Oncotarget

Clinical Research Papers:

Improvement of T stage precision by integration of surgical and pathological staging in radically resected stage pT3-pT4b gastric cancer

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Oncotarget. 2017; 8:46506-46513. https://doi.org/10.18632/oncotarget.14828

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Hong-Hu Wang, Kai Li, Hao Xu, Zhe Sun, Zhen-Ning Wang and Hui-Mian Xu _

Abstract

Hong-Hu Wang1, Kai Li1, Hao Xu1, Zhe Sun1, Zhen-Ning Wang1 and Hui-Mian Xu1

1 Department of Surgical Oncology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China

Correspondence to:

Hui-Mian Xu, email:

Keywords: surgical staging, pathological staging, prognosis, gastric cancer

Received: May 16, 2016 Accepted: January 16, 2017 Published: January 26, 2017

Abstract

Background: Both surgical TNM (sTNM) and pathological TNM (pTNM) staging are important clinicopathologic indexes of gastric cancer (GC). However, surgeons and pathologists might assess tumor depth differently in the same patient. To investigate the prognostic significance of sTNM status in patients with radically resected stage pT3-pT4b GC, we examined the relationship between sTNM and pTNM.

Methods: Clinicopathologic and survival data of 1289 patients with stage pT3-pT4b GC were studied retrospectively, in the aftermath of radical surgery.

Results: The unconformity for assessing tumor invasion depth were frequently exhibited between sT and pT staging. Comparison of 5-year OS among them, no significant differences were observed (pT3/sT3 vs pT3/sT4a, p=0.962; pT4a/sT4b vs pT4b/sT4b, p=0.508). Also, pT3/sT4b, pT4a/sT3 and pT4a/sT4a were homogeneity in prognosis. We proposed a revised pT stage in which surgical macroscopic T4b (sT4b) was incorporated into the pT stage, namely, patients in the pT3 stage with sT4b cancers were reclassified as being in the r-pT4a stage; patients in the pT4a stage with sT4b cancers were reclassified as being in the r-pT4b stage. In two-step multivariate analysis, revised pT stage proved more suitable for determining prognosis, surpassing both UICC/AJCC pT stage and sT stage as an independent prognostic index.

Conclusions: Surgical T stage is a significant and independent prognostic index of overall survival (OS) in patients with radically resected advanced GC. Patients in the pT3/4a stage with sT4b cancers, are potentially underestimated, and should be considered higher stage in terms of prognostic.


Introduction

Gastric cancer (GC) is a disease with one of the poorest prognoses, and remains the second leading cause of cancer deaths worldwide [1-4]. It is commonly accepted that accurate/optimal staging of primary tumor invasion (pT stage) and regional lymph nodal metastasis (pN stage) is critical for assessing prognosis and decision-making proper adjuvant therapy after curative resection [5-8]. Nonetheless, they are always insufficient for predicting prognosis [9, 10]. Recently, in order to find more suitable prognostic index, many scholars had done a lot and some changes had been done to the pN stage than the pT stage [11-16].

In our previous study, there is another staging system called surgical TNM (sTNM), which is applied to stage and assess in colon and rectum cancer, and it potentially influences patient auxiliary treatment decisions [17]. The sTNM staging is also based on the primary tumors, regional lymph nodes, and metastasis but is defined by surgeons according to the intraoperative findings [18-20]. However, few studies have investigated the prognostic significance of sTNM in gastric cancer. Based on our extensive clinical experience, assessment differences were frequently exhibited between sTNM (macroscopic view) and pathological TNM (pTNM) (microscopic view) staging, especially for patients at T4b stage.

In light of these considerations, the aim of the present study was to investigate prognosis of T3-T4b stage GC patients with inconsistent assessments of tumor invaion between surgical and pathological staging. We also evaluated to integrate the surgical T (sT) stage with pathological T (pT) stage in terms of survival.

materials and Methods

All patients with gastric cancer who underwent surgery at the Department of Oncology, First Affiliated Hospital of China Medical University from January 1985 to December 2010 were entered into a prospectively maintained database. A total of 1352 patients without distant metastasis or positive peritoneal cytology who underwent curative (R0) surgery (with D2/D3 lymphadenectomy) for primary GC, histologically proven and ultimately were confirmed as stage pT3-pT4b. Of these, 35 died in the postoperative period and were excluded. Follow-up of the entire study population was conducted until cancer related death or the cutoff date (December 31, 2011), by means of outpatient clinic consultation, and/or communication with patients through telephone or letter. Median and mean follow-up period were 29 and 48.55 months (range 1-312 months), respectively. At the time of the last follow-up, 28 were lost and were also excluded, leaving a total of 1289 patients for study enrollment. None received neoadjuvant chemotherapy.

