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Research Papers:

Tumor deposits counted as positive lymph nodes in TNM staging for advanced colorectal cancer: a retrospective multicenter study

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Oncotarget. 2016; 7:18269-18279. https://doi.org/10.18632/oncotarget.7756

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Jun Li, Shengke Yang, Junjie Hu, Hao Liu, Feng Du, Jie Yin, Sai Liu, Ci Li, Shasha Xing, Jiatian Yuan, Bo Lv, Jun Fan, Shusheng Leng, Xin Zhang and Bing Wang _

Abstract

Jun Li1, Shengke Yang2, Junjie Hu3, Hao Liu4, Feng Du5, Jie Yin6, Sai Liu7, Ci Li8, Shasha Xing9, Jiatian Yuan1, Bo Lv1, Jun Fan1, Shusheng Leng1, Xin Zhang1 and Bing Wang1

1 General Surgery Department, Affiliated Hospital/Clinical Medical College of Chengdu University, Chengdu, People’s Republic of China

2 General Surgery Department, Sichuan Cancer Hospital/Institution, Chengdu, People’s Republic of China

3 Gastrointestinal Tumor Surgery Department, Hubei Cancer Hospital, Wuhan, People’s Republic of China

4 General Surgery Department, 2nd Affiliated Hospital of Jilin University, Changchun, People’s Republic of China

5 Internal Medicine-Oncology, Cancer Institute/Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China

6 General Surgery Department, Xuzhou Central Hospital, Xuzhou, People’s Republic of China

7 Surgical Department of Gastrointestinal Diseases, Youan Hospital of Capital Medical University, Beijing, People’s Republic of China

8 Department of Pathology, Affiliated Hospital/Clinical Medical College of Chengdu University, Chengdu, People’s Republic of China

9 Central Laboratory, Affiliated Hospital/Clinical Medical College of Chengdu University, Chengdu, People’s Republic of China

Correspondence to:

Jun Li, email:

Shengke Yang, email:

Junjie Hu, email:

Hao Liu, email:

Keywords: colorectal cancer, tumor deposits, lymph nodes

Received: October 20, 2015 Accepted: February 13, 2016 Published: February 26, 2016

Abstract

We investigated the possibility of counting tumor deposits (TDs) as positive lymph nodes (pLNs) in the pN category and evaluated its prognostic value for colorectal cancer (CRC) patients. A new pN category (npN category) was calculated using the numbers of pLNs plus TDs. The npN category included 4 tiers: npN1a (1 tumor node), npN1b (2-3 tumor nodes), npN2a (4-6 tumor nodes), and npN2b (≥7 tumor nodes). We identified 4,121 locally advanced CRC patients, including 717 (11.02%) cases with TDs. Univariate and multivariate analyses were performed to evaluate the disease-free and overall survival (DFS and OS) for npN and pN categories. Multivariate analysis showed that the npN and pN categories were both independent prognostic factors for DFS (HR 1.614, 95% CI 1.541 to 1.673; HR 1.604, 95% CI 1.533 to 1.679) and OS (HR 1.633, 95% CI 1.550 to 1.720; HR 1.470, 95% CI 1.410 to 1.532). However, the npN category was superior to the pN category by Harrell’s C statistic. We conclude that it is thus feasible to consider TDs as positive lymph nodes in the pN category when evaluating the prognoses of CRC patients, and the npN category is potentially superior to the TNM (7th edition) pN category for predicting DFS and OS among advanced CRC patients.


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INTRODUCTION

The TNM staging system for colorectal cancer (CRC) has been changed several times on the basis of a small expert panel consensus. The 5th edition TNM (TNM5) classification was the first to evaluate tumor deposits (TDs) and proposed the 3-mm rule in 1997 [1, 2]. The next edition (TNM6) concerned the presence of TDs in mesorectal and pericolic fat with the primary tumor, and defined TDs as positive lymph nodes (pLNs) when they had the form and smooth contour of lymph nodes (LNs) while irregular TDs with venous invasion remained in the T category [3, 4]. Recently, the presence of TDs has been reported as an important prognostic factor [5-9].

TDs were again taken into account in the American Joint Committee on Cancer (AJCC) 7th edition TNM classification (TNM7) for CRC, and a new pN1c category was proposed which states that T1 and T2 lesions that lack regional positive lymph node(s) but have tumor deposit(s) will be classified in addition as pN1c. However, it is not consistent in that in pN1c is also an option for pT3/4a tumors in the CRC staging table [10]. Despite the fact that TNM7 states that the number of TDs should be counted according to this categorization strategy, it does not point out the association of the number of TDs with stage III. There are also no clear guidelines on how to classify TDs in patients with pLNs and TDs simultaneously. This potentially impacts the accuracy of the classification and evaluation of the prognosis of CRC patients.

