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Solitary lymph node metastasis is a distinct subset of colon cancer associated with good survival: a retrospective study of surveillance, epidemiology, and end-results population-based data

  • Qingguo Li1,
  • Yuwei Wang1,
  • Guoxiang Cai1,
  • Dawei Li1 and
  • Sanjun Cai1Email author
Contributed equally
BMC Cancer201414:368

DOI: 10.1186/1471-2407-14-368

Received: 15 January 2014

Accepted: 20 May 2014

Published: 24 May 2014

Abstract

Background

Colon cancer with lymph node metastases has been considered as advanced stage and to have poor survival. We postulated that patients with solitary lymph node metastasis are a distinct subset with better colon cancer-specific survival than those with multiple lymph node metastases.

Methods

In this retrospective study, we searched Surveillance, Epidemiology, and End-Results (SEER) population-based data and identified 86,674 patients who had been diagnosed with colon cancer without distant metastases and with less than three metastatic nodes between 1991 and 2005. We divided lymph node status into three subgroups: pN0, pN1a, and pN1b and obtained 5-year colon cancer-specific survival for each pT stage. We used Kaplan–Meier and multivariate Cox regression models to assess correlations between risk factors and survival outcomes.

Results

Analysis of SEER data confirmed that patients with solitary lymph node metastases had better 5-year cancer-specific survival than pN1b according to both univariate and multivariate analysis. This finding was confirmed by further analyses in five pT subgroups. Cancer-specific survival of patients with pT1-2N1a was comparable to that of those with pIIA but higher than those with pIIB. In addition, survival of patients with pT3-4aN1a was better than those with pIIC.

Conclusion

Colon cancer patients with solitary lymph node metastasis are a distinct subset with a favorable prognosis; full consideration should be given to this in clinical practice.

Keywords

Colon Cancer Lymph node metastasis Surgery Survival analysis

Background

Colorectal cancer (CRC), one of the commonest malignancies, is the third leading cause of cancer-related deaths in the United States [1]. The incidence of CRC in Asian countries is increasing rapidly and is likely similar to that in Western countries [2, 3]. In China, both the incidence and mortality rate of CRC are increasing [4]. Surgical resection remains the mainstay of treatment of local and regional disease. Lymphadenectomy, a critical component of surgical procedures for patients with CRC, is performed with the aim of achieving complete resection of lesions. In 2000, the National Comprehensive Cancer Network (NCCN) recommended pathologic examination of at least 12 lymph nodes (LNs) in the staging of colon cancer (CC). The number of metastatic LNs has been identified as an independent prognostic factor [57]. In the seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual for CC, N1 lesions were subdivided into N1a (solitary LN metastasis, SLNM) and N1b (2–3 positive LNs); however, in the current staging system N1a and N1b have been combined. Patients with SLNM might be a distinct subset of those with involved LNs, a subset without the high incidence of systematic disease and poor prognosis of patients with multiple metastases in LNs. In this study, we used data from the Surveillance, Epidemiology and End-Results (SEER) registries to analyze the role of SLNM in the long-term survival of patients with CC and to assess the appropriateness of the N1 classification in the seventh edition of the TNM staging system.

Methods

The current SEER database consists of 17 population-based cancer registries that represent approximately 28% of the population of the United States. The SEER data contain no identifiers and are publicly available for studies of cancer-based epidemiology and health policy. The National Cancer Institute’s SEER*Stat software (Surveillance Research Program, National Cancer Institute SEER*Stat software, http://www.seer.cancer.gov/seerstat) was used to identify patients who received a pathologic diagnosis of adenocarcinoma, mucinous adenocarcinoma, or signet-ring carcinoma of the CC (C18.0–19.9) between 1991 and 2005.

Only CC as a single primary tumor was included in current study due to the available information for cause specific survival analysis in SEER database. Patients diagnosed after 2006 were excluded to ensure adequate duration of follow-up. Other exclusion criteria were as follows: incomplete TNM staging, no LNs examined pathologically, more than three LNs with metastases (N2), synchronous distant metastases, patients who had died within 30 days of surgery, and age younger than 18 or older than 80 years.

This study is based on public data from the SEER database: we obtained permission to access the research data files in the SEER program (reference number 12768-Nov2012). Because this study did not involve interaction with human subjects or use personal identifying information, informed consent was not required. The study was approved by the Review Board of Fudan University, Shanghai Cancer Center, Shanghai, China.