The tumor of each gastric cancer was completely examined, furthermore the final macroscopic depth of invasion was confirmed by all of the surgeons present after tumor exploration. Subsequently the pathologists evaluated the postoperative tumor staging, named pT staging. Macroscopic assessment of tumor depth by surgeons during the operation named sT staging was performed as follows: sT3 lesions were diagnosed when tumor invaded subserosal connective tissue, did not invaded through the serosa; sT4a lesions when serosal involvement were visible and sT4b lesions were tumor invaded the adjacent structures. sT staging was prospectively determined by three surgeons, immediately after the abdominal cavity being opened. Disagreement
about the diagnosis was resolved unanimously after discussion with all three surgeons present.

The study was approved by the Research Ethics Committee of China Medical University. Written informed consent was obtained from all patients prior to participation in this study.

All statistical computations relied on standard software (SPSS version 19.0; IBM Corporation, Armonk, NY, USA). Overall survival rates (OS) were determined by Kaplan-Meier method, using log-rank test was used to identify differences between survival curves of different patient groups. Cox’s proportional hazard model (forward-stepwise method) was used for multivariate analysis to identify independent factors predicting prognosis. All p-values were two-tailed, with statistical significance set at p < 0.05.

Results

Clinicopathological characteristics of the 1289 patients of this cohort were summarized in Table 1. In our study, there were patients of 748 pT3 (58.03%), 506 pT4a (39.26%) and 35 pT4b (2.72%); but sT3: 238 (18.46%), sT4a: 580 (45.00%); sT4b: 471 (36.54%). Univariate analysis identified age, tumor location, tumor size, UICC/AJCC pT stage, sT stage, UICC/AJCC pN stage, histologic type, lymphovascular invasion and Borrmann type were significantly correlated with prognosis (Table 1).

Table 1: Clinicopathologic features of 1289 patients with gastric cancers.

Patient Characteristic

Na

5-YSR(%)b

P

Gender

0.267

Male

939

34.8

Female

350

32.7

Age

0.014

≤ 60 years

697

37.0

>60 years

592

32.7

Tumor location

0.000

Entire

95

15.2

Lower 1/3

766

37.7

Middle 1/3

226

39.9

Upper 1/3

202

28.7

Tumor size

0.000

≤4cm

376

40.5

>4cm

913

32.8

UICC/AJCC pT stage

0.000

pT3

748

44.9

pT4a

506

22.7

pT4b

35

10.1

sT stage

0.000

sT3

238

45.9

sT4a

580

39.4

sT4b

471

24.8

UICC/AJCC pN stage

0.000

pN0

348

56.2

pN1

263

38.4

pN2

296

29.8

pN3

382

17.4

Histologic type

0.001

Differentiated

449

40.0

Undifferentiated

840

32.5

Lymphovascular invasion

0.000

Negative

862

39.9

Positive

358

24.3

Borrmann type

0.000

Borrmann 1

31

45.2

Borrmann 2

197

46.7

Borrmann 3

915

34.4

Borrmann 4

136

19.5

Borrmann 5

10

40.0

Abbreviations: na: Number of patients. 5-YSRb: 5-year accumulative survival rate.

As shown in Figure 1, prognosis differed significantly among patients of GC in stage pT3-pT4b and sT3-sT4b (each, p = 0.000). Comparison 5-year OS in every group of pT stage and sT stage respectively, we found that 5-year OS of patients differed significantly among various pT stages, but not in sT stage (Figure 1B). Subsequently, 5-year OS of various sT stages were compared by pT stage. For pT3 or pT4a stage, there were significant prognostic differences between sT3 and sT4b stage, as well as sT4a and sT4b stage, but not in sT3 and sT4a stage (Figure 2).

Comparison of survival curves among patients according to the pT and sT stage (each,

Figure 1: Comparison of survival curves among patients according to the pT and sT stage (each, p = 0.000). A., Survival curves of patients with various pT stage. B., Survival curves of patients with various sT stage.

Comparison of survival curves among patients of various sT stage by pT stage.

Figure 2: Comparison of survival curves among patients of various sT stage by pT stage. A. For patients in pT3 stage, there was no prognostic difference between sT3 and sT4a cancer (p = 0.962). B. For patients in pT4a stage, there was no prognostic difference between sT3 and sT4a cancer (p = 0.542).

