Surg Endosc DOI 10.1007/s00464-015-4184-z

and Other Interventional Techniques

REVIEW

Redefining early gastric cancer Savio G. Barreto1 • John A. Windsor2,3

Received: 25 November 2014 / Accepted: 19 March 2015 Ó Springer Science+Business Media New York 2015

Abstract Background The problem is that current definitions of early gastric cancer allow the inclusion of regional lymph node metastases. The increasing use of endoscopic submucosal dissection to treat early gastric cancer is a concern because regional lymph nodes are not addressed. The aim of the study was thus to critically evaluate current evidence with regard to tumour-specific factors associated with lymph node metastases in ‘‘early gastric cancer’’ to develop a more precise definition and improve clinical management. Methods A systematic and comprehensive search of major reference databases (MEDLINE, EMBASE, PubMed and the Cochrane Library) was undertaken using a combination of text words ‘‘early gastric cancer’’, ‘‘lymph node metastasis’’, ‘‘factors’’, ‘‘endoscopy’’, ‘‘surgery’’, ‘‘lymphadenectomy’’ ‘‘mucosa’’, ‘‘submucosa’’, ‘‘lymphovascular invasion’’, ‘‘differentiated’’, ‘‘undifferentiated’’ and ‘‘ulcer’’. All available publications that described tumour-related factors associated with lymph node metastases in early gastric cancer were included.

& John A. Windsor [email protected] Savio G. Barreto [email protected] 1

Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Gurgaon, India

2

HBP/Upper GI Unit, Department of General Surgery, Auckland City Hospital, Auckland, New Zealand

3

Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

Results The initial search yielded 1494 studies, of which 42 studies were included in the final analysis. Over time, the definition of early gastric cancer has broadened and the indications for endoscopic treatment have widened. The mean frequency of lymph node metastases increased on the basis of depth of infiltration (mucosa 6 % vs. submucosa 28 %), presence of lymphovascular invasion (absence 9 % vs. presence 53 %), tumour differentiation (differentiated 13 % vs. undifferentiated 34 %) and macroscopic type (elevated 13 % vs. flat 26 %) and tumour diameter (B2 cm 8 % vs.[2 cm 25 %). Conclusion There is a need to re-examine the diagnosis and staging of early gastric cancer to ensure that patients with one or more identifiable risk factor for lymph node metastases are not denied appropriate chemotherapy and surgical resection. Keywords Stomach
Early gastric cancer, definitions, endoscopy
Outcome Gastric cancer is the fourth most common cancer in the world [1]. With an overall 5-year survival rate of \20 % [2], gastric cancer accounts for 10 % of cancer-related deaths worldwide [3, 4]. The main reason for the dismal outcome associated with gastric cancer stems from the fact that while curative surgery holds the only hope for cure [5], patients often present at a late stage of the disease [2, 6] when performance of this curative surgery is not feasible or warranted. Buried in these dismal statistics lies a subset of patients with so-called early gastric cancer who have reported 5-year survival rates approaching 99 % [7–9]. Early gastric cancer is more commonly reported in Japan [10, 11] owing to widespread screening programmes and a greater awareness of gastric cancer owing to the high incidence of disease. However, the incidence appears to be rising in other parts of the world, as well [7, 12, 13].

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At the same time, there has been the emergence of less invasive treatments of early gastric cancer. Curative resection (open or laparoscopic) remains the cornerstone treatment of gastric cancer, but chemotherapy and radiotherapy have had an increasing role [14, 15, 16]. More recently, therapeutic endoscopy has emerged as a treatment option for patients with early gastric cancer [17, 18]. And while excellent outcomes have been reported, there have been concerns about increased rates of local recurrence and early cancer-related deaths after therapeutic endoscopy [19–21]. It is agreed that patients selected for therapeutic endoscopy should have an early gastric cancer limited to the mucosa or submucosa, without lymph node metastasis and in whom a complete excision can be performed with negative margins [22, 23]. The problem is that the current definition of early gastric cancer does not fully reckon with the issue of lymph node status [24–26]. This dilemma is important, especially with the trend to tackle early gastric cancers with more aggressive endoscopic techniques (including endoscopic mucosal resection/EMR and endoscopic submucosal dissection/ESMD [22]), and raises two practical questions. The first question is ‘‘What is the acceptable level of risk for lymph node metastases in patients with early gastric cancer who are treated endoscopically?’’ The second question is ‘‘How accurate and reliable is the prediction of lymph node metastases based on the histological features within an endoscopically resected specimen?’’ The aim of this study is to critically examine the current definitions of early gastric cancer with a focus on tumourspecific factors associated with the risk of lymph node metastasis in this setting. This will provide the basis for the proposal that early gastric cancer should be redefined in the era of endoscopic treatment and adjuvant chemotherapy.