Ethics statement

This study was conducted in compliance with the Helsinki Declaration. Permission to access the research data files in the SEER program was obtained (reference number 12768-Nov2012).

Statistical analysis

Age, sex, race, extent of primary tumor invasion, total number of LNs examined, number of involved LNs, tumor grade, histological type of tumor, survival time, and cause of death were retrieved from the SEER database. All cases were restaged based on the AJCC-7 guidelines. The primary endpoint of this study, colon cancer cause-specific survival (CCSS), was calculated from the date of diagnosis to the date of cause-specific death. Deaths attributed to the cancer of interest were treated as events and deaths from other causes as censored observations.

χ 2 tests were used to test independence, and Student’s t-test to compare continuous data between the three groups (pN0, pN1a, and pN1b). Exact 95% confidence intervals (CIs) for proportions were calculated. Survival curves were generated using Kaplan–Meier estimates; differences between the curves were analyzed by the log-rank test. Multivariate Cox regression models were used to analyze correlations between risk factors and survival outcomes in T1-4 N0-1b patients. All statistical analyses were performed with the statistical software package SPSS for Windows, version 17 (SPSS, Chicago, IL, USA). Statistical significance was set at two-sided P < 0.05.

Results

Impact of SLNM on CC survival outcomes

We identified 86,674 eligible patients over the 15 years covered by the study. These comprised 61,696 patients with no LN metastases, 12,416 with SLNM, and 12,562 with two or three LN metastases. Relevant patient characteristics and pathological features are summarized in Table 1. LN status was correlated with age, race, pathological grading, histological type of tumor, number of LNs dissected, and pT stage.
Table 1

Characteristics of patients from SEER Database by LN involvement

 

Total

N0

N1a

N1b

P value

Characteristic

(n = 86674)

(n = 61696)

(n = 12416)

(n = 12562)

Media follow up (mo)

85

90

78

69

<0.001

 (IQR)

(54–121)

(62–124)

(39–116)

(30–108)

Years of diagnosis

    

0.102

 1988-1993

17214

12196

2489

2529

 

 1994-1999

24641

17436

3629

3576

 

 2000-2003

32064

17436

6298

6457

 

Sex

    

0.818

 Male

43210

30798

6177

6235

 

 Female

43464

30898

6239

39876327

 

Age

    

<0.001

 <60

27442

18170

4293

4439

 

 ≥60

59232

42986

8123

8123

 

Race

    

<0.001

 White

69850

50278

9667

9905

 

 Black

9407

6337

1574

1496

 

 Other

7154

4872

1145

1137

 

 Unknown

263

209

30

24

 

Pathological grading

    

<0.001

 High/moderate

41097

28840

6121

6136

 

 Poor/anaplastic

7723

4503

1434

1786

 

 Unknown

1750

1232

251

267

 

Histotype

    

<0.001

 Adenocarcinoma

76387

54697

10817

10873

 

 Mucinous cell

9667

6671

1480

1516

 

 Signet ring cell

486

239

96

151

 

T stage

    

<0.001

 T1

12141

11055

746

340

 

 T2

14570

11995

1531

1044

 

 T3

28192

18982

4532

4678

 

 T4a

27669

17195

4860

5614

 

 T4b

4102

2469

747

886

 

No. of LNs dissected

    

<0.001

 <12

47920

34671

6693

6556

 

 ≥12

38754

27025

5723

6006

 
The median duration of follow-up was 85 months (range 54–121 months) and the overall 5-year CCSS was 83.0%. The 5-year CCSS of pN0 patients, patients with pN1a and patients with pN1b stage was 88.3% ± 0.1%, 74.6% ± 0.4%, and 65.1% ± 0.4%, respectively (P < 0.001). There were significant differences in survival between pN0 patients and those with SLNM (P < 0.001), between patients with SLNM and with pN1b (P < 0.001), and between patients with pN0 and pN1b (P < 0.001). We then made a further comparison by pT stages and found significant differences between all five of them (P < 0.05) (Figure 1).
https://static-content.springer.com/image/art%3A10.1186%2F1471-2407-14-368/MediaObjects/12885_2014_Article_4616_Fig1_HTML.jpg
Figure 1