Furthermore, 1289 patients were divided into 7 groups by pT and sT stage, i) pT3/sT3: 183(14.20%); ii) pT3/sT4a: 336(26.07%); iii) pT3/sT4b: 230(17.84%); iv) pT4a/sT3: 55(4.27%); v) pT4a/sT4a: 244(18.93%); vi) pT 4a/sT4b: 206(15.98%); vii) pT4b/sT4b: 35(2.72%). Comparison of 5-year OS among them, as shown in Figure 3, no significant differences were observed (pT3/sT3 vs pT3/sT4a, p = 0.962; pT4a/sT4b vs pT4b/sT4b, p = 0.508), interestingly pT3/sT4b, pT4a/sT3 and pT4a/sT4a was homogeneity in prognosis (pT3/sT4b vs pT4a/sT3, p = 0.547; pT3/sT4b vs pT4a/sT4a, p = 0.893; pT4a/sT3 vs pT4a/sT4a, p = 0.542, respectively)(Table 2). Based on these results, we proposed a revision of pT staging (r-pT), whereby patients at stages pT3/sT4a, pT4a/sT4b were reclassified as stage pT4a, pT4b disease, respectively. Five-year OS curves by pT stage differed significantly for both UICC/AJCC pT staging and r-pT staging (each, p = 0.000; Figure 4).

Table 2: Comparison of prognosis among patients which were divided into 7 groups by pT and sT stage.

VS.

pT3/sT3

pT3/sT4a

pT3/sT4b

pT4a/sT3

pT4a/sT4a

pT4a/sT4b

pT4b/sT4b

X2

p

X2

p

X2

p

X2

p

X2

p

X2

p

X2

p

pT3/sT3

0.002

0.962

17.741

0.000

9.986

0.002

15.967

0.000

57.752

0.000

30.712

0.000

pT3/sT4a

0.002

0.962

25.381

0.000

12.309

0.000

23.791

0.000

83.443

0.000

34.751

0.000

pT3/sT4b

17.741

0.000

25.381

0.000

0.363

0.547

0.018

0.893

19.597

0.000

13.722

0.000

pT4a/sT3

9.986

0.002

12.309

0.000

0.363

0.547

0.371

0.542

4.265

0.037

4.268

0.039

pT4a/sT4a

15.967

0.000

23.791

0.000

0.018

0.893

0.371

0.542

20.017

0.000

12.169

0.000

pT4a/sT4b

57.752

0.000

83.443

0.000

19.597

0.000

4.265

0.037

20.017

0.000

0.439

0.508

pT4b/sT4b

30.712

0.000

34.510

0.000

13.722

0.000

4.268

0.039

12.169

0.000

0.439

0.508

Univariate analysis identified age, tumor location, tumor size, UICC/AJCC pT stage, sT stage, UICC/AJCC pN stage, histologic type, lymphovascular invasion and Borrmann type were significantly correlated with prognosis (Table 1). To decide which pT staging approach was more suitable as a prognostic index, a two-step multivariate analysis of prognosis in stage pT3-pT4b GC was conducted. In step 1, all significant prognostic factors of univariate analysis were considered, with exception of r-pT stage. We found that age, location of primary tumor, pT stage, sT atsge, pN stage, lymphovascular invasion, and Borrmann type were independent factors in predicting prognosis. However, once r-pT stage was added in step 2, it surpassed both UICC/AJCC pT stage and sT stage as a critical prognostic factor (Table 3).

