Digestive Endoscopy 2015; 27: 551–561
doi: 10.1111/den.12471
Review
Helicobacter pylori-negative gastric cancer: Characteristics and endoscopic findings Yorimasa Yamamoto, Junko Fujisaki, Masami Omae, Toshiaki Hirasawa and Masahiro Igarashi Division of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan Helicobacter pylori (H. pylori) leads to chronic gastritis and eventually causes gastric cancer. The prevalence of H. pylori infection is gradually decreasing with improvement of living conditions and eradication therapy. However, some reports have described cases of H. pylori-negative gastric cancers (HpNGC), and the prevalence was 0.42–5.4% of all gastric cancers. Diagnostic criteria of HpNGC vary among the different reports; thus, they have not yet been definitively established. We recommend negative findings in two or more methods that include endoscopic or pathological findings or serum pepsinogen test, and negative urease breath test or serum immunoglobulin G test and no eradication history the minimum criteria for diagnosis of HpNGC. The etiology of gastric cancers, excluding H. pylori infection, is known to be associated with several factors including lifestyle, viral infection, autoimmune disorder and germline mutations, but the main causal factor of HpNGC is still unclear. Regarding the characteristics of HpNGC,
the undifferentiated type (UD-type) is more frequent than the differentiated type (D-type). The UD-type is mainly signet ring-cell carcinoma that presents as a discolored lesion in the lower or middle part of the stomach in relatively young patients. The gross type is flat or depressed. The D-type is mainly gastric adenocarcinoma of the fundic gland type that presents as a submucosal tumor-like or flat or depressed lesion in the middle and upper part of the stomach in relatively older patients. Early detection of HpNGC enables minimally invasive treatment which preserves the patient’s quality of life. Endoscopists should fully understand the characteristics and endoscopic findings of HpNGC.
INTRODUCTION
cancer in one-third of patients.5 Due to the results of these studies, eradication therapy of H. pylori became covered by the Japanese national health insurance in 2013 and was given extensively to patients infected with H. pylori. Thus, a combination of extensive eradication therapy and improvement of living conditions and sanitation has led to the recent decrease in the prevalence of H. pylori infection,6 and the mortality rate of gastric cancer in the last decade has declined 3–4% per year in Japan.7 In contrast, some recent reports have described the occurrence of gastric cancer in patients without H. pylori infection, also referred to as H. pylori-negative gastric cancer (HpNGC).8,9 Other gastric cancers, which are not associated with H. pylori infection, have been reported as lesions related to autoimmune gastritis,10 Epstein-Barr virus (EBV) infection11 and genetic factors.12 Some gastric cardia cancers are not associated with H. pylori, and the incidence is increasing in Western countries.13 In Japan, there is an increasing trend in the rate of adenocarcinoma of the esophagogastric junction (EGJ).14 EGJ cancers include some HpNGC, but as the differentiation between some HpNGC and Barrett’s esophageal cancer is often difficult, we opted
CCORDING TO THE report by the International Agency for Research on Cancer, gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, with an incidence of one million people per year.1 Helicobacter pylori (H. pylori) was discovered as a pathogen of gastroduodenal ulcers in 1983.2 World Health Organization certified H. pylori as a definite carcinogen in 1994.3 It is well known that H. pylori leads to chronic gastritis by persistent infection of the stomach and eventually causes gastric cancer. According to a prospective cohort study by Uemura et al., gastric cancer occurs only in patients with H. pylori infection, but not in those without H. pylori infection.4 Fukase et al. showed in another prospective study that eradication of H. pylori reduced the incidence of metachronous gastric
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Corresponding: Yorimasa Yamamoto, Division of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135–8550, Japan. Email: [email protected] Received 30 July 2014; accepted 12 March 2015.
Key words: endoscopic finding, gastric adenocarcinoma of the fundic gland type, Helicobacter pylori-negative gastric cancer, signet ring-cell carcinoma, undifferentiated-type gastric cancer
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to exclude the discussion on EGJ cancers in the present review. In the near future, although the prevalence of all gastric cancers will continue to decrease with a decline in H. pylori infection, the frequency of HpNGC may relatively increase. At present, the diagnostic criteria, prevalence, etiology, patient characteristics and endoscopic findings of HpNGC are still unclear. In this review, we will introduce and discuss some recent studies on HpNGC, and present some representative lesions.
Diagnostic criteria and prevalence of HpNGC HpNGC is an adenocarcinoma that occurs in the stomach without active or previous H. pylori infection. There are some diagnostic methods and tests for H. pylori infection that can be divided into three categories: endoscopic, pathological and clinical methods. By endoscopic diagnosis, lack of mucosal atrophy and presence of regular arrangement of collecting venules on the mucosal surface of the antrum denote H. pylori negativity15 (Fig. 1). In Japan, the Kimura-Takemoto classification is generally used for the evaluation of mucosal atrophy using conventional endoscopy.16 The endoscopic features of mucosal atrophy are characterized by differences in both color and niveau of the mucosa, and the capillary network is visible
in the atrophic mucosa. By using this classification, we can determine the degree of mucosal atrophy. Further, the Kimura-Takemoto endoscopic classification correlates with histological findings and serum pepsinogen level in the evaluation of atrophy.17 In addition, Watanabe et al. reported linear erythema, hemorrhage and fundic gland polyp as other endoscopic findings of H. pylori negativity, and atrophic change as well as mottled patchy erythema as endoscopic findings of H. pylori-eradicated mucosa.18 Thus, endoscopic findings are useful for determining H. pylori infection status in Japan. However, according to guidelines from Western countries, conventional endoscopy cannot be relied upon to correctly identify patients with atrophy or intestinal metaplasia; thus, the inclusion of gastric biopsy during diagnostic endoscopy is recommended.19 By pathological methods, biopsy specimens taken from the stomach are evaluated by pathologists according to the updated Sydney System,20 and non-atrophic mucosa without H. pylori infection is graded with regard to glandular atrophy (0), intestinal metaplasia (0 or 1), mononuclear cells (0 or 1), neutrophils (0) and H. pylori density (0). The updated Sydney System recommends five biopsies: two from the antrum (3 cm from the pylorus, and greater and lesser curvatures), one from the incisure and two from the corpus (one from the lesser curvature 4 cm proximal to the incisure, and one from the middle
Figure 1 Endoscopic findings of a stomach specimen without Helicobacter pylori infection. (a) Antrum. (b) Body, lesser curvature. (c) Body, greater curvature. (d) Regular arrangement of collecting venules (RAC). There was no atrophic change in the mucosa. RAC are recognized at the mucosal surface (yellow arrows).
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21
34
1
35 14
Matsuo et al.31 2011 Japan
2011 South Korea
2012 Japan
Yoon et al.32
Ono et al.29
Fujisaki et al.30 2014 Japan
Yaita et al.33
PG I >70 ng/mL and PG I/II ratio > 3.0.
Negativity in three biopsy specimens (antrum GC, body GC, body LC) Negative for resected specimens Negativity in resected and biopsy specimens
Pathological findings
–
Negative serum Ab test
Clinical findings
Negative serum Ab test, negative UBT or RUT Negative culture (two 5.4 (34/627) – Negativity in four biopsy specimens), RUT specimens (antrum GC and LC, body GC, body LC) (two specimens) and serum Ab test Negative RUT, UBT, Negativity in five biopsy 0.42 (1/240) No atrophy culture and serum (Kimura-Takemoto specimens (antrum and Ab test body GC, LC, angulus LC) classification) 2.3 (36/1597) No atrophy Negativity in ESD specimens Negative UBT and serum Ab test Negative for resected or Negative RUT or UBT 1.31 (14/1065) No atrophy or serum Ab test (Kimura-Takemoto biopsy specimens classification)
–
–
0.66 (21/3161) No atrophy
3.11 (12/386)
2.0 (15/748)
Endoscopic findings
Diagnostic criteria Past history
–
Negative pattern
Negative pattern
Excluded severe atrophy‡
–
–
–
No eradication
No eradication
No eradication, no past infection
–
–
Negative pattern† No eradication
Serum pepsinogen test
PG I ≦ 30 ng/mL and PG I/II ratio ≦ 2.0. Ab, antibody; ESD, endoscopic submucosal dissection; GC, greater curvature; HpNGC, H. pylori-negative gastric cancer; LC, lesser curvature; pts, patients; RUT, rapid urease test; UBT, urease breath test.
