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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

BMC Cancer 1/2017

Negative lymph node count is an independent prognostic factor for patients with rectal cancer who received preoperative radiotherapy

Zeitschrift:
BMC Cancer > Ausgabe 1/2017
Autoren:
Xinxing Li, Hao Lu, Kai Xu, Haolu Wang, Xiaowen Liang, Zhiqian Hu
Abbreviations
LN
Lymph node
NLN
Negative lymph node
Pre-RT
Preoperative radiotherapy
RC
Rectal cancer
SEER
Surveillance, Epidemiology, and End Results Program

Background

Rectal cancer (RC) is one of the most common malignancies in the USA, and the incidence of RC in Asian countries is increasing rapidly and has been considered to be similar to that of the Western countries [1]. Preoperative radiotherapy (Pre-RT) has become part of standard practice offered to improve treatment outcomes in patients with RC because of the oncologic benefit of reduced local recurrence rate [2]. But till now, there is still lack of effective means for accurate prognostic evaluation on the survival.
It is widely thought that lymph node (LN) metastasis indicates worse tumor response grade and poorer survival. According to the guidelines for RC from the National Comprehensive Cancer Network, a minimum of twelve lymph nodes must be retrieved and examined for accurate staging and the number of metastatic LNs was validated as an independent prognostic factors [3]. While the node-positive patients with RC are heterogeneous and the prognosis of these patients cannot be stratified by the node-stage only [3, 4]. Therefore, the concept of negative lymph node (NLN) counts has attracted attention recently as a prognostic indicator in various cancers, including breast [5], cervical [6], and esophagus [7]. It has been reported that the number of NLNs was an independent prognostic factor for patients with colon cancer [8]. However, Pre-RT can yield tumor downstaging, reduce the burden of residual microscopic disease at surgery and reduce the number of LNs retrieved in operation [9]. With the decreased LNs retrieval, the prognostic value of the LN count might also diminish [10]. It has been reported that increased number of NLNs is associated with improved survival in pathological IIIB and IIIC RC treated with Pre-RT [7]. While it is still unclear whether NLN still has prognostic value count on survival of all patients with RC, including stage I and II, who received Pre-RT. The purpose of this study was to assess the association between NLN count and survival of patients with RC of all stages who received Pre-RT. In order to get convincing results in a larger series patients, we used the SEER (Surveillance, Epidemiology and End Results)-registered database to analyze this association, and determine the optimal cutoff value of NLN count.

Methods

Study population and data extracted

The SEER (Surveillance, Epidemiology, and End Results Program) database and SEER-stat software (SEER∗Stat 8.3.2) were used to identify patients whose pathological diagnosis as RC between 2004 and 2010. Only patients who underwent Pre-RT and surgical treatment with age of diagnosis more than 18 years were included. Histological type were limited to adenocarcinoma (8140/3), carcinoma (8010/3; 8020/3; 8021/3 and 8145/3) and signet ring cell carcinoma (8490/3). Patients were excluded if they had only local excision following Pre-RT, multiple primary malignant neoplasms, incomplete TNM staging, with distant metastasis (M1), no evaluation on LNs, died within 30 days after surgery or information on CSS and survival months unavailable.
Year of diagnosis, age, sex, race, grade, histologic type, ypT stage, number of LNs examined, number of positive LNs and CSS were assessed. TNM classification was restaged according to the criteria described in the AJCC Cancer Staging Manual (7th edition, 2010).

Statistical analysis

The NLNs cutoff points were determined using the X-tile program, which identified the cutoff value with the minimum P values from log-rank χ2 statistics for the categorical NLNs in terms of CSS. Baseline characteristics were compared using the X2 test for nominal variables. Survival curves were generated using Kaplan-Meier analyses, and the differences between the curves were analyzed by log-rank test. Cox regression models were built for analysis of risk factors for survival outcomes. Statistical analyses were performed using the statistical software package SPSS for Windows, version 19.0 (SPSS Inc., Chicago, IL). All P values were two-sided. P < 0.05 was considered statistically significant.

Results

Patient characteristics from SEER database

In SEER database, we selected a total of 6068 patients with RC who received Pre-RT, including 3881 male and 2187 female from 2004 to 2010. The median age of patients was 59 years. There were 4042 patients with stage ypN0, 1352 with stage ypN1 and 674 with stage ypN2.