Early gastric cancer: the definitions and issues Early gastric cancer is most often defined when the depth of invasion is limited to the submucosal layer of the stomach on histological examination, irrespective of lymph node metastasis [24, 26, 27]. This definition was adopted by the Japanese Gastric Cancer Association in the 1998 edition [28] and remains the accepted definition to this day [22]. Early gastric cancer, labelled type 0 [22], has been further subdivided into protruding (type 0-I), superficial elevated (type 0-IIA), superficial flat (type 0-IIB), superficial depressed (type 0-IIC) and excavated (type 0-III). Another definition for early gastric cancer was proposed in Paris in 2002. Here superficial neoplasms of the stomach were subdivided into types I, II and III by a ‘‘simple and internationally unified’’ approach [29]. Accordingly, the classification of type 0 lesions is based on the distinction between polypoid (type 0-I); non-polypoid, non-excavated

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(type 0-II); and non-polypoid, excavated (type 0-III) lesions. In addition, type 0-II lesions are divided with respect to the absence (type 0-IIa and 0-IIb) or the presence of a depression (type 0-IIc). There are a number of contentious issues with these proposed definitions. The first is that lymph node status is not taken into account. When the treatment of early gastric cancer is by therapeutic endoscopy, information about lymph node status is not available [30, 31]. This is despite the fact that tumour infiltrating into the submucosa of the stomach is associated with a significant increase in the incidence of lymph node metastases (approximately 3–20 %) [18, 32–35] and a significant impact on survival [36]. Degiuli et al. [37] found 17/189 (9 %) patients with three or more positive lymph nodes in their randomised controlled trial of lymphadenectomy had early gastric cancer. Other surgeons have reported positive N3 lymph nodes in patients labelled as having early gastric cancer [38, 39]. If lymph node status was known, there would be significant change in the management of these patients. This would mean that endoscopic treatment of patient with early gastric cancer will result in suboptimal treatment in those with lymph node metastases. This is tacitly acknowledged by the recommendations of The National Comprehensive Cancer Network (NCCN) [40] and the European Society of Medical Oncology (ESMO) [41] which advise adjuvant chemotherapy for patients with T1 (early gastric cancer) and node-positive disease. The current definitions of early gastric cancer were developed when open surgery was considered to be the sole curative treatment for gastric cancer. Given the demonstrable benefit of adjuvant therapy in patients with lymph node metastases [14, 42–46] and the staging limitations imposed by therapeutic endoscopy, we contend that the definition of early gastric cancer and its treatment must be revisited to ensure that a small but significant proportion of patients are not overlooked for resection, lymphadenectomy and/or chemotherapy.

Therapeutic endoscopy in early gastric cancer: evolving indications The indications for endoscopic treatment of early gastric cancer have undergone changes as the pioneering techniques of the Japanese have evolved [9, 35, 47–50]. When the National Cancer Centre Hospital (NCCH) in Japan first introduced their indications for EMR in 1987 [51], the lesions had to be less than 15 mm. However, by 2001 [51] their indications for EMR had evolved to include early gastric cancer that fulfilled all of the following criteria: (1) (2)

Well- or moderately differentiated-type adenocarcinoma Superficial, elevated or depressed macroscopic appearance (types I, IIa, IIc)

Surg Endosc

(3) (4) (5)

No ulceration Diameter \30 mm No apparent invasive findings

The indications for therapeutic EMR and ESMD by the Japanese Gastric Cancer Association (JGCA) [22] recognise that tumours more than 2 cm have a risk of lymph node involvement. The JGCA indications for EMR, which have also been adopted by the ESMO [41], require the following criteria to be fulfilled. (A) (B) (C) (D)

