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Lymph nodes regression grade is a predictive marker for rectal cancer after neoadjuvant therapy and radical surgery

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Oncotarget. 2016; 7:16975-16984. https://doi.org/10.18632/oncotarget.7703

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Jun Li _, Jiatian Yuan, Hao Liu, Jie Yin, Sai Liu, Feng Du, Junjie Hu, Ci Li, Xiangke Niu, Bo Lv and Shasha Xing

Abstract

Jun Li1, Jiatian Yuan1, Hao Liu2, Jie Yin3, Sai Liu4, Feng Du5, Junjie Hu6, Ci Li7, Xiangke Niu8, Bo Lv1, Shasha Xing9

1General Surgery Department, Affiliated Hospital/Clinical Medical College of Chengdu University, Chengdu, P.R. China

2General Surgery Department, Second Affiliated Hospital of Jilin University, Changchun, P.R. China

3General Surgery Department, Xuzhou Central Hospital, Xuzhou, P.R. China

4Surgical Department of Gastrointestinal Diseases, Beijing Youan Hospital of Capital Medical University, Beijing, P.R. China

5Internal Medicine-Oncology, Cancer Institute/Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, P.R. China

6Gastrointestinal Tumor Surgery, Hubei Cancer Hospital, Wuhan, P.R. China

7Department of Pathology, Affiliated Hospital/Clinical Medical College of Chengdu University, Chengdu, P.R. China

8Department of Radiology, Affiliated Hospital/Clinical Medical College of Chengdu University, Chengdu, P.R. China

9Central Lab, Affiliated Hospital/Clinical Medical College of Chengdu University, Chengdu, P.R. China

Correspondence to:

Jun Li, e-mail: junl_paper@sina.com

Jiatian Yuan, e-mail: jiatianyuan_pro@sina.com

Shasha Xing, e-mail: xingshasha1230@126.com

Keywords: lymph node, regression grading, rectal cancer, neoadjuvant therapy

Received: October 10, 2015    Accepted: February 08, 2016    Published: February 25, 2016

ABSTRACT

Neoadjuvant therapy (NT) for rectal cancer (RC) reduces primary tumors and involved lymph nodes. While a prognostic value of tumor regression grade (TRG) has been identified, involved lymph node regression grade (LRG) has not been systematically evaluated. Here, we evaluated the association of LRG with oncologic outcomes of RC patients after NT followed by radical surgery. 347 patients with locally advanced RC who received NT and then underwent radical surgery were retrospectively recruited between 2004 and 2011. Response to NT was evaluated by a 3-tier LRG and TRG based on the ratio of residual tumor to fibrosis. LRG was assessed in all patients (LRG 0, 170 patients [49.0%]; LRG 1, 100 patients [28.8%]; and LRG 2, 77 patients [22.2%]). LRG correlated with 5-year distant metastasis and 5-year disease free survival (p=0.029 and 0.023, respectively). LRG also correlated with TRG (p=0.017). We conclude that the LRG system may be an independent predictive factor of long-term oncologic outcomes of rectal cancer patients after NT and radical surgery.


INTRODUCTION

Neoadjuvant therapy (NT) in rectal cancer (RC) downstages primary tumors and reduces local recurrence in locally advanced rectal cancer [1, 2]. Large numbers of NT trials have explored the use of tumor regression grading (TRG) as a primary end-point. Various grading systems, including the Manard, Dowrak, Dowark/Rodel, AJCC and MSKCC have been proposed. All of these use the percentage of tumor cells relative to fibrosis. However, TRG scores do not account for the involvement of lymph nodes, which is an important prognostic parameter [3]. In this regard, Perez et al. [4] reported that histologic regression could be observed in mesorectal lymph nodes after NT. Furthermore, studies indicated that TRG of primary tumors may predict lymph node responses [5, 6]. While Caricato et al. [7] demonstrated that LRG correlated with TRG in primary tumors, but they did not examine the impact of LRG on oncologic outcomes. We therefore evaluated the impact of LRG on oncologic outcomes including local recurrence (LR), distant metastasis (DM), and 5-year disease-free survival (DFS), and the LRG correlation with TRG in primary RC tumors.