The optimal cutoff value for NLN count calculated by X-tile

To assess the influence of different NLN count on CSS, we analyzed the individual result using different NLN count ranging from 0 to 23. The 5-year CSS was calculated for patients with N (NLNs number) or more nodes and less than N nodes. As shown in Table 1, NLN count in patients with RC who received Pre-RT was a prognosis factor for number ranging from 0 to 23. With the NLN count increased from 0 to 23, the 5-year CSS rate increased from 51.8 to 88.8% (Table 1). Next X-tile plots were constructed and the maximum χ2 log-rank value of 78.060 (the number as 9, Fig. 1, P < 0.001) was produced, applying 9 as the optimal cutoff value to divide the cohort into high and low risk subsets in terms of CSS. There was a significant improvement in 5-year CSS between two subsets (74.3% v.s. 82.8%, Table 1). As shown in Table 2, the year of diagnosis, sex, age and the average number of LNs dissected were significantly different between patients with NLN ≤ 9 or >9 (P < 0.05).
Table 1
Univariate analysis of the influence of different NLN count on CSS in RC patients who received Pre-RT
LNs
No.
5-year CCS
χ2
P value
LNs
No.
5-year CCS
χ2
P value
≤0
72
51.8%
41.745
0.000
≤12
3685
76.5%
42.763
0.000
>0
5996
79.5%
>12
2383
83.3%
≤1
230
63.5%
50.100
0.000
≤13
4022
76.9%
38.747
0.000
>1
5838
79.7%
>13
2046
83.6%
≤2
444
68.2%
44.132
0.000
≤14
4320
77.3%
33.939
0.000
>2
5624
80.0%
>14
1748
83.7%
≤3
720
69.0%
54.496
0.000
≤15
4585
77.3%
36.435
0.000
>3
5348
80.5%
>15
1483
84.8%
≤4
1015
70.0%
67.375
0.000
≤16
4822
77.6%
33.037
0.000
>4
5053
81.0%
>16
1246
85.3%
≤5
1314
71.8%
68.432
0.000
≤17
5013
72.8%
27.827
0.000
>5
4754
81.2%
>17
1055
85.4%
≤6
1625
72.5%
74.979
0.000
≤18
5177
78.0%
23.546
0.000
>6
4443
81.6%
>18
891
85.5%
≤7
1974
73.5%
74.302
0.000
≤19
5302
78.0%
25.448
0.000
>7
4094
81.9%
>19
766
86.8%
≤8
2285
74.2%
70.405
0.000
≤20
5422
78.2%
25.257
0.000
>8
3783
82.1%
>20
646
87.2%
≤9
2613
74.3%
78.060
0.000
≤21
5528
77.9%
21.120
0.000
>9
3455
82.8%
>21
540
87.5%
≤10
2973
75.0%
67.236
0.000
≤22
5606
78.4%
21.730
0.000
>10
3095
83.1%
>22
462
88.0%
≤11
3320
75.6%
57.663
0.000
≤23
5671
78.5%
18.872
0.000
>11
2748
83.4%
>23
397
88.8%
Table 2
Comparison of clinical characteristics of patients with NLN ≤ 9 or NLN > 9
Characteristic
Total
NLN ≤ 9
NLN > 9
P value
6068
2613
3455
Follow up
Median (IQU)
58 (42-81) months
Year of diagnosis
    
0.000
 
2004–2007
3122
1553
1569
 
 
2008–2010
2946
1060
1886
 
Sex
    
0.007
 
Male
3881
1625
2256
 
 
Female
2187
988
1199
 
Age
    
0.000
 
<60
3368
1365
2003
 
 
≥60
2700
1248
1452
 
Race
    
0.593
 
White
4927
2137
2790
 
 
Black
511
214
297
 
 
Others
630
262
368
 
Grade
    
0.222
 
Grade I/ II
5098
2184
2914
 
 
Grade III/ IV
970
429
541
 
Histologic type
    
0.430
 
Adenocarcinoma
5517
2367
3150
 
 
Mucinous adenocarcinoma
490
215
275
 
 
Signet ring cell carcinoma
61
31
30
 
ypT stage
 
386
189
197
0.062
 
1
957
425
532
 
 
2
4306
1820
2486
 
 
3
419
179
240
 
 
4
    
LNs dissected
 
12.79
6.92
17.23
0.000

Impact of the NLN count on CSS in RC patients who received Pre-RT

According to univariate analysis, age (≥ 60), race (black persons), grade (III/IV), histologic type (signet ring cell carcinoma), ypT stage (ypT3 and ypT4) and NLNs (≤ 9) were associated with poor outcomes in patients with RC who received Pre-RT (P < 0.001) (Table 3). In multivariate Cox analysis, age, grade, histologic type, ypT stage and NLN counts were independently prognostic factors (P < 0.001, Table 3). NLN counts (> 9) exhibited a favorable effect on survival (HR = 1.623, 95% CI 1.457 ~ 1.809, P < 0.001, Table 3).
Table 3
Univariate and multivariate survival analyses of RC patients who received Pre-RT
Characteristic
5-year CCS
Univariate analysis
Multivariate analysis
χ2 test
P
HR(95%CI)
P
Year of diagnosis
 
