Gastric cancer in patients with Helicobacter pylori-negative autoimmune gastritis

Abstract

Although Helicobacter pylori (H. pylori) is implicated in the development of most cases of gastric cancer with autoimmune gastritis, cases of gastric cancer have been reported in patients testing negative for H. pylori. Here, we aimed to outline the current research status of the factors involved in the development of gastric cancer in H. pylori-negative autoimmune gastritis. Predictive pathological conditions for the development of gastric cancer in H. pylori-negative autoimmune gastritis are postulated to be: (1) Severe atrophy; (2) Hypergastrinemia; (3) Bile reflux; and (4) Low acidity, which are directly related to the pathophysiology of autoimmune gastritis, as well as smoking and family history, which are not related to autoimmune gastritis. In autoimmune gastritis, where there is a possibility of spontaneous disappearance of H. pylori in advanced atrophy, it is difficult to assess H. pylori. Since H. pylori infection begins in the antrum and subsequently progresses to the proximal stomach, it is interpreted as H. pylori-negative autoimmune gastritis if histologically consistent with autoimmune gastritis in the body with spared antrum, and negative for other H. pylori tests. However, it is essential to examine whether the currently prevailing histological interpretation used to evaluate H. pylori infection status is appropriate.

Key Words: Helicobacter pylori; Autoimmune gastritis; Gastric cancer; Gastrointestinal pathology; Gastrin; Atrophic gastritis; Endoscopy

Core Tip: Although in cases of autoimmune gastritis, Helicobacter pylori (H. pylori) is often implicated in gastric cancer development, there are reports of gastric cancer in patients with H. pylori-negative cases. Pathological factors for the development of gastric cancer in H. pylori-negative autoimmune gastritis include severe atrophy, hypergastrinemia, bile reflux, and low acidity. In the diagnosis of H. pylori infection in autoimmune gastritis, it is difficult to accurately diagnose cases of previous infection. When current H. pylori infection is ruled out in autoimmune gastritis sparing antrum, the patient is considered H. pylori-negative; however, this should be re-evaluated in the future.

INTRODUCTION

Autoimmune gastritis is characterized by the destruction of parietal cells through an autoimmune mechanism, causing the appearance of anti-parietal cell antibodies and resulting in localized atrophy of the gastric corpus[1]. It was first reported as "type A gastritis" and was considered a different disease concept from type B gastritis, which is a predominance of the antrum[2]. Autoimmune gastritis is diagnosed on the basis of the presence of two findings of “pure autoimmune gastritis” [Helicobacter pylori (H. pylori)-negative autoimmune gastritis]: Positive autoantibodies (anti-parietal cell antibodies and/or anti-intrinsic factor antibodies) and characteristic pathologic findings[3]. In contrast to H. pylori gastritis, in which atrophy progresses from the antrum to the corpus, autoimmune gastritis atrophy progresses from the corpus. Thus, the main pathological findings are as follows: (1) Advanced atrophy of the corpus sparing the antrum; (2) A marked decrease or disappearance of parietal cells, hyperplasia of enterochromaffin-like (ECL) cells, intestinal metaplasia, and pseudo pyloric metaplasia in the corpus; and (3) Hyperplasia of G cells in the antrum[4,5]. However, the diagnostic criteria differ among researchers, with some reports suggesting that autoimmune gastritis can be diagnosed based solely on autoantibodies and endoscopic findings[6].