Differentiated-type adenocarcinoma Without ulcerative findings Depth of invasion clinically diagnosed as T1a and Diameter B2 cm

The JGCA has more recently provided certain ‘‘expanded’’ indications for ESMD only [22] for investigational purposes. These expanded indications [48] [47] include that the tumour is T1a (mucosal only) and: (a) (b) (c)

Of differentiated type, ulcerative findings (UL) (-), but [2 cm in diameter Of differentiated type, UL (?) and B3 cm in diameter Of undifferentiated type, UL (-) and B2 cm in diameter, where UL is intratumoural ulceration.

It can be readily seen how the indications for the endoscopic treatment of early gastric cancer have been evolving. Figure 1 summarises the evolution in the maximum diameter of the early gastric cancer for therapeutic endoscopy over time. Such liberalisation of indications is associated with an increased risk of recurrent and/or metastatic disease [9, 19]. The Japanese Gastric Cancer Association has also provided clear guidelines for when therapeutic endoscopy is not indicated and when patients should undergo surgical resection [22]. The NCCN and ESMO do not provide any guidelines for this [40, 41]. The JGCA criteria are failing to achieve an en bloc endoscopic resection, maximum tumour diameter of[2 cm, undifferentiated tumour,[pT1a, positive margins (horizontal and/or vertical) and lymphovascular infiltration. It is therefore apparent that with the development and increasing use of therapeutic endoscopy techniques to treat early gastric cancer there has been a liberalisation or expansion of the criteria. This evolution must be associated with an increased risk of lymph node metastases.

Early gastric cancer: risk factors for lymph node metastasis Given the concern about the increased risk of lymph node metastases with the broader definition of EGC and the wider indications for endoscopic treatment, it is important

Fig. 1 Change in the maximum tumour diameter for the diagnosis of early gastric cancer based on leading guidelines (NCCH—National Cancer Centre Hospital, JGCA—Japanese Gastric Cancer Association) [22, 51]

to re-examine the risk factors for lymph node metastases. A systematic review of the literature was undertaken to identify macroscopic and microscopic tumour characteristics associated with the likelihood of metastatic lymph nodes in early gastric cancer.

Literature search A systematic and comprehensive search of major reference databases (MEDLINE, EMBASE, PubMed and the Cochrane Library) was undertaken using a combination of text words ‘‘early gastric cancer’’, ‘‘lymph node metastasis’’, ‘‘factors’’, ‘‘endoscopy’’, ‘‘surgery’’, ‘‘lymphadenectomy’’, ‘‘mucosa’’, ‘‘submucosa’’, ‘‘lymphovascular invasion’’, ‘‘differentiated’’, ‘‘undifferentiated’’ and ‘‘ulcer’’. The search was restricted to human studies published in literature but was not language-restricted. Articles were compiled into a database, and duplicates were removed. The abstracts were then screened for relevance. Subsequently, the reference lists of relevant trials, reviews and international guidelines were hand-searched. Reference lists of the retrieved literature were cross-searched manually for additional publications. All available publications describing tumour-related factors associated with lymph node metastasis in early gastric cancer were evaluated. The inclusion criteria were all types of study (randomised, prospective observational and retrospective observational) that investigated lymph node metastases in early gastric cancer patients. The articles that did not report on the proportions/frequencies of lymph node metastasis on the basis of the tumour-related factors were excluded. Review articles, letters to the editor, comments and editorials were also excluded.

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Results The search yielded 1494 studies of which 47 [13, 19, 32–34, 37, 39, 47, 48, 52–89] were retrieved for further evaluation. Of the 47 studies retrieved, five manuscripts [76, 79, 80, 83, 89] were excluded from the final analysis as they did not report proportion of lymph node metastasis for the variables of interest (Fig. 2). Table 1 summarises the 42 studies that include 32,193 patients [13, 19, 32–34, 37, 39, 47, 48, 52–75, 77, 78, 81, 82, 84–88]. The majority originated from Japan, South Korea and China and were both single and multi-institutional. There are also studies from Italy (4), Germany (2) and single studies from France, Poland, Russia and the UK. The mean frequency of lymph node metastases increased on the basis of depth of infiltration (mucosa 6 % vs. submucosa 28 %), presence of lymphovascular invasion (absence 9 % vs. presence 53 %), tumour differentiation (differentiated 13 % vs. undifferentiated 34 %) and macroscopic type (elevated

