Helicobacter ISSN 1523-5378 doi: 10.1111/hel.12112

OLGA and OLGIM Stage Distribution According to Age and Helicobacter pylori Status in the Korean Population Ji Hyung Nam,* Il Ju Choi,† Myeong-Cherl Kook,† Jong Yeul Lee,† Soo-Jeong Cho,† Su Youn Nam* and Chan Gyoo Kim* *National Cancer Center, Center for Cancer Prevention and Detection, Goyang, Korea, †National Cancer Center, Center for Gastric Cancer, Goyang, Korea

Keywords Operative link for gastritis assessment staging, operative link on gastric intestinal metaplasia assessment staging, Helicobacter pylori, atrophic gastritis, age. Reprint requests to: Il Ju Choi National Cancer Center, Center for Gastric Cancer, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 410-769, Korea. E-mail: [email protected]

Abstract Background: The Operative Link for Gastritis Assessment (OLGA) and the Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) staging systems have been suggested to provide risk assessment for gastric cancer. This study aimed to evaluate the distribution of OLGA and OLGIM staging by age and Helicobacter pylori status. Materials and Methods: We studied 632 subjects who underwent esophagogastroduodenoscopy for gastric cancer screening. Helicobacter pylori status and histologic changes were assessed using the updated Sydney system. Stage III and IV OLGA or OLGIM stages were considered as high-risk stages. Results: The rate of H. pylori infection was 59.0% (373/632). Overall, the proportion of high OLGA and OLGIM stages was significantly increased with older age (p < .001 for both). Old age (OR = 5.17, 6.97, and 12.23 for ages in the 40’s, 50’s, and 60’s, respectively), smoking (OR = 2.54), and H. pylori infection (OR = 8.46) were independent risk factors for high-risk OLGA stages. These risk factors were the same for high-risk OLGIM stages. In the H. pylori-positive subgroup, the proportion of high-risk OLGA stages was low (6.9%) before the age of 40, but increased to 23.0%, 29.1%, and 41.1% for those in their 40s, 50s, and 60s, respectively (p < .001). High-risk OLGIM stages showed a similar trend of 2.8% before the age of 40 and up to 30.1% for those in their 60s. High-risk OLGA and OLGIM stages were uncommon in the H. pylori-negative group, with a respective prevalence of 10.3% and 3.4% even among those in their 60s. Conclusions: Because high-risk OLGA and OLGIM stages are uncommon under the age of 40, H. pylori treatment before that age may reduce the need for endoscopic surveillance for gastric cancer.

Helicobacter pylori (H. pylori) was classified in 1994 as a type I carcinogen of gastric cancer by the International Agency for Research on Cancer (IARC) [1]. Chronic atrophic gastritis and intestinal metaplasia are known to be precancerous histologic alterations that occur in the gastric mucosa, and patients with such premalignant gastric conditions are at considerable risk of gastric cancer [2]. It is generally acknowledged that chronic H. pylori infection is a major cause of the premalignant histologic changes [3,4]. As a histologic evaluation for gastric mucosa, the updated Sydney system provides no estimation for gastric cancer risk. Therefore, the Operative Link for Gastritis Assessment (OLGA)-staging

© 2014 John Wiley & Sons Ltd, Helicobacter 19: 81–89

system has been recommended to simplify assessment of gastric atrophy [5]. This staging system reflects the severity and extent of atrophic gastritis by combining antral and oxyntic/corpus mucosal atrophy scores using the updated Sydney system, and the staging system can then rank the histologic phenotypes of gastritis with a progressively increasing gastric cancer risk [6,7]. A high-risk stage, defined as stages III or IV of the OLGA classification, is strongly correlated with an increased risk of invasive or noninvasive neoplastic lesions in cross-sectional and cohort studies [6,8,9]. In addition, the Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) staging system is an alternative to

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the OLGA-staging system and has been suggested to predict gastric cancer risk because of a strong positive correlation with OLGA and its higher interobserver agreement [10]. The prevalence of gastric atrophy and intestinal metaplasia is increased with older age [11], and the histologic progression mainly results from long-standing H. pylori infection. A nationwide test-and-treat approach to H. pylori infection has been proposed in Japan as H. pylori eradication alone in those with nonatrophic gastritis would prevent subsequent development of gastric cancer [12]. In Korea, there is still no primary prevention strategy even though H. pylori infection is a major risk factor for gastric cancer and that gastric cancer was the second most common cancer in Korea in 2010 [13,14]. The aim of this study was to evaluate the distribution of OLGA and OLGIM staging by age and according to H. pylori status in order to suggest an appropriate age for H. pylori eradication.