Recently, there has been discussion of the feasibility of TDs being counted as positive lymph nodes in the TNM staging system for CRC. Belt EJ et al. [11] declared lymph node negative CRC (stage II) with TDs should be classified and treated as stage III. Song YX et al. [5] reported that the counting of TDs as pLNs in the TNM staging system is potentially superior to the classification in the TNM7 to assess prognosis and survival for CRC patients. However, both of these studies included small numbers of patients (870 and 513 cases, respectively). In addition, in TNM7 gastric cancer staging, pathologic assessment of the regional pLNs entails their removal and histologic examination to evaluate the total number of nodes and TDs without evidence of residual LN tissue that were considered as pLN [12]. Thus, it is necessary to provide more effective data to validate the feasibility of counting the number of TDs as pLNs in the TNM classification criteria.

Here, we collected large-scale and multicenter data consisting of 4,121 stage II and III CRC patients who received initial radical surgery in order to investigate whether TDs can be counted as metastatic LNs using the AJCC TNM7 staging system for stage III CRC by calculating and comparing the 5-year disease-free survival (DFS) and overall survival (OS).

RESULTS

A total of 4,456 patients with CRC experienced initial radical surgery. According to the exclusion criteria, 180 cases with pTis/T1 stage, 45 with simultaneous distant metastasis, and 110 with other reasons were excluded. Finally, 4,121 cases were included in this retrospective study.

Clinicopathological characteristics of patients

In total, we identified 17.4% (717/4,121) of patients with TDs. The male: female ratio was 1.33:1 (2,352/1,769). The median age was 58.0 ± 12.1 years (range: 14-87). Clinicopathological features are listed in Table 1. In pN category (7th), the percentages of pN0-2b were 50.2%, 12.9%, 13.1%, 6.8%, 9.1% and 7.8%, respectively (P < 0.0001). By contrast, the percentages of npN0-2b were 50.2%, 12.8%, 15.3%, 12.0% and 9.7%, respectively (P < 0.0001). TDs were associated with preoperative carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA19-9) levels, pT or pN category, npN category, differentiation grade, pathological category, and histological type (all P < 0.05). Patients with and without TDs were similar with respect to gender, age, tumor location (colon vs. rectum), and tumor size (diameter) (all P > 0.05). Additionally, the rates of patients with or without TDs who received adjuvant therapy were 17.0% and 18.2% (P = 0.343).

Table 1: Association of TDs with clinical and pathological characteristics

Variable

All Patients (n = 4121)

Patients with TDs (n = 717)

X2

P

No.

%

No.

%

Gender

Male

2352

57.1

411

17.5

0.022

0.882

Female

1769

42.9

306

17.3

Age, year

≤60

2312

56.1

407

17.6

0.154

0.695

>60

1809

43.9

310

17.1

Tumor location

Colon

1449

35.2

278

19.2

0.51

0.475

Rectum

2671

64.8

439

16.4

Tumor size, diameter

≤5.0 cm

2866

69.5

508

17.7

0.68

0.410

>5.0 cm

1254

30.4

209

16.7

Preoperative CEA levels

<5.0 ng/ml

2479

60.2

360

14.5

39.429

<0.0001

≥5.0 ng/ml

1161

28.2

238

20.5

Unknown

481

11.7

119

24.7

Preoperative CA199 levels

<29.0 u/ml

2820

68.4

465

16.5

8.565

0.014

≥29.0 u/ml

459

11.1

101

22

Unknown

842

20.4

151

17.9

pT category (7th)

pT 2

128

3.1

4

3.1

66.154

<0.0001

pT 3

2851

69.2

323

11.3

pT 4

2242

54.4

390

17.4

pN category (7th)