Fig. 2 Quorum chart

13 % vs. flat 26 %) and tumour diameter (B2 cm 8 % vs. [2 cm 25 %). Infiltration of the muscularis mucosae was not significantly associated with lymph node metastasis and was not included. Table 2 summarises the results from the studies in regard to the likelihood of lymph node metastases for the different tumour-specific factors. It can be seen that the likelihood of lymph node metastases was 7.19 more likely if the tumour was infiltrating the submucosa (versus mucosa), 6.29 if there was lymphovascular invasion (versus not), 4.69 if there was ulceration (vs. not), 3.89 if it was Lauren’s diffuse type (vs. intestinal type), 3.29 if it was undifferentiated (vs. differentiated), 2.59 if it was distal stomach (vs. proximal) and 2.39 if it was a depressed lesion (vs. elevated). The studies predicting the frequency of lymph node metastasis based on the tumour diameter used a range of cut-off values from \1 to [3 cm. Table 3 shows the number of studies that used different cut-offs for the diameter of

Studies identified from literature search and retrieved (n=1494) Extra articles identified bibliography search (n=1)

from

92 articles excluded – duplicate publications Articles retrieved for more detailed evaluation (n=1402)

1349 articles excluded – failed inclusion/exclusion criteria or not related to lymph node metastasis in early gastric cancer after reading title/abstract

Potential articles to be included in the systematic review (n=53) 6 articles excluded - failed inclusion/exclusion criteria after reading full text. 5 articles, although shortlisted for discussion, excluded from the analysis for not reporting proportions of lymph node metastasis for the described variables Total number of articles included for final analysis (n=42)

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Surg Endosc Table 1 Summary of studies included in the analysis Author (Ref.)

Year

Country

Total number of patients (N) percentage of patients with EGC within the study cohort (%)

Type of series

Hayes et al. [54]

1996

UK (S)

156 (18 %)

Prospective Retrospective

Koufuji et al. [55]

1997

Japan (S)

1845 (41.5 %)

Kitamura et al. [57]

1997

Japan (S)

634 (100 %)

Retrospective

Bosing et al. [56]

1998

Germany (S)

57 (100 %)

Retrospective

Tachibana et al. [32]

1999

Japan (S)

197 (50.7 %)

Retrospective

Gotoda et al. [49]

2000

Japan (M)

5265 (100 %)

Retrospective

Borie et al. [60]

2000

France (M)

332 (100 %)

Retrospective

Folli et al. [30]

2001

Italy (M)

584 (100 %)

Retrospective

Seto et al. [88]

2001

Japan (M)

6209 (100 %)

Retrospective

Popiela et al. [31]

2002

Poland (M)

238 (100 %)

Retrospective

Hyung et al. [58]

2004

Japan (S)

668 (100 %)

Retrospective

Kim et al. [59]

2004

South Korea (S)

748 (100 %)

Retrospective

Park et al. [84]

2004

South Korea (S)

105 (100 %)

Retrospective

Song et al. [90] Skoropad et al. [11]

2004 2005

South Korea (S) Russia (S)

120 (100 %) 149 (100 %)

Retrospective Retrospective

Son et al. [89]

2005

South Korea (S)

124 (100 %)

Retrospective

Nasu et al. [61]

2006

Japan (S)

332 (100 %)

Retrospective Retrospective

Roviello et al. [62]

2006

Italy (M)

652 (100 %)

Degiuli et al. [63]

2006

Italy (S)

714 (26.4 %)

Retrospective

An et al. [37]

2007

South Korea (S)

1043 (100 %)

Retrospective

Ishikawa et al. [18]

2007

Japan (S)

278 (100 %)

Retrospective

Xu et al. [64]

2007

China (S)

322 (100 %)

Retrospective

Ohashi et al. [91]

2007

Japan (S)

201 (100 %)

Retrospective

Ha et al. [65]

2008

South Korea (S)

1520 (100 %)

