Staging of intestinal- and diffuse-type gastric cancers with the OLGA and OLGIM staging systems

Transcription

1 Alimentary Pharmacology and Therapeutics Staging of intestinal- and diffuse-type gastric cancers with the OLGA and OLGIM staging systems S.-J. Cho*, I. J. Choi*, M.-C. Kook*, B.-H. Nam, C. G. Kim*, J. Y. Lee*, K. W. Ryu* & Y.-W. Kim* *Center for Gastric Cancer, National Cancer Center, Goyang, Korea. Center for Clinical Trials, National Cancer Center, Goyang, Korea. Correspondence to: Dr I. J. Choi, Center for Gastric Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi , Korea. Publication data Submitted 23 July 2013 First decision 4 August 2013 Resubmitted 10 September 2013 Accepted 10 September 2013 EV Pub Online 6 October 2013 SUMMARY Background Operative link on gastritis assessment (OLGA) and Operative link on gastric intestinal metaplasia assessment (OLGIM) staging systems have been proposed for gastric cancer (GC) risk estimation. Aim To validate the OLGA and OLGIM staging systems in a region with high risk of GC. Methods This retrospective study included 474 GC patients and age- and sexmatched health screening control persons in a cancer centre hospital. We classified gastritis patterns according to the OLGA and OLGIM systems using the histological database that a pathologist prospectively evaluated using the updated Sydney system. GC risk according to the OLGA and OLGIM stages was evaluated using logistic regression analysis. Results More GC patients had OLGA stages III IV (46.2%) than controls (26.6%, P < 0.001), particularly among patients with intestinal-type GCs (62.2%) compared with diffuse-type GCs (30.9%). OLGA stages III and IV were significantly associated with increased risk of GC [odds ratios (ORs), 2.09; P = and 2.04; P = respectively] in multivariate analysis. The association was more significant for intestinal-type (ORs, 4.76; P = and 4.19; P = respectively), but not diffuse-type GC. OLGIM stages from I to IV were significantly associated with increased risk of both intestinal-type (ORs, 3.64, 5.15, 7.89 and respectively) and diffuse-type GC (ORs, 1.84, 2.59, 5.08 and 6.32 respectively) with a significantly increasing trend. Conclusion As high OLGA and OLGIM stages are independent risk factors for gastric cancer, the staging systems may be useful for risk assessment in high-risk regions, especially for intestinal-type gastric cancer. Aliment Pharmacol Ther 2013; 38: doi: /apt.12515

2 OLGA and OLGIM staging systems and gastric cancer INTRODUCTION Chronic inflammation of the gastric mucosa can trigger a cascade of genotypic and phenotypic derangements that may eventually result in gastric cancer (GC). 1 The presence of atrophic gastritis, intestinal metaplasia (IM) and dysplasia of the gastric mucosa are important risk factors for intestinal-type GC. 1 Surveillance of patients with these lesions may therefore detect GC early and improve prognosis. 2 However, diagnoses of atrophic gastritis, IM and dysplasia are often disregarded in clinical practice. 2 The updated Sydney system recommends several biopsy specimens from the antrum, corpus and incisura angularis for assessment of gastritis, including atrophic gastritis and IM. 3 Because this method rarely helps to estimate GC risk directly, Operative link on gastritis assessment (OLGA) staging system was proposed for clinical purposes to simplify the assessment of GC risk using gastric atrophy. 4 The gastritis staging integrates the atrophy score using the updated Sydney system (obtained by biopsy) and atrophy topography (antral and oxyntic/corpus). Several studies have shown the association of low OLGA stage (0, I, II) with low risk of GC and high OLGA stage (III, IV) with increased risk of GC. 5 7 The recently proposed Operative link on gastric intestinal metaplasia assessment (OLGIM) staging system 8 basically adopts the OLGA frame, but replaces the atrophy score with IM score, which was suggested to have low inter-observer variation. 8 The OLGIM and OLGA staging systems must be validated in predicting risk of GC, and several studies have approached this issue. However, these were limited to small numbers of cancer cases 6, 7 in regions with low incidence of 5, 6, 9 GC. Gastric cancers have different clinicopathological characteristics according to Lauren s system, 10 which histopathologically classifies them as intestinal- and diffuse-type carcinomas. Helicobacter pylori is a causal factor in the atrophic gastritis-im-intestinal-type GC sequence. 