In clinical practice, autoimmune gastritis is often suspected endoscopically, suggesting that the endoscopic images are also characteristic. The "corpus dominant advanced atrophy," in which the atrophy of the antrum is less severe than that of the gastric body, is the most common finding for the initial diagnosis, and advanced atrophy extending to the greater curvature of the gastric body, hyperplastic polyps, and sticky mucus are useful endoscopic findings[6,7]. Hypergastrinemia was reported as a risk factor for polyps (most of which are hyperplastic polyps)[8]. The study by Jin et al[9] published in the recent issue of the World Journal of Gastrointestinal Oncology also explored endoscopic findings of autoimmune gastritis and confirmed the significance of polyps in evaluating the clinical stage of autoimmune gastritis. They have suggested that polyps reflect advanced atrophy, e.g., hypergastrinemia and ECL cell hyperplasia in patients with autoimmune gastritis[9]. The prevalence of autoimmune gastritis ranges from 0.5%-2%[10,11], and it should be clearly recognized as a different disease from H. pylori gastritis, which accounts for most cases of gastritis, for three reasons: (1) The risk of developing gastric cancer and neuroendocrine tumors is high in autoimmune gastritis[12]; (2) Autoimmune gastritis often occurs in combination with other autoimmune diseases (including autoimmune thyroiditis and type 1 diabetes mellitus) and may be the trigger for diagnosis[13]; and (3) The potential for autoimmune gastritis to cause vitamin B12 deficiency, allowing the diagnosis of neurological disorders that often have sequelae and pernicious anemia, both often asymptomatic until late stages[14].

Here, we aimed to outline the current research status of the factors involved in the development of gastric cancer, especially in H. pylori-negative autoimmune gastritis cases.

CURRENT FINDINGS OF GASTRIC CANCER COMPLICATING AUTOIMMUNE GASTRITIS

Clinical characteristics, risk factors, and pathogenesis of gastric cancer complicating autoimmune gastritis irrespective of H. pylori infection

The incidence of gastric cancer complicating autoimmune gastritis ranges from 2.4%-9.8%[15-17]. Gastric cancer occurring in autoimmune gastritis often occurs in the proximal region, is usually discovered when detecting pernicious anemia, has a low metastasis rate and good prognosis, and is often the protruding type[18,19]. There are a few reports examining risk factors for gastric cancer associated with autoimmune gastritis. A study comparing autoimmune gastritis-associated gastric cancer with non- autoimmune gastritis reported that the incidence of pernicious anemia as an endoscopic trigger was significantly higher [odds ratio (OR), 22.0] in autoimmune gastritis-associated gastric cancer[19]. A meta-analysis reported that patients with pernicious anemia had a 6.8-fold (95%CI: 2.6-18.1) higher relative risk of having gastric cancer compared to those without[20]. Given that most cases of pernicious anemia are caused by autoimmune gastritis, the risk of gastric cancer in patients with autoimmune gastritis and pernicious anemia should be considered.

There have been several reports on the mechanism of gastric cancer carcinogenesis in autoimmune gastritis. A recent report suggested that methylation of the promoter CpG island of the tumor suppressor gene was weaker in autoimmune gastritis than in H. pylori gastritis, and the expression levels of IL1B and IL8 secreted by macrophages were also lower[21]. The authors concluded that this could explain the lower incidence of gastric cancer in autoimmune gastritis than in H. pylori gastritis; however, since it was also higher in autoimmune gastritis than in healthy people, it could also be interpreted as an explanation for carcinogenesis in autoimmune gastritis.

Some studies report that incomplete intestinal metaplasia is lower in autoimmune gastritis than in H. pylori gastritis, and this is thought to explain the low rate of carcinogenesis in autoimmune gastritis. However, this is not usually seen in healthy individuals and may be involved in the carcinogenesis of autoimmune gastritis[22]. Recently, there have been some interesting reports about this incomplete intestinal metaplasia. In both autoimmune gastritis and H. pylori gastritis, a metaplastic cell subtype similar to incomplete intestinal epithelial metaplasia, characterized by the expression of the cancer-related biomarker ANPEP/CD13, has been observed and is attracting attention as a mechanism of carcinogenesis in autoimmune gastritis[23].