Retrospective

Ye et al. [66]

2008

South Korea (S)

591 (100 %)

Retrospective

Haruta et al. [67]

2008

Japan (S)

1389 (100 %)

Retrospective

Park et al. [68]

2008

South Korea (S)

234 (100 %)

Retrospective

Li et al. [77]

2008

South Korea (S)

646 (100 %)

Retrospective

Wu et al. [69] Shen et al. [70]

2009 2009

China (S) China (S)

157 (100 %) 410 (100 %)

Retrospective Retrospective

Kunisaki et al. [71]

2009

Japan (M)

573 (100 %)

Retrospective

Hirasawa et al. [47]

2009

Japan (M)

3843 (100 %)

Retrospective

Holscher et al. [72]

2009

Germany (S)

915 (13.7 %)

Retrospective

Nesi et al. [87]

2009

Italy (S)

841 (14 %)

Retrospective

Kang et al. [73]

2010

South Korea (S)

478 (100 %)

Retrospective

Li et al. [75]

2010

China (S)

2322 (10.4 %)

Retrospective

Lee et al. [76]

2010

South Korea (S)

1362 (100 %)

Cross-sectional cohort

Lim et al. [78]

2011

South Korea (S)

376 (100 %)

Retrospective

Ren et al. [74]

2013

China (M)

202 (100 %)

Retrospective

Fujii et al. [85]

2013

Japan (S)

130 (100 %)

Retrospective

Wang et al. [80]

2014

China (S)

518 (100 %)

Retrospective

Wang et al. [81]

2014

China (S)

136 (100 %)

Retrospective

EGC early gastric cancer, S single centre, M Multi-centre

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the lesion. Thirty-three of the 42 studies used 2 cm. Figure 3 demonstrates that there is strong relationship between the diameter of the lesion and the risk of lymph node metastases. The mean frequency of lymph node metastases for each of the separate cut-off values for the diameter of the early gastric cancer is summarised in Table 4. It can be seen that there is mean frequency of lymph node metastases of 5.4 % for early gastric cancers B2 cm in diameter. This means there is a 1:18.5 risk of a positive lymph node in patients with an early gastric cancer of 2 cm or less in diameter, but the risk will increase further when factors other than size are added in. There are other studies not included in the systematic review that noted other factors that increased the risk of lymph node metastases. Fukuhara et al. [76] noted that nonAsian ethnicity, lymphovascular invasion and younger age were significant predictors of lymph node metastasis in early gastric cancer. Yang et al. [79] found deep submucosal invasion, antral location of the tumour and venous invasion to be predictive of lymph node metastases in patients with early gastric cancer. Gotoda et al. [48] noted that the incidence of lymph node involvement sharply rose (9 to 24 %) as the depth of tumour infiltration increased within the submucosal layer itself. Shida et al. [80] noted that lymphatic invasion and venous invasion were independent predictors of lymph node metastasis based on which they provided a formula for predicting the likelihood of lymph node metastasis. This review confirms a number of risk factors for lymph node metastases in early gastric cancer. Together they highlight the concern that even for lesions \2 cm in diameter, there is an appreciable risk of lymph node metastases. Quantifying the risk of lymph node metastases in the individual patient is the challenge we must face, as the risk cannot be ignored. Factors that would need to be considered include the depth of infiltration (more than the mucosa), presence of ulceration or lymphovascular invasion, lack of differentiation, location of the tumour within the stomach and diffuse (Lauren) type of cancer.

Redefining early gastric cancer: the way forward There have been some attempts to update the definition of early gastric cancer and to improve on the ability to determine the risk factors associated with the likelihood of lymph node metastases. The definition of early gastric cancer was refined by the Paris classification in 2003 [29] where the term ‘‘early cancer’’ was used to suggest a localised tumour with potential for complete cure after complete resection. The problem with this classification is that it stops short of defining the risk factors that would allow such assurance that endoscopic treatment would be curative.