Survival curves in CC patients according to lymph node status. (a) pT1-4 stage N0 vs. N1a, χ 2 = 1762.258, P < 0.001; N1a vs. N1b, χ 2 = 263.886, P < 0.001. (b) pT1 stage: N0 vs. N1a, χ 2 = 53.979, P < 0.001; N1a vs. N1b, χ 2 = 21.414, P < 0.001. (c) pT2 stage: N0 vs. N1a, χ 2 = 101.579, P < 0.001; N1a vs. N1b, χ 2 = 5.597, P = 0.02. (d) pT3 stage: N0 vs. N1a, χ 2 = 374.208, P < 0.001; N1a vs. N1b, χ 2 = 86.490, P < 0.001. (e) pT4a stage: N0 vs. N1a, χ 2 = 420.664, P < 0.001; N1a vs. N1b, χ 2 = 71.364, P < 0.001. (f) pT4b stage: N0 vs. N1a, χ 2 = 94.180, P < 0.001; N1a vs. N1b, χ 2 = 10.257, P = 0.001.

According to univariate and multivariate survival analyses, pT stage, year of diagnosis, patient age, race, and LN status were significantly associated with CCSS in all patients. pT2-4a stage female patients had better CCSS than male patients. Tumor grade was an independent factor for CCSS in patients with pT1 and pT3-4b. Except in patients with pT1 stage, the number of LNs dissected was significantly associated with CCSS according to both univariate and multivariate survival analysis. However, histological type of tumor was not a prognostic factor according to both univariate and multivariate survival analyses (Tables 2, 3, 4, 5 and 6).
Table 2

Univariate and multivariate survival analyses by pN stage in patients with pT1 stage CC

 

Univariate analysis

Multivariate analysis

Variable

5-year CCS

Log rank χ 2test

P

HR (95% CI)

P

Years of diagnosis

 

15.944

<0.001

 

<0.001

 1988-1993

94.9%

  

Reference

 

 1994-1999

95.6%

  

0.815 (0.784-0.848)

 

 2000-2003

96.6%

  

0.692 (0.667-0.718)

 

Sex

 

0.706

0.401

 

NI

 Male

96.0%

    

 Female

96.2%

    

Age

 

45.295

<0.001

 

<0.001

 <60

97.6%

  

Reference

 

 ≥60

95.3%

  

1.467 (1.419-1.516)

 

Race

 

16.447

<0.001

 

<0.001

 White

96.3%

  

Reference

 

 Black

93.4%

  

1.428 (1.152-1.770)

 

 Othera

97.6%

  

0.718 (0.528-0.976)

 

Grade

 

19.124

<0.001

 

<0.001

 High/moderate

96.2%

  

Reference

 

 Poor/anaplastic

93.1%

  

1.281 (1.234-1.330)

 

 Unknown

96.8%

  

0.871 (0.802-0.946)

 

Histotype

 

0.923

0.337

 

NI

 Adenocarcinoma

96.1%

    

Mucinous/signet ring cell

96.8%

    

No. of LNs dissected

 

0.413

0.520

 

NI

 <12

95.9%

    

 ≥12

96.5%

    

LNs status

 

221.646

<0.001

 

<0.001

 N0 (pI)

96.7%

  

0.456 (0.439-0.473)

 

 N1a

92.6%

  

Reference

 

 N1b

83.2%

  

1.424 (1.365-1.486)

 

aOther includes American Indian/Alaska native, Asian/Pacific Islander, and unknown.

NI: not included in multivariate survival analyses.

Table 3

Univariate and multivariate survival analyses by pN stage in patients with pT2 stage CC

 

Univariate analysis

Multivariate analysis

Variable

5-year CCS

Log rank χ 2test

P

HR (95% CI)

P

Years of diagnosis

 

30.763

<0.001

 

<0.001

 1988-1993

90.9%

  

Reference

 

 1994-1999

92.0%

  

0.903 (0.789-1.033)

 

 2000-2003

93.6%

  

0.727 (0.637-0.830)

 

Sex

 

27.577

<0.001

 

<0.001

 Male

91.8%

  

Reference

 

 Female

93.5%

  

0.734 (0.664-0.812)

 

Age

 

77.274

<0.001

 

<0.001

 <60

95.4%

  

Reference

 

 ≥60

91.5%

  

1.823 (1.612-2.061)

 

Race

 

35.396

<0.001

 

<0.001

 White

92.8%

  

Reference

 

 Black

89.6%

  

1.517 (1.306-1.762)

 

 Othera

94.9%

  

0.692 (0.558-0.858)

 

Grade

 

