Mediators of Inflammation
Volume 2016 (2016), Article ID 5396747, 8 pages
http://dx.doi.org/10.1155/2016/5396747

Research Article

A Novel Inflammation-Based Stage (I Stage) in Patients with Resectable Esophageal Squamous Cell Carcinoma

Peng-Cheng Chen and Ji-Feng Feng

Department of Thoracic Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, China

Received 23 February 2016; Accepted 29 March 2016

Academic Editor: Czar L. Gaston

Copyright © 2016 Peng-Cheng Chen and Ji-Feng Feng. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background. Inflammation plays a key role in cancer. In the current study, we proposed a novel inflammation-based stage, named I stage, for patients with resectable esophageal squamous cell carcinoma (ESCC). Methods. Three hundred and twenty-three patients with resectable ESCC were enrolled in the current study. The I stage was calculated as follows: patients with high levels of C-reactive protein (CRP) (>10 mg/L), neutrophil-to-lymphocyte ratio (NLR) (>3.5), and platelet-count-to-lymphocyte ratio (PLR) (>150) were defined as I3. Patients with two, one, or no abnormal value were defined as I2, I1, or I0, respectively. The prognostic factors were evaluated by univariate and multivariate analyses. Results. There were 112 patients for I0, 97 patients for I1, 66 patients for I2, and 48 patients for I3, respectively. The 5-year cancer-specific survival (CSS) in patients with I0, I1, I2, and I3 was 50.0%, 30.9%, 18.2%, and 8.3%, respectively (I0 versus I1, ; I1 versus I2, ; I2 versus I3, ). Multivariate analyses revealed that I stage was an independent prognostic factor in patients with resectable ESCC (). Conclusion. The inflammation-based stage (I stage) is a novel and useful predictive factor for CSS in patients with resectable ESCC.

1. Introduction

The cancer incidence and mortality have been increasing worldwide. Esophageal cancer (EC) is one of the most common cancers and remains the 4th leading cause of cancer death [1]. There are two major histologic types of EC: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC is the most common pathological type in China [2, 3]. However, the prognosis for patients with ESCC is still poor [3]. Therefore, assessing the prognostic factors in ESCC patients will become more and more important.

Recent reports revealed that inflammation plays an important role in cancer [4, 5]. Therefore, a series of inflammation-based biomarkers, such as C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), and platelet-count-to-lymphocyte ratio (PLR), have been analysed in various cancers [6–11]. However, the prognostic values of these biomarkers in patients with ESCC remain uncertain [12–17]. In addition, most of these studies only evaluated one or two biomarkers without considering others. In the current study, therefore, we proposed a novel inflammation-based stage, named I stage (combination of CRP, NLR, and PLR), for predicting the prognosis for patients with resectable ESCC.

2. Patients and Methods

A retrospective analysis was conducted for patients with ESCC in our hospital from January 2005 to December 2008. Patients with ESCC were confirmed by histopathology. All patients underwent surgery with curative esophagectomy and standard lymphadenectomy. Patients who had received preoperative therapy were excluded. Patients with any form of acute infection or chronic inflammatory disease were also excluded. At last, 323 patients were enrolled in our study. In the current study, a cancer-specific survival (CSS) analysis was ascertained. The last follow-up was on 30 June 2013. This study was approved by the Ethical Committees of Zhejiang Cancer Hospital (Hangzhou, China). All patients were staged according to the 7th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging [18].

Routine laboratory results (including CRP, neutrophil, lymphocyte, and platelet count) were extracted in retrospective medical records. The definitions of NLR and PLR were described as follows: NLR is neutrophil-to-lymphocyte ratio and PLR is platelet-count-to-lymphocyte ratio. The cut-off values for CRP, NLR, and PLR were 10 mg/L, 3.5, and 150 according to the previous studies [12, 13, 16, 17]. Therefore, the I stage was calculated as follows: patients with high levels of CRP (>10 mg/L), NLR (>3.5), and PLR (>150) were defined as I3. Patients with two, one, or no abnormal value were defined as I2, I1, or I0, respectively.

2.1. Statistical Analysis

The 5-year CSS was analysed by the Kaplan-Meier method. Univariate and multivariate Cox analyses were performed to analyse the prognostic factors. Pearson correlation analyses were performed to analyse the correlation. Receiver operating characteristic (ROC) curves were plotted to determine the accuracy of CRP, NLR, and PLR. A was considered to be statistically significant. Statistical analyses were conducted with SPSS 17.0 (SPSS Inc., Chicago, IL, USA).