‡
†
12
Kakinoki et al.9 2009 Japan
2014 Japan
15
2007 Japan
No. pts Prevalence (%)
Kato et al.8
Country
Year
Study
Table 1 Diagnostic criteria and prevalence of HpNGC
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of the greater curvature). This biopsy protocol generally correctly establishes H. pylori status and chronic gastritis. The endoscopic and pathological findings can diagnose not only current H. pylori infection, but also any past infection by evaluating atrophic change and intestinal metaplasia.18,21,22 By clinical methods, H. pylori negativity is confirmed by two or more tests, such as the urease breath test (UBT), serum or urine antibody test, stool antigen test and rapid urease test, because each test may give false negativity for H. pylori infection.23 Clinical methods can diagnose current infection of H. pylori; however, if the results are negative, we cannot distinguish between infection-naive cases and cases of past infection. Serum pepsinogens (PG) are related to atrophic changes in the gastric mucosa, and consist of pepsinogen I (PGI) and pepsinogen II (PGII).24,25 With the development of atrophic gastritis, both PGI and PGII may decrease, but PGI usually shows a more marked decrease than PGII. Thus, a low PGI level and a low PGI/II ratio are good indicators of atrophic changes in the gastric mucosa.26 Patients with PGI ≤70 and PGI/II ratio ≤3.0 are regarded as PG positive, which indicates the presence of atrophic gastritis.27 Patients with PGI >70 and PGI/II ratio >3.0 are regarded as PG negative, which indicates no atrophic change. Thus, measurement of serum PG levels is a non-invasive method for predicting atrophic gastritis. However, Ohkusa et al. reported that serum PG levels were improved after H. pylori eradication;28 serum PG levels in H. pylori-positive patients became similar to those in H. pylori-negative patients 12–15 months after eradication of the infection. As it may be difficult to completely refute past infection of H. pylori by the serum PG method, confirmation of H. pylori eradication history is necessary. Diagnostic criteria and prevalence of HpNGC that were previously reported are demonstrated in Table 1. There are two reports using a strict criteria for diagnosis of HpNGC.29,30
In the strict criteria, patients required assessment by endoscopic, pathological and two or more clinical methods, the serum pepsinogen test and determination of eradication history in order to accurately determine H. pylori negativity (Table 2). Prevalence of HpNGC was calculated as 0.42%29 and 2.3%.30 In addition, five other reports have shown that the prevalence of HpNGC ranges from 0.66% to 5.4%.8,9,31–33 Yoon et al. reported a HpNGC incidence rate of 5.4%,32 which was much higher than those of the other reports. They used serum PG level to evaluate mucosal atrophy and excluded only those with a severe atrophy pattern (PGI ≤30 and PGI/II ≤2.0) as indication of history of H. pylori infection. Therefore, some cases with a history of H. pylori infection showing mild atrophy may have been included. Further, the prevalence of HpNGC may vary according to geographical region, because all the other reports were from Japan whereas this study was done in South Korea. Kakinoki et al. reported a HpNGC prevalence of 3.11% which was the highest reported rate in Japan.9 They diagnosed HpNGC by resected specimens using only the updated Sydney System; thus, it is possible that cases with past infection were included. The other three reports from Japan did not met the strict criteria mentioned above, but the reported prevalence of HpNGC was 0.66%,31 1.31%,33 and 2.0%8 in these studies, which were very similar to the two reports that met the strict criteria (Table 1). From these results, patients may not be required to meet the strict criteria for an accurate diagnosis of HpNGC. We recommend the following minimum criteria for diagnosis of HpNGC based on the three reports (Table 2). The minimum criteria require negative findings in two or more methods that include endoscopic or pathological findings or serum PG test, and negative UBT or serum IgG test, as well as no eradication history. If the minimum criteria are met, the patient may be considered as negative for H. pylori infection.
Table 2 Criteria for diagnosis of HpNGC
Endoscopic findings Pathological findings (updated Sydney System) Serum pepsinogen test Clinical findings History of eradication of H. pylori
Strict criteria
Minimum criteria
No mucosal atrophy and RAC is recognized on mucosal surface Glandular atrophy (0), intestinal metaplasia (0 or 1), mononuclear cells (0), neutrophils (0), H. pylori density (0) Negative Negativity in two or more tests (e.g. RUT, UBT, serum IgG, stool antigen) None
Negative findings in two or more methods (endoscopic, pathological, serum pepsinogen test)
Negative UBT or serum IgG test None
HpNGC, H. pylori-negative gastric cancer; IgG, immunoglobulin G; RAC, regular arrangement of collecting venules; RUT, rapid urease test; UBT, urease breath test.
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In light of all these findings, we estimate that the prevalence of HpNGC is approximately 1% in Japan. The detection rate of gastric cancer by screening endoscopy is 0.45%.34 It may be difficult to detect HpNGC by screening endoscopy, but detection may be increased if the characteristics of HpNGC are well understood by endoscopists.
Etiology of HpNGC The etiology of gastric cancers, excluding those caused by H. pylori infection, is known to be associated with several factors including lifestyle, viral infection, autoimmune disorder and germline mutations. • Lifestyle, viral infection and autoimmune disorder Lifestyle factors include intake of salt-preserved food,35 smoking,36 hyperglycemia37 and low serum cholesterol level,38 although it is believed that not all of these factors can cause gastric cancer alone. Among viral infections, EBV is known to be associated with gastric cancer.39 EBV-associated gastric cancers morphologically resemble nasopharyngeal lymphoepithelioma; thus, they are named lymphoepithelioma-like carcinomas (LELC).40 EBV-positive LELC account for 1–4% of all gastric cancers.11,41 These lesions are commonly recognized as being of undifferentiated type (UD-type) of the upper body and have a lower rate of H. pylori infection than EBV-negative gastric cancers.42 However, most EBV-positive cancers are associated with atrophic gastritis,43 although this is not considered a single risk factor for HpNGC. Pernicious anemia (PA) is a type of autoimmune gastritis with atrophic change of the stomach body.44 Patients with
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PA are at an increased risk for gastric cancer.10 Although the prevalence of H. pylori infection in PA patients is very low in Japan,45 PA can be one of the causes of HpNGC. A recent meta-analysis showed that the overall relative risk of gastric cancer in patients with PA is 6.8 (95% CI: 2.6–18.1).46 However, as the incidence rate of gastric cancer is only 0.27% per person/year, PA may contribute only slightly to HpNGC. • Germline mutation and familial clustering In Western countries, 10% of gastric cancer patients show familial clustering suggestive of a genetic predisposition.12 Further, germline mutations in the CDH1 gene, which encodes the epithelial cell adhesion protein E-cadherin, is a wellknown cause of diffuse-type gastric cancer,47 and patients with hereditary diffuse gastric cancer (HDGC) also harbor germline mutations in the CDH1 gene.48 The lifetime cancer-specific risks associated with germline CDH1 mutations are thought to be >70% for gastric cancer and up to 40% for lobular breast cancer in women.49 Total gastrectomy is the recommended treatment option for CDH1 mutation carriers because signet ring-cell cancers associated with HDGC are multifocal and distributed throughout the entire stomach;50 pathological findings of the resected stomach demonstrate multiple small foci (≤4 mm) of signet ring-cell carcinoma in the gastric cardia and proximal fundus.51 According to previous studies, the detection rate of CDH1 germline mutations in Japanese patients with familial gastric cancer (FGC) was low compared with that in European patients.52,53 The difference in the detection rate may be due to differences in the analytical methods. Recently,
Table 3 Clinical characteristics of HpNGC Study
No. patients
Age, years (mean)
Gender (%)
Histology (%)
Tumor stage (%)
Kato et al.