RESULTS

Patient characteristics and association of LRG with clinicopathologic factors

347 patients with locally advanced rectal cancer who received radical surgery in 6-8weeks after NT were identified in this retrospective study. A complete pathologic regression (pCR, ypT0N0) was seen in 46 patients (13.3%). In sum, 4012 lymph nodes were detected in all patients; the mean number of LNs was 11.6±2.3 (range: 1-44 nodes). Of note, 66 (19.0%) patients had the number of LNs less than 10. In total, 676 metastasis mesorectal lymph nodes (16.8%) were found; the mean numbers of positive LNs were 2.1±0.3 and 6.3±1.1 in ypN1-2, respectively. LRG was assessed in all patients (LRG 0, 170 patients [49.0%]; LRG 1, 100 patients [28.8%]; LRG 2, 77 patients [22.2%]). cT stage and cN stage did not predict LRG (P =0.815 and 0.432, respectively) (Table 1).

Table 1: Association of LRG with pretreatment and tumor characteristics in 347 patients

Variable

LRG 0

LRG 1

LRG 2

Total

X2

p

No.

%

No.

%

No.

%

No.

Overall

170

49.0

100

28.8

77

22.2

347

Age, years

 ≤60

88

46.3

58

30.5

44

23.2

190

1.216

0.544

 >60

82

52.2

42

26.8

33

21.0

157

Gender

 Male

105

50.7

62

30.0

40

19.3

207

2.443

0.295

 Female

65

46.4

38

27.1

37

26.4

140

Distance from anal verge, cm

 ≤5

93

49.2

55

29.1

41

21.7

189

0.062

0.97

 >5

77

48.7

45

28.5

36

22.8

158

Preoperative CEA

 negative

90

47.4

54

28.4

46

24.2

190

1.261

0.868

 positive

70

51.5

40

29.4

26

19.1

136

 unknown

10

47.6

6

28.6

5

23.8

21

Preoperative treatment

 Preoperative CRT

104

48.8

61

28.6

48

22.5

213

0.039

0.981

 Radiotherapy only

66

49.3

39

29.1

29

21.6

134

cT stage

 cT2

70

50.7

39

28.3

29

21.0

138

2.948

0.815

 cT3

58

47.5

34

27.9

30

24.6

122

 cT4

41

48.8

25

29.8

18

21.4

84

 unknown

1

33.3

2

66.7

0

0.0

3

cN stage

 cN0

90

51.4

45

25.7

40

22.9

175

1.679

0.432

 cN+

80

46.5

55

32.0

37

21.5

172

The association of LRG with histopathologic factors is recorded in Table 2. Radical resection of the primary tumor (R0) was performed in all patients. LRG correlated with TRG score, ypT stage, ypN stage, and venous invasion (P<0.05). No significant association was found between LRG and tumor differentiation degree, lymphatic invasion, and tumor deposits after radical surgery.

Table 2: Association of LRG with pathological factors after NT and radical surgery

Variable

LRG 0

LRG 1

LRG 2

Total

X2

P

No.

%

No.

%

No.