3. Results

Clinicopathologic characters were shown in Table 1. The mean CRP, NLR, and PLR were (mg/L), , and , respectively. The histograms of CRP, NLR, and PLR were shown in Figure 1. There were significant positive correlations in CRP and NLR (, ), CRP and PLR (, ), and NLR and PLR (, ) (Figure 2). ROC curves for CSS prediction were shown in Figure 3. The area under the curve (AUC) was 0.713 (95% CI: 0.653–0.772, ) for CRP, 0.650 (95% CI: 0.589–0.711, ) for NLR, and 0.685 (95% CI: 0.626–0.744, ) for PLR.

Table 1: Clinicopathological characteristics for patients with ESCC.

Cases (, %)

Age (years, mean ± SD)
59.1 ± 7.9

Gender

    Female
42 (13.0)

    Male
281 (87.0)

Tumor length (cm, mean ± SD)
4.3 ± 1.9

Tumor location

    Upper
17 (5.3)

    Middle
151 (46.7)

    Lower
155 (48.0)

Differentiation

    Good
44 (13.6)

    Moderate
216 (66.9)

    Poor
63 (19.5)

T grade

    T1
55 (17.0)

    T2
55 (17.0)

    T3
179 (55.4)

    T4
34 (10.6)

N stage

    N0
174 (53.9)

    N1
87 (26.9)

    N2
37 (11.5)

    N3
25 (7.7)

TNM stage

    I
81 (25.1)

    II
104 (32.2)

    III
138 (42.7)

I stage

    I0
112 (34.7)

    I1
97 (30.0)

    I2
66 (20.4)

    I3
48 (14.9)

CRP (mg/L, mean ± SD)
9.7 ± 13.5

NLR (mean ± SD)
3.3 ± 2.8

PLR (mean ± SD)
160.9 ± 70.6

(a)

(b)

(c)

Figure 1: The histograms of the CRP (a), NLR (b), and PLR (c).

(a)

(b)

(c)

Figure 2: Pearson correlation analysis. Positive correlations in CRP and NLR (, ; (a)), CRP and PLR (, ; (b)), and NLR and PLR (, ; (c)).

Figure 3: ROC curves for CSS prediction. The area under the curve (AUC) was 0.713 (95% CI: 0.653–0.772, ) for CRP, 0.650 (95% CI: 0.589–0.711, ) for NLR, and 0.685 (95% CI: 0.626–0.744, ) for PLR.

Of the 323 patients, 112 (34.7%) were allocated an I stage 0, 97 (30.0%) were allocated an I stage 1, 66 (20.4%) were allocated an I stage 2, and 48 (14.9%) were allocated an I stage 3, respectively. The relationships between the I stage and clinicopathological characteristics were shown in Table 2. Our study demonstrated that I stage was associated with tumor length (), perineural invasion (), T stage (), N stage (), and TNM stage (). In addition, our study revealed that CRP, NLR, and PLR were significantly higher in patients with high I stage (, Figure 4).

Table 2: The relationship between I stage and clinicopathological characteristics.

I stage 0
I stage 1
I stage 2
I stage 3
value

()
()
()
()

Age (years)

0.817

    ≤60
66
58
37
25

    >60
46
39
29
23

Gender

0.375

    Female
18
14
5
5

    Male
94
83
61
43

Tumor length (cm)

<0.001

    ≤3
45
31
9
4

    >3
67
66
57
44

Tumor location

0.488

    Upper
8
4
1
4

    Middle
51
49
28
23

    Lower
53
44
37
21

Vessel involvement

0.385

    Negative
99
79
54
38

    Positive
13
18
12
10

Perineural invasion

0.043

    Negative
98
70
52
40

    Positive
14
27
14
8

Differentiation

0.310

    Good
17
10
12
5

    Moderate
80
65
41
30

    Poor
15
22
13
13

T stage

<0.001

    T1
33
18
3
1

    T2
23
14
11
7

    T3
50
58
42
29

    T4
6
7
10
11

N stage

<0.001

    N0
71
55
32
16

    N1
30
30
12
15

    N2
6
9
12
10

    N3
5
3
10
7

TNM stage

<0.001

    I
46
21
9
5

    II
31
41
22
10

    III
35
35
35
33

(a)

(b)

(c)

Figure 4: The CRP (a), NLR (b), and PLR (c) were significantly higher in patients with high I stage (). The “*” and “•” were created by SPSS statistical software.