1 The prevalence of H. pylori infection seems to 11, 12 be greater in intestinal-type than in diffuse-type GCs. However, there have been no studies validating the OLGA and OLGIM systems according to the Lauren s types. In the present study, we validated the OLGA and OL- GIM staging systems by comparing patients with GC and control subjects in Korea, where GC incidence is high. 13 We also evaluated differences in the OLGA and OLGIM staging systems according to histopathological types of GC. METHODS Study population This cross-sectional study was conducted at the National Cancer Center Hospital (Goyang, Korea). We retrospectively identified GC patients from our database of subjects who underwent oesophagogastroduodenoscopy (EGD) between January 2006 and December We classified gastritis patterns according to the OLGA and OLGIM systems using the histological database that the pathologist prospectively evaluated with the updated Sydney system 3. During the period, 1300 individuals who were diagnosed with gastric adenocarcinomas provided written informed consent for obtaining biopsy specimens to evaluate H. pylori and histological diagnoses. Among them, we excluded 610 patients for the following reasons: multiple GCs (n = 114), cardia cancer (n = 64), history of H. pylori eradication (n = 102), history of neoadjuvant chemotherapy (n = 18), uncertain H. pylori infection status (n = 17), insufficient clinical information (n = 2), unavailable biopsy samples for evaluation of glandular atrophy in the antrum (n = 170) or corpus (n = 123) due to the tumour involvement of predetermined biopsy sites. There were 690 eligible GC patients. Control subjects were enrolled from a pool of healthy adults who participated in the National Cancer Screening Program and underwent EGD for GC screening. 14 Between July 2007 and April 2010, there were 678 subjects who provided informed consent. We excluded 46 patients for the following reasons: subjects who were diagnosed as having gastric adenocarcinoma (n = 3), history of previous H. pylori eradication (n = 5) or inadequate histological samples for evaluation of glandular atrophy (n = 38). The 632 remaining subjects were eligible for inclusion. A sex-matched control was selected within a 3-year age range for each GC patient, resulting in 474 pairs being selected for analysis. The study protocol was approved by the Institutional Review Board of the National Cancer Center, Korea (NCCNCS ). EGD and H. pylori testing During EGD, biopsy specimens were taken to confirm diagnosis of GC and seven additional biopsy specimens were also obtained to evaluate H. pylori status and underlying histology. Four experienced endoscopists (IJ Choi, S-J Cho, CG Kim, JY Lee) performed EGD according to the following protocol. The biopsy specimens were Aliment Pharmacol Ther 2013; 38:

3 S.-J. Cho et al. taken from the antrum lesser curvature, corpus lesser curvature (2 cm posterior aspect of the body near the midline) and corpus greater curvature. Among the biopsy sites recommended by the updated Sydney system, these were considered essential for adequate histological evaluation. 15 Two biopsy specimens were obtained from each site, and one additional specimen was obtained from the corpus greater curvature for rapid urease test (Pronto Dry; Medical Instruments Corporation, Solothurn, Switzerland). 16 Gastric mucosa was considered infected with H. pylori if either of the following criteria were positive: the rapid urease test or a histological evaluation using the updated Sydney system. 3 Histology Biopsy specimens collected for histological examination were immediately fixed in neutral-buffered 10% formalin and embedded in paraffin. Histological sections were stained with haematoxylin eosin and Wright Giemsa and examined by a single pathologist (M-C Kook). Based on the updated Sydney system recommendation, 3 H. pylori density, polymorphonuclear cell (polymorph) activity, chronic inflammation, glandular atrophy and IM were graded as absent, mild, moderate or marked (0 3 respectively), using a visual analogue scale. Atrophy was defined as loss of appropriate glands with or without metaplasia, 3, 17 which includes shrinkage or complete disappearance of glandular units, being replaced by expanded (fibrotic) lamina propria and replacement of the native glands by metaplastic glands featuring a new commitment (intestinal and/or pseudopyloric metaplasia). 