Current view on the relationship between H. pylori and gastric cancer complicating autoimmune gastritis

There is a debate about the relationship between gastric cancer and H. pylori infection in autoimmune gastritis. Many cases of stomach cancer that develop in autoimmune gastritis are associated with current or past H. pylori infection. Two previous reports on this subject state that H. pylori infection is essential for the development of stomach cancer in autoimmune gastritis. Rugge et al[24] observed 211 patients with H. pylori-negative autoimmune gastritis over 7.5 years and found that six cases of low-grade intraepithelial neoplasia occurred but not gastric cancer or high-grade dysplasia; thus, they concluded that invasive gastric cancer does not occur in H. pylori-negative autoimmune gastritis. Moreover, they suggested that the high frequency of pseudo pyloric metaplasia, which is protective against neoplastic changes, in the body of the stomach in H. pylori-negative autoimmune gastritis may prevent cancer development. Their definition of autoimmune gastritis was based on the following strict criteria: The presence of either corpus-restricted or dominant inflammation and the exclusion of current and past H. pylori infection by multiple modalities. Additionally, Miceli et al[25] reported that in a 20-year follow-up of 282 patients with autoimmune gastritis, excluding those with persistent H. pylori infection, and atrophic pangastritis, they did not find any cases of advanced gastric cancer, as did Rugge et al[24].

As H. pylori can be eradicated with antibiotics, it would be interesting to know if there is a relationship between H. pylori eradication and gastric cancer development in autoimmune gastritis. Some reports state that autoimmune gastritis improves with H. pylori eradication, while others say it gets worse. Those stating that autoimmune gastritis improves with H. pylori eradication[26,27] suggest a mechanism in which H. pylori and autoimmune gastritis share a common antigen[28], and the report that H. pylori eradication worsens the condition[29] suggests a mechanism in which H. pylori suppresses the Th1 response that promotes autoimmune gastritis[30], and no definitive view has been reached. Therefore, although eradication is desirable in autoimmune gastritis, it is unclear whether H. pylori eradication suppresses or promotes the development of gastric cancer in autoimmune gastritis.

CURRENT FINDINGS OF GASTRIC CANCER IN H. PYLORI-NEGATIVE AUTOIMMUNE GASTRITIS

Reported cases of gastric cancer among patients with H. pylori-negative autoimmune gastritis

There are a small number of reports of gastric cancer developing in H. pylori-negative cases of autoimmune gastritis. Weise et al[19], who investigated this in a longitudinal study, reported 14 cases of H. pylori-negative gastric cancer in autoimmune gastritis. Unfortunately there is no description of the details of this clinical picture. We published a case report and literature review of five cases of gastric cancer in autoimmune gastritis, where H. pylori infection was strictly excluded[31]. In these cases, two or more tests for H. pylori infection were negative, with no medical history of eradication, and the corpus-restricted inflammation and atrophy sparing antrum were observed, which are now widely accepted as findings of H. pylori-negative autoimmune gastritis. In our literature review, four of five cases were positive for anti-intrinsic factor antibodies and endocrine cell micronests, and had high gastrin levels at > 2500 pg/mL (normal range: 37-172 pg/mL) and low pepsinogen I at < 10 ng/mL and I/II level at < 1.2 (normal pepsinogen level: pepsinogen I > 70 ng/mL or I/II ratio > 3.0), both suggesting an advanced stage of autoimmune gastritis. Therefore, although it is difficult to make a definitive conclusion due to the small number of cases in this literature review, a high risk of developing gastric cancer is suggested, especially in cases of autoimmune gastritis with severe atrophy even in H. pylori-negative cases, thereby necessitating surveillance.

Factors related to autoimmune gastritis that are thought to promote carcinogenesis in H. pylori-negative autoimmune gastritis

Unlike H. pylori-infected gastritis, autoimmune gastritis has the following clinicopathological features: Marked atrophy, low acidity and high gastrin level. These are thought to be factors that directly cause gastric cancer, so we will discuss them below, as shown in Table 1.

Table 1 Estimated factors to be considered as promoting gastric carcinogenesis in Helicobacter pylori-negative autoimmune gastritis.

