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Histopathology-based prognostic score is independent prognostic factor of gastric carcinoma

  • Zhi Zhu1, 2,
  • Xuren Sun3,
  • Jinou Wang4,
  • Zhe Sun1, 2,
  • Zhenning Wang1, 2,
  • Xinyu Zheng1, 2, 4 and
  • Huimian Xu1, 2Email author
Contributed equally
BMC Cancer201414:663

https://doi.org/10.1186/1471-2407-14-663

Received: 10 May 2014

Accepted: 22 August 2014

Published: 11 September 2014

Abstract

Background

The aim of our study was to evaluate the histological characteristics and prognosis of gastric cancer.

Methods

Clinicopathlogical variables of 932 patients with gastric carcinoma admitted to the Department of Surgical Oncology at the First Hospital of China Medical University were analyzed retrospectively. Different histological characteristics of gastric cancer were summarized and assigned score according to the malignancy defined by WHO classification, the scores were stratified into 4 stage, the prognosis of different stages were analyzed by Kaplan-Meier analysis and cox regression.

Results

Among the 932 patients, 246 (26.39%) had mixed histology type of gastric cancer. Compared to the pure histological type, mixed histological type of gastric cancer was significant associated with tumor size, lymph node metastasis and depth of invasion (all P < 0.05). The 5-year survival rates of advanced and early gastric cancer patients with mixed type were 40.8% and 83.5% respectively, which were lower than those with pure type (50.0% and 95.8%, P < 0.01). Statistically significant difference with stratification of early and advanced stage could be observed between patients with the histological grading score. The data showed that the histological score could be the independent factor of prognosis.

Conclusions

The histological score is an independent factor of gastric cancer, it exerts an excellent ability to classify survival of patients with gastric carcinoma. It also provides a new strategy and parameter for evaluating the biological behavior and prognosis of gastric cancer.

Keywords

Gastric cancer Histological type Tumor differentiation Prognosis

Background

It might be easily thought out that tumor-related factors such as tumor size, lymphatic invasion, and venous invasion could be an indicator for progressive potential of malignant tumors [13]. However, except for stage of the tumor, there have not been any criteria using histopathological tumor-related factors to determine the outcome of the patients with gastric carcinoma.

Histopathological type is an important prognosis factor, it is also to determine the extent of surgical resection and formulated the basis for reasonable surgical plan [4, 5]. It plays an important role in prognostic score for a variety of tumors, such as Gleason score for prostate cancer [6], Child-pugh classification for hepatocellular carcinoma [7], SBR, WHO score for breast cancer [8], but the prognostic effect of histopathology has never been reported in gastric cancer. Moreover, there is not any effective way to identify the prognosis of early gastric cancer.

The coexistence of different histological types of gastric cancer determines the the complex characteristics of clinical behavior and prognosis, the mixed histological type accounted for over 25% of all gastric cancer [9, 10]. Since major diagnostic principles are used, the highly heterogeneous histological features of gastric cancer were ignored, tumor biological behavior and prognostic value of minor histological type were coved up [11]. We currently evaluated the prognostic significance of WHO histological classification of gastric cancer with a new histological scoring method, which makes the histopathological variable to be an independent prognostic factor.

In this study, we attempted to evaluate the histological characteristics and establish simple criteria using the results of histopathological tumor-related factors to predict prognosis of patients with gastric carcinoma.

Methods

All patients with gastric cancer who underwent surgery at the Department of Surgical Oncology, First Hospital of China Medical University, during January 1980 to December 2006 were entered into a prospectively maintained database. Ethical approval for this research was obtained from the Research Ethics Committee of China Medical University, China. In total, 1077 patients underwent D2 lymphadenectomy and achieved radical (R0) resection for histologically proven gastric carcinoma. Follow-up was complete for the entire study population to June 2005. Among them, 24 died in the postoperative period and 43 were lost to follow-up. Thus, 145 patients were excluded. Of the remaining 932 patients, Median and mean follow-up period were 31 and 54 months (range: 3–313 months), respectively. Patients were treated exclusively by total or subtotal gastrectomy with lymphadenectomy, according to tumor location, adjuvant therapy or postoperative chemotherapy was not administered to any patient. Cancer-specific survival was calculated from the date of primary surgical resection to the date of gastric cancer associated death or to the date of recorded cancer progression. Tumor invasion (T), lymph node involvement (N) and TNM stage were classified according to the 7th UICC/AJCC (2012) staging systems.