18 Advanced histological change for atrophy and IM was defined as grade 2 or 3. Gastritis stage was assessed according to the OLGA staging system 4, which integrates the atrophy score using the updated Sydney system (obtained by biopsy) and the atrophy topography (antral and oxyntic/corpus). We also assessed the gastritis stage based on the OLGIM staging system. 8 The antrum lesser curvature was considered non-oxyntic gastric mucosa (antrum score), and corpus lesser curvature was considered oxyntic gastric mucosa (corpus score). Combining the antrum and corpus score for atrophic gastritis resulted in the OLGA gastritis stage score, and combining the IM scores resulted in the OL- GIM staging score. Pathological evaluation for gastric carcinoma After pathological examination following endoscopic or surgical resection, early GC was defined as a tumour that was confined to the mucosa or submucosa regardless of lymph node involvement, and advanced GC was defined as a tumour that invaded proper muscle or beyond. If resection was not performed (i.e. in cases of metastatic GC), the stage was determined by endoscopic and computed tomographic findings. A pathologist determined tumour differentiation according to the World Health Organization criteria 19 and histological type according to Lauren s classification. 10 Statistical analysis Baseline characteristics were compared using Student s t-test for continuous variables and Pearson s v 2 test for categorical variables. Fisher s exact test or v 2 tests (both two-tailed) were used to compare proportions of histological grades. The logistic regression models (unconditional forward stepwise method) were used to estimate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs). OLGA and OLGIM stages were not included in the same model because they were closely related to each other. Demographic characteristics (age, sex, H. pylori infection, family history of GC and smoking habit) were taken into account in comparing GC patients and control subjects. In addition, the c statistic as a goodness of fit measure of a model was used to evaluate how well each staging system can discriminate cancer and control subjects at different levels of stage. 20 The c values of were regarded as moderately good discrimination and values of 0.8 and above as excellent discrimination ability. 21 A P-value <0.05 was regarded as statistically significant. All statistical analyses were performed using STATA version 11 (Stata Corp LP, College Station, TX, USA). RESULTS Demographic and underlying gastritis Table 1 shows demographic characteristics of the study subjects. Helicobacter pylori positivity was higher among GC patients (90.1%) than among controls (65.0%, P < 0.001). Smoking status and family history of GC were also more common in GC patients than in controls (Table 1). At the antrum, the proportion of moderate-to-marked polymorphonuclear cell infiltration was higher in control subjects than in GC patients (P = 0.035). At the lesser and greater curvatures of the corpus, the proportion of moderate-to-marked polymorphonuclear infiltration was higher in GC patients than in control individuals (Table 2). The proportion of moderate-to-marked monocyte infiltration, 1294 Aliment Pharmacol Ther 2013; 38:

4 OLGA and OLGIM staging systems and gastric cancer Table 1 Baseline characteristics of gastric cancer patients and control subjects Gastric cancer patients Control subjects P-value Age, mean s.d Sex (male), n (%) 308 (65.0) 308 (65.0) H. pylori-positive, n (%) 427 (90.1) 308 (65.0) <0.001 Smoking, n (%) Current smoker 197 (41.6) 110 (23.2) <0.001 Ex-smoker 93 (19.6) 138 (29.1) Alcohol consumption, n (%) Current drinker 297 (62.7) 293 (61.8) Ex-drinker 33 (7.0) 31 (6.5) Family history of gastric cancer,* n (%) 107 (22.6) 38 (8.0) <0.001 s.d., standard deviation. * Family history of first-degree relatives. glandular atrophy and IM were all higher in GC patients than in control subjects from all three sites of the stomach (Table 2). Table 2 Comparison of gastric histology based on the updated Sydney system between gastric cancer and control subjects Gastric cancer patients Control subjects P-value Acute inflammation* (moderate-to-marked), n (%) Antrum LCv 163 (34.4) 194 (40.9) Corpus LCv 251 (53.0) 171 (36.1) <0.001 Corpus GCv 290 (61.2) 133 (28.1) <0.001 Chronic inflammation (moderate-to-marked), n (%) Antrum LCv 375 (79.1) 282 (59.5) <0.001 Corpus LCv 402 (84.8) 256 (54.0) <0.001 Corpus GCv 369 (77.8) 197 (41.6) <0.001 Glandular atrophy (moderate-to-marked), n (%) Antrum LCv 314 (66.2) 232 (48.9) <0.001 Corpus LCv 223 (47.0) 124 (26.2) <0.001 Corpus GCv 34 (7.2) 12 (2.5) Intestinal metaplasia (moderate-to-marked), n (%) Antrum LCv 232 (48.9) 89 (18.8) <0.001 Corpus LCv 168 (35.4) 65 (13.7) <0.001 Corpus GCv 17 (3.6) 7 (1.5) GCv, greater curvature; LCv, lesser curvature. * Polymorphonuclear cell infiltration based on the updated Sydney system. Lymphocyte infiltration based on the updated Sydney system. Gastritis staging using OLGA and OLGIM On comparison of OLGA and OLGIM gastritis staging systems, GC patients had higher OLGA and OLGIM stages than control subjects (Table 3). There were 7.8% GC patients and 19.0% of controls with OLGA stage 0, compared to 23.0% cancer patients and 56.1% controls with OLGIM stage 0. Subjects with stage III or IV were more common in the GC group than in the control group for both OLGA (46.2% vs. 26.6%, P < 0.001) and OLGIM staging systems (43.0% vs. 14.6%, P < 0.001; Table 3). Pearson s v 2 value for OLGIM staging ( , df = 4, P < 0.001) was higher than that for OLGA (58.986, df = 4, P < 0.001), which suggests better discriminating ability for the OLGIM system compared with OLGA staging. Logistic regression analysis for the risk of GC Multivariate analysis confirmed that well-known risk factors, including H. pylori infection, current smoking habit and family history of GC, were significantly associated with the risk of GC. The OLGA stages III and IV were associated with higher risk of GC (OR, 2.09; 95% CI, and OR 2.04; 95% CI respectively) compared with OLGA stage 0 even after adjusting for the above risk factors (Table 3). However, stages I and II in the OLGA system were not associated with higher risk of GC compared with OLGA stage 0. For the OLGIM staging system, the ORs were higher even in stages I (OR, 2.38; 95% CI, ) and II (OR, 2.97; 95% CI, ) in addition to stages III (OR, 5.50; 95% CI, ) and IV (OR, 8.91; 95% CI, ; Table 3). In addition, adjusted ORs increased with stages for both OLGA and OLGIM (P for trend and < respectively). The c value showed moderately good discrimination for both OLGA (0.724) and OLGIM (0.783) staging systems, 20 but greater in OLGIM than in OLGA staging. Characteristics of GC according to OLGA staging system In our data, 53.8% (255/474) of GC patients had OLGA stages 0 II, defined as low-risk stages for GC. To identify characteristics of such patients, we compared the clinical and tumour-related factors between OLGA stages 0 II (low-risk group) and stages III IV in GC patients. Younger age and female sex were more frequent in the patients with low-risk OLGA stages than in those with high-risk OLGA stages. Smoking habit and family Aliment Pharmacol Ther 2013; 38:

5 S.-J. Cho et al. Table 3 Univariate and multivariate analyses of the risk of gastric cancer in subjects according to gastritis OLGA and OLGIM staging systems Gastric cancer patients Control subjects Crude OR (95% CI) Adjusted OR (95% CI) H. pylori positivity, n (%) 427 (90.1) 308 (65.0) 4.90 ( ) 3.94 ( )* Smoking, n (%) Nonsmoker 184 (38.8) 226 (47.7) Ex-smoker 93 (19.6) 138 (29.1) 0.83 ( ) 1.11 ( )* Current smoker 197 (41.6) 110 (23.2) 2.20 ( ) 2.71 ( )* Family history, n (%) 107 (22.6) 38 (8.0) 3.35 ( ) 2.99 ( )* OLGA stage, n (%) 0 37 (7.8) 90 (19.0) I 82 (17.3) 131 (27.6) 1.52 ( ) 1.12 ( )* II 136 (28.7) 127 (26.8) 2.61 ( ) 1.54 ( )* III 114 (24.1) 69 (14.6) 4.02 ( ) 2.09 ( )* IV 105 (22.2) 57 (12.0) 4.48 ( ) 2.04 ( )* P for trend < c value OLGIM stage, n (%) (23.0) 266 (56.1) I 91 (19.2) 86 (18.1) 2.58 ( ) 2.38 ( ) II 70 (14.8) 53 (11.2) 3.22 ( ) 2.97 ( ) III 98 (20.7) 41 (8.6) 5.83 ( ) 5.50 ( ) IV 106 (22.4) 28 (5.9) 9.24 ( ) 8.91 ( ) P for trend < < c value OLGA, Operative link on gastritis assessment; OLGIM, Operative link on gastric intestinal metaplasia assessment; OR, odds ratio. * Adjusted for age, sex, smoking, H. pylori infection, family history and OLGA stage using the logistic regression models. Family history of first-degree relatives. Adjusted for age, sex, smoking, H. pylori infection, family history and OLGIM stage using the logistic regression models. c statistic as a goodness of fit measure of a model was used to evaluate how well each staging system can discriminate cancer and control subjects at different levels of stage. The c values of were regarded as moderately good discrimination and values of 0.8 as excellent discrimination ability. history of GC were less frequent in the patients with low-risk OLGA stages than in those with high-risk OLGA stages (Table 4). Among