%

Overall

170

49.0

100

28.8

77

22.2

347

TRG score

 0

46

66.7

23

33.3

0

0.0

69

37.733

<0.0001

 1

65

48.9

39

29.3

29

21.8

133

 2

59

38.1

38

24.5

58

37.4

155

ypT stage

 ypT0

33

47.8

21

30.4

15

21.7

69

31.178

<0.0001

 ypT1

60

49.6

40

33.1

21

17.4

121

 ypT2

55

57.9

20

21.1

20

21.1

95

 ypT3

16

50.0

14

43.8

2

16.2

32

 ypT4

6

20.0

5

16.7

19

63.3

30

ypN stage

 ypN0

155

78.3

0

0.0

43

21.7

198

68.109

<0.0001

 ypN1

9

5.9

82

82.0

11

10.8

102

 ypN2

6

12.8

18

18.0

23

48.9

47

Tumor differentiation degree

 poor

39

48.8

23

28.8

18

22.5

80

0.033

0.997

 moderate

59

49.2

35

29.2

26

21.7

120

 well

72

49.0

42

28.6

33

22.5

147

Lymphatic invasion

 negative

134

48.9

79

28.8

61

22.3

274

0.005

0.997

 positive

36

49.3

21

28.8

16

21.9

73

Venous invasion

 negative

119

49.0

60

24.7

64

26.3

243

11.076

0.004

 positive

51

49.0

38.5

28.9

13

12.5

104

Tumor deposits

 negative

136

48.8

72

25.8

51

18.3

279

5.823

0.054

 positive

34

50.0

28

41.2

26

38.2

68

LRG as a prognostic factor for DFS

The 5-year DFS rate for 347 patients after radical surgery was 80.4%. 34 patients had local recurrence, and 34 patients had distant metastasis. None of the patients suffered from both local recurrence and distant metastasis. 148 (85.9%), 78 (78.0%) and 55 (71.4%) patients with LRG 0, 1, and 2 experienced a 5-year DFS, respectively. TRG correlated with 5-year distant metastasis (P =0.035), but failed to correlate with both 5-year local recurrence and 5-year DFS (P = 0.531 and 0.576, respectively). LRG correlated with 5-year distant metastasis and 5-year DFS (P=0.029 and 0.023, respectively). Disease free survival curve for LRG scores is shown in Figure 1. As listed in Table 3, other factors that correlated with DFS by univariable analysis included the ypT and ypN stage, lymphatic invasion and venous invasion (all P<0.05). Using multivariable analysis, the results indicated that two variables including ypT and ypN were independent risk factors for three end-points. LRG was a significant independent predictor of 5-year distant metastasis and 5-year DFS but not for 5-year local recurrence (Table 4).

Association of LRG with disease free survival.

Figure 1: Association of LRG with disease free survival. Disease-free survival curves showed a significant relation to LRG. Data for all 347 cases were available. The 5-year disease-free survival rates for LRG 0-2 were 85.9% (146/170), 78.0% (78/100), and 71.4% (55/77), respectively.

Table 3: Influence of different clinical and pathologic factors on 5-year prognosis after NT and radical surgery

Variables

No. of Patients

Local Recurrence

P

Distant Metastasis

P

5-Year Disease Free Survival

p

No.

%

No.

%

Overall

347

34

9.8

34

9.8

80.4%

Age, years

 ≤60

190

19

10.0

0.9

18

9.5

0.077

80.5%

0.983

 >60

157

15

9.6

16

10.2

80.3%

Gender

 Male

207

23

11.1

0.363

22

10.6

0.566

78.3%

0.688

 Female

140

11

7.9

12

8.6

83.6%

ypT stage

 ypT0

69

1

1.4

0.014

1

1.4

0.001

97.1%

0.024

 ypT1

121

9

7.4

9

7.4

85.1%

 ypT2

95

11

11.6

8

8.4

80.0%

 ypT3

32

6

18.8

6

18.8

62.5%

 ypT4

30

7

23.3

10

33.3

43.3%

ypN stage

 ypN0

198

9

4.5

0.001

15

7.6

0.044

87.9%

<0.0001

 ypN1

102

13

12.7

9

8.8

78.4%

 ypN2

47

12

25.5

10

21.3

53.2%

Tumor differentiation degree

 poor

80

13

16.3

0.089

13

16.3

0.083

67.5%

0.468

 moderate

120

12

10.0

11

9.2

80.8%

 well

147

9

6.1

9

6.1

87.8%

Lymphatic invasion

 negative

274

13

4.7

<0.0001

13

4.7

<0.0001

90.5%

0.001

 positive

73

21

28.8

21

28.8

42.5%

Venous invasion

 negative

243

9

3.7

<0.0001

11

4.5

<0.0001

91.8%

0.005

 positive

104

25

24.0

23

22.1

53.8%

Tumor deposits

 negative

279

26

9.3

0.584

25

9.0

0.341

88.9%

0.406

 positive

68

8

11.8

9

13.2

75.0%

Postoperative chemotherapy

 Yes

285

22

7.7

0.014

25

8.8

0.219

83.5%

0.287

 No

62

12

19.4

9

14.5

66.1%

TRG score

 0 (total)

