Background
Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer-related death worldwide [
1]. Histologically, GC is classified into intestinal and diffuse types [
2]. The intestinal type is related to corpus-dominant gastritis with intestinal metaplasia, whereas the diffuse type usually originates from superficial pangastritis without atrophy [
3]. The intestinal type is often associated with
Helicobacter pylori (
H. pylori) infection, while the diffuse type is more often associated with genetic abnormalities [
4].
Signet ring cell (SRC) carcinoma is a form of adenocarcinoma whose histologic diagnosis is based on microscopic characteristics defined by the World Health Organization (WHO) [
1]. SRC is classified as diffuse type and non-SRC (NSRC) is mostly classified as intestinal type according to Lauren’s classification [
5]. SRC and NSRC are considered distinct biologic entities originating from different pathways of carcinogenesis [
5,
6].
Epidemiologically, the worldwide decline in GC incidence has mainly been associated with a decrease in intestinal-type GC in western countries [
7]. By contrast, the incidence of diffuse-type GC, particularly SRC, is reported to have increased [
7,
8]. SRC represented 28–70% of GC in western countries [
8‐
10]. Moreover, SRC incidence has significantly increased by 6.5% per year on average, representing an approximately 10-fold increase from 1973 to 2000 [
8]. However, the trends in the incidence of SRC after 2000 have not been fully examined.
GC rates in Japan are one of the highest in the world, presumably because of the high
H. pylori infection rate [
11]. However, the prevalence of
H. pylori infection has drastically decreased, i.e., from 80 to 90% in older generations born before around 1950 to < 10% currently in individuals aged < 20 years [
12]. According to a previous study using Joinpoint regression analysis, the prevalence of
H. pylori infection in subjects born between 1927 and 1949 decreased from 48.6 to 43.5%, with a decline of 0.2% per year. Subsequently, a rapid decline in the prevalence of
H. pylori infection in those born between 1949 (43.5%) and 1961 (22.7%) was found, with a decline of 1.7% per year. Another decrease was observed between 1961 (22.7%) and 1988 (6.3%), with a decline of 0.6% per year. The drastic decline in the prevalence of
H. pylori infection by birth year can be explained by the change in sanitary conditions during childhood, when
H. pylori infection is predominantly acquired [
13].
Treatment for
H. pylori infection was developed in 2000; however, governmental health insurance plan coverage of this treatment was limited to patients with peptic ulcers. In February 2013, the indications for treatment were expanded to include chronic gastritis. Subsequently, it was estimated that the number of patients with successful
H. pylori eradication drastically increased after 2013, doubling to > 1,300,000 from approximately 650,000 per year between 2001 and 2012 [
14].
In 2006, the Japanese government began to encourage hospitals to create cancer registries. In 2013 the government changed the law to mandate these registries, and enforcement began in 2016. Our hospital voluntarily initiated a cancer registry in 2006, and since then we have accumulated information on all malignant neoplasms seen at our hospital. From 2007 to 2018, our registry enrolled 22,674 patients with various cancer types. Using the registry data, we evaluated the changes in the incidence of GC, SRC, and NSRC over time in comparison to changes in H. pylori infection rates over time using time series analysis.
Discussion
The morbidity and mortality of patients with GC have drastically decreased in the past 70 years [
26]. Up to the 1980s, environmental factors, such as nutrition and socioeconomic conditions, were presumed to play a major role in the development of GC [
27]. However, after the discovery of
H. pylori in 1984 [
28], the opinion on carcinogenesis of the stomach completely changed. In 1994, the International Agency for Research on Cancer classified
H. pylori as a type I (definite) carcinogen in human beings [
29]. Although GC is caused by multiple factors,
H. pylori infection has been regarded as a main risk factor.
H. pylori has been linked to chronic atrophic gastritis, which is an established precursor of the intestinal type of gastric carcinoma [
30]. Thus, elimination of
H. pylori has been considered the most important goal of GC reduction worldwide [
30,
31].
In Japan, a dramatic decline in the prevalence of
H. pylori infection, possibly attributable to improved hygiene, was observed in those born between 1949 and 1961 (43.5 and 22.7%, respectively) [
13]. In addition, the number of patients who have been cured of
H. pylori infection by drug treatment is rapidly increasing in Japan. The nationwide estimated number of patients who were successfully treated was approximately 0.6 million per year between 2001 and 2012, which rapidly increased to around 1.4 million in 2013 [
32].