Item	Related factors
Autoimmune gastritis related factors	Hypergastrinemia
	Bile acid reflux
	Advanced gastric mucosal atrophy
	Hypoacidity and the resultant overgrowth of bacteria
Non-autoimmune gastritis related factors predicted by Helicobacter pylori-negative gastric cancer	Cigarette smoking
	Family history of gastric cancer

Hypergastrinemia: Unlike H. pylori gastritis, in pure autoimmune gastritis, G cells in the antrum are not destroyed and gastric acidity is extremely low; thus, compensatory hypergastrinemia is often observed. Accordingly, several reports have suggested that the serum gastrin level can be used to differentiate autoimmune gastritis from H. pylori gastritis[32-34].

Hypergastrinemia increases the risk of proximal gastric cancer and intestinal-type gastric cancer by ORs of 6.1 and 3.8, respectively[35], and gastric cancer with hypergastrinemia may have a poor prognosis and short survival time[36]. Additionally, the administration of proton pump inhibitors (PPIs), which pharmacologically induce hypergastrinemia, increases the risk of gastric cancer by 3.38 times[37], and a meta-analysis suggested that PPIs increase the development of gastric cancer[38]. There are few reports discussing the relationship between PPIs and carcinogenesis in autoimmune gastritis, but there is a report that the incidence of gastric neoplastic lesions (low-grade dysplasia to carcinoma) is high, with an OR of 9.6 in patients with autoimmune gastritis prescribed PPIs for 12 months or more[39]. It is thought that PPIs act on the remaining parietal cells in autoimmune gastritis to further increase gastrin production. Hence, these findings raise the possibility that hypergastrinemia may induce carcinogenesis in H. pylori-negative autoimmune gastritis, as in H. pylori gastritis.

Bile acid reflux: Gastric mucosal damage caused by bile acid reflux may induce gastric cancer. Bile acid reflux may be an independent factor in the development of gastric cancer[40], or a risk factor for gastric cancer and precancerous lesions[41]. In advanced autoimmune gastritis, gastric acid secretion is highly suppressed; consequently, it is believed that the gastric mucosal damage caused by the alkalis associated with bile acid reflux may be more severe in advanced autoimmune gastritis than in H. pylori gastritis. Moreover, this may be particularly associated with a greater curvature of the proximal and posterior parts of the gastric body in gastric cancer due to the fluidity and gravity of the bile juice. Similarly, bile reflux may increase the possibility of carcinogenesis in the body of the stomach, where gastric cancer often occurs in patients with autoimmune gastritis.

Gastric mucosal atrophy: Gastric mucosal atrophy also causes gastric cancer. The risk of gastric cancer increases when the atrophy grade is open type according to the Kimura―Takemoto classification[42] and when it is a stage III/IV according to the Operative Link on Gastritis Assessment staging system[43]. These findings suggest that gastric mucosal atrophy caused by H. pylori may lead to the development of gastric cancer. For this reason, the American Gastroenterological Association guidelines[44] recommend endoscopic surveillance every three years for cases with advanced atrophy.

The low pepsinogen I and I/II ratios indicate severe atrophy of the gastric corpus and are the theoretical basis for serological gastric cancer screening methods such as the ABC method. The fact that most reported cases of gastric cancer in H. pylori-negative autoimmune gastritis also have low pepsinogen levels suggests that severe atrophy may be involved in carcinogenesis in H. pylori-negative autoimmune gastritis. It remains unknown whether gastric mucosal atrophy caused by purely autoimmune mechanisms can lead to the development of gastric cancer; however, it seems theoretically unlikely that in autoimmune gastritis, which is often associated with inflammatory cell infiltration and metaplasia, severe atrophy does not lead to the development of gastric cancer.

Hypoacidity and bacterial overgrowth: Hypoacidity occurs at a higher rate in patients with gastric cancer than in healthy individuals[45]. In autoimmune gastritis, hypoacidity increases the number of bacteria that are normally present, including urease-positive bacteria, which commonly cause false-positive results on the urea breath test in patients with autoimmune gastritis[46]. The sticky mucus often seen on endoscopy in autoimmune gastritis is believed to be a manifestation of this abnormal bacterial growth[47], and this excessive overgrowth of microorganisms in the stomach caused by low acidity induces N-nitrosation, which is strongly associated with the carcinogenesis of gastric cancer[48]. This hypoacidity and resultant bacterial overgrowth may be speculated as the cause of carcinogenesis in patients with autoimmune gastritis.