Histological grading

According to highly heterogeneous histological features and WHO classification of gastric cancer, we propose the novel histological grading system. Aiming to develop and validate the scoring system, the following statistical computing methodologies were applied in the order indicated:

(1) According to the previous studies of histological differentiation and malignant degree of gastric carcinoma, non-mucinous adenocarcinoma (papillary adenocarcinoma and high, medium and low differentiated tubular adenocarcinoma) were assigned as 1–3 points, respectively. Mucinous adenocarcinoma was assigned as 3 points, signet ring cell carcinoma was assigned as 4 points, undifferentiated carcinoma was assigned as 4 points, a special type of stomach cancer as 4 points (these score still needs further refinement) (Table  1).(2) The total score of gastric carcinoma was summed by the original score of the primary histological type and secondary type of gastric carcinoma. Then the total score was divided by the number of histological types to calculate the final score (The mean of the total score). If it was composed of three or more histological type of gastric tissues, The scores will aggregate all score of histological type, then divideded by the number of histological types to get the final score, as presented in Figure  1. If the carcinoma was composed of a pure histological type (All tumors were constituted by the primary type), the score remains the final score.
Table 1

Histological grading points of different subtypes of gastric carcinoma

Gastric carcinoma

Score

Papillary carcinoma

1

Tubular carcinoma

 

  Well-differentiated

1

  Medium-differentiated

2

  Poorly-differentiated

3

Mucinous gastric carcinoma

3

signet-ring cell

4

Undifferentiated gastric carcinoma

5

Special type gastric carcinoma

4

  Adeno-squamous carcinoma

 

  Squamous cell carcinoma

 

  Sarcomatoid type gastric cancer

 

  Liver adenocarcinoma

 

  Micro papillary carcinoma

 

  Neuroendocrine carcinoma

 

  Eosinophilic cell carcinoma

 
Figure 1

Mixed histological type of gastric cancer in WHO classification. (A) high differentiated tubular adenocarcinoma mixed with mucinous adenocarcinoma, final score: (1 + 3)/2 = 2, (B) medium differentiated tubular adenocarcinoma mixed with mucinous adenocarcinoma, final score: (2 + 3)/2 = 2.5 (C) high differentiated tubular adenocarcinoma mixed with signet ring cell carcinoma and mucinous adenocarcinoma, final score: (1 + 3 + 4)/3 = 2.7, (D) high differentiated mixed with undifferentiated gastric cancer, final score: (1 + 5)/2 = 3.

  1. (3)

    Histological grading stage (H Stage) was divided into four groups according to their scores, as follows: H1 (≤2 points), H2 (2–3 points), H3 (3–4 points) and H4 (4–5 points).

     

Statistical analysis

Each variable was used as an independent variable in a Cox proportional hazards analysis run using the Kaplan-Meier method. This was done to screen the variables for later inclusion in a multivariable model. To be included in the multivariable analysis, a variable had to be significant at α of 0.1 for the Wald test. This was a test of the null hypothesis that the coefficient for all levels of the variable of interest was equal to zero.

All significant variables of the univariate analysis were included in the first run of a multivariable Cox proportionate hazard regression. In subsequent Cox regressions, significantly different variables in their hazard ratios were remained sequentially based on the z-statistic for the individual levels of each categorical variable. To remain in the final model, a variable had to be significant at α of 0.05 at all levels.

Results

As stated above, the study included 932 patients undergoing gastrectomy for gastric carcinoma from 1980 to 2005. All patients followed until death or for a maximum 313 months. The overall 5-year survival rate was 41.1%. Adjuvant and chemotherapy treatment was rarely applied in this series. The frequencies of patient characteristics and epidemiological results are summarized in Table 2.
Table 2

Univariate analysis of the prognostic factors for patients with gastric cancer in overall and early stage

Variables

Overall

Early stage

 

Cases

n(%)

5-year OS(%)

P value

Cases

n(%)

5-year OS(%)

P value

Gender

932

  

0.311

90

 

82.2

0.07

  Male

669

71.8

37.8

 

65

72.2

86.2

 

  Female

263

28.2

43.1

 

25

27.8

72.0

 

Age(years)

   

0.062

   

0.32

  ≤65

533

57.2

34.3

 

66

73.3

83.3

 

  >65

399

42.8

43.0

 

24

26.7

79.2

 

Size

   

<0.001

   

0.714

  ≤4 cm

224

24.0

59.2

 

57

63.3

82.5

 

  >4 cm

708

76.0

33.0

 

33

36.7

81.8

 

Location

   

<0.001

   

0.149

  Lower

672

72.1

42.1

 

75

83.3

85.3

 

  Middle

99

10.6

37.6

 

9

10.0

66.7

 

  Upper

115

12.3

36.5

 

6

6.7

66.7

 