Table 3: Two-step multivariate analysis of prognostic factors for 1289 patients

Characteristics

Multivariate analysis step 1 a

Multivariate analysis step 2 B

HR

95%CI

p

HR

95%CI

p

Age

0.000

0.000

≤ 60 years

>60 years

1.311

1.148-1.498

1.301

1.139-1.485

Tumor location

0.000

0.000

Entire

Lower 1/3

0.679

0.523-0.881

0.683

0.527-0.886

Middle 1/3

0.679

0.509-0.906

0.684

0.514-0.911

Upper 1/3

1.037

0.772-1.393

1.057

0.789-1.416

UICC/AJCC pT stage

0.000

pT3

pT4a

1.549

1.350-1.777

pT4b

1.728

1.109-2.693

sT stage

0.000

sT3

sT4a

0.849

0.697-1035

sT4b

1.322

1.079-1.619

UICC/AJCC pN stage

0.000

0.000

pN0

pN1

1.489

1.213-1.827

1.477

1.204-1.812

pN2

1.752

1.434-2.140

1.725

1.413-2.105

pN3

2.597

2.141-3.149

2.569

2.120-3.114

Lymphovascular invasion

0.002

0.002

Negative

Positive

1.258

1.088-1.454

1.256

1.087-1.451

Borrmann type

0.004

0.004

Borrmann 1

Borrmann 2

0.790

0.497-1.257

0.801

0.504-1.272

Borrmann 3

1.032

0.665-1.601

1.048

0.676-1.623

Borrmann 4

1.355

0.836-2.194

1.371

0.847-2.218

Borrmann 5

0.900

0.358-2.261

0.919

0.367-2.298

Revised pT stage

0.000

rT3

rT4a

1.490

1.279-1.736

rT4b

2.299

1.911-2.767

Abbreviations: UICC, International Union Against Cancer; AJCC, American Joint Committee on Cancer; HR, hazard ratio; CI, confidence interval.

a: Step 1, with consideration of all significantly important prognostic factors in univariate analysis, except for the revised pT stage

b: Step 2, with consideration of all significantly important prognostic factors in univariate analysis, including the revised pT stage

Comparison of survival curves among patients which were divided into 7 groups by pT and sT stage.

Figure 3: Comparison of survival curves among patients which were divided into 7 groups by pT and sT stage.

Comparison of survival curves among patients according to the revised T stage (

Figure 4: Comparison of survival curves among patients according to the revised T stage (p = 0.000).

Discussion

In the present study of GC patients in T3-T4b stage, comparison 5-year OS in every group of pT stage and sT stage respectively, we found that survival of patients differed significantly among various pT stage, and also in sT stage. In the next step, 1289 patients were divided into 7 groups by pT and sT stage. Our data revealed that there were no significant prognostic differences between pT4a/sT3-4a and pT3/sT4b, as well as pT4a/sT4b and pT4b/sT4b. Based on these results, we therefore formulated our r-pT staging, where pT3/sT4b and pT4a/sT4b stages GC were incorporated as stage pT4a and pT4b disease, respectively. In this setting, univariate analysis revealed that both sT and pT were important independent prognostic factors. Two-step multivariate analysis confirmed that r-pT stage surpassed both UICC/AJCC pT stage and sT stage as a critical prognostic factor in the prognostic hierarchy.

Our previous study explained some possible reasons of uncomformity between pT stage and sT stage [19, 21]. Major present study additions to this line of investigation were as follows: (1) our study focused on stage T3-T4b GC, because it was difficult to perform accurate assessment of stage T1-T2 GC during the operation; (2) patients were divided into 7 subgroups by pT and sT stage, furthermore were grouped into 3 groups in terms of prognosis; (3) we proposed the revised T stage, importantly integrated macroscopic tumor invasion into TNM stage.

Although primary tumor invasion is significantly and independently predictive of 5-year OS in GC patients, UICC/AJCC pT stage remains always insufficient for predicting prognosis, and recently many scholars have reported that some novel T stages based on several indexes was more suitable in predicting survival [10, 14, 22, 23]. According to numerous previous studies and our practice, the unconformity for assessing tumor invasion depth were frequently exhibited between sT and pT staging [21]. Our finding revealed that there were 835 patients with inconsistent depth of invasion in this setting, therein 436 patients were T4b stage. Pathologists and surgeons have respective difficulty in determining whether tumor invaded the adjacent structures or not. It may be the cause that pathologists and surgeons lack for enough intraoperative finding and sufficient histologic proof during operation, respectively.

The integration of sT and pT staging has distinct advantages and alluring prospects in clinical application [17]. Macroscopic T stage is easily assigned by surgeons, based on gross serosal appearances during open laparotomy, providing a simple and effective method to assess patient prognosis [14, 24]. Likewise, microscopic T stage is routinely reported by pathologists after operation. We may use the macroscopic and microscopic integration to infer the most accurate depth of primary tumor infiltration, thus avoiding a migration in postoperative pT stage. In consideration of the prognostic value of macroscopic and microscopic integration in our hands, we think that its status is critical in deciding whether and how intraoperative and postoperative adjuvant therapy is administered. Thus, further studies are needed to test this premise.

Several limitations of this investigation are acknowledged. The surgical T stage mainly depends on gross macroscopic observations, which may partially vary by individual. Also, This retrospective study (n = 1289) was confined to a single Chinese institution. Larger international multicenter samplings should be analyzed to confirm our findings.

In conclusion, our data demonstrate that both surgical T stage and pathological T stage are independent factors for predicting prognosis in patients with radically resected stage pT3-pT4b GC. Importantly, their integration could be applied to more accurately predict the patient prognosis.

Conflicts of interests

The authors declare that they have no competing interests.

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