tumour-related factors, diffuse-type cancer or signet-ring cell carcinoma were more frequent in the OLGA stage 0 II group than in stage III IV group. Intestinal-type GC, well-differentiated or moderately differentiated tubular adenocarcinomas were less frequent in the OLGA stages 0 II group. However, tumour stage, tumour location and tumour size were not different between groups (Table 4). Subgroup analyses in terms of Lauren s classification Helicobacter pylori positivity and current smoking habit were significantly associated with the risk of both intestinal- and diffuse-type GC. As expected, only stages III and IV in the OLGA system were associated with the risk of intestinal-type GC (OLGA stage III, OR 4.76; stage IV, OR 4.19), and the magnitudes of OR were almost double when we considered both Lauren types (OLGA stage III, OR 2.09; stage IV, OR 2.04). In the OLGIM staging system, stages I and II were also associated with intestinal-type GC in addition to stages III and IV. As OLGIM stage increased, the magnitudes of OR gradually increased stepwise (OLGIM stages I, II, III and IV; 3.64, 5.15, 7.89 and 13.20, respectively, P for trend <0.0001). The v 2 value for the OLGIM staging system (86.411, df = 4, P < 0.001) was higher than that for OLGA (50.655, df = 4, P < 0.001). The c value showed good discrimination for OLGA (0.783) and excellent discrimination for the OLGIM staging systems (0.833). 20 Both evaluation results suggest that OLGIM system has better discrimination ability compared with OLGA system according to the stage distribution (Table 5) Aliment Pharmacol Ther 2013; 38:

6 OLGA and OLGIM staging systems and gastric cancer Table 4 Comparisons of the characteristics between low OLGA stage group (stages 0 II) and high OLGA stage group (stages III IV) in gastric cancer patients () Low-risk stages (Stages 0 II) n = 255 High-risk stages (Stages III IV) n = 219 P-value Age (years), mean s.d <0.001 Sex (male), n (%) 144 (56.5) 164 (74.9) <0.001 H. pylori-positive, n (%) 228 (89.4) 199 (90.9) Smoking, n (%) Current smoker 94 (36.9) 103 (47.0) <0.001 Ex-smoker 40 (15.7) 53 (24.2) Family history of gastric cancer*, n (%) 44 (17.3) 63 (28.8) Stage, n (%) EGC 137 (53.7) 128 (58.4) AGC 118 (46.3) 91 (41.6) TNM stage, n (%) Stage IA, IB 175 (68.6) 157 (71.7) Stage II 36 (14.1) 23 (10.5) Stage IIIA, IIIB 22 (8.6) 23 (10.5) Stage IV 22 (8.6) 16 (7.3) Longest tumour diameter (mean s.d., cm) Tumour location, n (%) Upper 37 (14.5) 33 (15.1) Middle 63 (24.7) 48 (21.9) Lower 155 (60.8) 138(63.0) Lauren s classification, n (%) Intestinal 73 (28.6) 120 (54.8) <0.001 Diffuse 148(58.0) 66 (30.1) Mixed 20 (7.8) 19 (8.7) Not evaluable 14 (5.5) 14 (6.4) Histological classification, n (%) Tubular adenocarcinoma Well-differentiated 34 (13.3) 72 (32.9) <0.001 Moderately differentiated 40 (15.7) 47 (21.5) Poorly differentiated 72(28.2) 54(24.7) Papillary adenocarcinoma 1 (0.4) 3 (1.4) Mucinous adenocarcinoma 5 (2.0) 5 (2.3) Signet-ring cell carcinoma 103 (40.4) 38 (17.4) AGC, advanced gastric cancer; EGC, early gastric cancer; GC, gastric cancer; OLGA, Operative link on gastritis assessment; s.d., standard deviation. * Family history of first-degree relatives. Post-operative pathological stage using the 6 th edition of the International Union Against Cancer/American Joint Committee on Cancer TNM classification system. Using the Japanese Classification of Gastric Cancer. World Health Organization histological classification. In diffuse-type GC, OLGA stage lost significance even in stages III and IV, which was a major difference compared with intestinal-type. However, OLGIM stages (I IV) were associated with diffuse-type GC (OLGIM stages I, II, III and IV; 1.84, 2.59, 5.08 and 6.32, respectively, P for trend <0.0001), although the magnitudes of the ORs were lower than those for intestinal-type cancer. The v 2 value for OLGIM staging (36.085, df = 4, P < 0.001) was higher than that for OLGA (7.782, df = 4, P = 0.100). The c value showed good discrimination for both OLGA (0.721) and OL- GIM (0.768) staging systems, 20 with a higher value for OLGIM than for OLGA staging. These results also suggest better discriminating power for the OLGIM system in diffuse-type as well as in intestinal-type GC than for OLGA staging system (Table 6). DISCUSSION In this age- and sex-matched case control study, high OLGA and OLGIM staging systems were significantly Aliment Pharmacol Ther 2013; 38:

7 S.-J. Cho et al. Table 5 Univariate and multivariate analyses of the risk of intestinal-type gastric cancer in subjects according to OLGA and OLGIM staging systems Intestinal-type gastric cancer Gastric cancer patients n = 193 Control subjects n = 193 Crude OR (95% CI) Adjusted OR (95% CI) Age (years), mean s.d Sex (male), n (%) 151 (78.2) 151 (78.2) H. pylori-positive, n (%) 167 (86.5) 122 (63.2) 3.74 ( ) 2.79 ( )* Smoking, n (%) Nonsmoker 51 (26.4) 74 (38.3) Ex-smoker 53 (27.5) 68 (35.2) 1.13 ( ) 1.36 ( )* Current smoker 89 (46.1) 51 (26.4) 2.53 ( ) 2.75 ( )* Family history, n (%) 56 (29.0) 10 (5.2) 7.48 ( ) 7.84 ( )* OLGA stage, n (%) 0 9 (4.7) 42 (21.8) I 23 (11.9) 45 (23.3) 2.39 ( ) 1.47 ( )* II 41 (21.2) 48 (24.9) 3.99 ( ) 2.20 ( )* III 62 (32.1) 29 (15.0) 9.98 ( ) 4.76 ( )* IV 58 (30.1) 29 (15.0) 9.33 ( ) 4.19 ( )* P for trend < c value OLGIM stage, n (%) 0 24 (12.4) 102 (52.8) I 27 (14.0) 32 (16.6) 3.59( ) 3.64 ( ) II 35 (18.1) 21 (10.9) 7.08 ( ) 5.15 ( ) III 43 (22.3) 20 (10.4) 9.14 ( ) 7.89 ( ) IV 64 (33.2) 18 (9.3) ( ) ( ) P for trend < < c value OLGA, Operative link on gastritis assessment; OLGIM, Operative link on gastric intestinal metaplasia assessment; s.d., standard deviation. * Adjusted for age, sex, smoking, H. pylori infection, family history and OLGA stage using the logistic regression models. Family history of first-degree relatives. Adjusted for age, sex, smoking, H. pylori infection, family history and OLGIM stage using the logistic regression models. c statistic as a goodness of fit measure of a model was used to evaluate how well each staging system can discriminate cancer and control subjects at different levels of stage. The c values of were regarded as moderately good discrimination and values of 0.8 as excellent discrimination ability. associated with GC. OLGIM staging seems to have more discriminating ability than OLGA based on its greater magnitude of ORs for cancer risk and higher c value than OLGA staging. OLGA stages III or IV were significantly associated with the risk of intestinal-type, but not diffuse-type, GC. In contrast, OLGIM staging was significantly associated with both types of GC. In addition, GC risk increased in a stepwise pattern, starting from OL- GIM stage I. Our study has the strength that OLGA and OLGIM systems were evaluated in a large number of GC patients from a high-risk region. Atrophic gastritis and IM are regarded as pre-neoplastic lesions of GC, but surveillance strategies have not been defined. The OLGA staging system is beneficial because it presents information on clinical outcome of gastritis. 6 In 5 7, 9, 22 previous studies regarding OLGA stage and GC risk, only small number of GC or dysplasia cases were included and 6, 7, 9 studies were mainly performed in Western countries. 5, 6, 9 The grades of atrophic gastritis or IM were reported to be much higher in Japanese subjects than in Indonesian or English people. 23, 24 Therefore, it is uncertain whether the staging system can be applied to high-risk regions, such as Japan or Korea. Our study has the strength that OLGA and OLGIM systems were evaluated in a large number of GC patients from a high-risk region. Inter-observer agreement for gastric atrophy as a main parameter of the OLGA system is low, even after the 3, 25, 26 updated Sydney system using visual analogue scale, despite recent attempts to overcome this disagreement. 17 The OLGIM system, which uses IM, results in fewer patients in stages III to IV, 9, 27 creating a small population suitable for endoscopic surveillance. 8 In a recent study, 1298 Aliment Pharmacol Ther 2013; 38:

8 OLGA and OLGIM staging systems and gastric cancer Table 6 Univariate and multivariate analyses of the risk of diffuse-type gastric cancer in subjects according to OLGA and OLGIM staging systems Diffuse-type gastric cancer Gastric cancer patients n = 214 Control subjects n = 214 Crude OR (95% CI) Adjusted OR (95% CI) Age (years), mean s.d Sex (male), n (%) 108 (50.5) 108 (50.5) H. pylori-positive, n (%) 198 (92.5) 143 (66.8) 6.14 ( ) 6.90 ( )* Smoking, n (%) Nonsmoker 109 (50.9) 125 (58.4) Ex-smoker 25 (11.7) 48 (22.4) 0.60 ( ) 0.87 ( )* Current smoker 80 (37.4) 41 (19.2) 2.24 ( ) 3.62 ( )* Family history, n (%) 34 (15.9) 26 (12.1) 1.37 ( ) 1.19 ( )* OLGA stage, n (%) 0 22 (10.3) 32 (15.0) I 47 (22.0) 65 (30.4) 1.05 ( ) 0.79 ( )* II 79 (36.9) 63 (29.4) 1.82 ( ) 0.97 ( )* III 38 (17.8) 32 (15.0) 1.73 ( ) 0.89 ( )* IV 28 (13.1) 22 (10.3) 1.85 ( ) 0.70 ( )* P for trend c value OLGIM stage, n (%) 0 71 (33.2) 125 (58.4) I 50 (23.4) 44 (20.6) 2.00 ( ) 1.84 ( ) II 27 (12.6) 21 (9.8) 2.26 ( ) 2.59 ( ) III 38 (17.8) 16 (7.5) 4.18 ( ) 5.08 ( ) IV 28 (13.1) 8 (3.7) 6.16 ( ) 6.32 ( ) P for trend < <0.001 c value OLGA, Operative link on gastritis assessment; OLGIM, Operative link on gastric intestinal metaplasia assessment; s.d., standard deviation. * Adjusted for age, sex, smoking, H. pylori infection, family history and OLGA stage using the logistic regression models. Family history of first-degree relatives. Adjusted for age, sex, smoking, H. pylori infection, family history and OLGIM stage using the logistic regression models. c statistic as a goodness of fit measure of a model was used to evaluate how well each staging system can discriminate cancer and control subjects at different levels of stage. The c values of were regarded as moderately good discrimination and values of 0.8 as excellent discrimination ability. gastric cancer patients had higher prevalence of OLGIM stage II IV, but not OLGA stages, than duodenal ulcer controls. 28 In the present study, ORs for OLGIM staging increased more steeply than for OLGA system. Atrophic gastritis and IM have traditionally been evaluated as one entity, and IM has been considered as an evidence of atrophic gastritis. 29 Gastric carcinogenesis has been increasingly recognised as a multistep cascade, and IM is now mostly evaluated as a separate entity in accordance with the updated Sydney system. 30 IM is more closely linked to GC, as supported by higher hazard or odds ratios for IM than for atrophy. 12, 31, 32 Therefore, IM, rather than atrophy, may be a more significant risk factor for GC. The OLGA staging system has been classified as lowrisk (OLGA stages 0 II) and high-risk (OLGA stages III or IV) for GC in previous studies. 5, 9 In the present study, combining OLGA stages III and IV into one category (high-risk) seems reasonable because the OR magnitudes were similar between OLGA stages III and IV and ORs of stage I and II were not significantly increased compared with stage 0. Meanwhile, OLGIM stages increased stepwise from stages I to IV, leading to a difficulty in determining a cut-off value between highand low-risk subjects for GC. Based on our data, we suggest that OLGIM stages I and II cannot be considered low-risk stages in contrast to OLGA stages I and II. We also recommend that subjects with OLGIM stage I or more be followed up with GC surveillance even after H. pylori eradication. In our study, OLGA stages III or IV were significantly associated with the risk of intestinal-type GC, while stages Aliment Pharmacol Ther 2013; 38:

9 S.-J. Cho et al. 0 to II were not. Interestingly, OLGA stage was only associated with intestinal-type, but not diffuse-type, GC. In contrast, high OLGIM stages were associated with diffuse-type as well as intestinal-type carcinomas with stepwise increase in ORs. Thus, the OLGIM staging system seems to be a better predictor of GC risk that is applicable to both types of GC. Although diffuse-type cancers are not typically thought to be associated with gastric atrophy or IM, 33, 34 several studies reported that IM is more distributed in the gastric mucosa of patients with diffuse-type GC than in that of controls, despite less association compared with intestinal-type cancer, 35, 36 which is in line with our finding. Although H. pylori is less related to diffuse-type GC than intestinal-type, it is also accepted as a causal factor for diffuse-type GC, too. 37 H. pylori may cause diffuse-type cancer through unclear carcinogenic mechanisms compared with intestinal-type GC. To identify the population at high risk of GC that would benefit from surveillance, cut-off values of OLGA or OLGIM stages need to be defined. Until now, subjects with higher OLGA or OLGIM stages (III IV) were suggested as a population suitable for surveillance. 9, 27 However, those studies were conducted in Western countries. In Korea, where the prevalence of gastric pre-malignant lesion and GC is very high, 22 application of this surveillance strategy is questioned, because approximately one-quarter of GC cases in our study developed in OLGA stages 0 and I, and OLGIM stage 0. In comparing low- (stages 0 II) and high-risk OLGA stages (stages III and IV) in GC patients, GCs were found in the low-risk stage group at about 50%. The GC patients with low-risk OLGA stages were relatively younger and more likely to be female and have diffuse-type GC, including predominantly signet-ring cell type, compared with the high-risk group (OLGA stages III and IV). Therefore, high-risk OLGA stage (stages III and IV) alone is not sufficient in defining subjects who require surveillance in Korea. In terms of biopsy location, a tutorial on OLGA staging 38 recommends anterior and posterior walls of the corpus. 