SRC is a unique type of GC. Our data showed that 211 of 2532 GC cases (8.3%) had SRC. The etiology and pathogenesis of SRC are completely unknown. SRC that is detected late is associated with an extremely poor outcome [
7]. Clinically, we often treat relatively young female patients with diffuse-type GC (stage IV).
Several clinical studies have demonstrated the association of
H. pylori infection with SRC. Asaka et al. reported that 86.4% of diffuse-type GC had a positive serology for
H. pylori [
33], and Kikuchi et al. reported that the frequency of positive
H. pylori antibody in diffuse-type GC was 87.8% [
34]. Huang et al. reviewed ten published studies and reported that 82.2% of patients with diffuse-type GC were seropositive for
H. pylori [
35]. On the contrary, there has been a long-held opinion that SRC is so unique that it is not related to
H. pylori infection. Buruk et al. reported that
H. pylori was found in 88% of the intestinal type and in only 55% of the diffuse type (
P < 0.05) GCs [
1,
24,
25]. Moreover, the implementation rate of clinical examination for
H. pylori infection in SRC was low in this study, reflecting the prevalent opinion that diffuse-type GC or SRC is related to genetic or unknown factors rather than to obvious
H. pylori infection (Table
2). However, with the addition of genomic detection targeting 16S rRNA of
H. pylori and IHC detection of
H. pylori utilizing FFPE,
H. pylori infection was found in 81.1% of our registered SRC cases (Table
4).
GC is considered the end result of a long-lasting
H. pylori infection leading to stomach epithelium atrophy with accumulated somatic mutations [
36]. Thus, changes in overall GC incidence due to eradication of the bacteria would be expected to occur extremely slowly. Nevertheless, an interesting finding was reported in an institution in Taiwan. A universal hepatitis B vaccination program in 1984 resulted in an immediate 50% decrease in the incidence of hepatocellular carcinoma in children within 13 years [
37]. Previously it was thought that such a reduction in hepatocellular carcinoma incidence would take 30 to 40 years. The most common age range for the onset of hepatitis B-related hepatocellular carcinoma was 50 to 60 years, following development of chronic hepatitis and cirrhosis. Thus, the immediate effect was an unexpected result and led to postulating that hepatitis B virus may directly induce hepatocellular carcinoma without preceding chronic hepatitis and cirrhosis.
Of further interest, marked atrophy was less common (5.7%, 7/123) in patients with SRC than in those with NSRC (20.5%, 149/726) (Table
5). These data indicated that despite the rate of
H. pylori infection being the same as that of NSRC incidence the bacteria may not cause severe atrophy and may trigger SRC in the stomach in the short term instead (Table
6). Several clinical as well as basic studies on the pathogenesis of SRC have been conducted. Uemura et al. reported that diffuse-type GC is associated with active inflammation and not necessarily with marked atrophy [
38]. Moreover, several important genetic abnormalities in GC have been reported. Approximately 1–3% of GC occurs because of an inherited gastric cancer predisposition [
39]. Linkage analysis has implicated
CDH1 (also known as E-cadherin) mutations in approximately 25% of families with an autosomal-dominant predisposition to diffuse-type GC [
40]. The causal role of
H. pylori infection for specific alterations in DNA methylation patterns was demonstrated in the gastric mucosa of
H. pylori-infected patients and in GC cell lines [
41]. Interestingly,
CDH1 gene methylation is reported in sporadic diffuse-type GC associated with
H. pylori infection, and the methylation of the
CDH1 promoter could be reversed by the eradication of
H. pylori [
42]. Hence,
H. pylori eradication therapy may decrease the incidence of diffuse-type GC by suppressing inflammation [
43] and specific alterations of DNA methylation.
Our study has several limitations. First, we evaluated patients retrospectively; thus, we could not exclude various biases entirely. Second, this was a single-institutional study, so a small number of patients with SRC were evaluated. However, our data showed that the SRC incidence significantly decreased. Currently, although all available data indicate that the incidence of SRC continues to increase worldwide, no obvious explanation for the direct contribution of
H. pylori infection to the development of SRC exists. However, studies on the increase in SRC incidence were published before 2005 [
7,
8]. The government mandated national registry discussed earlier, by collecting cases from the entire nation of Japan, will enable epidemiological studies which may answer the question of whether SRC incidence is truly decreasing.
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