4.629

0.099

 

NI

 High/moderate

92.9%

    

 Poor/anaplastic

90.9%

    

 Unknown

91.4%

    

Histotype

 

0.190

0.663

 

NI

 Adenocarcinoma

92.9%

    

Mucinous/signet ring cell

92.5%

    

No. of LNs dissected

 

20.732

<0.001

 

<0.001

 <12

91.7%

  

Reference

 

 ≥12

94.0%

  

0.846 (0.761-0.941)

 

LNs status

 

223.132

<0.001

 

0.002

 N0

94.2%

  

0.485 (0.423-0.556)

 

 N1a

87.2%

  

Reference

 

 N1b

83.8%

  

1.270 (1.060-1.521)

 

aOther includes American Indian/Alaska native, Asian/Pacific Islander, and unknown.

NI: not included in multivariate survival analyses.

Table 4

Univariate and multivariate survival analyses by pN stage in patients with pT3 stage CC

 

Univariate analysis

Multivariate analysis

Variable

5-year CCS

Log rank χ 2test

P

HR (95% CI)

P

Years of diagnosis

 

39.995

<0.001

 

<0.001

 1988-1993

80.3%

  

Reference

 

 1994-1999

82.6%

  

0.874 (0.808-0.946)

 

 2000-2003

84.6%

  

0.820 (0.763-0.881)

 

Sex

 

25.387

<0.001

 

<0.001

 Male

82.7%

  

Reference

 

 Female

84.3%

  

0.855 (0.811-0.901)

 

Age

 

169.293

<0.001

 

<0.001

 <60

87.3%

  

Reference

 

 ≥60

81.7%

  

1.542 (1.453-1.638)

 

Race

 

103.809

<0.001

 

<0.001

 White

84.1%

  

Reference

 

 Black

77.7%

  

1.461 (1.355-1.574)

 

 Othera

86.2%

  

0.801 (0.733-0.896)

 

Grade

 

15.823

<0.001

 

0.032

 High/moderate

84.0%

  

Reference

 

 Poor/anaplastic

80.8%

  

1.098 (1.024-1.178)

 

 Unknown

83.5%

  

1.003 (0.851-1.182)

 

Histotype

 

1.212

0.271

 

NI

 Adenocarcinoma

83.5%

    

Mucinous/signet ring cell

83.8%

    

No. of LNs dissected

 

270.983

<0.001

 

<0.001

 <12

80.0%

  

Reference

 

 ≥12

86.8%

  

0.668 (0.633-0.705)

 

LNs status

 

1209.713

<0.001

 

<0.001

 N0 (pIIA)

88.4%

  

0.510 (0.476-0.546)

 

 N1a

77.8%

  

Reference

 

 N1b

69.4%

  

1.449 (1.334-1.561)

 

aOther includes American Indian/Alaska native, Asian/Pacific Islander, and unknown.

NI: not included in multivariate survival analyses.

Table 5

Univariate and multivariate survival analyses by pN stage in patients with pT4a stage CC

 

Univariate analysis

Multivariate analysis

Variable

5-year CCS

Log rank χ 2test

P

HR (95% CI)

P

Years of diagnosis

 

61.405

<0.001

 

<0.001

 1988-1993

72.8%

  

Reference

 

 1994-1999

77.1%

  

0.836 (0.792-0.883)

 

 2000-2003

77.8%

  

0.848 (0.803-0.896)

 

Sex

 

35.224

<0.001

 

<0.001

 Male

75.1%

  

Reference

 

 Female

77.2%

  

0.859 (0.822-0.898)

 

Age

 

136.610

<0.001

 

<0.001

 <60

79.9%

  

Reference

 

 ≥60

74.5%

  

1.383 (1.316-1.454)

 

Race

 

85.397

<0.001

 

<0.001

 White

76.7%

  

Reference

 

 Black

69.1%

  

1.357 (1.270-1.450)

 

 Othera

79.7%

  

0.845 (0.777-0.918)

 

Grade

 

52.978

<0.001

 

0.032

 High/moderate

77.3%

  

Reference

 

 Poor/anaplastic

71.5%

  

1.178 (1.116-1.244)

 

 Unknown

75.5%

  

1.053 (0.917-1.210)

 

Histotype

 

0.011

0.915

 

NI

 Adenocarcinoma

76.2%

    

Mucinous/signet ring cell

76.0%

    

No. of LNs dissected

 

266.370

<0.001

 

<0.001

 <12

72.4%

  

Reference

 

 ≥12

80.4%

  

0.708 (0.676-0.740)

 

LNs status

 

1213.378

<0.001

 

<0.001

 N0 (pIIB)

82.7%

  

0.559 (0.528-0.592)

 

 N1a

69.9%

  

Reference

 

 N1b

61.7%

  

1.317 (1.239-1.401)

 

aOther includes American Indian/Alaska native, Asian/Pacific Islander, and unknown.