69

4

5.8

0.531

2

2.9

0.035

91.3%

0.576

 1 (intermediate)

133

13

9.8

10

7.5

82.7%

 2 (minor and no)

155

17

11.0

22

14.2

73.5%

LRG score

 0 (total)

170

12

7.1

0.237

12

7.1

0.029

85.9%

0.023

 1 (intermediate)

100

12

12.0

10

10.0

78.0%

 2 (minor and no)

77

10

13.0

12

15.6

71.4%

Table 4: Multivariate analysis for three end-points after NT and radical surgery

Variables

5-Year Local Recurrence

5-Year Distant Metastasis

5-Year Disease Free Survival

HR

95.0% CI

P

HR

95.0% CI

P

HR

95.0% CI

P

ypT

0.47

(0.29 to 0.80)

0.021

0.55

(0.39 to 0.90)

0.040

0.54

(0.31 to 0.71)

0.033

ypN

2.37

(1.74 to 2.95)

0.006

1.80

(1.45 to 2.02)

0.039

2.58

(2.25 to 3.05)

<0.0001

Lymphatic invasion

1.47

(0.99 to 1.87)

0.083

1.13

(0.90 to 1.28)

0.480

1.03

(0.94 to 1.17)

0.086

Venous invasion

1.12

(0.69 to 1.47)

0.835

0.89

(0.71 to 1.07)

0.713

1.20

(0.99 to 1.47)

0.823

Postoperative chemotherapy

1.24

(0.93 to 1.43)

0.051

TRG

1.15

(0.90 to 1.29)

0.198

LRG

1.37

(1.11 to 1.53)

0.032

1.68

(1.31 to 2.59)

0.027

Relationship between TRG and primary tumor

All cases were enrolled into the model of correlation test. Spearman correlation test was 3.22 and p value was statistically significant (P = 0.017). LRG correlated with TRG.

In 198 patients with ypN0, we examined the preoperative CT and MRI images and found that 31 patients had LN+ lesions. Based on this finding, we assumed that NT killed all the tumor cells but pathologists could not find the residual lymph nodes; this group of patients should have good tumor regression in lymph nodes. Thus, these 31 cases (15.6%) were considered as LRG 0. We found that patients with fibrosis (139 cases) and without fibrosis (31 cases) had similar 5-year DFS (83.9% vs. 86.3%, P=0.080) (Table 5).

Table 5: Association of ypN0 with oncologic outcomes in patients with and without fibrosis after NT and radical surgery

Variables

No. of Patients

No. of Local Recurrence

5-Year Local Recurrence (p)

No. of Distant Metastasis

5-Year Distant Metastasis (p)

5-Year Disease Free Survival

p

All Cases

5-Year Cases

All Cases

5-Year Cases

LRG 0

170

13

12

14

12

85.9%

 ypN0 without fibrosis

31

3

3

0.529

3

2

0.814

83.9%

0.080

 ypN0 with fibrosis

139

10

9

11

10

86.3%

DISCUSSION

Salzer-Kuntschik et al [8] first described tumor regression grade in osteosarcoma after chemotherapy in 1983. In 2002, Bouzorene et al. [9] retrospectively reviewed the resection specimens from 102 patients with locally advanced rectal cancer after preoperative radiotherapy and indicated that tumor regression was a predictive factor for survival. Mandard et al. [10] defined tumor regression in five grades based on residual tumor and fibrosis. In recent years, the TRG grading systems, including the Manard, Dowrak, Dowark/Rodel, AJCC and MSKCC systems, have been proposed. These systems are all based on the percentage of tumor cells relative to fibrosis. However, TRG scores do not account for the involvement of lymph nodes, which are an important parameter of prognosis. In 2007, Caricato et al. [7] reported mesorectal LRG in rectal cancer after NT, but they lacked the long-term data needed to analyze DFS. As far as we know, our study is the first to evaluate the association of LRG with long-term oncologic outcomes.

