62.5)

Undifferentiated

10 ( 5.9)

6 (10.3)

3 ( 9.4)

No

102 (60.4)

33 (56.9)

16 (50.0)

Yes

67 (39.6)

25 (43.1)

16 (50.0)No

102 (60.4)

36 (62.1)

14 (43.8)

Yes

67 (39.6)

22 (37.9)

18 (56.2)

Age
Location of tumor

Depth of tumor
0.005

Histology*
0.679

Nodal metastasis
0.536

Lymphatic invasion
0.182

Venous invasionNo

130 (76.9)

48 (82.8)

24 (75.0)

Yes

39 (23.1)

10 (17.2)

8 (25.0)I

57 (33.7)

12 (20.7)

2 ( 6.2)

II

45 (26.6)

21 (36.2)

14 (43.8)

III67 (39.7)

25 (43.1)

16 (50.0)

0.592

Tumor stage

CLS, CRP/Lymphocyte Score
Values in the parenthesis are the percentages.

0.013

The Journal of Medical Investigation Vol. 66 August 2019

Fig. 2. CLS and survival curves among patients who had beentreated with curative resection.
Significant difference was observed between survival of CLS 0 and 1patients (P = 0.003) and between survival of CLS 1 and 2 patients (P= 0.030).
Table 4. Factors independently correlated with prognosis of thepatients treated with curative resection

Hazard Ratio

P-value

CLS(0, 1 vs 2)

6.17 (2.74-13.9)< 0.0001

Histologic type
(Differentiated vsUndifferentiated)

5.88 (2.25-15.4)

0.0003

Stage of tumors(I, II vs III)2.85 (1.05-7.76)

0.040

Variablewith colorectal carcinoma.
Significant correlation between CLS and curability was observed, which could demonstrate an utility of CLS as an indicator for malignant potential of the tumor and preoperative
predictor for possible curative resection of colorectal carcinoma.
Moreover, in this study, indeed, a significant correlation was
found between CLS and an incidence of non-curative resection
due to the co-existence of distant metastasis or peritoneal dissemination. Suppressed physical condition caused by the cachexia derived from far advanced carcinoma with distant metastasis
could influence the both the values of serum level of CRP andlymphocyte ratio in the peripheral blood. Therefore, analysis
restricted to the cases who had been treated with curative resection was additionally done and nevertheless the significance of
CLS as an independent prognostic indicator in colorectal carcinoma was elucidated.
Incidentally, also from the multivariate analysis in the current
study, pathological incidence of poorly differentiated colorectal
carcinoma could contain more progressive potential, as having
been reported in the previous study (4, 14).
In conclusion, this newly devised simple and convenient criteria, CLS, can be measured using a basic examinations would
strictly classify the prognosis in colorectal carcinoma and would
provide a beneficial information regarding the clinical course ofpatients with colorectal carcinoma.

DISCLOSURE
Authors declare that we have no financial interest or conflictof interest.

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These findings promoted us to possibly construct a new criteria to determine a malignant potential and/or prognosis ofpatients with colorectal carcinoma based on the two elements,
serum elevation of CRP and decrease in lymphocyte in peripheral blood, which similarly influence the prognosis of the patients

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