  Entire

46

4.9

25.4

 

0

0.0

0.0

 

Macroscopic Type

   

<0.001

    

  Early stage

90

10.7

81.0

     

  Borrmann I

30

2.1

42.1

     

  Borrmann II

145

15.6

40.7

     

  Borrmann III

614

65.9

34.2

     

  Borrmann IV

52

5.6

13.7

     

Lauren grade

   

0.003

   

0.218

  Intestinal

455

48.8

50.4

 

38

42.2

86.5

 

  Diffuse

477

51.2

37.1

 

52

57.8

73.1

 

Histologic type

   

0.334

   

0.263

  Mixed-type

272

29.2

40.3

 

37

41.1

61.3

 

  Well-differentiated

61

6.5

57.9

 

7

7.8

83.7

 

  Medium-differentiated

112

12.0

43.7

 

8

8.9

53.9

 

  Poorly-differentiated

365

39.2

37.5

 

34

37.8

40.2

 

  Mucinous

58

6.2

38.6

 

1

1.1

100.0

 

  Signet-ring cell

29

3.1

47.8

 

3

3.3

33.3

 

  Undifferentiated

30

3.2

21.4

 

0

0.0

0.0

 

  Squamous cell

5

0.5

25.0

 

0

0.0

0.0

 

Histologic type 2

   

0.504

   

0.958

  Differentiated

380

40.8

37.6

 

59

65.6

83.1

 

  Undifferentiated

552

59.2

40.5

 

31

34.4

80.6

 

Histologic type 3

   

0.032

   

0.016

  Singal-type

684

73.3

39.3

 

56

62.2

89.1

 

  Mixed-type

246

26.4

39.3

 

34

37.8

72.4

 

Histologic Grading

   

<0.001

   

<0.001

  1

63

6.8

82.5

 

30

30.0

93.3

 

  2

352

37.7

62.0

 

45

50.0

88.6

 

  3

399

42.8

26.2

 

17

18.9

78.6

 

  4

118

12.6

6.8

 

1

1.1

0.0

 

T Stage

   

<0.001

    

  T1

90

9.7

82.2

     

  T2

185

19.8

50.8

     

  T3

418

44.8

36.5

     

  T4

239

25.6

19.0

     

N Stage

   

<0.001

   

0.06

  N0

288

30.9

63.8

 

65

72.2

86.2

 

  N1

168

18.0

43.7

 

13

14.4

76.9

 

  N2

189

20.3

34.0

 

10

11.1

70.0

 

  N3

287

22.5

12.2

 

2

2.2

50.0

 

Lymphovascular invasion

   

0.032

    

  Negative

208

22.3

40.7

     

  Positive

724

77.7

22.6

     

Peritoneal metastasis

   

0.022

    

  Absent

889

88.9

39.8

     

  Present

43

11.1

19.5

     

Hepatic metastasis

   

0.014

    

  Absent

878

90.3

38.7

     

  Present

54

9.6

16.8

     
Difference of survival reflected by tumor-related factors such as tumor size, tumor depth, lymph node metastasis was shown in Table 3. Compared to the pure histological type, mixed histological type gastric cancer was significant associated with tumor size, lymph node metastasis and depth of invasion (all P < 0.05). All the gastric cancer patients were stratified by advanced and early stage. The 5-year survival rates of advanced and early gastric cancer patients with mixed form were 40.8% and 83.5% respectively, which were lower than those with pure form (50.0% and 95.8%, P < 0.01) ( Figure 2).
Table 3

Relationship between the prognostic factors and histological types for patients with gastric cancer

Variables

Cases 932

Pure type 684 (73.61)

Mixed type 246 (26.39)

χ2

P value

Gender

   

0.532

0.466

  Male

669

488

181

  

  Female

263

198

65

  

Age(years)

   

0.039

0.843

  ≤65

533

391

142

  

  >65

399

295

104

  

Size

   

<0.001

0.983

  ≤4 cm

224

165

59

  

  >4 cm

708

521

187

  

Location

   

0.081

0.96

  Lower

672

495

178

  

  Middle

99

103

38

  

  Upper

115

88

30

  

  Entire

46

    

Macroscopic Type

   

11.173

0.018

  Early stage

90

66

34

  

  Borrmann I

30

13

7

  

  Borrmann II

145

119

26

  

  Borrmann III

614

453

161

  

  Borrmann IV

52

35

17

  

Lauren grade

   

0.189

0.003

  Intestinal

455

368

128

  

  Diffuse

477

318

118

  

T Stage

   

9.629

<0.001

  T1

90

56

34

  

  T2

185

140

45

  