15
63.5
M: 10 (66.7) F: 5 (33.3)
D-type: 5 (33.3) UD-type: 10 (66.7)
Early: 4 (26.7) Advanced: 10 (66.6) Unclear: 1 (6.7)
Kakinoki et al.9
12
64.9
Matsuo et al.31
21
56.5
Yoon et al.32
34
59.2
Ono et al.29 Fujisaki et al.30
1 35
– 57.2
D-type: 4 (33.3) UD-type: 8 (66.7) D-type: 7 (33.3) UD-type: 14 (66.7) D-type: 15 (44.1) UD-type: 19 (55.9) D-type: 1 (100) UD-type: 36† (100)
– Early: 17 (81.0) Advanced: 4 (19.0) Early: 15 (44.1) Advanced: 19 (55.9) Early: 1 (100) Early: 36† (100)
Yaita et al.33
14
59.3
M: 5 (41.7) F: 7 (58.3) M: 11 (52.4) F: 10 (47.6) M: 19 (55.9) F: 15 (44.1 – M: 19 (52.8) F: 16 (47.2) M: 10 (71.4) F: 4 (28.6)
D-type: 8 (57.1) UD-type: 6 (42.9)
Early: 8 (57.1) Advanced: 6 (42.9)
8
†
Only one patient out of 35 patients had two lesions.
D-type, differentiated type; HpNGC, H. pylori-negative gastric cancer; UD-type, undifferentiated type.
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Yamada et al. reported a Japanese FGC family with CDH1 germline mutations.54 They propose that screening for large germline rearrangements of CDH1 should be carried out by multiplex ligation-dependent probe amplification analysis. Further, the updated consensus guidelines for HDGC established by the International Gastric Cancer Linkage Consortium recommend that individuals with diffuse-type gastric cancer before the age of 40 years without a family history be included in the indication for genetic testing for CDH1 mutations.55 In the future, this type of testing may be required for juvenile patients with diffuse-type gastric cancer without H. pylori infection in Japan. Recently, a polymorphism in the prostate stem cell antigen (PSCA) gene was identified in a genome-wide association study in Japan as a genetic factor that is associated with predisposition to the sporadic form of diffuse-type gastric cancer; the odds ratio of genetic variation in PSCA was 1.62 for diffuse-type gastric cancer.56 However, although this study did not examine the association with H. pylori, they showed that the genetic variation in PSCA was not significantly correlated with intestinal-type gastric cancer, and the PSCA protein was predominantly localized to the isthmus of the gastric gland, which was considered as the presumed origin of diffuse-type gastric cancer.57 Interestingly, our data showed that most early HpNGC are of the UD-type (signet ring-cell carcinoma) which localize to the mucosal proliferative zone.30
Further studies are necessary to elucidate the association between UD-type gastric cancer without H. pylori infection and genetic variation in PSCA. Another germline aberration that is associated with gastric cancer is mutation of the adenomatous polyposis coli (APC) gene which causes familial adenomatous polyposis (FAP).58 Iwama et al. reported that the standardized mortality ratio of gastric cancer is 3.43, which is much lower than those of duodenal/small intestine and colorectal cancers (250 and 210, respectively).59 However, the mean age at death of gastric cancer in FAP patients is 48.3 ± 13.9 years old, which is dramatically lower than the mean age at death (73 years in 2000) of gastric cancer in the Japanese.60 Thus, periodic gastroduodenal screening endoscopy is recommended for patients with FAP.61 Recently, Ueyama et al. reported gastric adenocarcinoma of the fundic gland (chief cell predominant type, GA-FG-CCP) as a new entity of gastric cancer.62 They defined GA-FGCCP as a differentiated-type (D-type) adenocarcinoma with chief cell differentiation that is positively stained for pepsinogen I. GA-FG-CCP is thought to arise from the deeper zone of the gastric mucosa without chronic gastritis, atrophic change and intestinal metaplasia. Although this type of tumor is rare, the prevalence is 1.6% of all gastric cancers,63 it is attracting attention because it is classified a type of HpNGC. Ueyama et al. described GA-FG-CCP as a low-grade
Figure 2 Undifferentiated-type early gastric cancer (GC). The patient was a 36-year-old man. He had no symptoms and was detected with early GC by screening endoscopy. (a, b) There was no Helicobacter pylori infection in the stomach. (c) The lesion is slightly discolored, depressed and located at the upper body greater curvature (yellow arrows). Lesion size is 11 mm. (d) He underwent endoscopic submucosal dissection, and pathological findings revealed signet ring-cell carcinoma that was limited to the mucosal layer.
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Figure 3 Gastric cancer (GC) of fundic gland type. The patient was a 62-yearold man. He had no symptoms and was detected with early GC by screening endoscopy. (a,b) There was no Helicobacter pylori infection in the stomach. (c) The lesion is whitish, slightly depressed and located in the gastric cardia posterior wall. Dilated vessels are seen on the surface of the lesion (yellow arrows). Lesion size is 10 mm. (d) He underwent endoscopic submucosal dissection, and pathological findings revealed adenocarcinoma of the fundic gland type that was limited to the mucosal layer.
malignancy despite its ability to invade downward into the submucosal layer because none of the patients died or suffered recurrence during the follow-up period.62 However, highgrade malignant cases of GA-FG-CCP with vascular invasion have been reported.63,64 Hidaka et al. suggested that GA-FGCCP is associated with activation of the Wnt/β-catenin pathway because the tumors are characterized by nuclear β-catenin accumulation and mutation of the CTNNB1 or AXIN gene.63 The etiology of HpNGC is still not well understood, and further progress to validate germline mutations as a cause of HpNGC is expected in the future.
Patient characteristics and endoscopic findings of HpNGC Some reports have described the characteristics of HpNGC, but because of the rarity of HpNGC, they obtained data from only a small number of patients.8,9,29–33 Table 3 shows a compilation of the reported clinical characteristics. In four of these reports, the mean age was under 60 years, which is relatively young. There appeared to be no gender difference, as some reports showed that the male to female ratio was almost 1. Regarding the histology, the UD-type was the most common, and early-stage cancer was more frequent than advanced cancer because patients who underwent endoscopic resection
were included. We have previously reported that most HpNGC present as discolored and depressed tumors in the lower and mid body of the stomach, and the predominant histological type is signet ring-cell carcinoma (Fig. 2).30 Now, the standard treatment for early UD-type gastric cancer is surgery with lymph node dissection. If such lesions are detected in the early stage, such as mucosal tumors that measure ≤20 mm without ulceration, endoscopic submucosal dissection (ESD) can be carried out as clinical research to preserve the patient’s quality of life.65 In contrast, Yaita et al. reported that the main histological type in eight of 14 HpNGC was the D-type, and five of the eight lesions were GA-FG-CCP.33 Ueyama et al. also reported 10 patients with GA-GF-CCP,66 and the mean age was 66.6 years which was relatively high compared to the patients with UD-type. Six of these 10 lesions were located in the upper stomach, and the other 4 lesions were in the mid stomach, whereas there was no lesion in the lower stomach. GA-FGCCP was classified into two categories: submucosal tumor (60%) and flat or depressed type (40%). The most common endoscopic findings were submucosal tumor (60%), whitish color (70%), dilated vessels with branching architecture (50%) and background mucosa without atrophic change (90%) (Fig. 3). Also, incidental D-type gastric cancer without H. pylori infection is very rare, but some cases have been reported.8,9,29
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Figure 4 Gastric cancer (GC) associated with pernicious anemia (PA). The patient was a 54-year-old man who was diagnosed with PA 5 years prior. He was detected with early GC during follow-up endoscopy for PA. (a,b) His stomach had atrophic change only in the stomach body without Helicobacter pylori infection. (c) The lesion was slightly depressed and located at the antrum greater curvature (yellow arrows). (d) He underwent endoscopic submucosal dissection, and pathological findings revealed signet ring-cell carcinoma that was limited to the mucosal layer.
