ORIGINAL ARTICLES Characteristics of gastric cancer in endoscopic screening with combined serum assay for anti-helicobacter pylori antibody and pepsinogen levels Takayuki Nakamura 1 Yoichi Kon 1 Kunio Konuma 1 Toshio Sanada 1 Yasumi Suto 1 Kazuko Nakano 1 Noriko Takita 2 Noriko Kanai 2 Yukie Tamura 1 Sumie Onuki 1 Tomohiro Igeta 1 1 Division of Health Evaluation and Promotion, Fuji Heavy Industries Health Insurance Society, Ota Memorial Hospital 2 Division of Endoscopy, Fuji Heavy Industries Health Insurance Society, Ota Memorial Hospital ABSTRACT Objectives The purpose of this study was to clarify the clinicopathological characteristics of gastric cancer (GC) screened in the era of Helicobacter pylori (Hp) eradication. Screening programs should be designed with these characteristics in mind. Design The data from the endoscopic screening program for GC in Ota Memorial Hospital between June 2012 and July 2014 were reviewed in relation to the ABC method, Hp eradication history (Hp-er Hx), and endoscopic findings. Characteristics of GC cases detected in this program were analyzed retrospectively. Setting GC screening program with esophago-gastro-duodenoscopy (EGD) in one private screening center. Participants A total of 8,989 participants underwent a GC screening program with EGD. Of these, 8,242 individuals were screening using the ABC method. Excluding 115 post-gastrectomy cases, 8127 individuals participated in this study. Main outcome measures Individuals were classified using the ABC method, consistent with the recommendation used by the Japan Research Foundation of Prevention Diagnosis Therapy for Gastric Cancer. EGD was used to search neoplasms and inspect the underlined gastric mucosa for chronic atrophic gastritis (), which was evaluated using the Kimura-Takemoto classification system. Results Sixteen cases of GC were detected. Although seven of these were in group A, there was a high probability of previous exposure to Hp because of Hp-er Hx or. All GC cases were also diagnosed as and most were open type. Each GC lesion was located in the atrophic gastric mucosa. Conclusions The prevalence of GC in each group in the ABC method has altered because of the recent development of Hp-er. Individuals with Hp-er Hx or have a material risk of developing GC and certainly require periodic GC screening. Identification and inspection of atrophic gastric mucosae via EGD is crucial for early detection of GC. (HEP. 2015; 42: 439-443.) Key words gastric cancer, endoscopic screening, Helicobacter pylori, ABC method, atrophic gastritis Introduction Gastric cancer (GC) is the fifth most common cancer (952,000 cases in 2012) 1) and the third leading cause of cancer deaths (723,000 in 2012) 2) worldwide. The highest incidence rates are in Eastern Asia, Eastern Europe, and South America. Regional variations in part reflect differences in dietary patterns and the prevalence of Helicobacter pylori (Hp) infection 3). In Japan, the mortality rate has decreased due to the innovation of screening programs using radiofluorography (to carry out upper gastrointestinal series (UGI)). Moreover, with the development of endoscopy, cases of GC may be diagnosed at an early Received: April 1, 2015, Accepted: May 12, 2015 1 Address; Division of Health Evaluation and Promotion, Fuji Heavy Industries Health Insurance Society, Ota Memorial Hospital 455-1 Oshimacho, Ota, Gunma 373-8585, Japan TEL: +81-276-2205, FAX: +81-276-2205 E-mail: takanaka@ota-hosp.or.jp stage and many are now candidates for endoscopic resection or minimally invasive surgery. Screening for GC risk, using combined assay for serum anti- Hp immunoglobulin G antibody (HpAb) and serum pepsinogen (PG) levels, is known as the ABC method 4) and was introduced by Ohata et al 5). This approach classifies subjects into four different risk groups (A, B, C, or D). Individuals in group A (HpAb( )PG( )) have the lowest