  T3

418

321

97

  

  T4

239

169

70

  

N Stage

   

3.043

0.551

  N0

288

213

75

  

  N1

168

131

37

  

  N2

189

135

54

  

  N3

287

207

80

  

Lymphovascular invasion

   

8.794

0.038

  Negative

208

378

121

  

  Positive

724

300

124

  

Peritoneal metastasis

   

10.322

<0.001

  Absent

889

672

215

  

  Present

43

12

31

  

Hepatic metastasis

   

11.523

<0.001

  Absent

878

667

209

  

  Present

54

17

37

  
Figure 2

The 5-year survival rates of gastric cancer patients with mixed form were lower than those with pure form, especially for early stage. (A) Survival rates of all gastric cancer patients with mixed form were 48.2% and single form were 53.3%, P = 0.305. (B) Survival rates of early gastric cancer patients with mixed form were 83.5% and single form were 95.8%, P < 0.01. (C) Survival rates of early gastric cancer patients with mixed form were 40.8% and single form were 50.0%, P = 0.037.

Patients stratified by Histological grading of 214 (55.9%), 182 (28.4%), 492 (15.7%) and 44 (28.4%) defined Histological stage I, II, III and IV, respectively. Statistically significant difference with stratification of early and advanced stage could be observed between patients with the histological grading score, respectively. Mixed histological type gastric cancer had worse prognosis in early and advanced stage (Table 2). No significant difference was observed regarding gender and age of the patients. Significant correlation was observed between H grading scores and all of the tumor-related factors (Table 4).The T, N, and TNM stage are the best classification system to classify overall survival of patients with gastric carcinoma, however, there is no effective methodology to evaluate the prognosis of early stage. The 5-year survival rates of gastric cancer patients stratified by histological grading showed there is no superiority compared to T stage and N stage, but the 5-year survival rates of patients with early stage stratified by histological grading was much better than N stage in predicting the prognosis of the early stages, P < 0.01. Significant difference could be observed in survival curves between the early and advanced stage for the same patients, respectively (Figure 3).
Table 4

Comparison of relationship between Histological grading and prognositic factors

 

Histological grading

P

Variables

H1 (≤2)

H2 (2–3)

H3 (3–4)

H4 (4–5)

 

Size

    

<0.001

  ≤4 cm

61

39

117

7

 

  >4 cm

153

143

375

37

 

Location

     

  Lower

150

130

358

35

 

  Middle

34

25

76

6

 

  Upper

30

27

58

3

 

  Entire

     

Macroscopic Type

    

<0.001

  Early stage

31

18

49

2

 

  Borrmann I

10

2

7

1

 

  Borrmann II

43

33

63

6

 

  Borrmann III

127

123

334

30

 

  Borrmann IV

3

6

38

5

 

Lauren grade

    

<0.001

  Intestinal

169

127

194

6

 

  Diffuse

45

55

298

38

 

Histologic type

    

<0.001

  Differentiated

164

141

72

3

 

  Un-differentiated

50

41

420

41

 

Depth of tumor

    

<0.001

  T1

30

17

42

1

 

  T2

46

36

95

8

 

  T3

92

89

223

14

 

  T4

46

40

132

21

 

Node metastasis

    

<0.001

  N0

87

55

137

9

 

  N1

42

37

83

6

 

  N2

44

40

96

9

 

  N3

41

50

176

20

 

Lymphovascular invasion

    

<0.001

  Negative

145

104

240

10

 

  Positive

77

76

249

35

 

Peritoneal metastasis

     

  Absent

889

    

  Present

43

    

Hepatic metastasis

     

  Absent

878

    

  Present

54

    
Figure 3

The 5-year survival rates of gastric cancer patients stratified by histological grading. (A) showed there is no superiority compared to N stage (B) and T stage (C), but the 5-year survival rates of patients with early stage stratified by histological grading (D) was much better than N stage (E) in predicting the prognosis of the early stages, P < 0.01. Significant difference could be observed in survival curves between the early and advanced stage for the same patients, respectively.