Figure 5 Gastric cancer (GC) associated with familial adenomatous polyposis (FAP). The patient was a 40year-old woman. She was diagnosed with FAP 2 years prior. She was detected with early GC during followup endoscopy for FAP. (a,b) There was no Helicobacter pylori infection in her stomach. (b) Multiple fundic gland polyps are seen in her stomach. (c) The lesion is whitish, slightly depressed and located at the upper body greater curvature (yellow arrows). Lesion size is 24 mm. (d) She underwent endoscopic submucosal dissection, and pathological findings revealed welldifferentiated adenocarcinoma that was limited to the mucosal layer.
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Table 4 Endoscopic findings of HpNGC
CONFLICTS OF INTEREST
Signet ring-cell carcinoma
A
Gastric adenocarcinoma of the fundic gland type
Others
Tumors present as discolored lesions in the lower or middle part of the stomach in relatively young patients. Predominant gross type is flat or depressed. Lesions are usually located in the middle and upper part of the stomach in relatively older patients. Predominant gross type is submucosal tumor-like or flat or depressed. Lesions include GC of intestinal type and GC associated with PA, FAP and HDGC.
FAP, familial adenomatous polyposis; GC, gastric cancer; HDGC, hereditary diffuse gastric cancer; HpNGC, H. pylori-negative gastric cancer; PA, pernicious anemia.
Other gastric cancers include those associated with PA, FAP and HDGC. We show early gastric cancer lesions that occurred in patients with PA (Fig. 4) and FAP (Fig. 5). Both patients had no active or history of H. pylori infection. The lesions were completely removed by ESD which circumvented the need for gastrectomy. Such lesions are rare in Japan; however, the patient’s history should be clearly obtained before endoscopic examination for detection of early-stage gastric cancer. Finally, we summarized the endoscopic findings of HpNGC in Table 4.
CONCLUSION HE PREVALENCE OF HpNGC is thought to be approximately 1%. However, it is expected that the prevalence of HpNGC may become relatively higher in the future with the decline in H. pylori infection. At our institute, some patients were detected with HpNGC by surveillance endoscopy. Early detection of gastric cancer enables the performance of ESD as a minimally invasive treatment to preserve the patient’s quality of life. However, the etiology and clinical course of HpNGC are still unclear; thus, further studies are required to verify and broaden our understanding of them. In order to accurately diagnose and assess HpNGC, endoscopists should fully understand the characteristics and endoscopic findings. We expect that the present review of HpNGC will aid endoscopists in detecting lesions during routine examination in patients without H. pylori infection.
T
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UTHORS DECLARE NO conflicts of interest for this article.
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15 Yagi K, Aruga Y, Nakamura A, Sekine A. Regular arrangement of collecting venules (RAC): a characteristic endoscopic feature of Helicobacter pylori-negative normal stomach and its relationship with esophago-gastric adenocarcinoma. J. Gastroenterol. 2005; 40: 443–52. 16 Kimura K, Takemoto T. An endoscopic recognition of the atrophic border and its significance in chronic gastritis. Endoscopy 1969; 3: 87–97. 17 Takao T, Ishikawa T, Ando T et al. Multifaceted assessment of chronic gastritis: a study of correlations between serological, endoscopic, and histological diagnostics. Gastroenterol. Res. Pract. 2011; 2011: 631461. 18 Watanabe K, Nagata N, Nakashima R et al. Predictive findings for Helicobacter pylori-uninfected, -infected and -eradicated gastric mucosa: validation study. World J. Gastroenterol. 2013; 19: 4374–9. 19 Dinis-Ribeiro M, Areia M, de Vries AC et al. Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy 2012; 44: 74–94. 20 Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am. J. Surg. Pathol. 1996; 20: 1161–81. 21 Nagata N, Shimbo T, Akiyama J et al. Predictability of gastric intestinal metaplasia by mottled patchy erythema seen on endoscopy. Gastroenterol. Res. 2011; 4: 203–9. 22 Toyokawa T, Suwaki K, Miyake Y, Nakatsu M. Eradication of Helicobacter pylori infection improved gastric mucosal atrophy and prevented progression of intestinal metaplasia, especially in the elderly population: a long-term prospective cohort study. J. Gastroenterol. Hepatol. 2010; 25: 544–7. 23 Vaira D, Holton J, Menegatti M et al. Review article: invasive and non-invasive tests for Helicobacter pylori infection. Aliment. Pharmacol. Ther. 2000; 14 (Suppl 3): 13–22. 24 Bock OA, Arapakis G, Witts LJ, Richards WS. The serum pepsinogen level with special reference to the histology of the gastric mucosa. Gut 1963; 4: 106–11. 25 Stemmermann GN, Samloff IM, Nomura AM, Heilbrun LK. Serum pepsinogens I and II and stomach cancer. Clin. Chim. Acta 1987; 163: 191–8. 26 Miki K, Ichinose M, Ishikawa KB et al. Clinical application of serum pepsinogen I and II levels for mass screening to detect gastric cancer. Jpn. J. Cancer Res. 1993; 84: 1086–90. 27 Kitahara F, Kobayashi K, Sato T, Kojima Y, Araki T, Fujino MA. Accuracy of screening for gastric cancer using serum pepsinogen concentrations. Gut 1999; 44: 693–7. 28 Ohkusa T, Miwa H, Nomura T et al. Improvement in serum pepsinogens and gastrin in long-term monitoring after eradication of Helicobacter pylori: comparison with H. pylorinegative patients. Aliment. Pharmacol. Ther. 2004; 20 (Suppl 1): 25–32.