pN 0

2070

50.2

0

0

61.773

<0.0001

pN 1a

533

12.9

100

18.8

pN 1b

539

13.1

124

23

pN 1c

282

6.8

282

100

pN 2a

374

9.1

80

21.4

pN 2b

323

7.8

131

40.6

npN category

npN 0

2070

50.2

0

0

128.185

<0.0001

npN 1a

526

12.8

93

17.7

npN 1b

629

15.3

214

34

npN 2a

495

12

201

40.6

npN 2b

401

9.7

209

52.1

Venous invasion

Yes

268

6.5

87

32.5

70.306

<0.0001

No

3853

93.5

630

16.4

Lymphatic invasion

Yes

26

0.6

12

46.2

11.528

0.001

No

4095

99.4

705

17.2

Differentiation grade

Well

452

11

43

9.5

90.633

<0.0001

Moderately

3213

78

523

16.3

Poorly

456

11.1

146

32

Pathological category

Papillary or tubular adenocarcinoma

3856

93.6

660

17.1

8.991

0.003

Mucinous adenocarcinoma

220

5.3

38

17.3

Signet ring cell cancer

45

1.1

19

42.2

Histological type

Protrude

2733

66.3

477

17.5

17.184

<0.0001

Ulcer

1151

27.9

177

15.4

Infiltrative

237

5.8

63

26.6

Adjuvant therapy

Yes

2796

67.8

476

17

0.899

0.343

No

1325

32.2

241

18.2

TDs resulted in stage migration

A total of 1,798 TDs were detected in 717 (17.4%) patients according to the 3-mm (TNM5) and contour (TNM6) rules. The mean TD diameter was 8.5 ± 3.2 mm (range: 3-24 mm). By changing the definition of TDs to being counted as positive LNs, stage migration was likely to happen. Not surprisingly, the presence of TDs was associated with advanced npN category as compared to pN category (Table 2). TDs also more often presented with higher pT category (Table 1). In Table 2, we list stage migrations resulting from changes in the definition of TDs. Upstaging occurred in 330 of 717 patients (46.0%) with TDs that were in the pN category.

Table 2: pN stage migration according to TDs counted as pLNs

pN Category

npN Category

Sum

npN1a

npN1b

npN2a

npN2b

pN1a

433

74

18

8

533

pN1b

458

63

18

539

pN1c

93

97

85

7

282

pN2a

329

45

374

pN2b

323

323

Sum

526

629

495

401

2051

npN as a prognostic factor for DFS and OS

During follow-up, a total of 1215 patients (29.5%) suffered failure including 351 (8.5%) with local recurrence (LR), 973 (23.6%) with distant metastasis (DM) and 109 (2.6%) with both LR and DM. The 5-year DFS and OS rates for all 4,121 patients were 69.5% and 75.2%. The clinical and pathological data including the number of LR, DM, and all failures are listed in Table 2. The 5-year DFS rates for npN0-2b were 83.6%, 72.4%, 65.6%, 45.7% and 26.0%, respectively (P < 0.0001). By contrast, the 5-year DFS rates for pN0-2b were 83.6%, 71.4%, 57.8%, 69.9%, 39.5%, and 25.8%, respectively (P < 0.0001). The 5-year OS for npN0-2b were 87.9%, 76.2%, 69.1%, 57.9% and 37.1%, respectively (P < 0.0001). Compared to the npN category, the 5-year OS for pN0-2b were 87.9%, 74.3%%, 64.8%, 75.2%,50.1%, and 32.9%, respectively (P < 0.0001).

Table 3: Influence of different clinical and pathological factors on 5-year DFS and OS

Variable

No. of All patients

Local Recurrence

Distant Metastasis

All Failure

5-Years DFS Rate

P

5-Year OS Rate

P

No.

%

No.

%

No.

%

4121

351

8.5%

973

23.6%

1215

29.5%

69.5%

75.2%

Gender

Male

2352

219

9.3%

553

23.5%

713

30.3%

68.7%

0.081

74.9%

0.762

Female

1769

132

7.5%

420

24.7%

502

29.4%

70.6%

75.5%

Age, year

≤60

2312

173

7.5%

535

24.1%

652

29.2%

71.5%

0.087

78.0%

<0.0001

>60

1809

178

9.8%

438

24.2%

563

31.1%

66.9%

71.5%

Tumor location

Colon

1449

34

2.3%

364

25.1%

381

26.3%

73.2%

0.065

76.1%

0.132

Rectum

2671

317

11.9%

609

22.8%

834

31.2%

67.4%

74.7%

Tumor size, diameter

≤5.0 cm

2866

240

8.4%

670

23.4%

835

29.1%

70.1%

0.654

75.8%

0.251

>5.0 cm

1254

111

8.9%

303

24.1%

380

30.3%

68.2%

73.9%

Preoperative CEA levels

<5.0 ng/ml

2479

98

8.4%

463

18.7%

610

24.6%

75.0%

<0.0001

80.7%

<0.0001

≥5.0 ng/ml

1161

198

8.0%

401

34.5%

454

39.1%

58.6%

64.3%

Unknown

481

55

11.4%

109

22.7%

151

31.4%

67.0%

72.0%

Preoperative CA199 levels

<29.0 u/ml

2820

32

7.0%

490

20.8%

601

26.5%

73.1%

<0.0001

81.3%

<0.0001

≥29.0 u/ml

459

169

7.2%

179

39.0%

195

42.5%

54.9%

54.5%

Unknown

842

55

6.5%

109

12.9%

151

17.9%

80.2%

72.0%

pT category (7th)

pT 2

128

8

6.2%

20

15.6%

26

20.3%

78.5%

<0.0001

82.8%

<0.0001

pT 3

2851

141

8.1%

253

14.4%

353

20.2%

79.2%

83.4%

pT 4

2242

202

9.0%

700

31.2%

836

37.3%

61.3%

68.1%

pN category (7th)