NI: not included in multivariate survival analyses.

Table 6

Univariate and multivariate survival analyses by pN stage in patients with pT4b stage CC

 

Univariate analysis

Multivariate analysis

Variable

5-year CCS

Log rank χ 2test

P

HR (95% CI)

P

Years of diagnosis

 

37.575

<0.001

 

0.001

 1988-1993

44.4%

  

Reference

 

 1994-1999

49.2%

  

0.905 (0.807-1.014)

 

 2000-2003

55.7%

  

0.809 (0.726-0.902)

 

Sex

 

1.163

0.281

 

NI

 Male

51.9%

    

 Female

50.7%

    

Age

 

41.821

<0.001

 

<0.001

 <60

56.7%

  

Reference

 

 ≥60

48.0%

  

1.329 (1.213-1.456)

 

Race

 

19.460

<0.001

 

<0.001

 White

52.0%

  

Reference

 

 Black

42.3%

  

1.337 (1.175-1.522)

 

 Othera

56.4%

  

0.920 (0.781-1.084)

 

Grade

 

48.208

<0.001

 

<0.001

 High/moderate

54.3%

  

Reference

 

 Poor/anaplastic

44.8%

  

1.343 (1.219-1.479)

 

 Unknown

41.7%

  

1.324 (1.094-1.601)

 

Histotype

 

0.024

0.877

 

NI

 Adenocarcinoma

51.2%

    

Mucinous/signet ring cell

51.4%

    

No. of LNs dissected

 

158.496

<0.001

 

<0.001

 <12

42.4%

  

Reference

 

 ≥12

60.4%

  

0.598 (0.548-0.653)

 

LNs status

 

1213.378

<0.001

 

<0.001

 N0 (pIIC)

60.6%

  

0.596 (0.534-0.666)

 

 N1a

40.5%

  

Reference

 

 N1b

34.1%

  

1.201 (1.062-1.358)

 

aOther includes American Indian/Alaska native, Asian/Pacific Islander, and unknown.

NI: not included in multivariate survival analyses.

Comparison of CCSS between patients with pT1-4aN1a and those with pII stage CC

As presented in Tables 2, 3, 4, 5 and 6, the 5-year CCSS of patients with pIIA, pIIB, and pIIC CC were 88.40%, 82.70%, and 60.60%, respectively, all being lower than that of those with pT1N1a (92.60%). The 5-year CCSS of patients with pIIB and pIIC CC was lower than that of those with pT2N1a (87.20%) and that of patients with pIIC lower than that of those with pT3N1a (69.90%). According to AJCC-7 T classification in stage III, we made statistical comparison among pIIA-C, pT1-2N1a, pT1-2N1b, pT3-4aN1a, pT3-4aN1b, pT4bN1a and pT4bN1b to know whether there were significant differences in CCSS. According to multivariate analysis, the CCSS of patients with pT1-2N1a was similar to that of those with pIIA stage disease (HR, 0.937; 95% CI, 0.838–1.049; P = 0.259, using pIIA stage as the reference). Patients with stage pIIB disease had lower 5-year CCSS than those with pT1-2N1a (HR, 0.677; 95% CI, 0.606–0.757; P < 0.001, using stage pIIB as the reference) but similar 5-year CCSS to those with pT1-2N1b disease (HR, 0.971; 95% CI, 0.861–1.096; P = 0.634). Patients with stage pIIC disease had significantly lower 5-year CCSS than those with pT1-2N1a (HR, 0.254; 95% CI, 0.224–0.287; P < 0.001, using stage pIIC as the reference) and those with pT3-4aN1a (HR, 0.601; 95% CI, 0.560–0.645; P < 0.001), but higher 5-year CCSS than those with pT4bN1a disease (HR, 1.761; 95% CI, 1.576–1.966; P < 0.001) (Table 7).
Table 7

Comparison of 5-year CCSS of patients with SLNM and pII stage CC

Variable

HR (95% CI)