29 Ono S, Kato M, Suzuki 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. 30 Fujisaki J, Yamamoto N, Horiuchi Y et al. Characteristic endoscopic findings of Helicobacter pylori-negative early gastric undifferentiated adenocarcinoma. Stomach Intestine 2014; 49: 854–61. 31 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. 32 Yoon H, Kim N, Lee HS et al. Helicobacter pylori-negative gastric cancer in South Korea: incidence and clinicopathologic characteristics. Helicobacter 2011; 16: 382–8. 33 Yaita H, Kurahara K, Kawasaki K et al. Clinicopathological features of Helicobacter pylori-negative gastric cancer. Stomach Intestine 2014; 49: 863–73. 34 Nakashima H, Nagahama R, Yamamoto T, Ohkura Y. Mass screening for gastric cancer: how to select patients for endoscopic examination. Gastric Cancer 2010; 13: 78–83. 35 Joossens JV, Hill MJ, Elliott P et al. Dietary salt, nitrate and stomach cancer mortality in 24 countries. European Cancer Prevention (ECP) and the INTERSALT Cooperative Research Group. Int. J. Epidemiol. 1996; 25: 494–504. 36 La Torre G, Chiaradia G, Gianfagna F et al. Smoking status and gastric cancer risk: an updated meta-analysis of case–control studies published in the past ten years. Tumori 2009; 95: 13–22. 37 Ikeda F, Doi Y, Yonemoto K et al. Hyperglycemia increases risk of gastric cancer posed by Helicobacter pylori infection: a populationbased cohort study. Gastroenterology 2009; 136: 1234–41. 38 Asano K, Kubo M, Yonemoto K et al. Impact of serum total cholesterol on the incidence of gastric cancer in a populationbased prospective study: the Hisayama study. Int. J. Cancer 2008; 122: 909–14. 39 Burke AP, Yen TS, Shekitka KM, Sobin LH. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod. Pathol. 1990; 3: 377–80. 40 Anagnostopoulos I, Hummel M. Epstein-Barr virus in tumours. Histopathology 1996; 29: 297–315. 41 Nakamura S, Ueki T, Yao T, Ueyama T, Tsuneyoshi M. EpsteinBarr virus in gastric carcinoma with lymphoid stroma. Special reference to its detection by the polymerase chain reaction and in situ hybridization in 99 tumors, including a morphologic analysis. Cancer 1994; 73: 2239–49. 42 Wu MS, Shun CT, Wu CC et al. Epstein-Barr virus-associated gastric carcinomas: relation to H. pylori infection and genetic alterations. Gastroenterology 2000; 118: 1031–8. 43 Yanai H, Murakami T, Yoshiyama H et al. Epstein-Barr virusassociated gastric carcinoma and atrophic gastritis. J. Clin. Gastroenterol. 1999; 29: 39–43. 44 Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N. Engl. J. Med. 1997; 337: 1441–8. 45 Haruma K, Komoto K, Kawaguchi H et al. Pernicious anemia and Helicobacter pylori infection in Japan: evaluation in a country
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with a high prevalence of infection. Am. J. Gastroenterol. 1995; 90: 1107–10. Vannella L, Lahner E, Osborn J, Annibale B. Systematic review: gastric cancer incidence in pernicious anaemia. Aliment. Pharmacol. Ther. 2013; 37: 375–82. Oda T, Kanai Y, Oyama T et al. E-cadherin gene mutations in human gastric carcinoma cell lines. Proc. Natl Acad. Sci. USA 1994; 91: 1858–62. Guilford P, Hopkins J, Harraway J et al. E-cadherin germline mutations in familial gastric cancer. Nature 1998; 392: 402–5. Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001; 121: 1348–53. Norton JA, Ham CM, Van Dam J et al. CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer. Ann. Surg. 2007; 245: 873–9. Fujita H, Lennerz JK, Chung DC et al. Endoscopic surveillance of patients with hereditary diffuse gastric cancer: biopsy recommendations after topographic distribution of cancer foci in a series of 10 CDH1 mutated gastrectomies. Am. J. Surg. Pathol. 2012; 36: 1709–17. Iida S, Akiyama Y, Ichikawa W et al. Infrequent germ-line mutation of the E-cadherin gene in Japanese familial gastric cancer kindreds. Clin. Cancer Res. 1999; 5: 1445–7. Shinmura K, Kohno T, Takahashi M et al. Familial gastric cancer: clinicopathological characteristics, RER phenotype and germline p53 and E-cadherin mutations. Carcinogenesis 1999; 20: 1127–31. Yamada H, Shinmura K, Ito H et al. Germline alterations in the CDH1 gene in familial gastric cancer in the Japanese population. Cancer Sci. 2011; 102: 1782–8. Fitzgerald RC, Hardwick R, Huntsman D et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J. Med. Genet. 2010; 47: 436–44. Sakamoto H, Yoshimura K, Saeki N et al. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat. Genet. 2008; 40: 730–40.
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57 Taki K, Kuwabara N. Studies on histogenesis of the gastric carcinoma using minute cancers. Pathol. Res. Pract. 1981; 172: 176–90. 58 Wood LD, Salaria SN, Cruise MW, Giardiello FM, Montgomery EA. Upper GI tract lesions in familial adenomatous polyposis (FAP): enrichment of pyloric gland adenomas and other gastric and duodenal neoplasms. Am. J. Surg. Pathol. 2014; 38: 389–93. 59 Iwama T, Mishima Y, Utsunomiya J. The impact of familial adenomatous polyposis on the tumorigenesis and mortality at the several organs. Its rational treatment. Ann. Surg. 1993; 217: 101–8. 60 Inoue M, Tsugane S. Epidemiology of gastric cancer in Japan. Postgrad. Med. J. 2005; 81: 419–24. 61 Shibata C, Ogawa H, Miura K, Naitoh T, Yamauchi J, Unno M. Clinical characteristics of gastric cancer in patients with familial adenomatous polyposis. Tohoku J. Exp. Med. 2013; 229: 143–6. 62 Ueyama H, Yao T, Nakashima Y et al. Gastric adenocarcinoma of fundic gland type (chief cell predominant type): proposal for a new entity of gastric adenocarcinoma. Am. J. Surg. Pathol. 2010; 34: 609–19. 63 Hidaka Y, Mitomi H, Saito T et al. Alteration in the Wnt/betacatenin signaling pathway in gastric neoplasias of fundic gland (chief cell predominant) type. Hum. Pathol. 2013; 44: 2438–48. 64 Yao T, Ueyama H, Ueo T, Hidaka Y, Nomura R. Two types of neoplasia in fundic-gland mucosa without Helicobacter pylori infection: Gastric carcinoma and polyp with dysplasia. Stomach Intestine 2014; 49: 874–80. 65 Yamamoto Y, Fujisaki J, Hirasawa T et al. Therapeutic outcomes of endoscopic submucosal dissection of undifferentiated-type intramucosal gastric cancer without ulceration and preoperatively diagnosed as 20 millimetres or less in diameter. Dig. Endosc. 2010; 22: 112–8. 66 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.
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Review
Helicobacter pylori-negative gastric cancer: Characteristics and endoscopic findings Yorimasa Yamamoto, Junko Fujisaki, Masami Omae, Toshiaki Hirasawa and Masahiro Igarashi Division of Gastroenterology, Cancer Institute Hospital, Tokyo, Japan Helicobacter pylori (H. pylori) leads to chronic gastritis and eventually causes gastric cancer. The prevalence of H. pylori infection is gradually decreasing with improvement of living conditions and eradication therapy. However, some reports have described cases of H. pylori-negative gastric cancers (HpNGC), and the prevalence was 0.42–5.4% of all gastric cancers. Diagnostic criteria of HpNGC vary among the different reports; thus, they have not yet been definitively established. We recommend negative findings in two or more methods that include endoscopic or pathological findings or serum pepsinogen test, and negative urease breath test or serum immunoglobulin G test and no eradication history the minimum criteria for diagnosis of HpNGC. The etiology of gastric cancers, excluding H. pylori infection, is known to be associated with several factors including lifestyle, viral infection, autoimmune disorder and germline mutations, but the main causal factor of HpNGC is still unclear. Regarding the characteristics of HpNGC,
the undifferentiated type (UD-type) is more frequent than the differentiated type (D-type). The UD-type is mainly signet ring-cell carcinoma that presents as a discolored lesion in the lower or middle part of the stomach in relatively young patients. The gross type is flat or depressed. The D-type is mainly gastric adenocarcinoma of the fundic gland type that presents as a submucosal tumor-like or flat or depressed lesion in the middle and upper part of the stomach in relatively older patients. Early detection of HpNGC enables minimally invasive treatment which preserves the patient’s quality of life. Endoscopists should fully understand the characteristics and endoscopic findings of HpNGC.
INTRODUCTION
cancer in one-third of patients.5 Due to the results of these studies, eradication therapy of H. pylori became covered by the Japanese national health insurance in 2013 and was given extensively to patients infected with H. pylori. Thus, a combination of extensive eradication therapy and improvement of living conditions and sanitation has led to the recent decrease in the prevalence of H. pylori infection,6 and the mortality rate of gastric cancer in the last decade has declined 3–4% per year in Japan.7 In contrast, some recent reports have described the occurrence of gastric cancer in patients without H. pylori infection, also referred to as H. pylori-negative gastric cancer (HpNGC).8,9 Other gastric cancers, which are not associated with H. pylori infection, have been reported as lesions related to autoimmune gastritis,10 Epstein-Barr virus (EBV) infection11 and genetic factors.12 Some gastric cardia cancers are not associated with H. pylori, and the incidence is increasing in Western countries.13 In Japan, there is an increasing trend in the rate of adenocarcinoma of the esophagogastric junction (EGJ).14 EGJ cancers include some HpNGC, but as the differentiation between some HpNGC and Barrett’s esophageal cancer is often difficult, we opted
CCORDING TO THE report by the International Agency for Research on Cancer, gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, with an incidence of one million people per year.1 Helicobacter pylori (H. pylori) was discovered as a pathogen of gastroduodenal ulcers in 1983.2 World Health Organization certified H. pylori as a definite carcinogen in 1994.3 It is well known that H. pylori leads to chronic gastritis by persistent infection of the stomach and eventually causes gastric cancer. According to a prospective cohort study by Uemura et al., gastric cancer occurs only in patients with H. pylori infection, but not in those without H. pylori infection.4 Fukase et al. showed in another prospective study that eradication of H. pylori reduced the incidence of metachronous gastric
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Corresponding: Yorimasa Yamamoto, Division of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135–8550, Japan. Email: [email protected] Received 30 July 2014; accepted 12 March 2015.