risk and are not expected to develop GC. The risk of GC increases from group B (HpAb(+) PG( )) to group C (HpAb(+)PG(+)), and those in group D (HpAb( )PG(+)) are at the greatest risk of developing GC 4, 5). According to the Gastric Cancer Risk Screening Manual (GCRSM) (first edition) 6) from the Japan Research Foundation of Prevention Diagnosis Therapy for Gastric Cancer (JRF PDT GC), GC screening by esophago-gastro-duodenoscopy (EGD) is not necessary for individuals in group A, but is recommended every three years, every other year, and annually for those in groups B, C, and D respectively. The ABC method has been undertaken with imaging test (UGI or EGD) for the GC screening program at Ota Memorial Hospital HEP Vol.42, No.4, 2015 (439) 5
(OMH) since April 2011. The availability and prevalence of Hp eradication (Hp-er) therapy have dramatically increased in Japan since it began to be covered by insurance. It is now necessary for improving GC screening programs to clarify the clinicopathological characteristics of GC cases identified through screening and to understand the underlying condition of the stomach. Materials and Methods The data of the endoscopic GC screening program (EGD plus ABC method) at OMH from June 2012 through July 2014 were reviewed and all identified GC cases were analyzed. All subjects involved in our program completed a questionnaire regarding their past medical history including Hp-er (Hp-er Hx) and gastrectomy. Serum levels of pepsinogen 1 (PG1), pepsinogen 2 (PG2), and HpAb (EIA, E-plate, Eiken Chemical Co.) were recorded. The positive criteria for PG and HpAb in the ABC method are as follows: Individuals with a combination of PG1 70 ng/ml and PG1/PG2 ratio 3 are classified as PG(+). Those with PG1 > 70 ng/ml or PG1/PG2 ratio > 3 are classed as PG( ). Individuals with HpAb U/mL are categorized as HpAb(+) and those with HpAb < U/mL are classed as HpAb( ). GC was diagnosed histopathologically with an EGD biopsy specimen. We also investigated the condition of underlining gastric mucosa endoscopically regarding whether or not it was atrophic. The extent of atrophy was evaluated by means of the Kimura-Takemoto classification system 7). Results The 8,989 subjects (mean age ± SD: 55.2 ±.7 y, 5,815 male and 3,174 female) were examined in an endoscopic GC screening program at OMH. Overall, 27.7% were classed as HpAb(+), and the proportion of subjects who were HpAb(+) increased with age (Table 1, Fig. 1). The ABC method was undertaken by 8,242 individuals undergoing EGD screening. Of these, 115 cases were excluded from Table 1 Participants and their serum anti-hp immunoglobulin G antibody and ABC method details subject Number of cases total 8,989 male : female 5,815 : 3,174 age (mean ± SD) 55.2 ±.7 y Underwent HpAb test 8,254 HpAb + : 2,285 (27.7) : 5,969 (72.3) Underwent ABC method 8,242 Gastrectomy in ABC method 115 ABC method w/o gastrectomy 8,127 group A 5,806 (71.4) group B 1,524 (18.8) group C 708 (8.7) group D 89 (1.1) HpAb: serum anti-hp immunoglobulin G antibody the analysis due to the past history of gastrectomy, which influences serum PG level. The remaining 8,127 subjects were classified according to the ABC method as follows: 5,806 subjects were classified as group A (71.4%), 1,524 as group B (18.8%), 708 as group C (8.7%), and 89 as group D (1.1%) (Table 1). The proportion of individuals classed as group A declined with age, whereas the proportions allocated to each of the other three groups increased with age (Fig. 2). Malignant neoplasms were found in 21 individuals during the term considered. The malignancies diagnosed were as follows: three cases of esophageal cancer, one gastrointestinal stromal tumor of stomach (gastric GIST), one metastatic gastric tumor, and 16 cases of GC. The GC detection rate was 0.18% among the 8,989 individuals screened via EGD (Table 2). One individual Fig. 1 Percentage of subjects