The 5-year CSS in patients with I0, I1, I2, and I3 was 50.0%, 30.9%, 18.2%, and 8.3%, respectively (, Figure 5) (I0 versus I1, ; I1 versus I2, ; I2 versus I3, ). In addition, our study revealed that patients with CRP (>10.0 mg/L), NLR (>3.5), or PLR (>150) were significantly associated with decreased CSS, respectively (). Then, we further stratified patients into different groups based on TNM stage. Our results demonstrated that I stage was also significantly correlated with CSS based on TNM stage (Figure 6).

Figure 5: The 5-year CSS in patients with I0, I1, I2, and I3 was 50.0%, 30.9%, 18.2%, and 8.3%, respectively () (I0 versus I1, ; I1 versus I2, ; I2 versus I3, ).

(a)

(b)

(c)

Figure 6: The predictive values of I stage were significant in patients based on TNM stage. TNM I stage (, (a)), TNM II stage (, (b)), and TNM III stage (, (c)).

Among the above variables, univariate analyses revealed that tumor length (), vessel involvement (), perineural invasion (), TNM stage (), and I stage () were predictive of CSS (Table 3). In multivariate analyses, we demonstrated that I stage was an independent prognostic factor in patients with resectable ESCC () (Table 4).

Table 3: Univariate analyses for patients with ESCC.

5-year CSS (%)
value
HR (95% CI)
value

Age (years)

0.978

0.978

    ≤60
30.1

1.000

    >60
33.6

0.996 (0.762–1.302)

Gender

0.322

0.327

    Female
38.1

1.000

    Male
30.6

1.227 (0.815–1.848)

Tumor length (cm)

0.003

0.004

    ≤3
41.6

1.000

    >3
27.8

1.580 (1.157–2.157)

Tumor location

0.556

0.564

    Upper
41.2

1.000

    Middle
33.1

0.735 (0.385–1.404)
0.351

    Lower
29.0

0.908 (0.693–1.190)
0.483

Differentiation

0.198

0.207

    Good
38.6

1.000

    Moderate
31.0

1.185 (0.786–1.786)
0.417

    Poor
28.6

1.504 (0.933–2.424)
0.098

Vessel involvement

0.007

0.008

    Negative
34.1

1.000

    Positive
18.9

1.577 (1.129–2.202)

Perineural invasion

0.005

0.006

    Negative
35.0

1.000

    Positive
17.5

1.551 (1.135–2.119)

TNM stage

<0.001

<0.001

    I
51.9

1.000

    II
32.7

1.878 (1.269–2.780)
0.002

    III
18.8

2.943 (2.039–4.248)
<0.001

I stage

<0.001

<0.001

    I0
50.0

1.000

    I1
30.9

1.696 (1.189–2.420)
0.004

    I2
18.2

2.676 (1.837–3.900)
<0.001

    I3
8.3

4.372 (2.924–6.536)
<0.001

Adjuvant therapy

0.398

0.402

    No
32.0

1.000

    Yes
30.6

1.130 (0.849–1.504)

CRP (mg/L)

<0.001

<0.001

    ≤10.0
39.2

1.000

    >10.0
17.1

2.217 (1.692–2.906)

NLR

<0.001

<0.001

    ≤3.5
39.0

1.000

    >3.5
17.7

1.925 (1.471–2.519)

PLR

<0.001

<0.001

    ≤150
43.9

1.000

    >150
17.3

2.260 (1.729–2.955)

Table 4: Multivariate analyses for patients with ESCC.

HR (95% CI)
value

Tumor length (cm)

0.603

    ≤3
1.000

    >3
1.075 (0.818–1.412)

Vessel involvement

0.742

    Negative
1.000

    Positive
1.060 (0.747–1.505)

Perineural invasion

0.077

    Negative
1.000

    Positive
1.341 (0.968–1.857)

TNM stage

<0.001

    I
1.000

    II
1.586 (1.048–2.400)
0.029

    III
2.220 (1.456–3.384)
<0.001

I stage

<0.001

    I0
1.000

    I1
1.543 (1.076–2.214)
0.018

    I2
2.356 (1.602–3.466)
<0.001

    I3
3.594 (2.363–5.467)
<0.001

CRP (mg/L)

0.493

    ≤10.0
1.000

    >10.0
1.151 (0.770–1.719)

NLR

0.786

    ≤3.5
1.000

    >3.5
1.050 (0.740–1.488)

PLR

0.065

    ≤150
1.000

    >150
1.440 (0.978–2.121)

4. Discussion

In the current study, we initially proposed a novel inflammation-based prognostic system, named I stage (combination of CRP, NLR, and PLR), in patients with resectable ESCC. Our study revealed that I stage was associated with tumor length, perineural invasion, and TNM stage. In multivariate analyses, we revealed that I stage is a useful predictor of postoperative CSS in patients with resectable ESCC ().