Methods Study Design and Population This cross-sectional study included participants (n = 735) from gastric cancer screening programs in the National Cancer Center, Korea, between April 2006 and December 2007. Exclusion criteria were as follows: 1, participants younger than 20 or 70 years or older; 2, newly diagnosed or any previous history of a gastric malignancy; 3, any previous surgical intervention to the upper gastrointestinal tract; 4, incomplete endoscopy procedure; 5, inadequate gastric biopsy sampling; 6, inadequate H. pylori evaluation; 7, a history of H. pylori eradication; and 8, insufficient demographic data. This study was approved by the Institutional Review Board for the National Cancer Center (NCCNCS-13-729).

Endoscopy and H. pylori Evaluation All participants were scheduled to undergo upper endoscopy (GIF-H260; Olympus Optical Co., Ltd, Tokyo, Japan), at which time six gastric biopsy specimens were obtained for H. pylori and histologic evaluation: two from the mid-antrum of the lesser curvature (LC), two from the corpus of the LC approximately 4 cm distal to the gastroesophageal junction, and two from the corpus of the greater curvature (GC). An additional specimen was obtained from the corpus of the GC for rapid urease test (Pronto Dry; Medical Instruments Corporation, Solothurn, Switzerland). Blood sampling was performed to determine H. pylori IgG

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antibody titers using an enzyme-linked immunosorbent assay kit (ELISA) (H. pylori-EIA-Well; Radim, Rome, Italy). Any two positive findings among the five tests of three biopsy sites, rapid urease test, and anti-H. pylori IgG were considered positive for H. pylori infection. Those with only one positive result were regarded as having an inconclusive H. pylori evaluation. Helicobacter pylori-negative subjects were defined as having all negative results from the available tests. The presence of any focal lesions was recorded, including peptic ulcers and noninvasive or invasive neoplastic lesions.

Histology Study and Gastritis Staging The gastric biopsies were fixed in formalin (10%) and embedded in paraffin. Biopsy specimens were examined by a single experienced pathologist (M.C. Kook). Multiple sections obtained from paraffin block were stained with hematoxylin and eosin and Wright–Giemsa. Helicobacter pylori density, atrophic gastritis (defined as loss of appropriate gland), and intestinal metaplasia (defined as replacement of gastric epithelium by intestinal-type epithelium) [7] were scored according to the updated Sydney system using a visual analog scale (0 = absent; 1 = mild; 2 = moderate; 3 = severe) [15]. We used biopsy samples from the antrum and corpus of the LC for the evaluation of gastric atrophy and intestinal metaplasia. On the basis of the topographic locations of atrophy, the gastritis stage (0–IV) was determined by combining the severity scores of antral and oxyntic/corpus atrophy, according to the international OLGA proposal (Table 1) [5]. The same scoring system for the severity and topography of intestinal metaplasia was applied for OLGIM staging [10]. The high-risk stage was defined as stage III or IV for both OLGA and OLGIM classifications.

Statistical Analysis We compared baseline and clinicopathologic characteristics between H. pylori-positive and H. pylori-negative subjects using Pearson’s chi-square test for categorical variables. Student’s t-test was used to compare the mean age. Spearman’s correlation test was used to test the correlation between OLGA- and OLGIM-staging systems. The subjects were divided into five groups (those aged 20–29, 30–39, 40–49, 50–59, and 60– 69 years old). We evaluated the OLGA and OLGIM stage distribution by age and H. pylori status. In addition, p values were compared between H. pylori-positive and H. pylori-negative subjects to identify trends in the proportions of high-risk OLGA and OLGIM stages according to age. We analyzed the association of

© 2014 John Wiley & Sons Ltd, Helicobacter 19: 81–89

OLGA and OLGIM Stage According to Age

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Table 1 The OLGA- and OLGIM-staging system: In each compartment (i.e., mucous-secreting antral and oxyntic/corpus mucosa), atrophy or intestinal metaplasia are scored using a four-tiered scale (0–3) according to the visual analog scale of the Houston-updated Sydney system Corpus Histologic Score

No (score 0)

Mild (score 1)

Moderate (score 2)

Severe (score 3)

Antrum No (score 0) Mild (score 1) Moderate (score 2) Severe (score 3)

STAGE STAGE STAGE STAGE

STAGE STAGE STAGE STAGE

STAGE STAGE STAGE STAGE

STAGE STAGE STAGE STAGE

0 I II III

baseline and clinical characteristics with high-risk stages using logistic regression with odds ratios (ORs) and 95% confidence intervals (CIs). Multivariate logistic regression modeling and adjusted ORs were performed to analyze risk factors for the high-risk OLGA and OLGIM stages. STATA software version 10.1 (StataCorp, College Station, TX, USA) was used for all analyses. All p values are two-sided, and p values < .05 were considered significant.