who were HpAb(+) in each age band Percentage in each group 90 80 70 Percentage who were HpAb(+) 60 50 40 30 20 0 50 45 40 35 30 25 20 15 5 0-29 30-39 40-49 50-59 Age (years) 60-69 70-79 Fig. 2 Percentage of subjects allocated to each group using ABC method, split by age band -29 30-39 40-49 50-59 60-69 70-79 80- Age (years) 80- Table 2 Malignancies diagnosed in endoscopic screening program between June 2012 and July 2014 Malignancy Number of cases Esophageal cancer 3 Gastric GIST 1 Metastatic gastric tumor 1 Gastric cancer 16 (0.18) total 21 (0.23) shows the detection rate in 8,989 participants. GIST: gastrointestial stromal tumor. A B C D 6 (440) HEP Vol.42, No.4, 2015
Nakamura et al.: Endoscopic gastric cancer screening with serum assay for H. pylori and pepsinogen with GC did not take an HpAb test despite belonging to group C one year earlier. Excluding that case, five individuals in group C (0.71%) had GC, and 0.12%, 0.13%, and 1.12% of groups A, B, and D were diagnosed with GC respectively (Table 3). Seven individuals with GC were classified as group A. Five of these had Hp-er Hx and all seven were positive for chronic atrophic gastritis () endoscopically. The remaining nine patients with GC, who were not in group A, also had endoscopic findings of (Table 4). In group A, 23.4% of individuals had Hp-er Hx and 23.4% were diagnosed as. In group A, 29.2% showed features of either Hp-er Hx,, or both. This subgroup contained all the cases of GC present in group A. On the contrary, 70.7% of individuals in group A had neither Hp-er Hx nor and did not have any case of GC in this study (Tables 3 and 5). Every identified cancerous lesion was located in the atrophic gastric mucosae, while cases of GC were observed throughout the stomach. Most of the GC cases had open type, as described in the Kimura-Takemoto classification system 7) (Table 4). Discussion All 16 cases of GC discovered in our EGD screening program were diagnosed in their early stages and curative treatment was taken. Table 3 Helicobacter pylori eradication history and number of cases of gastric cancer and chronic atrophic gastritis in each group using ABC method Number GC (% in group) Hp-er Hx + unknown + A 5,806 (71.4) 1,524 (18.8) 708 (8.7) 89 (1.1) 8,127 (0) 7 (0.12) 2 (0.13) 5 (0.71) 1 (1.12) 15 (0.18) 4,436 (76.4) 1,360 (23.4) (0.2) 4,449 (76.6) 1,357 (23.4) B 1,250 272 2 120 1,404 C 680 26 2 14 694 D 78 11 0 4 85 total 6,444 (79.3) 1,669 (20.5) 14 (0.2) 4,587 3,540 GC: gastric cancer, Hp-er Hx: Helicobacter pylori eradication history, : chronic atrophic gastritis. Table 4 Clinicopathological characteristics of GC cases detected in EGD screening program at OMH Age/sex cstage Tx Pathology pt pstage location ABC Hp-er Hx extent background mucosa 72M 1A ESD intestinal 1a 1A M Les A + C3 atrophic mucosa 69M 1A DG intest.>diffuse 1b 1A M Les/Post A + + O1 atrophic mucosa 64F 1A ESD intestinal 1a 1A L Les A + + O1 atrophic mucosa 64M 1A ESD intestinal 1a 1A M Gre A + O2 atrophic mucosa 67M 1A DG intestinal 1a 1A M Les/Post A + + O2 atrophic mucosa 62M 1A DG diffuse 1b 1A M Post A + + O2 atrophic mucosa 70M 1A TG diffuse 1a 1A M Post A + + O2 atrophic mucosa 50M 1A ESD intestinal 1a 1A M Ant B + O1 atrophic mucosa 68M 1A ESD intestinal 1a 1A M Gre B + O1 atrophic mucosa 69M 1A ESD intestinal 1b1 1A U, M Ant, Les C + + O2 atrophic mucosa 74F 1A ESD intestinal 1a 1A L Les C + O2 atrophic mucosa 64M 1A ESD intestinal 1a 1A L Les C + O2 atrophic mucosa 70M 1A TG intestinal 1a 1A U Ant C + O3 atrophic mucosa 65F 1A ESD intestinal 1a 1A L Ant C + O3 atrophic mucosa 66M 1A ESD intestinal 1a 1A L Les (C)* + O3 atrophic mucosa 67M 1A ESD intestinal 1a 1A U Post D + O2 atrophic mucosa *: (C) didn t take HpAb test but had belonged to group C one year earlier. Tx: treatment for GC, ESD: endoscopic submucosal dissection, DG: distal gastrectomy, TG: total gastrectomy, Pathology: Lauren classification, U: upper part of stomach, M: middle part of stomach, L: lower part of stomach, Ant: anterior wall, Post: posterior wall, Les: lesser curverture, Gre: greater curverture, : chronic atrophic gastritis, extent: Kimura-Takemoto classification system. HEP Vol.42, No.4, 2015 (441) 7