Several hematological biomarkers have shown prognostic values in cancers. In particular, the CRP has been well validated. CRP is a representative acute-phase reactant for inflammation [19]. Recently, several previous studies have shown that CRP is associated with prognosis in several cancers, including ECs [6, 8–12]. In our study, patients with CRP ≤ 10.0 mg/L had a significantly better 5-year CSS than patients with CRP > 10.0 mg/L (39.2% versus 17.1%, ). However, CRP was not an independent prognostic factor in multivariate analyses ().

The prognostic values of NLR and PLR in patients with EC remain uncertain. Several reports demonstrated that NLR is an independent prognostic factor in patients with EC [14, 15]. However, Rashid et al. [13] and Dutta et al. [16] revealed that NLR does not correlate with prognosis for patients with EC. Moreover, there have been few studies regarding PLR in EC patients. Dutta et al. [16] demonstrated that PLR does not correlate with prognosis in patients with EC. A retrospective study by Liu et al. [20] on 326 ESCC patients revealed PLR to be a potential prognostic factor. In our study, NLR and PLR were correlated with survival; however, NLR and PLN were not independent prognostic factors in multivariate analyses.

At present, the prognosis of cancer is commonly based on the TNM staging system [21, 22]. Inflammation plays an important role in cancer. Therefore, in our study, we proposed a novel inflammation-based prognostic system (I stage) in resectable ESCC patients. A significant association was found between the I stage and clinical characteristics. In multivariate analyses, we revealed that I stage is a useful predictor of postoperative CCS in patients with resectable ESCC (). It may well be that the influence of I stage on the subgroup with TNM stage is important for the understanding of its role in patients with ESCC. Our results demonstrated that I stage was also significantly correlated with CSS based on TNM stage.

Limitations should be acknowledged. Firstly, our study was a retrospective study. Secondly, we excluded patients with neoadjuvant treatment, which may have influenced the results. Neoadjuvant treatment will inevitably have an impact on the systemic inflammation. Thus, evaluation of I stage in neoadjuvant therapy does not reflect the baseline impact of systemic inflammation for ESCC patients. Therefore, larger prospective studies will need to be performed to confirm these preliminary results.

In summary, there was a significant association between the I stage (combination of CRP, NLR, and PLR) and clinical characteristics. Based on the results of the current study, we believe that I stage is a novel and useful predictive factor for CSS in patients with resectable ESCC.

Competing Interests

The authors have no competing interests to disclose.

References

R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2015,” CA: A Cancer Journal for Clinicians, vol. 65, no. 1, pp. 5–29, 2015.

Y. Lin, Y. Totsuka, Y. He et al., “Epidemiology of esophageal cancer in Japan and China,” Journal of Epidemiology, vol. 23, no. 4, pp. 233–242, 2013.

K. K. Keditsu, S. Jiwnani, G. Karimundackal, and C. S. Pramesh, “Multimodality management of esophageal cancer,” Indian Journal of Surgical Oncology, vol. 4, no. 2, pp. 96–104, 2013.

F. Balkwill and A. Mantovani, “Inflammation and cancer: back to Virchow?” The Lancet, vol. 357, no. 9255, pp. 539–545, 2001.

A. Mantovani, P. Allavena, A. Sica, and F. Balkwill, “Cancer-related inflammation,” Nature, vol. 454, no. 7203, pp. 436–444, 2008.

T. Nakamura, A. Matsumine, K. Asanuma, T. Matsubara, and A. Sudo, “The role of C-reactive protein in predicting post-metastatic survival of patients with metastatic bone and soft tissue sarcoma,” Tumor Biology, vol. 36, no. 10, pp. 7515–7520, 2015.