P

HR (95% CI)

P

HR (95% CI)

 

pTNM stage

 

<0.001

 

<0.001

 

<0.001

 IIA

Reference

 

0.723 (0.688-0.759)

<0.001

0.271 (0.252-0.290)

<0.001

 IIB

1.384 (1.317-1.453)

<0.001

Reference

 

0.374 (0.350-0.401)

<0.001

 IIC

3.695 (3.443-3.966)

<0.001

2.671 (2.495-2.859)

<0.001

Reference

 

 T1-2N1a

0.937 (0.838-1.049)

0.259

0.677 (0.606-0.757)

<0.001

0.254 (0.224-0.287)

<0.001

 T3-4aN1a

2.221 (2.109-2.339)

<0.001

1.605 (1.529-1.685)

<0.001

0.601 (0.560-0.645)

<0.001

 T4bN1a

6.506 (5.886-7.192)

<0.001

4.703 (4.262-5.189)

<0.001

1.761 (1.576-1.966)

<0.001

 T1-2N1b

1.344 (1.189-1.518)

<0.001

0.971 (0.861-1.096)

0.634

0.364 (0.319-0.414)

<0.001

 T3-4aN1b

3.060 (2.915-3.211)

<0.001

2.212 (2.115-2.312)

<0.001

0.828 (0.774-0.886)

<0.001

 T4bN1b

8.011 (7.328-8.757)

<0.001

5.790 (5.307-6.317)

<0.001

2.168 (1.961-2.397)

<0.001

P values refer to comparison between each group and the reference group and were adjusted for year of diagnosis, age, sex, pathological grading, histological type of tumor, and number of LNs dissected as covariates.

Discussion

LN metastasis is a critical predictor of disease recurrence and CCSS, and therefore an important determinant of postoperative therapy [8]. Various variables, including pathological tumor stage, tumor grade, and degree of differentiation, have been identified as being associated with LN metastases [9, 10]. In this study, we found that patients’ age, race, pathological grading, histological type of tumor, pT stage and number of LNs dissected provided risk stratification for patients with LN metastasis. Tumors with solitary positive node always mean more deep tumors and worsen grading than those with negative LNs, and the seventh edition of the AJCC Cancer Staging Manual for colon classified any pT stage with solitary positive node into pIII or pIV, both which means worsen survival outcomes.

Patients with esophageal cancer and SLNM have been considered a distinct prognostic subgroup with cancer outcomes closer to that of patients with node-negative disease and better than any other node-positive subgroup [11]. It has even been suggested that there is no survival difference between patients with SLNM and those with N0 esophageal squamous cell carcinoma; that is, SLNM does not affect the prognosis [12]. Bardia et al. [13] reported that six rectal adenocarcinoma patients with a solitary inguinal LN metastasis survived a mean of 42 months from diagnosis, three of the six patients still being alive after a mean duration of 40 months of follow-up when the article was accepted for publication. It is important to investigate the prognosis of patients with SLNM; the presence of multiple LN metastases is already known to be associated with systematic disease and poor prognosis [14]. However, thus far no studies have investigated the prognosis of CC patients with SLNM.

In this study we analyzed the SEER data of 86,674 CC patients and found significant differences in survival between patients with SLNM and those with pN1b disease, verifying our hypothesis that SLNM is the earliest form of LN invasion and has heterogeneous outcomes. Soni et al. confirmed the sentinel node as the only site of metastasis in 41% of node-positive patients [10] and considered that the patients with SLNM did not have systemic disease. We further investigated survival differences by T stage category and found that patients with SLNM in all five pT stages had a significantly longer 5-year CCSS than did pN1b patients, indicating that CC with a SLNM may have an inherently favorable biologic character.