Results Population Of the 735 participants who underwent upper endoscopic procedures, 103 participants were excluded from the study for the following reasons: a diagnosis of early gastric cancer (n = 4) or gastric lymphoma (n = 1), incomplete endoscopy procedure (n = 6), inadequate biopsy specimens for gastritis staging (n = 38), inadequate H. pylori evaluation (n = 30), a history of H. pylori eradication (n = 15), age 70 years or older (n = 2), or insufficient demographic data (n = 7).

Clinicopathologic Characteristics and H. pylori The mean age of the 632 subjects enrolled was 48.2  10.8 years (range 21–68 years), and 49.2% were male. Table 2 summarizes the basic and clinicopathologic characteristics. The rate of H. pylori infection was 59.0%. The mean age was greater among H. pyloripositive subjects than among negative subjects (p < .001). Helicobacter pylori-positive subjects had significantly higher OLGA and OLGIM stage distributions compared with H. pylori-negative subjects (both p < .001). The percentage of subjects with OLGA stage III or IV were 3.5% (9/259) in H. pylori-negative subjects and 25.7% (96/373) in H. pylori-positive subjects. Whereas 38.2% of H. pylori-negative subjects were OLGA stage 0, only 4.6% were stage 0 in positive subjects. Low-grade dysplasia was found in two subjects

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I I II III

II II III IV

II III IV IV

aged 50 and 61 years. Both of them had H. pylori infection and were confirmed as OLGA stage III or IV. The distribution of OLGA stage was positively correlated with OLGIM stage (correlation coefficient: 0.71, p < .001).

OLGA Stage Distribution by Age Table 3 indicates the OLGA stage distribution according to age. Overall, a shift toward a higher OLGA stage was observed in subjects with older ages (p < .001). According to H. pylori status, the stage distribution became significantly higher as age increased in both H. pyloripositive and H. pylori-negative subjects (p < .001 and p = .003, respectively). All subjects in their 20s had OLGA stage 0 or I, irrespective of H. pylori status. However, for the subjects in their 30s, the percentage of subjects with OLGA stage 0 or I was different in H. pyloripositive and -negative subjects (36.5 vs 94.9%, respectively). Moreover, the OLGA stage II proportion increased to 55.6% in H. pylori-positive subjects, whereas it was only 5.1% in subjects without H. pylori infection. High-risk OLGA stages (i.e., stage III and IV) increased significantly as age increased in both H. pylori-positive and H. pylori-negative subjects, though this was more prominent in H. pylori-positive subjects. For H. pylori-positive subjects, the proportion of highrisk stages increased from 0% (0/9) in their 20s to 41.1% (30/73) in their 60s (p < .001). This increasing trend was less prominent in subjects without H. pylori infection, such that only 10.3% (3/29) of those in their 60s were high-risk stages (p = .007).

OLGIM Stage Distribution by Age The distribution of OLGIM stages also increased by age (p < .001) (Table 4). Only 1/122 subjects in their 30s were OLGIM stage II, whereas 38/122 subjects in their 30s were OLGA stage II. The proportion of highrisk OLGIM stages was more prominent among H. pylori-positive subjects than among those who were

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Table 2 Basic and clinicopathologic data

Mean age (years  SD) Male, n (%) Smoking, n (%) Current smoker Ex-smoker Alcohol, n (%) Current drinker Ex-drinker Family history of GCa, n (%) OLGA staging, n (%) 0 I II III IV OLGIM staging, n (%) 0 I II III IV Non-invasive neoplasia, n (%) Low grade High grade Peptic ulcer (scar), n (%) Gastric Duodenal

All (n = 632)

Helicobacter pylori ( ) (n = 259)

Helicobacter pylori (+) (n = 373)

p-Value

48.2  10.8 311 (49.2)

45.8  11.7 117 (45.2)

49.8  9.8 194 (52.0)