2.412
0.120
NI
 2004–2007
78.4%
    
 2008–2010
80.2%
    
Sex
 
1.655
0.198
NI
 Male
29.5%
    
 Female
78.4%
    
Age
 
21.805
0.000
 
0.000
 < 60
81.3%
  
Ref
 
 ≥ 60
76.4%
  
0.777 (0.697 ~ 0.866)
0.000
Race
 
14.873
0.000
 
0.909
 White
79.5%
  
Ref
 
 Black
72.7%
  
1.129 (0.937 ~ 1.364)
0.202
 Others
81.8%
  
1.585 (1.246 ~ 2.017)
0.000
Grade
 
112.363
0.000
 
0.000
 Grade I/ II
81.5%
  
Ref
 
 Grade III/ IV
66.9%
  
0.596 (0.523 ~ 0.680)
0.000
Histologic type
 
81.128
0.000
 
0.000
 Adenocarcinoma
80.4%
  
Ref
 
 Mucinous adenocarcinoma
69.2%
  
0.412 (0.308 ~ 0.635)
0.000
 Signet ring cell carcinoma
32.5%
  
0.601 (0.408 ~ 0.885)
0.010
ypT stage
 
148.323
0.000
 
0.000
 1
88.6%
  
Ref
 
 2
87.9%
  
0.293 (0.212 ~ 0.405)
0.000
 3
77.9%
  
0.303 (0.239 ~ 0.384)
0.000
 4
62.6%
  
0.584 (0.494 ~ 0.692)
0.000
LNs
 
2.234
0.135
NI
 ≤ 12
78.5%
    
 > 12
79.8%
    
NLN
 
78.060
0.000
 
0.000
 ≤ 9
74.3%
  
Ref
 
 > 9
82.8%
  
1.623 (1.457 ~ 1.809)
0.000

Impact of the NLN count on CSS in RC patients based on each pathological grade

We then further analyzed of the effects of NLN on survival in each subgroup of stage yp I, yp II and yp III. As shown in Fig. 2, subgroup analysis showed that NLN was a prognosis factor for patients with RC who received Pre-RT in stage ypI (χ2 = 7.080; P = 0.008), ypII (χ2 = 20.806; P < 0.001) and ypIII (χ2 = 33.138; P < 0.001), respectively. Moreover, as shown in Tables 4, 5 and 6, the NLN count was also an independently prognostic factor in stage ypII (HR: 1.520, 95%CI: 1.170 ~ 1.975; P = 0.002) and ypIII (HR: 1.466, 95%CI: 1.264 ~ 1.700; P < 0.001) after adjustment for potential confounders.
Table 4
Univariate and multivariate survival analyses of stage ypI RC patients who received Pre-RT
Characteristic
5-year CCS
Univariate analysis
Multivariate analysis
χ2 test
P
HR(95%CI)
P
Year of diagnosis
 
6.324
0.012
 
0.035
 2004–2007
87.9%
  
Ref
 
 2008–2010
92.2%
  
1.609 (1.029 ~ 2.517)
0.037
Sex
 
1.238
0.266
NI
 Male
90.0%
    
 Female
89.3%
    
Age
 
2.359
0.125
NI
 < 60
91.3%
    
 ≥ 60
88.0%
    
Race
 
6.222
0.045
 
0.053
 White
88.9%
  
Ref
 
 Black
81.0%
  
3.792 (1.201 ~ 11.968)
0.023
 Others
98.9%
  
4.392 (1.251 ~ 15.415)
0.021
Grade
 
0.483
0.487
NI
 Grade I/ II
90.0%
    
 Grade III/ IV
85.1%
    
Histologic type
 
3.218
0.200
NI
 Adenocarcinoma
89.8%
    
 Mucinous adenocarcinoma
89.5%
    
 Signet ring cell carcinoma
50.0%
    
ypT stage
 
0.001
0.972
NI
 1
90.5%
    
 2
89.4%
    
LNs
 
9.401
0.002
 
0.284
 ≤ 12
87.8%
  
Ref
 
 > 12
93.4%
  
1.702 (0.949 ~ 3.052)
0.074
NLN
 
7.080
0.008
 
0.600
 ≤ 9
87.6%
  
Ref
 
 > 9
91.6%
  
1.128 (0.682 ~ 1.866)
0.638
Table 5
Univariate and multivariate survival analyses of stage ypII RC patients who received Pre-RT
Characteristic
5-year CCS
Univariate analysis
Multivariate analysis
χ2 test
P
HR(95%CI)
P
Year of diagnosis
 