Factors unrelated to autoimmune gastritis that are thought to promote carcinogenesis in H. pylori-negative autoimmune gastritis

Regarding factors not related to the pathophysiology of autoimmune gastritis, although their involvement may be low, they are thought to be risk factors for gastric cancer development in autoimmune gastritis in H. pylori-negative cases as shown in Table 1. It is reasonable to assume that risk factors for gastric cancer development in H. pylori-negative cases may also be involved in carcinogenesis in H. pylori-negative autoimmune gastritis. Smoking and family history of gastric cancer have been reported as risk factors for H. pylori-negative gastric cancer[49]. Smoking has been reported as a significant risk factor for gastric cancer in several meta-analyses[50,51]. The association between gastric cancer and family history has also been reported in a meta-analysis[52], and since the pathogenesis of H. pylori-negative gastric cancer may be determined by genetic predisposition[53], it is possible that genetic factors are involved not only in H. pylori-negative cases without atrophy, but also in H. pylori-negative autoimmune gastritis. Autoimmune gastritis has more risk factors for carcinogenesis than H. pylori-negative gastritis, and it is reasonable to think that carcinogenesis due to these factors such as smoking and family history can occur.

DISCUSSION

H. pylori has been implicated in the development of gastric cancer in patients with autoimmune gastritis. However, the role of H. pylori infection in the development of all gastric cancer cases among patients with autoimmune gastritis remains unclear. Globally, the number of cases of gastric cancer is on the decrease, reflecting the decline in the rate of infection with H. pylori, but the number of cases of gastric cancer in people who have not been infected with H. pylori is on the rise[54]. In contrast to these H. pylori-negative cases, H. pylori-negative autoimmune gastritis cases exhibit numerous factors that induce carcinogenesis. The factors directly related to the pathogenesis of autoimmune gastritis are as follows: (1) Severe atrophy; (2) Hypergastrinemia; (3) Low acidity; and (4) Bile reflux. In addition, smoking and family history are not involved in the pathogenesis of autoimmune gastritis, but they may be risk factors for gastric cancer even in H. pylori-negative individuals. This is also thought to be the case for autoimmune gastritis. Therefore, it is reasonable to assume that patients with autoimmune gastritis, even in H. pylori-negative cases, face a markedly higher risk of cancer development than H. pylori-negative patients without autoimmune gastritis. Reports of cases of gastric cancer developing in patients with autoimmune gastritis without H. pylori infection exist. However, estimated carcinogenic risk of factors that may increase the risk of cancer in autoimmune gastritis, such as hypergastrinemia, low acidity, and bile reflux, have been confirmed in H. pylori gastritis, and it remains unclear whether this can be applied directly to autoimmune gastritis. We believe that future research should focus on collecting cases of autoimmune gastritis without H. pylori infection that have progressed to gastric cancer to identify the relevant risk factors.

If the underlying cause of autoimmune gastritis can be treated and the atrophy ameliorated (e.g., by immunomodulating medications), surveillance may not be required. However, it seems prudent to carefully monitor patients with autoimmune gastritis with endoscopic examinations to assess the possibility of gastric cancer development, whether they have H. pylori infection or not.

A significant challenge in discussing the relationship between carcinogenesis of autoimmune gastritis and H. pylori is the lack of established criteria for diagnosing current or past H. pylori infection in patients with autoimmune gastritis.