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The advent of endosonography (EUS) and node biopsy promised to advance the accurate detection of lymph node metastases [90]. However, the evidence to date is disappointing, with 64 % accuracy reported in the most recent meta-analysis [91]. While EUS-guided fine needle aspiration (EUS/FNA) presents a potentially useful tool in preoperative lymph node staging, it is not supported by the evidence [92] and is not part of the staging algorithm of presumed early gastric cancer. The use of 18 fluoro-deoxy glucose positron emission tomography (18-FDG PET-CT) scans has been advanced as a way to improve the accuracy of staging, but because of high false-negative rates related to tumour differentiation [93, 94] the overall accuracy of node staging is only 60 % according to a recent systematic review and meta-analysis [95]. As a result, 18-FDG PETCT scanning is not a routine part of the staging algorithm of presumed early gastric cancer [96]. Another nuclear radioisotope, 18 fluorothymidine (FLT) has not been shown to be more accurate than 18-FDG [94]. Sentinel lymph node biopsy has been advanced as another promising strategy to increase the accuracy of lymph node staging in early gastric cancer, with a pooled accuracy rate of 92 % [97]. The authors noted that higher lymph node identification rates were associated with a range of techniques including the use of combination tracers, submucosal injection and immunohistochemistry. A combination of laparoscopic sentinel lymph node biopsy followed by therapeutic endoscopy would provide more accurate lymph node staging and be a way forward [98]. On the basis of current definitions, the risk of lymph node metastases in patients with early gastric cancer is 15–24 % [11, 81, 99]. This cannot be ignored, and the argument to redefine early gastric cancer should be on the basis that the presence of lymph node metastases excludes early gastric cancer. This translates to the presence of lymph node metastases being an absolute contraindication to therapeutic endoscopy. This systematic review indicates that the most important factors associated with lymph node metastases are lesions that are ulcerated, undifferentiated, diffuse and depressed in the distal stomach and especially if they are associated with submucosal and lymphovascular invasion. It is a surprise, therefore, that none of the standard criteria for therapeutic endoscopy include lymphovascular invasion [22] [51, 100] even though the National Comprehensive Cancer Network (NCCN) acknowledges it as an important prognostic factor [40]. Given that the indications for therapeutic endoscopy do not take into account lymph node status, it appears reasonable that, at the very least, lymphovascular invasion be considered. Two recent approaches to predicting lymph node metastases have taken lymphovascular invasion into account [38, 80]. Shida et al. [80] looked to predict lymph node metastases

4:16

11:62 Kim et al. [60]

Skoropad et al. [13]

6:22

Xu et al. [64]

6:20

3:22

Park et al. [68] 4:16

2:18

Haruta et al. [67]

Li et al. [77]

3:27

Ye et al. [66] 13:63

Shen et al. [70]

2:23

Ha et al. [65]

15:35

Ohashi et al. [91]

3.8:23

Ishikawa et al. [19]

11:38

6:56

a

7:62

7:55

5:38

12:58

8:44 15:10:26

19:32

5:23 11:29

Roviello et al. [63]

Degiuli et al. [37]

a

23:85

5:68

An et al. [39]

5:24

Nasu et al. [62]

Son et al. [89]

0:20

3:21

Hyung et al. [59]

Song et al. [90]

3:18 6:21

Seto et al. [88]

4:23

Folli et al. [32]

Popiela et al. [33]

2:26 5:23

4:9

Tachibana et al. [34]

Gotoda et al. [51]

9:17 2:32

Bosing et al. [57]

9:45

6:38

Lymphovascular invasion Absent:present (%)

Borie et al. [61]

2:19 0.6:16

Kitamura et al. [58]

21:64

Koufuji et al. [56]

Hayes et al. [55]

Mucosa:submucosa (%)

Depth of invasion

15:16

9:15

0.5:3.4

No:yes (%)

Ulceration

9:27:28

13:50:48

4:NR:27

9:26:31

Intestinal:mixed:diffuse (%)

Lauren’s type

Table 2 Significant tumour-specific factors associated with lymph node metastasis in early gastric cancer

17:32

16:11

8:25

8:19

12:49

6:14

5.5:27

4:9

5:12:16

Upper:middle:lower (%)

Diff:undiffb (%)

0.4:4.2

Tumour location

Differentiation

2:15

57:50

6.5:17.5

0.5:2.7

Elevated:depressed (%)

Macroscopic type

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123 5:24 11:25

Holscher et al. [72]