The multivariate Cox stepwise proportional hazard model identified Macroscopic type (HR, 1.226, P <0.001), Histological grading (HR, 1.316, P <0.001), T stage (HR, 1.340, P <0.001), N stage (HR, 1.425, P <0.001) as independent predictors of prognosis. In the early gastric cancer, Histological grading (HR, 1.533, P <0.001), Tumor size (HR, 1.412, P <0.001) and N stage (HR, 1.213, P <0.001) as independent predictors of prognosis, histological grading were proved to be the highest HR (Table 5).
Table 5

Mutivariate analysis of the prognostic factors for patients with gastric cancer in overall and early stage

Variables

Overall

Early stage

 

HR

95% CI

P value

HR

95% CI

P value

Size

1.220

0.958-1.554

0.107

1.412

1.026-1.545

<0.001

Macroscopic type

1.226

1.086-1.385

<0.001

1.365

0.922-1.463

0.103

Lauren grade

1.181

0.894-1.076

0.684

1.133

0.754-1.042

0.725

Histologic type

1.136

0.764-1.352

0.722

1.136

0.764-1.352

0.722

Histologic grading

1.316

1.182-1.465

<0.001

1.533

0.838-1.734

<0.001

N Stage

1.425

1.328-1.529

<0.001

1.213

1.096-1.416

0.036

T Stage

1.340

1.181-1.522

<0.001

   

Distant metastasis

1.215

0.935-1.650

0.116

   

Discussion

Generally, tumor stage composed of depth of tumor, lymph node metastasis, and distant metastasis, might account for the most powerful indicator for the prognosis in the majority of malignant tumors [1215]. Conventional histopathological variables that have been correlated with prognosis of many malignant neoplasms plays an important role in prognostic score, such as Gleason score of prostate cancer, Child-pugh classification of hepatocellular carcinoma, SBR, WHO score of breast cancer [8, 16, 17].

Nevertheless, for gastric cancer, separated from other cancers, the prognostic value of these factors has not been consistently recognized. It has been reported that there is no relationship between gastric histological type and prognosis, there is no comprehensive pathological conditions or anything about gastric histopathological differentiation in the reflection of gastric cancer staging and prognosis [18].

However, the practical value of some of histopathological variables is limited due to complexity of gastric histological composition, coexistence of different malignancy subtypes and ambiguity of tumor biological behaviors [19]. Despite their histological variability, usually one of four patterns predominates. The diagnosis is based on the predominant histological pattern [20]. Histologically, most subtypes of carcinoma occur in early gastric cancer in either pure or mixed forms. We performed this study to compare pure or mixed gastric cancer forms of prognosis, The 5-year survival rates of advanced and early gastric cancer patients with mixed form were 40.8% and 83.5% respectively, which were lower than those with pure form (50.0% and 95.8%, P < 0.01).

Proportion of mixed forms gastric cancer patients with N0 stage were significantly lower than with a pure type, patients of mixed type are more likely to lymph node metastasis. Mixed forms were significantly correlated with T stage, so patients were stratified into early and advanced stage, univariate analysis and survival curve showed 5 -year survival of mixed type of early gastric cancer was significantly lower than that that of a pure type, and there was little difference in the advanced stage.

With the histological grading score, there is significantly different between the 5-year survival curves of H Stage, prognosis of early gastric cancer could be identified obviously, which is not reflected in any other current classification. Indeed, statistically significant difference with so strict stratification was observed between patients with H Stage 1–4.

The T, N, or TNM classification system could exert an excellent ability to classify overall survival of patients with gastric carcinoma also in the current study. However, in early gastric cancers, only small mucosal (<4 cm), superficial (>4 cm) and PenA, PenB may have a low incidence of lymph node metastasis with good prognosis after surgery [21]. There is no effective methodology to evaluate the prognosis of early gastric cancer. Our new histological grading provides a new tragedy to identify the prognosis of early gastric cancer.

Of course, TNM classification system could exert an excellent ability to classify survival of patients with gastric carcinoma also in the current study. Therefore, H grading system newly devised as well as TNM classification system could classify the prognosis of patients with gastric carcinoma with a strict stratification. This score system would provide objective information regarding the outcome of patients treated with curative resection for gastric carcinoma.

In conclusion, H Stage that can be utilized in the majority of the institutes would be quite simple criteria to predict prognosis of gastric carcinoma with a strict stratification.

Conclusions

The histological score that we developed in the research exert an excellent ability to classify survival of patients with gastric carcinoma, it could classify the prognosis of patients with gastric carcinoma with a strict stratification. The histological score is an independent factor of gastric cancer. It also provides a new strategy and parameter for evaluating the biological behavior and prognosis of gastric cancer.

Notes

Declarations

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81302129) and General Project of Liaoning Provincial Education Department (L2013291). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors’ Affiliations

(1)
Department of Surgical Oncology, First Affilated Hospital, China Medical University
(2)
Department of General Surgery, First Affiliated Hospital, China Medical University
(3)
Department of Gastroenterology, First Affiliated Hospital, China Medical University
(4)
Department of Pathology, Shengjing Hospital of China Medical University

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  22. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/663/prepub

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© Zhu 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/4.0), 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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