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. 2014 Sep 11;14:663. doi: 10.1186/1471-2407-14-663

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

Zhi Zhu 1,2,#, Xuren Sun 3,#, Jinou Wang 4, Zhe Sun 1,2, Zhenning Wang 1,2, Xinyu Zheng 1,2,4, Huimian Xu 1,2,
PMCID: PMC4242480  PMID: 25212951

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.

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.

  • (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.

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.

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.

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.

Footnotes

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

HX conceived and designed the study; ZZ, ZS and JW collected and analyzed the data; ZZ and XS wrote the manuscript; ZW and XZ provided critical revisions that are important for the intellectual content; HX approved the final version of the manuscript. All authors read and approved the final manuscript.

Contributor Information

Zhi Zhu, Email: zhuzhi@yeah.net.

Xuren Sun, Email: sxr679@126.com.

Jinou Wang, Email: jinouwang@126.com.

Zhe Sun, Email: asray@sina.com.

Zhenning Wang, Email: josieon826@sina.cn.

Xinyu Zheng, Email: xyzheng126@126.com.

Huimian Xu, Email: xuhuimian@126.com.

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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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