N. Jiang, J.-Y. Deng, Y. Liu, B. Ke, H.-G. Liu, and H. Liang, “The role of preoperative neutrophil-lymphocyte and platelet-lymphocyte ratio in patients after radical resection for gastric cancer,” Biomarkers, vol. 19, no. 6, pp. 444–451, 2014.

T. Nozoe, T. Iguchi, E. Adachi, A. Matsukuma, and T. Ezaki, “Preoperative elevation of serum C-reactive protein as an independent prognostic indicator for gastric cancer,” Surgery Today, vol. 41, no. 4, pp. 510–513, 2011.

T. Nakamura, A. Matsumine, T. Matsubara, K. Asanuma, A. Uchida, and A. Sudo, “The combined use of the neutrophil-lymphocyte ratio and C-reactive protein level as prognostic predictors in adult patients with soft tissue sarcoma,” Journal of Surgical Oncology, vol. 108, no. 7, pp. 481–485, 2013.

T. Nakamura, R. J. Grimer, C. L. Gaston, M. Watanuki, A. Sudo, and L. Jeys, “The prognostic value of the serum level of C-reactive protein for the survival of patients with a primary sarcoma of bone,” Bone & Joint Journal B, vol. 95, no. 3, pp. 411–418, 2013.

T. Nakamura, R. Grimer, C. Gaston et al., “The value of C-reactive protein and comorbidity in predicting survival of patients with high grade soft tissue sarcoma,” European Journal of Cancer, vol. 49, no. 2, pp. 377–385, 2013.

H. Shimada, Y. Nabeya, S.-I. Okazumi et al., “Elevation of pre-operative serum C-reactive protein level is related to poor prognosis in esophageal squamous cell carcinoma,” Journal of Surgical Oncology, vol. 83, no. 4, pp. 248–252, 2003.

F. Rashid, N. Waraich, I. Bhatti et al., “A pre-operative elevated neutrophil: lymphocyte ratio does not predict survival from oesophageal cancer resection,” World Journal of Surgical Oncology, vol. 8, article 1, 2010.

H. Sato, Y. Tsubosa, and T. Kawano, “Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic response to neoadjuvant chemotherapy in patients with advanced esophageal cancer,” World Journal of Surgery, vol. 36, no. 3, pp. 617–622, 2012.

R. Z. Sharaiha, K. J. Halazun, F. Mirza et al., “Elevated preoperative neutrophil: lymphocyte ratio as a predictor of postoperative disease recurrence in esophageal cancer,” Annals of Surgical Oncology, vol. 18, no. 12, pp. 3362–3369, 2011.

S. Dutta, A. B. C. Crumley, G. M. Fullarton, P. G. Horgan, and D. C. McMillan, “Comparison of the prognostic value of tumour- and patient-related factors in patients undergoing potentially curative resection of oesophageal cancer,” World Journal of Surgery, vol. 35, no. 8, pp. 1861–1866, 2011.

J.-F. Feng, Y. Huang, and Q.-X. Chen, “Preoperative platelet lymphocyte ratio (PLR) is superior to neutrophil lymphocyte ratio (NLR) as a predictive factor in patients with esophageal squamous cell carcinoma,” World Journal of Surgical Oncology, vol. 12, article 58, 2014.

T. W. Rice, V. W. Rusch, H. Ishwaran, and E. H. Blackstone, “Cancer of the esophagus and esophagogastric junction: data-driven staging for the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer Cancer Staging Manuals,” Cancer, vol. 116, no. 16, pp. 3763–3773, 2010.

E. E. Diehl, G. K. Haines III, J. A. Radosevich, and L. A. Potempa, “Immunohistochemical localization of modified C-reactive protein antigen in normal vascular tissue,” The American Journal of the Medical Sciences, vol. 319, no. 2, pp. 79–83, 2000.

J. S. Liu, Y. Huang, X. Yang, and J. F. Feng, “A nomogram to predict prognostic values of various inflammatory biomarkers in patients with esophagealsquamous cell carcinoma,” American Journal of Cancer Research, vol. 5, pp. 2180–2189, 2015.

B. P. L. Wijnhoven, K. T. C. Tran, A. Esterman, D. I. Watson, and H. W. Tilanus, “An evaluation of prognostic factors and tumor staging of resected carcinoma of the esophagus,” Annals of Surgery, vol. 245, no. 5, pp. 717–725, 2007.

C. G. Peyre, J. A. Hagen, S. R. DeMeester et al., “The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection,” Annals of Surgery, vol. 248, no. 4, pp. 549–556, 2008.