Key words: endoscopic finding, gastric adenocarcinoma of the fundic gland type, Helicobacter pylori-negative gastric cancer, signet ring-cell carcinoma, undifferentiated-type gastric cancer
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to exclude the discussion on EGJ cancers in the present review. In the near future, although the prevalence of all gastric cancers will continue to decrease with a decline in H. pylori infection, the frequency of HpNGC may relatively increase. At present, the diagnostic criteria, prevalence, etiology, patient characteristics and endoscopic findings of HpNGC are still unclear. In this review, we will introduce and discuss some recent studies on HpNGC, and present some representative lesions.
Diagnostic criteria and prevalence of HpNGC HpNGC is an adenocarcinoma that occurs in the stomach without active or previous H. pylori infection. There are some diagnostic methods and tests for H. pylori infection that can be divided into three categories: endoscopic, pathological and clinical methods. By endoscopic diagnosis, lack of mucosal atrophy and presence of regular arrangement of collecting venules on the mucosal surface of the antrum denote H. pylori negativity15 (Fig. 1). In Japan, the Kimura-Takemoto classification is generally used for the evaluation of mucosal atrophy using conventional endoscopy.16 The endoscopic features of mucosal atrophy are characterized by differences in both color and niveau of the mucosa, and the capillary network is visible
in the atrophic mucosa. By using this classification, we can determine the degree of mucosal atrophy. Further, the Kimura-Takemoto endoscopic classification correlates with histological findings and serum pepsinogen level in the evaluation of atrophy.17 In addition, Watanabe et al. reported linear erythema, hemorrhage and fundic gland polyp as other endoscopic findings of H. pylori negativity, and atrophic change as well as mottled patchy erythema as endoscopic findings of H. pylori-eradicated mucosa.18 Thus, endoscopic findings are useful for determining H. pylori infection status in Japan. However, according to guidelines from Western countries, conventional endoscopy cannot be relied upon to correctly identify patients with atrophy or intestinal metaplasia; thus, the inclusion of gastric biopsy during diagnostic endoscopy is recommended.19 By pathological methods, biopsy specimens taken from the stomach are evaluated by pathologists according to the updated Sydney System,20 and non-atrophic mucosa without H. pylori infection is graded with regard to glandular atrophy (0), intestinal metaplasia (0 or 1), mononuclear cells (0 or 1), neutrophils (0) and H. pylori density (0). The updated Sydney System recommends five biopsies: two from the antrum (3 cm from the pylorus, and greater and lesser curvatures), one from the incisure and two from the corpus (one from the lesser curvature 4 cm proximal to the incisure, and one from the middle
Figure 1 Endoscopic findings of a stomach specimen without Helicobacter pylori infection. (a) Antrum. (b) Body, lesser curvature. (c) Body, greater curvature. (d) Regular arrangement of collecting venules (RAC). There was no atrophic change in the mucosa. RAC are recognized at the mucosal surface (yellow arrows).
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21
34
1
35 14
Matsuo et al.31 2011 Japan
2011 South Korea
2012 Japan
Yoon et al.32
Ono et al.29
Fujisaki et al.30 2014 Japan
Yaita et al.33
PG I >70 ng/mL and PG I/II ratio > 3.0.
Negativity in three biopsy specimens (antrum GC, body GC, body LC) Negative for resected specimens Negativity in resected and biopsy specimens
Pathological findings
–
Negative serum Ab test
Clinical findings
Negative serum Ab test, negative UBT or RUT Negative culture (two 5.4 (34/627) – Negativity in four biopsy specimens), RUT specimens (antrum GC and LC, body GC, body LC) (two specimens) and serum Ab test Negative RUT, UBT, Negativity in five biopsy 0.42 (1/240) No atrophy culture and serum (Kimura-Takemoto specimens (antrum and Ab test body GC, LC, angulus LC) classification) 2.3 (36/1597) No atrophy Negativity in ESD specimens Negative UBT and serum Ab test Negative for resected or Negative RUT or UBT 1.31 (14/1065) No atrophy or serum Ab test (Kimura-Takemoto biopsy specimens classification)
–
–
0.66 (21/3161) No atrophy
3.11 (12/386)
2.0 (15/748)
Endoscopic findings
Diagnostic criteria Past history
–
Negative pattern
Negative pattern
Excluded severe atrophy‡
–
–
–
No eradication
No eradication
No eradication, no past infection
–
–
Negative pattern† No eradication
Serum pepsinogen test
PG I ≦ 30 ng/mL and PG I/II ratio ≦ 2.0. Ab, antibody; ESD, endoscopic submucosal dissection; GC, greater curvature; HpNGC, H. pylori-negative gastric cancer; LC, lesser curvature; pts, patients; RUT, rapid urease test; UBT, urease breath test.
‡
†
12
Kakinoki et al.9 2009 Japan
2014 Japan
15
2007 Japan
No. pts Prevalence (%)
Kato et al.8
Country
Year
Study
Table 1 Diagnostic criteria and prevalence of HpNGC
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of the greater curvature). This biopsy protocol generally correctly establishes H. pylori status and chronic gastritis. The endoscopic and pathological findings can diagnose not only current H. pylori infection, but also any past infection by evaluating atrophic change and intestinal metaplasia.18,21,22 By clinical methods, H. pylori negativity is confirmed by two or more tests, such as the urease breath test (UBT), serum or urine antibody test, stool antigen test and rapid urease test, because each test may give false negativity for H. pylori infection.23 Clinical methods can diagnose current infection of H. pylori; however, if the results are negative, we cannot distinguish between infection-naive cases and cases of past infection. Serum pepsinogens (PG) are related to atrophic changes in the gastric mucosa, and consist of pepsinogen I (PGI) and pepsinogen II (PGII).24,25 With the development of atrophic gastritis, both PGI and PGII may decrease, but PGI usually shows a more marked decrease than PGII. Thus, a low PGI level and a low PGI/II ratio are good indicators of atrophic changes in the gastric mucosa.26 Patients with PGI ≤70 and PGI/II ratio ≤3.0 are regarded as PG positive, which indicates the presence of atrophic gastritis.27 Patients with PGI >70 and PGI/II ratio >3.0 are regarded as PG negative, which indicates no atrophic change. Thus, measurement of serum PG levels is a non-invasive method for predicting atrophic gastritis. However, Ohkusa et al. reported that serum PG levels were improved after H. pylori eradication;28 serum PG levels in H. pylori-positive patients became similar to those in H. pylori-negative patients 12–15 months after eradication of the infection. As it may be difficult to completely refute past infection of H. pylori by the serum PG method, confirmation of H. pylori eradication history is necessary. Diagnostic criteria and prevalence of HpNGC that were previously reported are demonstrated in Table 1. There are two reports using a strict criteria for diagnosis of HpNGC.29,30
In the strict criteria, patients required assessment by endoscopic, pathological and two or more clinical methods, the serum pepsinogen test and determination of eradication history in order to accurately determine H. pylori negativity (Table 2). Prevalence of HpNGC was calculated as 0.42%29 and 2.3%.30 In addition, five other reports have shown that the prevalence of HpNGC ranges from 0.66% to 5.4%.8,9,31–33 Yoon et al. reported a HpNGC incidence rate of 5.4%,32 which was much higher than those of the other reports. They used serum PG level to evaluate mucosal atrophy and excluded only those with a severe atrophy pattern (PGI ≤30 and PGI/II ≤2.0) as indication of history of H. pylori infection. Therefore, some cases with a history of H. pylori infection showing mild atrophy may have been included. Further, the prevalence of HpNGC may vary according to geographical region, because all the other reports were from Japan whereas this study was done in South Korea. Kakinoki et al. reported a HpNGC prevalence of 3.11% which was the highest reported rate in Japan.9 They diagnosed HpNGC by resected specimens using only the updated Sydney System; thus, it is possible that cases with past infection were included. The other three reports from Japan did not met the strict criteria mentioned above, but the reported prevalence of HpNGC was 0.66%,31 1.31%,33 and 2.0%8 in these studies, which were very similar to the two reports that met the strict criteria (Table 1). From these results, patients may not be required to meet the strict criteria for an accurate diagnosis of HpNGC. We recommend the following minimum criteria for diagnosis of HpNGC based on the three reports (Table 2). The minimum criteria require negative findings in two or more methods that include endoscopic or pathological findings or serum PG test, and negative UBT or serum IgG test, as well as no eradication history. If the minimum criteria are met, the patient may be considered as negative for H. pylori infection.