0.255
0.614
NI
 2004–2007
84.1%
    
 2008–2010
84.7%
    
Sex
 
1.414
0.234
NI
 Male
85.1%
    
 Female
83.0%
    
Age
 
21.435
0.000
 
0.000
 < 60
87.2%
  
Ref
 
 ≥ 60
81.1%
  
0.677 (0.566 ~ 0.810)
0.000
Race
 
1.812
0.404
NI
 White
84.6%
    
 Black
81.4%
    
 Others
84.4%
    
Grade
 
24.552
0.000
 
0.000
 Grade I/ II
85.6%
  
Ref
 
 Grade III/ IV
76.2%
  
0.599 (0.479 ~ 0.748)
0.000
Histologic type
 
6.705
0.035
 
0.042
 Adenocarcinoma
85.0%
  
Ref
 
 Mucinous adenocarcinoma
75.9%
  
0.786 (0.249 ~ 2.481)
0.682
 Signet ring cell carcinoma
71.6%
  
1.103 (0.339 ~ 3.590)
0.871
ypT stage
 
21.301
0.000
 
0.000
 3
85.4%
  
Ref
 
 4
73.2%
  
0.591 (0.445 ~ 0.767)
0.000
LNs
 
9.648
0.002
 
0.892
 ≤ 12
82.5%
  
Ref
 
 > 12
86.7%
  
0.983 (0.749 ~ 1.289)
0.900
NLN
 
20.806
0.000
 
0.002
 ≤ 9
80.9%
  
Ref
 
 > 9
86.5%
  
1.520 (1.170 ~ 1.975)
0.002
Table 6
Univariate and multivariate survival analyses of stage ypIII RC patients who received Pre-RT
Characteristic
5-year CCS
Univariate analysis
Multivariate analysis
χ2 test
P
HR(95%CI)
P
Year of diagnosis
 