Table 5 Helicobacter pylori eradication history and cases of chronic atrophic gastritis in group A Hp-er Hx + unknown + case 1,021 (17.6) 339 (5.8) GC 6 0 case 334 (5.8) 4,2 (70.7) GC 0 case 2 (0.0) 8 (0.1) GC 0 0 Of these, 46.7% were classified as group A using the ABC method, and therefore would not have been expected to have GC 4-6). However, both one individual with Hp-er Hx, and another, who had endoscopic findings of, had a high probability of previous exposure to Hp. When individuals in group A had Hp-er Hx or, we described them as pseudo-group A. 29.2% of individuals in group A were categorized as pseudo-group A, and this included all cases of GC in group A. Otherwise, 70.7% of individuals in group A, who did not have both Hp-er Hx and, were known as true group A, and this did not have any case of GC (Table 5). GC screening could potentially be omitted for true group A, particularly in the case of national screening program, for which cost-benefit would be crucial. However, it could be difficult for private screening programs, such as ours, to accept that individuals in true group A should forego endoscopy because a limited number of cases of GC have been identified in this group through GC screening 8, 9). In fact, we personally experienced two such cases recently after this study. Although GC may be detected in any part of the stomach using EGD screening, special attention should be paid to the atrophic gastric mucosae in the cases with. Endoscopic inspection might require a contrast method with dyes, such as indigo carmine, and image enhanced endoscopy, using narrow banding image or blue LASER image. These techniques can be used to recognize tiny cancerous lesions in the heterogeneous color and irregular surface of the mucosae of individuals with. Whereas most cases of GC were detected in the stomach of individuals who had been exposed to Hp, those in true group A should also not be assumed to be cancer free. If the stomach of any individuals in true group A has any discolored area in its surface mucosa, it should be investigated carefully. Fujisaki et al. ) treated 36 diffuse type GCs (35 individuals) by endoscopic submucosal dissection. All cases were Hp negative, with no mucosal atrophy. When examined via endoscopy, 92% of these lesions looked whitish and only 8% were reddish. On the endoscopic findings, 83% were classed as superficial elevated type and 17% were flat type. Of the 36 lesions, 20 were located in the middle third of the stomach and 16 were in the lower third. No diffuse GC was found in the upper third ). Gastric adenocarcinoma of fundic type (chief cell predominant type) on the gastric fundus is increasingly being reported 11, 12). Endoscopically, the most common features of this are submucosal tumor shape (60%), whitish color (70%), dilated vessels with branching architecture (50%), and background mucosa without atrophic change (90%) 13). In this Hp-er era, these types of GC might be expected more frequently. The second edition of the GCRSM 14) was published by JRF PDT GC in November 2014. Several points have been changed in this new edition 14). A new category, group E, has been introduced, which includes individuals who took Hp-er Hx. Individuals in group E have a material risk of developing GC and require an imaging test for GC screening. In our study, 1,669 participants (20.5%) would have been classified as group E and 23.4% of our original group A would have belonged to this group (Table 3). The population of group E is increasing because Hp-er has been supported financially through insurance since February 2013 in Japan. The authors