The results of this study indicate that LRG can predict distant metastasis and DFS, and that LRG is an independent prognostic factor for RC after NT and radical surgery for both DM and DFS. Compared with TRG, we found that LRG correlated with 5-year distant metastasis. Based on the CAO/ARO/AIO-94 trial, Rodel et al. [11] concluded that TRG may be a predictive factor for 5-year distant metastasis. The study group then updated the results and concluded that TRG was a significant prognostic factor for 10-year distant metastasis and DFS [12]. However, our results indicate that TRG may not correlate with 5-year DFS. These differences may be caused by different treatment regimens, including radiation dose, medication used in chemotherapy and pathology practices, as well as differences in duration between NT and surgery. In fact, Kalady et al. [13] reported that patients with an incomplete response at 6 weeks might become pCR at 12 weeks. Accordingly, the interval time between NT and radical surgery was a predominant influence in a pCR, which may impact TRG classification and interfere with the result of the trials. Thus, we consider that TRG alone is not a reliable prognostic factor.

Our study shows that LRG correlates with TRG, as reported previously [57]. This indicates that the primary tumor and positive lymph nodes respond similarly to neoadjuvant therapy, which suggests TRG is predictive of the incidence of involved lymph nodes after NT; hence, some authors suggested that TRG might be helpful in selecting patients suitable for a surgically conservative procedure such as local excision [5] or a wait-and-see policy [1416]. However, in our previous study, we defined a new tumor regression grade (NTRG), which was calculated as the TRG score plus a lymph node score (pN category) and we indicated that NTRG was superior to TRG alone to predict the long-term prognosis of rectal cancer after NT followed by radical surgery [17]. We calculated NTRG using pN stage score not suing LRG, considering that LRG was similar to TRG according to the results of other authors. Interesting, in the present study, we conclude that LRG strongly correlates with TRG, and more surprising, LRG may be useful to assess the long-term prognosis of RC patients. Although our results indicate that LRG may predict long-term oncologic outcomes, some questions remain. First, it is difficult to assess how many of the ypN0 patients with only microscopic LN involvement have really been downstaged. Second, the number of retrieved lymph nodes from patients after NT is lower than in patients treated with radical surgery only. This indicates that NT damages the structure of LNs so that we could not assess whether a small focus of fibrotic tissue found was a pre-treatment normal or metastatic LN. Lastly, pathologists could not distinguish patients with LNs without fibrosis and residual tumor in ypN0 into LRG 0 (complete response) or LRG 2 (no response). Given that we found that patients with and without fibrosis had similar oncologic outcomes, in this study, we enrolled 31 ypN0 patients into LRG 0 (Table 5). But still, we should recognize that complete response in patients with clinical LN+ by MRI but nothing on pathology is not a safe assumption. Besides, does no fibrosis in LN really mean there was any tumor cell before NT, or does LN with fibrosis really mean there is tumor cell ever? These issues should be research in the future study.

Although more studies, including randomized clinical trials are needed, our results indicate that the LRG system may be an independent predictive factor for distant metastasis and DFS of rectal cancer patients after NT and radical surgery.

MATERIALS AND METHODS

Patients

The study was approved by local ethic committees of all participating institutions.

We examined records of 347 patients with primary mid-rectal or distal rectal cancer who had received preoperative neoadjuvant therapy followed by radical surgery at four hospitals between June 2004 and October 2011. The study inclusion/exclusion criteria were: (1) rectal adenocarcinoma confirmed by pretreatment biopsy and/or surgical resection with a total mesorectal excision; (2) locally advanced resectable disease (clinical stage II and III) with the distal margin located no farther than 10 cm from the anal verge; (3) no evidence of distant metastasis; and (4) patients underwent neoadjuvant therapy.