Table 2 Criteria for diagnosis of HpNGC
Endoscopic findings Pathological findings (updated Sydney System) Serum pepsinogen test Clinical findings History of eradication of H. pylori
Strict criteria
Minimum criteria
No mucosal atrophy and RAC is recognized on mucosal surface Glandular atrophy (0), intestinal metaplasia (0 or 1), mononuclear cells (0), neutrophils (0), H. pylori density (0) Negative Negativity in two or more tests (e.g. RUT, UBT, serum IgG, stool antigen) None
Negative findings in two or more methods (endoscopic, pathological, serum pepsinogen test)
Negative UBT or serum IgG test None
HpNGC, H. pylori-negative gastric cancer; IgG, immunoglobulin G; RAC, regular arrangement of collecting venules; RUT, rapid urease test; UBT, urease breath test.
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H. pylori-negative gastric cancer
In light of all these findings, we estimate that the prevalence of HpNGC is approximately 1% in Japan. The detection rate of gastric cancer by screening endoscopy is 0.45%.34 It may be difficult to detect HpNGC by screening endoscopy, but detection may be increased if the characteristics of HpNGC are well understood by endoscopists.
Etiology of HpNGC The etiology of gastric cancers, excluding those caused by H. pylori infection, is known to be associated with several factors including lifestyle, viral infection, autoimmune disorder and germline mutations. • Lifestyle, viral infection and autoimmune disorder Lifestyle factors include intake of salt-preserved food,35 smoking,36 hyperglycemia37 and low serum cholesterol level,38 although it is believed that not all of these factors can cause gastric cancer alone. Among viral infections, EBV is known to be associated with gastric cancer.39 EBV-associated gastric cancers morphologically resemble nasopharyngeal lymphoepithelioma; thus, they are named lymphoepithelioma-like carcinomas (LELC).40 EBV-positive LELC account for 1–4% of all gastric cancers.11,41 These lesions are commonly recognized as being of undifferentiated type (UD-type) of the upper body and have a lower rate of H. pylori infection than EBV-negative gastric cancers.42 However, most EBV-positive cancers are associated with atrophic gastritis,43 although this is not considered a single risk factor for HpNGC. Pernicious anemia (PA) is a type of autoimmune gastritis with atrophic change of the stomach body.44 Patients with
555
PA are at an increased risk for gastric cancer.10 Although the prevalence of H. pylori infection in PA patients is very low in Japan,45 PA can be one of the causes of HpNGC. A recent meta-analysis showed that the overall relative risk of gastric cancer in patients with PA is 6.8 (95% CI: 2.6–18.1).46 However, as the incidence rate of gastric cancer is only 0.27% per person/year, PA may contribute only slightly to HpNGC. • Germline mutation and familial clustering In Western countries, 10% of gastric cancer patients show familial clustering suggestive of a genetic predisposition.12 Further, germline mutations in the CDH1 gene, which encodes the epithelial cell adhesion protein E-cadherin, is a wellknown cause of diffuse-type gastric cancer,47 and patients with hereditary diffuse gastric cancer (HDGC) also harbor germline mutations in the CDH1 gene.48 The lifetime cancer-specific risks associated with germline CDH1 mutations are thought to be >70% for gastric cancer and up to 40% for lobular breast cancer in women.49 Total gastrectomy is the recommended treatment option for CDH1 mutation carriers because signet ring-cell cancers associated with HDGC are multifocal and distributed throughout the entire stomach;50 pathological findings of the resected stomach demonstrate multiple small foci (≤4 mm) of signet ring-cell carcinoma in the gastric cardia and proximal fundus.51 According to previous studies, the detection rate of CDH1 germline mutations in Japanese patients with familial gastric cancer (FGC) was low compared with that in European patients.52,53 The difference in the detection rate may be due to differences in the analytical methods. Recently,
Table 3 Clinical characteristics of HpNGC Study
No. patients
Age, years (mean)
Gender (%)
Histology (%)
Tumor stage (%)
Kato et al.
15
63.5
M: 10 (66.7) F: 5 (33.3)
D-type: 5 (33.3) UD-type: 10 (66.7)
Early: 4 (26.7) Advanced: 10 (66.6) Unclear: 1 (6.7)
Kakinoki et al.9
12
64.9
Matsuo et al.31
21
56.5
Yoon et al.32
34
59.2
Ono et al.29 Fujisaki et al.30
1 35
– 57.2
D-type: 4 (33.3) UD-type: 8 (66.7) D-type: 7 (33.3) UD-type: 14 (66.7) D-type: 15 (44.1) UD-type: 19 (55.9) D-type: 1 (100) UD-type: 36† (100)
– Early: 17 (81.0) Advanced: 4 (19.0) Early: 15 (44.1) Advanced: 19 (55.9) Early: 1 (100) Early: 36† (100)
Yaita et al.33
14
59.3
M: 5 (41.7) F: 7 (58.3) M: 11 (52.4) F: 10 (47.6) M: 19 (55.9) F: 15 (44.1 – M: 19 (52.8) F: 16 (47.2) M: 10 (71.4) F: 4 (28.6)
D-type: 8 (57.1) UD-type: 6 (42.9)
Early: 8 (57.1) Advanced: 6 (42.9)
8
†
Only one patient out of 35 patients had two lesions.
D-type, differentiated type; HpNGC, H. pylori-negative gastric cancer; UD-type, undifferentiated type.