discuss the fact that some members of group A have been exposed to Hp, similar to those in our pseudo-group A. This part of group A has a material GC risk and certainly requires periodic GC screening. The best way to exclude them from group A remains controversial and no consensus has been reached. The second edition of the GCRSM abolished the guideline regarding the frequency of imaging tests due to insufficient evidence. More research and data is therefore required to establish the adequate frequency of screening tests. Conclusions The prevalence of GC in each group in the ABC method has altered because of the recent development of Hp-er. Individuals with Hp-er Hx or have a material risk of developing GC and certainly require periodic GC screening. Identification and inspection of atrophic gastric mucosae via EGD is crucial for early detection of GC. The more research and data is required to evaluate the altered characteristics of GC in the era of Hp-er. The authors state that they have no Conflict of Interest (COI). REFERENCES 1) World Cancer Research Fund International (Internet). Data on specific cancers. Stomach cancer statistics; 2015. (Accessed April 26, 2015, at http://www.wcrf.org/int/cancer-facts-figures/dataspecific-cancers/stomach-cancer-statistics). 2) World Health Organization (Internet). Media centre. Cancer; 2015. (Accessed April 26, 2015, at http://www.who.int/mediacentre/ factssheets/fs297/en/). 3) Jamal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global Cancer Statistics. CA Cancer J Clin 2011; 61: 69-90. 4) Miki K. Gastric cancer screening by combined assay for serum anti-helicobacter pylori IgG antibody and serum pepsinogen levels ABC method. Proceeding of the Japan Academy, Series B 2011; 87(7): 405-14. 5) Ohata H, Kitauchi S, Yoshimura N, Mugitani K, Iwane M, Nakamura H, et al. Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer 2004; 9: 138-43. 6) Japan Research Foundation of Prevention Diagnosis Therapy for Gastric Cancer. Gastric cancer risk screening manual 1st ed. 2009 8 (442) HEP Vol.42, No.4, 2015
Nakamura et al.: Endoscopic gastric cancer screening with serum assay for H. pylori and pepsinogen (in Japanese). 7) Kimura K, Takemoto T. An endoscopic recognition of the atrophic border and its significance in chronic gastritis. Endoscopy 1969; 1(3): 87-97. 8) Matsuo T, Ito M, Takata S, Tanaka S, Yoshihara M, Chayama K. Low prevalence of Helicobacter pylori-negative gastric cancer among Japanese. Helicobacter 2011; 16: 415-9. 9) Ono S, Kato M, Suzuki M, Ishigaki S, Takahashi M, Haneda M, et al. Frequency of Helicobacter pylori-negative gastric cancer and gastric mucosal atrophy in a Japanese endoscopic submucosal dissection series including histological, endoscopic and serological atrophy. Digestion 2012; 86: 59-65. ) Fujisaki J, Yamamoto N, Horiuchi Y, Ohsumi H, Miyamoto Y, Morishige K, et al. Characteristic endoscopic findings of Helicobacter pylori-negative early gastric undifferentiated adenocarcinoma. Stomach and Intestine (Tokyo) 2014; 49(6): 854-61 (in Japanese). 11) Ueyama H, Yao T, Nakashima Y, Hirakawa K, Oshiro Y, Hirahashi M, et al. Gastric adenocarcinoma of fundic gland type (chief cell predominant type): proposal for a new entity of gastric adenocarcinoma. Am J Surg Pathol 20; 34: 609-19. 12) Yao T, Ueyama H, Kushima R, Nakashima Y, Hirakawa K, Oshiro Y, et al. New type of gastric carcinoma-adenocarcinoma of the fundic gland type: its clinicopathological features and tumor development. Stomach and Intestine (Tokyo) 20; 45(7): 1192-202 (in Japanese). 13) Ueyama H, Matsumoto K, Nagahara A, Hayashi T, Yao T, Watanabe S. Gastric adenocarcinoma of the fundic gland type (chief cell predominant type). Endoscopy 2014; 46: 153-7. 14) Japan Research Foundation of Prevention Diagnosis Therapy for Gastric Cancer. Gastric cancer risk screening manual 2nd ed. 2014 (in Japanese). HEP Vol.42, No.4, 2015 (443) 9