Of interest is that, in our study, the 5-year CCSS of patients with pT1N1a CC was 92.6%, which is higher than that of those with pIIA (88.4%). The 5-year CCSS of patients with pT1-2N1a stage was similar to that of those with stage pIIA, but significantly greater than that of those with pIIB disease. Patients with pT3-4N1a disease had a better 5-year CCSS than those with pIIC. What could explain why patients with SLNM have a better CCSS than those with no LN metastases? We postulate that the major reasons are incomplete surgical resection and/or inadequate node sampling, resulting in inaccurate TNM staging. In the United States, more than 60% of colon cancer is under-staged after surgery [15]. At least 12 examined LNs is the benchmark for accurately ascertaining pathological node stage. Numerous observational studies of the impact of the number of LNs retrieved in patients with CC have shown a clear survival benefit with increasing numbers of LNs examined, especially in stage II patients [1618]; our findings are consistent with these data. The more nodes that are examined and found negative, the more likely that a stage II patient is really node-negative, whereas lower nodal counts increase the risk that a node-positive patient will be misclassified as node-negative. When the technique of sentinel lymph node mapping is used, there is a 15% absolute increase in nodal positivity [10]. Such under-staging leads to under-treatment: many under-staged patients do not receive the adjuvant chemotherapy that is essential for survival benefit. About 15% to 20% of stage I/II colon patients develop recurrence within 5 years of diagnosis [19]. The benefits of increased nodal counts in node-positive patients remain controversial. Because we used the number of LNs dissected as a co-variable in our univariate and multivariate survival analyses, our findings suggest that SLNM CC has inherently favorable biologic behavior.

Despite this, patients with positive LNs are routinely referred for adjuvant therapy [20]. NCCN guidelines (version I.2014) recommend adjuvant chemotherapy for stage pIII CC patients, including those with stage pT1-2N1a, but do not recommend adjuvant chemotherapy for stage pII patients who are assessed as low risk. Many physicians assume that pII stage patients have a better CCSS than pIII patients. Also patients with pII stage are less willing to undergo chemotherapy than pIII stage patients in clinical practice [21, 22]. Thus, stage pT1-2N1a CC patients may be over-treated and stage pII patients under-treated. Unfortunately, because information about chemotherapy is not available in the SEER database, we were not able to analyze this issue further. Postoperative adjuvant treatment with fluorouracil and levamisole reportedly reduces the mortality rate by more than 30% in patients with stage III CC [2325]. However, with CCSS as high as 92.6% in patients with pT1N1a stage disease, does adjuvant chemotherapy benefit all patients in this subgroup? AJCC staging was initiated to assess survival and guide clinical practice; we believe it should emphasize the distinctive characteristics of patients with SLNM.

Although this is a large population-based study evaluating the subgroup of CC patients with SLNM, it has several potential limitations. First, the SEER database lacks data concerning several important tumor characteristics (e.g., perineural and lymphovascular invasion), chemotherapy (neoadjuvant and adjuvant), and patient outcome (recurrence and metastasis). Thus, our analyses could not adjust for these potential confounding factors. Second, there may be minor misclassification of pT4 stage. In the first years of this century, the AJCC defined pT4a as CCs infiltrating adjacent organs or structures without perforation of visceral peritoneum and pT4b as those perforating the visceral peritoneum [26]. However, in the 7th AJCC edition, a CC is classified as pT4a when it infiltrates the serosa and as pT4b when it infiltrates adjacent organs: this may influence the classification of pT4a and T4b CCSS. Third, because SEER data provide no information about the distribution of SLNM, we could not tell whether a SLNM was a skip metastasis and therefore could not ascertain whether there is a difference in survival between skip and no skip groups.

Conclusion

In conclusion, our study shows that patients with SLNM have a better 5-year CCSS than patients with pN1b disease. Patients with pT1-2N1a stage and those with p IIA have a similar 5-year CCSS. Patients with pT3-4aN1a stage have a higher 5-year CCSS rate than those with pIIC disease. The overwhelming advantage in long-term survival of CC patients with SLNM over those with pN1b stage warrants careful attention in clinical practice and TNM stage revision.

Notes

Abbreviations

AJCC: 

American Joint Committee on Cancer

CCSS: 

colorectal cancer cause-specific survival rate

CRC: 

colorectal cancer

CC: 

colon cancer

LN: 

lymph node

NCCN: 

National Comprehensive Cancer Network

SEER: 

National Cancer Institute’s Surveillance, Epidemiology, and End Results

SLNM: 

solitary lymph node metastasis.

Declarations

Acknowledgments

This study used the linked SEER database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Surveillance, Epidemiology, and End-Results (SEER) Program tumor registries in the creation of the SEER database.

Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 81001055; 81101586), Shanghai Pujiang Program (No. 13PJD008), National High Technology Research and Development Program (863 Program, No. 2012AA02A506) and Shanghai Shenkang Program (No. SHDC12012120).

Authors’ Affiliations

(1)
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University

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  27. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/368/prepub

Copyright

© Li et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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