6, 9, 39 In previous studies of OLGA staging, biopsy locations were lesser and greater curvatures of the corpus 7, 8, 40 according to the updated Sydney system. 3 Atrophy or metaplastic grades differ markedly between the lesser and greater curvatures of the corpus, as they rarely develop in the greater curvature as shown in previous Korean studies. Thus, averaging scores from 41, 42 lesser and greater curvatures may underestimate corpus atrophy and subsequently reduce the discriminating power of OLGA or OLGIM systems. Therefore, we included only lesser curvature in determining OLGA and OLGIM staging systems and did not include scores from greater curvature of corpus. A recent study showed that obtaining at least two respective biopsies from the antrum and the corpus increases the detection of IM compared with obtaining biopsies from either the antrum or the corpus. 43 A recent study performed in a Hispanic population in North America reported that the Sydney system underestimated corpus atrophy compared with a protocol taking biopsy at low body greater curvature, which is more distal to the corpus recommended by the Sydney system. 44 According to the updated Sydney system, 3 both OLGA and OLGIM systems require a set of biopsy samples, including incisura angularis. Antral and incisura angularis specimens can generally be placed in the same bottle, and the corpus biopsies in another. 18 In a recent report, compared with original OLGA and OLGIM systems, modified OLGA and OLGIM systems (with exclusion of the incisura angularis biopsy) showed 15% and 30% stage downgrading, respectively. 27 In the present study, biopsy samples were not taken from the incisura angularis based on the previous study. 15 Several recent studies suggested that angular biopsy provides little additional information compared with biopsies of the antrum and corpus. 27, 45 Recently proposed European guidelines for the management of precancerous conditions and lesions in the stomach also excluded biopsy of the incisura angularis for staging. 46 This study has several limitations. First, the cross-sectional design makes it difficult to speculate on the chronological development of gastric atrophy and GC. Second, a hospital-based study may lead to selection bias. However, control groups were recruited from participants of National Cancer Screening Program, which invites almost 100% of the Korean population aged over 40 years biennially. Thus, controls may reflect the general population. Third, we did not consider other causes of atrophic gastritis, such as autoimmune gastritis. However, autoimmune gastritis is very rare in Korea. 47 Fourth, inflammatory infiltrates may prevent proper assessment of glandular atrophy, resulting in not evaluable in assessing atrophy, which may lead to exclusion from the analysis. In conclusion, high-risk OLGA stages (OLGA staging III and IV) are an independent risk factor for intestinal-type GC in a region where incidence of GC is high. OLGIM stages I to IV are associated with increased incidence of both intestinal- and diffuse-type GCs. Because these were risk factors even after adjusting H. pylori infection, periodic surveillance is strongly recommended for individuals with advanced OLGA or OLGIM stages even after H. pylori eradication Aliment Pharmacol Ther 2013; 38:

10 OLGA and OLGIM staging systems and gastric cancer AUTHORSHIP Guarantor of the article: None. Author contributions: Soo-Jeong Cho: Analysis and integration of data, drafting of the manuscript. Il Ju Choi: Conception and design of the study, revision of the manuscript, obtained funding, study supervision. Myeong-Cherl Kook: Acquisition and analysis of pathological data. Byung-Ho Nam: Statistical analysis. Chan Gyoo Kim: Acquisition of data. Jong Yeul Lee: Acquisition of data, Keun Won Ryu: Critical revision of the manuscript, Young-Woo Kim: Critical revision of the manuscript. All authors approved the final version of the manuscript. ACKNOWLEDGEMENTS Declaration of personal interests: None. Declaration of funding interests: This study was supported by grant from the National Cancer Center, Korea. REFERENCES 1. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. 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