pN 0

2070

106

5.1%

252

12.2%

332

16.0%

83.6%

<0.0001

87.9%

<0.0001

pN 1a

533

39

7.3%

121

22.7%

149

28.0%

71.4%

74.3%

pN 1b

539

43

8.0%

187

34.7%

215

39.1%

57.8%

64.8%

pN 1c

282

42

14.9%

47

16.7%

87

30.9%

69.9%

75.2%

pN 2a

374

56

15.0%

171

45.7%

207

55.3%

39.5%

50.1%

pN 2b

323

65

20.1%

195

40.6%

225

69.7%

25.8%

32.9%

npN category

npN 0

2070

106

5.1%

252

12.2%

332

16.0%

83.6%

<0.0001

87.9%

<0.0001

npN 1a

526

32

6.1%

116

22.1%

141

26.8%

72.4%

76.2%

npN 1b

629

51

8.1%

179

28.5%

207

22.9%

65.6%

69.1%

npN 2a

495

72

14.5%

198

40.0%

252

50.9%

45.7%

57.9%

npN 2b

401

90

22.4%

228

56.9%

283

60.6%

26.0%

37.1%

Tumor deposits (TDs)

Positive

717

131

18.3%

281

39.2%

389

54.3%

44.6%

<0.0001

57.7%

<0.0001

Negative

3404

220

6.5%

692

20.3%

826

24.3%

74.9%

78.9%

Venous invasion

Yes

268

47

17.5%

136

50.7%

157

58.6%

36.8%

<0.0001

45.7%

<0.0001

No

3853

304

7.9%

837

21.7%

1058

27.5%

71.7%

77.1%

Lymphatic invasion

Yes

26

8

30.8%

10

38.5%

16

61.5%

29.2%

<0.0001

35.6%

<0.0001

No

4095

343

9.4%

963

23.5%

1199

29.3%

69.8%

75.4%

Differentiation grade

Well

452

22

4.9%

54

11.9%

73

16.2%

82.7%

<0.0001

88.2%

<0.0001

Moderately

3213

275

8.6%

725

22.6%

922

28.7%

70.4%

75.8%

Poorly

456

54

11.8%

194

42.5%

220

48.2%

50.0%

57.8%

Pathological category

Papillary or tubular adenocarcinoma

3856

325

8.4%

888

23.0%

1121

29.1%

69.9%

<0.0001

75.9%

<0.0001

Mucinous adenocarcinoma

220

20

9.1%

63

28.6%

68

30.9%

68.2%

70.1%

Signet ring cell cancer

45

6

13.7%

22

49.9%

26

57.8%

40.8%

41.5%

Histological type

Protrude

2733

230

8.4%

561

20.5%

722

26.4%

73.0%

<0.0001

78.5%

<0.0001

Ulcer

1151

98

8.5%

322

28.0%

386

33.5%

64.8%

70.1%

Infiltrative

237

23

9.7%

90

38.0%

107

45.1%

52.1%

61.2%

Adjuvant therapy

Yes

2796

228

8.2%

672

24.0%

825

29.5%

70.1%

0.361

76.7%

0.002

No

1325

123

9.3%

301

22.7%

390

29.4%

68.2%

71.8%

Univariate analysis showed that the preoperative CEA or CA199 levels, pT, pN, npN, TDs, venous or lymphatic invasion, differentiation grade, pathological category and histological type were all correlated with DFS and OS (all P < 0.0001). Additionally, age and adjuvant chemotherapy were prognostic factors for OS but not DFS. The DFS and OS curves for both npN and pN are shown in Figure 1. Considering the fact that the npN category can be considered as an adjusted classification of the pN category, making the pN and npN categories highly correlated, multivariate models for all patients were calculated separately for each variable to avoid potential bias (Tables 4, 5). As the result, both the npN and pN categories were identified as independent prognostic factors for DFS (HR 1.614, 95% CI 1.541 to 1.673; HR 1.604, 95% CI 1.533 to 1.679) and OS (HR 1.633, 95% CI 1.550 to 1.720; HR 1.470, 95% CI 1.410 to 1.532) by multivariate analyses ( all P < 0.0001).

Table 5: Multivariate analysis for 5-year DFS and OS when pN category enrolled

Variables

5-Year DFS

5-Year OS

HR

95.0% CI

P

HR

95.0% CI

P

Age

1.371

(1.181 to 1.592)

<0.0001

Preoperative CEA

0.901

(0.792 to 1.024)

0.111

0.970

(0.837 to 1.123)

0.683

PreoperativeCA199

0.987

(0.844 to 1.154)

0.867

0.843

(0.711 to 0.994)

0.041

pT category

1.461

(1.280 to 1.668)

<0.0001

1.533

(1.312 to 1.791)

<0.0001

pN category

1.367

(1.313 to 1.422)

<0.0001

1.462

(1.398 to 1.529)

<0.0001

TDs

0.591

(0.509 to 0.687)

<0.0001

1.103

(1.039 to 1.200)

0.036

Venous invasion

0.729

(0.594 to 0.895)

0.003

0.816

(0.648to 1.027)

0.083

Lymphatic invasion

0.455

(0.276 to 0.750)

0.002

0.555

(0.323 to 0.954)