Neoadjuvant therapy schedule

Because there is currently no international consensus with regard to the indications for neoadjuvant chemoradiation therapy, patients managed with preoperative radiochemotherapy or preoperative radiotherapy were identified in our retrospective study. All patients received preoperative radiotherapy (50 Gy/2 Gy/25 f). Among those, 213 (61.4%) patients were concurrently treated with chemotherapy (capecitabine, 825 mg/m2/bid), and the rest received radiotherapy alone. All patients received the same capecitabine regimen (1000 mg/m2/bid, d1-14, 4-6 cycles) 3 weeks after radical surgery, except 62 (17.9%) patients who rejected chemotherapy due to their age, poor physical condition, or side effects.

Pathologic examination

All sections of resection specimens were examined specially by local pathologists blinded to patients’ clinical outcomes according to a standardized protocol that included AJCC TNM category, stage grouping, numbers of examined and involved lymph nodes, presence or absence of lymphatic, venous invasion, tumor deposits, TRG and LRG. The lymphatic or venous invasion was identified by morphology using Hematoxylin-Eosin (HE) staining. TDs were assessed using the 3-mm (TNM5) and contour (TNM6) rules.

Lymph nodes regression grading

Pathologic evaluation of primary tumor regression was performed according to Dworak et al [18], by determining the amount of viable tumor versus fibrotic tissue, which ranged from the lack of tumor regression to complete response with no viable tumor detected. The three groups of TRG and LRG scores were as follows: score 0, total regression (no viable tumor cells; fibrotic mass only); score 1, intermediate regression; score 2, minor regression (dominant tumor mass with obvious fibrosis ≤ 25% of tumor mass), and no regression. Non-metastatic lymph nodes were distinguished from LRG 0 (pCR) by absence of fibrosis. Nodal metastasis regression was evaluated using the same parameters of tumor regression grading referring to each metastatic lymph node. When different LRG scores were identified in one patient, only the most severe score was considered. However, we checked the preoperative CT and MRI pictures and found some patients had LN+ lesions, while pathologists did not found any LN with residual tumor cells and fibrosis (ypN0). Based on that, we assumed that NT killed all the tumor cells but pathologists could not find the residual lymph nodes. This group of patients should have good tumor regression in lymph nodes; thus, these patients (31 cases; 15.6%) were enrolled into LRG 0. Besides, we also found 43 patients (12.4%) with ypN0 but with TRG 2. After evaluating CT and MRI images, the 43 patients were categorized as cN0 and enrolled in LRG 2.

Follow-up

The follow-up results were collected from all four hospitals databases. The end-point of the follow-up was March 2015. The median time of follow-up was 60 months (26-129 months).

Statistical analysis

Spearman correlation test was used to assess relationship between TRG and LRG. Local recurrence and distant metastasis analyses were performed for all eligible patients who received R0 resection without distant metastasis found at time of surgery after neoadjuvant therapy. All time-to-event end-points were measured from date of radical surgery. Disease-free survival (DFS) was calculated from radical resection to finding evidence of recurrence and/or distant metastasis. Statistical analysis was performed using SPSS software (version 18). Differences were evaluated with the log-rank test. Analyses for local recurrence and distant metastasis were calculated as cumulative incidences. Mutivariable models were performed using the Cox proportional hazards model. All significant variables in the univariable analysis were included in multivariable 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. A two-sided p value less than 0.05 was considered significant.

CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

Author contributions

All authors contributed to this work. JL, JTY and SSX conceived and designed the study. JL, JTY, HL, JY, JJH, CL, XKN and BL provided study materials and analyzed the patient data. JL, SL and FD prepared figures and tables. JL, SSX and JTY wrote the manuscript. All authors reviewed the manuscript.

Editorial note

This paper has been accepted based in part on peer-review conducted by another journal and the authors’ response and revisions as well as expedited peer-review in Oncotarget.

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