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Yamada et al. reported a Japanese FGC family with CDH1 germline mutations.54 They propose that screening for large germline rearrangements of CDH1 should be carried out by multiplex ligation-dependent probe amplification analysis. Further, the updated consensus guidelines for HDGC established by the International Gastric Cancer Linkage Consortium recommend that individuals with diffuse-type gastric cancer before the age of 40 years without a family history be included in the indication for genetic testing for CDH1 mutations.55 In the future, this type of testing may be required for juvenile patients with diffuse-type gastric cancer without H. pylori infection in Japan. Recently, a polymorphism in the prostate stem cell antigen (PSCA) gene was identified in a genome-wide association study in Japan as a genetic factor that is associated with predisposition to the sporadic form of diffuse-type gastric cancer; the odds ratio of genetic variation in PSCA was 1.62 for diffuse-type gastric cancer.56 However, although this study did not examine the association with H. pylori, they showed that the genetic variation in PSCA was not significantly correlated with intestinal-type gastric cancer, and the PSCA protein was predominantly localized to the isthmus of the gastric gland, which was considered as the presumed origin of diffuse-type gastric cancer.57 Interestingly, our data showed that most early HpNGC are of the UD-type (signet ring-cell carcinoma) which localize to the mucosal proliferative zone.30
Further studies are necessary to elucidate the association between UD-type gastric cancer without H. pylori infection and genetic variation in PSCA. Another germline aberration that is associated with gastric cancer is mutation of the adenomatous polyposis coli (APC) gene which causes familial adenomatous polyposis (FAP).58 Iwama et al. reported that the standardized mortality ratio of gastric cancer is 3.43, which is much lower than those of duodenal/small intestine and colorectal cancers (250 and 210, respectively).59 However, the mean age at death of gastric cancer in FAP patients is 48.3 ± 13.9 years old, which is dramatically lower than the mean age at death (73 years in 2000) of gastric cancer in the Japanese.60 Thus, periodic gastroduodenal screening endoscopy is recommended for patients with FAP.61 Recently, Ueyama et al. reported gastric adenocarcinoma of the fundic gland (chief cell predominant type, GA-FG-CCP) as a new entity of gastric cancer.62 They defined GA-FGCCP as a differentiated-type (D-type) adenocarcinoma with chief cell differentiation that is positively stained for pepsinogen I. GA-FG-CCP is thought to arise from the deeper zone of the gastric mucosa without chronic gastritis, atrophic change and intestinal metaplasia. Although this type of tumor is rare, the prevalence is 1.6% of all gastric cancers,63 it is attracting attention because it is classified a type of HpNGC. Ueyama et al. described GA-FG-CCP as a low-grade
Figure 2 Undifferentiated-type early gastric cancer (GC). The patient was a 36-year-old man. He had no symptoms and was detected with early GC by screening endoscopy. (a, b) There was no Helicobacter pylori infection in the stomach. (c) The lesion is slightly discolored, depressed and located at the upper body greater curvature (yellow arrows). Lesion size is 11 mm. (d) He underwent endoscopic submucosal dissection, and pathological findings revealed signet ring-cell carcinoma that was limited to the mucosal layer.
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Figure 3 Gastric cancer (GC) of fundic gland type. The patient was a 62-yearold man. He had no symptoms and was detected with early GC by screening endoscopy. (a,b) There was no Helicobacter pylori infection in the stomach. (c) The lesion is whitish, slightly depressed and located in the gastric cardia posterior wall. Dilated vessels are seen on the surface of the lesion (yellow arrows). Lesion size is 10 mm. (d) He underwent endoscopic submucosal dissection, and pathological findings revealed adenocarcinoma of the fundic gland type that was limited to the mucosal layer.
malignancy despite its ability to invade downward into the submucosal layer because none of the patients died or suffered recurrence during the follow-up period.62 However, highgrade malignant cases of GA-FG-CCP with vascular invasion have been reported.63,64 Hidaka et al. suggested that GA-FGCCP is associated with activation of the Wnt/β-catenin pathway because the tumors are characterized by nuclear β-catenin accumulation and mutation of the CTNNB1 or AXIN gene.63 The etiology of HpNGC is still not well understood, and further progress to validate germline mutations as a cause of HpNGC is expected in the future.
Patient characteristics and endoscopic findings of HpNGC Some reports have described the characteristics of HpNGC, but because of the rarity of HpNGC, they obtained data from only a small number of patients.8,9,29–33 Table 3 shows a compilation of the reported clinical characteristics. In four of these reports, the mean age was under 60 years, which is relatively young. There appeared to be no gender difference, as some reports showed that the male to female ratio was almost 1. Regarding the histology, the UD-type was the most common, and early-stage cancer was more frequent than advanced cancer because patients who underwent endoscopic resection
were included. We have previously reported that most HpNGC present as discolored and depressed tumors in the lower and mid body of the stomach, and the predominant histological type is signet ring-cell carcinoma (Fig. 2).30 Now, the standard treatment for early UD-type gastric cancer is surgery with lymph node dissection. If such lesions are detected in the early stage, such as mucosal tumors that measure ≤20 mm without ulceration, endoscopic submucosal dissection (ESD) can be carried out as clinical research to preserve the patient’s quality of life.65 In contrast, Yaita et al. reported that the main histological type in eight of 14 HpNGC was the D-type, and five of the eight lesions were GA-FG-CCP.33 Ueyama et al. also reported 10 patients with GA-GF-CCP,66 and the mean age was 66.6 years which was relatively high compared to the patients with UD-type. Six of these 10 lesions were located in the upper stomach, and the other 4 lesions were in the mid stomach, whereas there was no lesion in the lower stomach. GA-FGCCP was classified into two categories: submucosal tumor (60%) and flat or depressed type (40%). The most common endoscopic findings were submucosal tumor (60%), whitish color (70%), dilated vessels with branching architecture (50%) and background mucosa without atrophic change (90%) (Fig. 3). Also, incidental D-type gastric cancer without H. pylori infection is very rare, but some cases have been reported.8,9,29
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Figure 4 Gastric cancer (GC) associated with pernicious anemia (PA). The patient was a 54-year-old man who was diagnosed with PA 5 years prior. He was detected with early GC during follow-up endoscopy for PA. (a,b) His stomach had atrophic change only in the stomach body without Helicobacter pylori infection. (c) The lesion was slightly depressed and located at the antrum greater curvature (yellow arrows). (d) He underwent endoscopic submucosal dissection, and pathological findings revealed signet ring-cell carcinoma that was limited to the mucosal layer.
Figure 5 Gastric cancer (GC) associated with familial adenomatous polyposis (FAP). The patient was a 40year-old woman. She was diagnosed with FAP 2 years prior. She was detected with early GC during followup endoscopy for FAP. (a,b) There was no Helicobacter pylori infection in her stomach. (b) Multiple fundic gland polyps are seen in her stomach. (c) The lesion is whitish, slightly depressed and located at the upper body greater curvature (yellow arrows). Lesion size is 24 mm. (d) She underwent endoscopic submucosal dissection, and pathological findings revealed welldifferentiated adenocarcinoma that was limited to the mucosal layer.
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Table 4 Endoscopic findings of HpNGC
CONFLICTS OF INTEREST
Signet ring-cell carcinoma
A
Gastric adenocarcinoma of the fundic gland type
Others
Tumors present as discolored lesions in the lower or middle part of the stomach in relatively young patients. Predominant gross type is flat or depressed. Lesions are usually located in the middle and upper part of the stomach in relatively older patients. Predominant gross type is submucosal tumor-like or flat or depressed. Lesions include GC of intestinal type and GC associated with PA, FAP and HDGC.
FAP, familial adenomatous polyposis; GC, gastric cancer; HDGC, hereditary diffuse gastric cancer; HpNGC, H. pylori-negative gastric cancer; PA, pernicious anemia.
Other gastric cancers include those associated with PA, FAP and HDGC. We show early gastric cancer lesions that occurred in patients with PA (Fig. 4) and FAP (Fig. 5). Both patients had no active or history of H. pylori infection. The lesions were completely removed by ESD which circumvented the need for gastrectomy. Such lesions are rare in Japan; however, the patient’s history should be clearly obtained before endoscopic examination for detection of early-stage gastric cancer. Finally, we summarized the endoscopic findings of HpNGC in Table 4.
CONCLUSION HE PREVALENCE OF HpNGC is thought to be approximately 1%. However, it is expected that the prevalence of HpNGC may become relatively higher in the future with the decline in H. pylori infection. At our institute, some patients were detected with HpNGC by surveillance endoscopy. Early detection of gastric cancer enables the performance of ESD as a minimally invasive treatment to preserve the patient’s quality of life. However, the etiology and clinical course of HpNGC are still unclear; thus, further studies are required to verify and broaden our understanding of them. In order to accurately diagnose and assess HpNGC, endoscopists should fully understand the characteristics and endoscopic findings. We expect that the present review of HpNGC will aid endoscopists in detecting lesions during routine examination in patients without H. pylori infection.
T
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UTHORS DECLARE NO conflicts of interest for this article.
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