0.033

Differentiation grade

1.387

(1.209 to 1.591)

<0.0001

1.425

(1.222 to 1.663)

<0.0001

Pathological category

1.112

(1.006 to 1.229)

0.037

1.160

(1.036 to 1.298)

0.010

Histological type

0.924

(0.774 to 1.103)

0.381

1.131

(0.940 to 1.361)

0.193

Adjuvant Chemotherapy

1.660

(1.413 to 1.950)

<0.0001

Table 4: Multivariate analysis for 5-year DFS and OS when npN category enrolled

Variables

5-Year DFS

5-Year OS

HR

95.0% CI

P

HR

95.0% CI

P

Age

1.346

(1.160 to 1.563)

<0.0001

Preoperative CEA

0.901

(0.793 to 1.023)

0.108

0.950

(0.822 to 1.099)

0.493

Preoperative CA199

0.976

(0.837 to 1.138)

0.755

0.839

(0.709 to 0.993)

0.041

pT category

1.448

(1.270 to 1.651)

0.000

1.517

(1.300 to 1.769)

<0.0001

npN category

1.519

(1.444 to 1.598)

<0.0001

1.653

(1.560 to 1.752)

<0.0001

TDs

0.665

(0.570 to 0.775)

<0.0001

1.108

(1.007 to 1.202)

0.032

Venous invasion

0.730

(0.595 to 0.897)

0.003

0.791

(0.629 to 0.995)

0.045

Lymphatic invasion

0.466

(0.283 to 0.769)

0.003

0.534

(0.311 to 0.917)

0.023

Differentiation grade

1.333

(1.163 to 1.529)

<0.0001

1.384

(1.187 to 1.613)

<0.0001

Pathological category

1.094

(0.989 to 1.210)

0.082

1.140

(1.108 to 1.277)

0.023

Histological type

0.936

(0.784 to 1.117)

0.463

1.139

(0.947 to 1.371)

0.168

Adjuvant Chemotherapy

1.747

(1.488 to 2.052)

<0.0001

The pN and npN categories were calculated by Harrell’s C statistic to identify which one had superior predictive capacity. The npN category (Harrell’s C = 0.716, 95% CI: 0.709 to 0.728) was found to be superior to the pN category (Harrell’s C = 0.707, 95% CI: 0.695 to 0.718) for DFS. Also, the npN category was a more accurate predictor than pN category for OS (Harrell’s C = 719, 95% CI: 0.700 to 0.736; 712, 95% CI: 0.696 to 0.731, respectively). To identify whether one TD and one pLN had the same weight in patient outcome, we compared the 5-year DFS and OS rates for patients with pure pLNs with patients with pLNs plus TDs. The results are shown in Table 6 and indicate no prognostic heterogeneity meaning that TDs had the same weight as the pLNs (all P < 0.05).

Table 6: Influence of TDs on 5-year DFS and OS in subgroups of npN category

npN Category

No. of All Patients

All Failure

with TDs

All Failure

without TDs

5-Years DFS Rate

5-Years OS Rate

No.

%

No.

%

npN 1a

526

27

29.00%

114

26.30%

72.1% vs.73.6%

76.0% vs.76.2%

npN 1b

629

73

34.10%

134

32.30%

65.4% vs.65.7%

68.9% vs.69.9%

npN 2a

495

107

53.20%

145

49.30%

44.8% vs.46.3%

57.3% vs.58.5%

npN 2b

401

150

71.80%

133

69.30%

25.4% vs.27.6%

36.8% vs.37.5%

Note: the 5-year DFS rates of the subgroups with or without TDs in npN1a, 1b, 2a, 2b were similar (all P < 0.05), and the 5-year OS rates of the subgroups had the similar results (all P < 0.05).

The DFS and OS curves for npN and pN categories.

Figure 1: The DFS and OS curves for npN and pN categories. A. The 5-year DFS rates of npN0-2b were 83.6%, 72.4%, 65.6%, 45.7%, 26.0%,respectively (P < 0.0001), and the 5-year DFS rates of each group from npN 0 to 2b were different (all P < 0.05). B. The 5-year DFS rates of pN0-2b were 83.6%, 71.4%, 57.8%, 69.9%, 39.5%, and 25.8%, respectively (P < 0.0001). pN1a and 1c had similar 5-year DFS rates (P = 0.862). C. The 5-year OS rates of npN0-2b were 87.9%, 76.2%, 69.1%, 57.9% and 37.1%, respectively (P < 0.0001), and the 5-year DFS rates of each group from npN 0 to 2b were different (all P < 0.05). D. The 5-year OS rates of pN0-2b were 87.9%, 74.3%, 64.8%, 75.2%, 50.1% and 32.9%, respectively (P < 0.0001), and the 5-year DFS rates of each group from pN 0 to 2b were different (all P < 0.05). Of note, pN1c had a similar 5-year OS rate with pN1a (P = 0.303).