9:23

Ren et al. [74]

Average Ratio

1:6.2

19 (46)

5:44

15:33

4:32

6:43

8:54 11:71

8:44

Lymphovascular invasion Absent:present (%)

1:4.6

2 (5)

15:34

No:yes (%)

Ulceration

1:2.6:3.8

6 (15)

6:NR:23

Intestinal:mixed:diffuse (%)

Lauren’s type

1:3.2

11 (27)

10:18

Upper:middle:lower (%)

Diff:undiffb (%)

b

Dff = differentiated, undiff = undifferentiated

Lymphovascular invasion was the only significant factor influencing lymph node metastasis in multi-variate analysis

EGC early gastric cancer, NR not reported

a

1:1.5:2.5

4 (10)

5:5:19

8:15:15

14:12:16

Tumour location

Differentiation

In this table, the percentages reflect the incidence of lymph node metastasis for each factor, and the results are expressed as a ratio

34 (83) 1:7.1

n (%)

Number of studies reporting factor

3:24 4:19

Wang et al. [80]

Wang et al. [81]

14:30

Fujii et al. [85]

8:37 3:18

Lim et al. [78]

Kang et al. [73] Li et al. [75]

Lee et al. [76]

0:15 3:25 5:28

Nesi et al. [87]

6.5:24

2:22

Hirasawa et al. [50]

Mucosa:submucosa (%)

Depth of invasion

Kunisaki et al. [71]

Table 2 continued

1:2.3

8 (20)

16:14

30:10

23:10

Elevated:depressed (%)

Macroscopic type

Surg Endosc

Surg Endosc Table 3 Table summarising the various tumour diameter cut-off values and the number of studies reporting them Tumour diameter (cut-off value) (cm)

Number of studies using this value

References

\1

3

[39, 69, 80]

1–2

3

[39, 69, 80]

B2

21

[32, 33, 47, 51, 58, 59, 60, 63, 65, 66, 69, 70, 71, 73, 75, 76, 77, 78, 81, 84, 87]

[2

12

[33, 47, 65, 66, 70, 71, 75, 76, 77, 78, 80, 81]

2–3

5

[32, 60, 63, 84, 87]

2–4

2

[39, 58]

B3 [3 cm

3 7

[51, 59, 73] [32], [51], [60], [63], [73], [84], [87]

Fig. 3 Average frequency of lymph node metastases according to diameter (mean ± standard error of the mean) of early gastric cancer, using three cut-off values: 1, 2 and 3 cm. (black—less than or equal to, grey—greater than)

for submucosal lesions diagnosed following ESMD in which the tumour depth was 500 microns below the muscularis mucosae. They scored both lymphatic and venous invasions. Tumours were classified into low or high risk depending on this score. Patients at high risk could be offered a standard gastrectomy. Clinical decision analysis of this approach fell short of what is required for accurate decision-making in individual patients (sensitivity 70 %, specificity 62 %, false positive 38 %, false negative 30 % and accuracy of just 63 %). Gertler et al. [38] proposed a nomogram to predict the risk of lymph node metastases in early gastric and oesophageal cancers using multiple factors, including age, tumour depth and differentiation, tumour multi-focality and lymphovascular invasion. They internally validated the nomogram using a tenfold cross-validation in which they divided the original data set randomly into 10 independent subsets of approximately the same size. A concordance index (c-index) was measured which ranged from 0.68 to 0.93 (mean = 0.82; 99.5 % confidence interval: 0.65–0.99). A drawback of this nomogram is that it combined oesophageal and gastric tumours as well as squamous cell

carcinomas and adenocarcinomas. Another drawback, based on the present review, is that there are some important risk factors that have not been incorporated, including ulceration, location and histological subtype. What is important is that this approach points to the way forward, where all appropriate gastric adenocarcinoma specific risk factors, derived from endoscopy/biopsy/ EMR/ESMD and appropriately weighted in a nomogram, could be used to calculate the risk of lymph node metastases in an individual patient. Such a tool would be welcomed in the critical decision whether to proceed with endoscopic treatment or surgical treatment with lymphadenectomy. At the present time and until the development of such a tool, and given the inadequacy of clinical staging to accurately identify patients at risk of lymph node metastases with early gastric cancer, ESMD and EMR remain a valid initial treatment option for early gastric cancer (as defined below). Absence or presence of the above factors associated with the risk of lymph node metastases in the excised specimen should help guide clinicians to direct their patients towards surveillance or salvage surgery accordingly.