0.038
0.846
NI
 2004–2007
65.6%
    
 2008–2010
67.0%
    
Sex
 
0.026
0.872
NI
 Male
65.9%
    
 Female
66.2%
    
Age
 
17.245
0.000
 
0.000
 < 60
69.3%
  
Ref
 
 ≥ 60
60.9%
  
0.747 (0.654 ~ 0.866)
0.000
Race
 
17.535
0.000
 
0.625
 White
66.8%
  
Ref
 
 Black
51.6%
  
1.125 (0.880 ~ 1.436)
0.347
 Others
71.3%
  
1.767 (1.290 ~ 2.421)
0.000
Grade
 
41.722
0.000
 
0.000
 Grade I/ II
69.5%
  
Ref
 
 Grade III/ IV
53.9%
  
0.670 (0.566 ~ 0.794)
0.000
Histologic type
 
24.617
0.000
 
0.037
 Adenocarcinoma
67.4%
  
Ref
 
 Mucinous adenocarcinoma
60.7%
  
0.562 (0.378 ~ 0.836)
0.004
 Signet ring cell carcinoma
41.8%
  
0.588 (0.383 ~ 0.904)
0.016
ypT stage
 
66.241
0.000
 
0.000
 1
73.0%
  
Ref
 
 2
83.7%
  
0.442 (0.242 ~ 0.810)
0.008
 3
65.1%
  
0.276 (0.195 ~ 0.391)
0.000
 4
46.8%
  
0.564 (0.451 ~ 0.704)
0.000
LNs
 
1.975
0.160
NI
 ≤ 12
64.9%
    
 > 12
67.0%
    
NLN
 
33.138
0.000
 
0.000
 ≤ 9
60.5%
  
Ref
 
 > 9
71.4%
  
1.466 (1.264 ~ 1.700)
0.000

Discussion

LN metastasis is considered as one of the most significant prognostic factors in RC [11]. The total number of LNs retrieved is fundamental in most pathological staging systems for RC. Inadequate LN evaluation is associated with worse outcomes in terms of tumor recurrence and patient survival [12]. Thus, looking for effective means of assessment of LNs on survival can provide more accurate prognostic information.
According to the AJCC-7 RC staging system, a 12-node minimum is required for proper tumor stage and associated with a good survival outcome in patients treated with surgery [3]. Yet, the number of positive LN is often affected by many facts such as neoadjuvant therapy, and the number of LN retrieved and inspected [3]. Once the range of LN retrieved is not enough, the prediction of survival would be inaccurate. Therefore, the concept of NLN has been developed recently. NLN count has a unique advantage that it is little influenced by the number of LN retrieved [13]. The more NLN count is, the better the survival would be. Li et al. [12] reported that the optimal cutoff value of 10 was validated as an independent prognostic factor in stage ypIIIB and ypIIIC RC patients treated with Pre-RT. In this study, we found that the NLN count was an independent prognosis factor for all patients with RC who received Pre-RT. And we identified the optimal cutoff value for NLN count as 9. Obviously, NLN count is a good supplement for LN stage and TNM stage on evaluating the prognosis of patients with RC who received Pre-RT, respectively for patients with stage ypI, ypII and ypIII. Until now, there has been no report confirming the mechanism of NLNs influencing on the prognosis of RC. But it is suggested that lymphatic micrometastasis is a key etiology of recurrence and metastasis after resection of RC [14]. LN micrometastasis, is common in nodes with the size ranging from 0.2 to 2.0 mm which determined to be negative by HE staining, but positive for cytokeratin (CK) by immunohistochemical staining [15]. Because it is difficult to find lymphatic micrometastasis during operation, we can retrieve more NLNs to reduce the residual micrometastases, in order to improve the prognosis of RC.
The intended purpose of Pre-RT is tumor down-staging by decreasing the primary tumor bulk and reducing the burden of residual associated LN metastases at surgery, thus increasing the potential of margin-negative resections [9]. It has been reported that Pre-RT may cause radiation-induced lymphocyte destruction and stromal fibrosis resulting in alterations of the morphology of the LNs, making LN detection during operation more difficult [9]. Some researchers found that a decreased LN count after Pre-RT was related to good survival [16, 17]. The NLN count is particularly useful in the prediction of survival because it is little influenced by the number of LN retrieved, and has potential to reflect the dissection of lymphatic micrometastasis. In this study, we revealed that NLN count was an independent prognostic factor for patients with RC who received Pre-RT. Subgroup analysis showed that NLN was a prognosis factor for patients with RC who received Pre-RT in stage ypI (χ2 = 7.080; P = 0.008), ypII (χ2 = 20.806; P < 0.001) and ypIII (χ2 = 33.138; P < 0.001), respectively. It might provide more accurate prognostic information than the N stage alone in patients with Pre-RT.
This study has several limitations. First, the SEER database does not include information of therapeutic options such as detailed information of chemotherapy, targeted therapy, immunotherapy, recurrence and metastasis, which may also impact patients’ prognosis. Second, this data lack detailed description of preoperative clinical grading and the information about tumor and LN recession response to treatment, and our analyses could not adjust for these potential confounding factor. Third, different operative approaches, doctors and even pathologist would affect the detective rate of total LN and metastatic LN, but the SEER do not include these information [10]. Although future clinical research will be required to confirm the role of NLN, our study has its convincing power for it is one of the largest population based study until now.

Conclusions

Our results firmly demonstrated that NLN count was an independent prognostic factor for patients with RC who received Pre-RT. It could provide more accurate prognostic information for RC patients with Pre-RT (stage ypI, ypII and ypIII, respectively).

Acknowledgements

The authors acknowledged the efforts of the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER database. The interpretation and reporting of these data were the sole responsibility of the authors.

Funding

The design of the study and collection, analysis, and interpretation of data were supported by National Natural Science Foundation of China to Xinxing Li (Grant No. 81402002).

Availability of data and materials

The cohort data are available to researchers and should be requested under the approval of the SEER Program administration. The other datasets supporting the conclusions of this article are included within the article.

Authors’ contributions

ZQH conceived and designed the study, XXL, HLW and XWL performed the analyses, KX, HLW and XWL provided assistance in writing the manuscript and support in interpreting results. All authors discussed the results and implications of the analysis and commented on the manuscript at all stages. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Because the patients in the SEER database could not be identified, the analysis and reporting of the data in our study were exempt from review by the Ethics Board of Changzheng Hospital, the Second Military Medical University. The requirement for written informed consent to participate was waived. We were permitted to have Internet access after our signed data-use agreement (http://​seer.​cancer.​gov/​data/​sample-dua.​html) was approved by the SEER administration.

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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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