DISCUSSION

Changes in definitions of what should be considered as positive lymph nodes (pLNs) and tumor deposits (TDs) have been causing great confusion and having a large impact on patient prognosis and selection for postoperative chemoradiotherapy. Although tumor deposits are defined as focal aggregates of adenocarcinoma located in the pericolic or perirectal fat discontinuous with the primary tumor and unassociated with a lymph node, it is difficult to distinguish TDs and nodes. Thus, TNM5 proposed the 3-mm rule, which defined a tumor nodule > 3mm in diameter without histological evidence of residual lymph node tissue as a TD [1]. However, this rule was reported as being based on unpublished data, which were not substantiated. In TNM6, the new definition of TDs based on contour replaced the 3-mm rule, and defined TDs to be classified as pLNs when they had the form and smooth contour of lymph nodes, while irregular TDs were classified in the pT category and as venous invasion [3]. Still, this contour rule lacks support from clinical evidences and reproducibility is poor because of the absence of appropriate guidelines [8].

Currently, the TNM7 proposed a novel pN category (pN1c) in stage III in the absence of lymph node (LN) metastasis which states T1 and T2 lesions that lack regional positive lymph node(s) but have tumor deposit(s) be classified in addition as pN1c, though it is not consistent in that in pN1c is also an option for pT3/4a tumors in the CRC staging table [10]. However, this new edition does not propose guidelines on the definition of TDs, which might impact reproducibility because of subjective opinion from pathologists. Although the TNM staging system changed several times with lack of appropriate guidelines, it is still the most important determinant of prognosis in CRC and it is the basis for the patient management guidelines that influence most patient management decisions [5].

The prevalence of TDs ranges from 6% to 64% in CRC and 17% to 55% in colon cancer [13]. The TNM7 abandoned the 3-mm rule and retained the contour rule so that classification of TDs is left to the discretion of the pathologists and pN1c is designated for TDs. However, when we investigated the use of the new definition for TDs, we found that all studies selected TDs depending, in part, on the definition. In other words, TDs selection is still lacking in guidelines. Still, it is difficult to distinguish pLNs and TDs especially when nodes are replaced completely by tumor cells. In fact, the TNM7 gastric cancer staging system has considered TDs as metastatic lymph nodes and the number of TDs was included for pathologic staging [12]. Additionally, TDs were considered as pLNs in Japanese classification of CRC [14]. Song YX et al [5] declared that tumor deposits can be counted as metastatic lymph nodes in TNM staging system for CRC. Based on the above evidence, we attempted to consider all TDs as pLNs and re-designate the pN category.

In the present study, we considered all TDs as pLNs and the npN category was determined by the number of pLNs plus TDs. By using the npN category, we simplified the node category and investigated the feasibility and effects. The 5-year DFS and OS rates of patients with or without TDs were 44.6% vs. 74.9% and 57.7% vs. 78.9% (P < 0.0001, respectively), which indicatapproved that patients with TDs had a worse DFS and OS compared with patients without TDs. This result was similar with to a previous study [8]. By using univariateble and multivariateble analyses, we concluded that TDs could be potentially an independent and adverse prognostic factor for colorectal cancer. Of note, in multivariable analysis, we found that both the npN and pN category were independent predictors for long-term outcome, including DFS and OS in CRC. And then we declared that, however, the npN category was superior to the pN category for DFS (Harrell’s C = 0.716, 95% CI: 0.709 to 0.728 vs. 0.707, 95% CI: 0.695 to 0.718) and OS (Harrell’s C = 719, 95% CI: 0.700 to 0.736 vs. 0.712, 95% CI: 0.696 to 0.731). Thus, we proposed that the TDs can be counted as pLNs in TNM staging system and the npN category is feasible and superior to the pN category for predicting the long-term outcomes in CRC.

The origins of TDs remain controversial. Some studies propose that 3 types of TDs can be identified. They define TDs as “vascular invasion type,” “TDs other than the vascular invasion type,” and “tumor deposits, extramural venous and perineural types of invasion” [15, 16]. Recent studies have declared strong correlations between the presence of TDs and vascular invasion [7, 17, 18]. However, in the present study, we did not differentiate between types of TDs and reported that 32.5% (87/268) of the TDs was with venous invasion, which was lower than previous studies. Besides, 46.2% (12/26) of the patients with TDs also had lymphatic invasion. In our study, we differentiated venous invasion from lymphatic invasion by hematoxylin-eosin (H-E) staining, which may reduce the accuracy of recognizing venous and lymphatic invasion. In fact, many other factors such as the histological sectioning, which is only a 2-demensional sample of the 3-demensional structure, could cause us to underestimate the association of TDs with vessels.

Whether or not TDs should be considered pLNs or satellite tumor nodules for the purposes of staging may be difficult to determine. It is thus necessary and reasonable to consider TDs as pLNs. Using the npN category, pathologists and clinicians can simplify the TNM staging system and make suitable suggestions for patient postoperative treatment.