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Surg Endosc Table 4 Percentage of lymph node metastasis in early gastric cancer for different maximum diameters References

Size and frequency (%) B1 cm

1–2 cm

B2 cm

Kitamura et al. [58]

3

Gotoda et al. [51]

0.5

Folli et al. [32]

8

[2 cm

2–3 cm

2–4 cm

B3 cm

[3 cm

1

5

8 11

22

Popiela et al. [33]

8.5

Hyung et al. [59]

4

Kim et al. [60]

2

14

29

Park et al. [84] Roviello et al. [63]

11 9

27 20

27 30

An et al. [39]

7

20 12

11

15

Ha et al. [65]

2.5

15

Ye et al. [66]

3a

18a

Wu et al. [69]

0

6

22

Shen et al. [70]

7

20

Kunisaki et al. [71]

0

2b 16

Hirasawa et al. [47]

7

Nesi et al. [87]

0

Kang et al. [73]

7

Li et al. [75]

3

30

Lee et al. [76]

4

10

7

Li et al. [77]

7

13

Lim et al. [78]

2

13

3

22 17

5.4 ± 4.9

16.3 ± 6.8

Wang et al. [80] Wang et al. [81]

3

Mean ± SD

3.3 ± 3.5

9 8.6 ± 2.5

15.8 ± 7.8

22

11.5 ± 4.9

15

19

9.3 ± 7.3

22 ± 8.5

SD standard deviation a

2.5 cm

b

2.4 cm if submucosal

Table 5 Evolution in the definition of early gastric cancer—comparison of the original definition proposed by Murakami et al. in the 1970s [27] to the Japanese Gastric Cancer Association (JGCA) [28] and Paris [29] classifications to the present definition Author (Ref) Year

Murakami T (27) 1971

Macroscopic (endoscopy) features

Nil

JGCA (28) 1998

Paris (29) 2002

Present definition 2014

Protruding (type 0-I),

Polypoid (type 0-I)

B2 cm diameter

Superficial elevated (type 0-IIA)

Non-polypoid, nonexcavated (type 0-II) Non-polypoid, excavated (type 0-III)

No ulceration

Superficial flat (type 0-IIB), Superficial depressed (type 0-IIC), & Excavated (type 0-III)

Microscopic (histology) features

Limited to submucosa

Lymph node status

±LN metastasis

Nil

Nil

Proximal location in stomach

Limited to mucosa Well differentiated No lymphovascular invasion Intestinal-type histology

123

LN metastases not addressed

LN metastases referred to, but not specifically addressed

LN metastases should not be present or very low risk

Surg Endosc

Conclusion The broadening definitions of early gastric cancer (Table 5), the liberalisation of indications for endoscopic treatment without due regard for the status of regional lymph nodes, result in a proportion of patients being undertreated. We posit that this would occur less frequently if early gastric cancer were redefined, as follows: An early gastric cancer is one that infiltrates the mucosa of the stomach without lymph node metastases. On biopsy or endoscopic specimen an early gastric cancer is \2 cm in maximum diameter, well differentiated, intestinal type, non-ulcerated, not depressed, located in the proximal stomach, and without infiltration beyond the mucosal layer or evidence of lympho-vascular invasion. On the surgical specimen an early gastric cancer is also without evidence on lymph node metastases from at least a D1 lymphadenectomy. Until the development of an accurate and practical algorithm for lymph node staging of early gastric cancer, this definition should reduce the number of patients undergoing therapeutic endoscopy with lymph node metastases. It should also ensure that patients with lymph node metastases, where appropriate, will not be denied potentially curative surgery and/or chemotherapy. The new definition will require further discussion and ultimately prospective validation. Acknowledgments We thank Mr. Sanjay Talole, (Biostatistician, Tata Memorial Centre, Mumbai) for help with statistics. Disclosures S. G. Barreto and John A. Windsor have no conflicts of interest or financial ties to disclose.

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