Since H. pylori may disappear spontaneously in patients with severe gastric mucosal atrophy[55], a negative H. pylori test result and no past medical history of eradication treatment cannot rule out past infection. In such cases, histological confirmation of previous H. pylori infection is necessary. The widely accepted histological definition of a H. pylori-negative state in autoimmune gastritis involves histological findings consistent with autoimmune gastritis in the corpus of the stomach, sparing the antrum, as shown in Table 2. Figure 1 shows the generally accepted interpretation for evaluating the presence or absence of H. pylori infection in autoimmune gastritis. In H. pylori gastritis, atrophy progresses from the antrum, and in advanced cases, pangastritis develops. In autoimmune gastritis without H. pylori infection, gastritis progresses from the body of the stomach but does not involve the antrum. In autoimmune gastritis with H. pylori infection, atrophy begins in both the antrum and the corpus, and in advanced cases, pangastritis develops. There are two problems with this view: (1) It is difficult to differentiate the etiology when pangastritis is observed; and (2) The question remains whether an antrum showing normal histologic findings without atrophy, intestinal metaplasia, and inflammatory cell infiltration truly represents a case of uninfected H. pylori. Histological atrophy of the antrum can improve over time following H. pylori eradication[56,57], suggesting that the current histological definition of H. pylori negativity in patients with autoimmune gastritis may require re-evaluation.

Figure 1 Schematic representation of lesion progression in Helicobacter pylori infected gastritis, autoimmune gastritis, and cases of combined disease. Blue indicates healthy mucosa and orange indicates mucosa with atrophy or inflammatory cell infiltration. A: In Helicobacter pylori (H. pylori) gastritis, the lesion progresses from the antrum to pangastritis in advanced cases; B: In autoimmune gastritis without H. pylori infection, the lesion progresses from the corpus but does not extend to the antrum, even in the advanced phase; C: In autoimmune gastritis with H. pylori infection, the lesion begins in both the antrum and the corpus, and in advanced cases, it becomes pangastritis. The arrows indicate the direction of disease progression. In the presence of H. pylori infection (A and C), it is difficult to distinguish whether autoimmune gastritis is present in the advanced phase. H. pylori: Helicobacter pylori.

Table 2 Current prevailing definition of Helicobacter pylori-negative autoimmune gastritis.

Definition
Exclusion of past medical history of Helicobacter pylori eradication treatment
Exclusion of a current Helicobacter pylori infection as assessed by a multiple Helicobacter pylori test
Confirmation of absence of previous Helicobacter pylori infection as assessed by histologic findings of corpus predominant atrophy with sparing of the antrum

To verify this, a cohort study should be conducted involving patients with autoimmune gastritis who are definitively infected with H. pylori and the histologic changes and clinical findings observed over a long period of time before and after successful eradication treatment.

CONCLUSION

Although H. pylori is presumably involved in many cases of gastric cancer development among patients with autoimmune gastritis, there have been reported gastric cancer cases of autoimmune gastritis in which H. pylori is not involved. Pathological factors for the development of gastric cancer in H. pylori-negative autoimmune gastritis are as follows: (1) Severe atrophy; (2) Hypergastrinemia; (3) Bile reflux; and (4) Low acidity, which are directly related to intragastric environment in autoimmune gastritis; and smoking and family history, which are not related to autoimmune gastritis. Thus, regular endoscopic surveillance is necessary not only for neuroendocrine tumors, but also for gastric cancer, regardless of whether the patient is infected with H. pylori or not. While it is difficult to determine whether a patient with autoimmune gastritis has been infected with H. pylori in the past by the H. pylori test, histological findings may provide clues to determine whether a patient has had an H. pylori infection. However, there are no established criteria in autoimmune gastritis for identifying histological findings suggestive of H. pylori infection based on cohort studies, and this is the greatest challenge in autoimmune gastritis research. To accurately examine H. pylori infection status by histology, future studies of autoimmune gastritis with current H. pylori infection should be conducted over a long period after eradication to evaluate any histologic changes, including those in the antrum.

ACKNOWLEDGEMENTS

We would like to thank Dr. Kenji Nakamura, Department of Gastroenterology, Ichikawa General Hospital, Tokyo Dental College, for his constructive criticism of this manuscript.