The results from this study are constrained by all the flaws and biases inherent to a nonrandomized trial, although this study included large-scale and multicenter data. Additionally, there are no clear and regular guidelines on how to identify the TDs from lymph nodes, which also may potentially influence the conclusions. The ideal trial design to investigate TDs according to sections of whole specimens would be a prospective clinical trial, which may be helpful to get more reliable data.

In sum, we found that it was feasible to consider TDs as positive lymph nodes in the pN category for evaluating the prognoses of CRC patients, and the npN category was potentially superior to the 7th pN category for predicting the disease-free and overall survival of advanced CRC patients. Whether the npN category has any additional significant practical impact on patients management needs more data to validate.

PATIENTS AND METHODS

Ethics considerations

Ethical approval was obtained from the appropriate ethics committees of all participating study sites before the enrolment of patients started. Informed consent was obtained by the investigator at each center from all patients before patient enrollment.

Patients

A total of 4,121 patients with stage II and III colorectal adenocarcinoma who received an initial radical surgery were identified at seven study centers in China between January 2004 and December 2011, and all relevant data were retrospectively collected including age, gender, serum CEA and CA199 levels, date of surgery, location of the primary tumor (colon and rectal), date and site of recurrence, pathological result, adjuvant chemoradiotherapy and cause of death (CRC related or other cause). We defined colon cancer including tumors locating in cecum to sigmoid colon, and rectal cancer containing tumors locating in rectum or rectosigmoid junction according to the definition from Chok KS et al. [19].

The exclusion criteria were as follows: 1) patients who received neoadjuvant chemoradiotherapy (NCRT, resulting in less nodes detection in specimens); 2) patients with distant metastasis such as liver metastasis found pre- or perioperatively; 3) patients with multiple adenocarcinomas of colon and rectum; 4) patients with synchronous or metachronous tumors; 5) patients who had suffered from colorectal cancer before; 6) patients who died in the immediate postoperative period (within 1 month); 7) patients with positive circumferential resection margins; and 8) patients without complete pathological slides.

Treatments

All patients initially received R0 resection without preoperative radiotherapy and/or chemotherapy. For rectal cancer patients, the standard total mesorectal excision was performed. After surgery, patients were treated with radiotherapy and/or chemotherapy or not according to body situation and TNM staging system except some patients who rejected adjuvant therapy. Patients with rectal cancer received adjuvant chemoradiotherapy (40-50Gy/2Gy/20-25F and Xeloda basically), while colon cancer patients were treated with Xeloda and 5-Fu regimens basically. 1325 patients did not received adjuvant therapy, including 83.1% (1101/1325) of patients who were in low risk, and other 16.9% (224/1325) who were in high risk (venous invasion, lymphatic invasion, poor differentiation, or advanced stage) but rejected adjuvant therapy (46.4%, 104/224), or were in poor body situation and could not tolerate adjuvant therapy (53.6%, 120/224).

Pathologic examination

Sections from all resected specimens were examined by local pathologists from seven hospitals. The standardized protocol included determination of the AJCC TNM classification, stage grouping, differentiation degree, histological type, pathological number of examined and involved lymph nodes, and presence or absence of lymphatic or venous invasion. All slides were reviewed for the presence of TDs, defined as either macroscopic or microscopic depositions of carcinoma, without any residual lymph node structures. TDs were assessed using the 3-mm (TNM5) and contour (TNM6) rules [7, 8]. For a regular tumor nodule, we classify it as a positive LN. For an irregular node without any residual tissues of LN we consider it as a TD if the diameter > 3mm measured by a ruler, otherwise, we consider the irregular node as pT3 if the diameter ≤3mm.The reference pathologist tested pathological sections and then recorded the findings in a standardized document.

Classification methods

All patients were classified depending on TNM7, and then we counted TDs as pLNs in a new pN category. In this study, the pN category which combined with the number of TDs was recorded as npN category [5].

Follow-up

The follow-up result was collected from all seven hospitals’database. The end point of follow-up was May 2015. The median time of follow-up was 66 months (range: 2-136 months).

Statistical analysis

Local recurrence and distant metastasis analyses were performed for all eligible patients who received R0 resection without distant metastasis found at time of surgery. All time-to-event end points were measured from date of radical surgery. Disease-free survival (DFS) and overall survival (OS) was calculated from radical resection to finding evidence of local recurrence and/or distant metastasis. Statistical analysis was performed using SPSS software (version 19). Differences were evaluated with the log-rank test. Analyses for local recurrence and distant metastasis were calculated as cumulative incidences. Mutivariate models were performed using the Cox proportional hazards model. All significant variables in the univariate analysis were included in multivariate Cox regression models in a forward-step procedure. The variables were entered in the order according to clinical relevance into the regression models with increasing complexity, and significance was assessed using analysis of variance analysis. The predictive power of the individual models was evaluated using Harrell’C statistic. A model with perfect predictive capacity (sensitivity and specificity of 100%) would have a Harrell’C statistic of 1.00 and the highest Harrell’C statistic was chosen as the best model [20]. A two-sided p value less than 0.05 was considered to be significant.

Authors’ contributions

JL, SKY, JJH, and HL conceived of and designed the study. JL, SKY, HL, JJH, FD, JY, SL, CL, JF, SSL, XZ, BW, JTY and BL provided study materials or patients. JL, SSX, and SKY performed the analyses. JL, SL and FD prepared all figures and tables. JL, HL, SKY and JJH wrote the main manuscript. All authors reviewed the manuscript.

CONFLICTs OF INTEREST

None of the authors have any conflicts of interest to declare.

REFERENCES

1. Sobin LH, Wittekind C (eds): International Union Against Cancer TNM Classification of Malignant Tumours (ed 5). Hoboken, NJ, John Wiley & Sons, 1997.

2. Fleming ID, Cooper JS, Henson DE (eds): AJCC Cancer Staging Manual (ed 5). Philadelphia, PA, Lippincott Raven, 1998.

3. Sobin LH, Wittekind C (eds): International Union Against Cancer TNM Classification of Malignant Tumours (ed 6). Hoboken, NJ, John Wiley & Sons, 2002

4. Greene FL, Page DL, Fleming ID (eds): AJCC Staging Handbook (ed 6). New York, NY, Springer, 2002.

5. Song YX, Gao P, Wang ZN, Liang JW, Sun Z, Wang MX, Dong YX, Wang XF, Xu HM. Can the tumor deposits be counted as metastatic lymph nodes in the UICC TNM staging system for colorectal cancer? PLoS One. 2012; 7:e34087.

6. Lin Q, Wei Y, Ren L, Zhong Y, Qin C, Zheng P, Xu P, Zhu D, Ji M, Xu J. Tumor deposit is a poor prognostic indicator in patients who underwent simultaneous resection for synchronous colorectal liver metastases. Onco Targets Ther. 2015; 22:233-40. 

7. Nagtegaal ID, Tot T, Jayne DG, McShane P, Nihlberg A, Marshall HC, Pahlman L, Brown JM, Guillou PJ, Quirke P. Lymph nodes, tumor deposits, and TNM: are we getting better? J Clin Oncol. 2011; 29:2487-92. 

8. Nagtegaal ID, Quirke P. Colorectal tumour deposits in the mesorectum and pericolon: a critical review. Histopathology. 2007; 51:141-9. 

9. Tateishi S, Arima S, Futami K, Kawahara K, Tachikawa D, Naritomi K, Iwashita A. A clinicopathological investigation of ‘‘tumor nodules’’ in colorectal cancer. Surg Today. 2005; 35:377-84.

10. Sobin LH, Gospodarowicz MK, Wittekind C (2010). TNM classification of malignant tumours, 7th edition.

11. Belt EJ, van Stijn MF, Bril H, de Lange-de Klerk ES, Meijer GA, Meijer S, Stockmann HB. Lymph node negative colorectal cancers with isolated tumor deposits should be classified and treated as stage III. Ann Surg Oncol. 2010; 17:3203-11.

12. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL (eds). AJCC cancer staging handbook, 7th edition. New York: Springer. 149 p, 2010.

13. Ono C, Yoshinaga K, Enomoto M, Sugihara K. Discontinuous rectal cancer spread in the mesorectum and the optimal distal clearance margin in situ. Dis Colon Rectum. 2002; 45:744–749.

14. Kanehara &Co., LTD Tokyo. Japanese Society for Cancer of the Colon and Rectum: Japanese classification of Colorectal Carcinoma, First English Edition.1997.

15. Sternberg A, Mizrahi A, Amar M, Groisman G. Detection of venous invasion in surgical specimens of colorectal carcinoma: the efficacy of various types of tissue blocks. J Clin Pathol. 2006; 59:207–210.

16. Ueno H, Mochizuki H, Hashiguchi Y, Ishiguro M, Miyoshi M, Kajiwara Y, Sato T, Shimazaki H, Hase K. Extramural cancer deposits without nodal structure in colorectal cancer: optimal categorization for prognostic staging. Am J Clin Pathol. 2007; 127:287–294.

17. Prabhudesai A, Arif S, Finlayson CJ, Kumar D. Impact of microscopic extranodal tumor deposits on the outcome of patients with rectal cancer. Dis Colon Rectum. 2003; 46:1531–7.

18. Ueno H, Mochizuki H, Tamakuma S. Prognostic significance of extranodal microscopic foci discontinuous with primary lesion in rectal cancer. Dis Colon Rectum. 1998; 41:55–61.

19. Chok KS, Law WL . Prognostic factors affecting survival and recurrence of patients with pT1 and pT2 colorectal cancer. World J Surg. 2007; 31: 1485–90.

20. Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996; 15:361–387.


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