TO THE EDITOR
Esophageal carcinoma (EC) is a malignancy that affects the esophagus and mainly consists of four types: Esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), undifferentiated carcinoma, and other types. According to GLOBOCAN 2020 data, EC is the eighth most common cancer worldwide, with an estimated 604100 new cases and 544076 deaths per year[1]. In terms of clinical manifestations, the early symptoms of EC are not obvious, but with the development of the disease, patients can experience progressive dysphagia, swallowing pain, reflux, and vomiting, which seriously affect their quality of life[2,3]. In terms of treatment methods, the main treatment methods for esophageal cancer include endoscopic therapy (endoscopic mucosal resection, endoscopic submucosal dissection, etc.), surgery, chemotherapy, radiotherapy, immunotherapy, targeted drug therapy, and biological therapy. Although early EC can be cured through endoscopic therapy, the treatment of advanced esophageal cancer is relatively difficult and expensive, which places a heavy economic burden on patients and their families. Therefore, exploring the risk factors and protective factors for esophageal cancer and the underlying mechanisms will contribute to the prevention and treatment of EC in the future.
Helicobacter pylori (H. pylori) is a gram-negative, spiral, flagellated, microaerophilic bacterium that colonizes the gastric mucosa of humans. This bacterium invades the submucosal membrane of the stomach through fecal-oral or fecal-fecal transmission, leading to gastric and duodenal diseases. In different countries, the prevalence of H. pylori ranges from approximately 34.7% to 50.8%[4]. It is a well-known pathogen involved in various gastric diseases, including chronic gastritis, peptic ulcers, mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma[5]. However, in addition to being a risk factor for stomach-related diseases, H. pylori may have potential protective effects on certain autoimmune diseases, such as asthma and inflammatory bowel disease[6]. Notably, the results of previous studies on the relationship between H. pylori and EC are contradictory, with some studies suggesting that H. pylori has a protective effect on EC, whereas others suggest that H. pylori has no protective effect[7-11].
Proton pump inhibitors (PPIs) are a class of medications that inhibit the hydrion ion potassium ion-ATPase in parietal cells, leading to a reduction in gastric acid secretion. These drugs are commonly used to treat various gastrointestinal disorders such as peptic ulcers, esophagitis, hyperacidity, H. pylori infection, and gastroesophageal reflux disease (GERD). However, PPIs have additional effects beyond acid suppression, which inhibits bone resorption and decreases urinary calcium excretion, potentially impacting bone health[12]. Therefore, considering the long-term use of PPIs to control GERD in clinical practice, their role in EC is also worth exploring.
Although many previous studies have investigated the relationship between H. pylori and EC, the conclusions drawn by different studies are inconsistent. In addition, the incidence of H. pylori and EC is extremely different in different regions. Here, we pay special attention to the study by López-Gómez et al[13] in the latest issue of the World Journal of Gastroenterology, analyzing the prevalence of H. pylori in EC patients from a tertiary hospital in Madrid, Spain, and discussing its possible mechanism.
The relationship between H. pylori infection and EC
The relationship between H. pylori infection and EC is very complex. Previous research results are often contradictory due to the influence of dietary habits, age, region, and other factors. Considering that the risk factors and mechanisms of EAC and ESCC are inconsistent, we discuss them separately.
Many previous meta-analyses have shown that H. pylori is associated with a reduction in the risk of EAC[7-9]. Barrett’s esophagus (BE), which can develop from GERD, can develop into EAC. A meta-analysis investigated the relationships between H. pylori and BE or GERD, and the results revealed that H. pylori was associated with a low risk of both BE and GERD[14]. These findings suggest that H. pylori may play a role in multiple stages of tumorigenesis. The underlying mechanisms may include the following aspects[15]: (1) H. pylori infection may promote gastric emptying by inhibiting ghrelin levels, thereby reducing the risk of BE and EAC; (2) Excessive secretion of gastric acid promotes the pathogenesis of GERD and BE. Atrophy of the gastric mucosa after H. pylori infection can reduce gastric acid secretion and reflux, thereby reducing the risk of EAC; (3) H. pylori can promote the apoptosis of EAC cells; (4) Eradication of H. pylori may promote the occurrence of EAC by affecting the distribution of esophageal microorganisms; and (5) H. pylori may increase the pressure on the lower esophageal sphincter by promoting gastrin secretion, thereby reducing the occurrence of GERD.
In contrast, the relationship between H. pylori and ESCC is inconclusive. Some retrospective studies have shown that H. pylori has a protective effect on ESCC[10,11]. The meta-analysis suggested that H. pylori did not have a protective effect on ESCC in the overall population [odds ratio (OR) = 0.84; 95% confidence interval (CI): 0.64-1.09], whereas the subgroup analysis suggested that H. pylori had a protective effect in the Middle East (OR = 0.34; 95%CI: 0.22-0.52) or East Asia population (OR = 0.66; 95%CI: 0.43-0.89)[7,8]. These results may be related to the inconsistent dietary habits, drinking habits and genetic factors across different regions. To date, ESCC still accounts for the vast majority of ECs. Therefore, it is necessary to study the different roles played by H. pylori in the ESCC of different regions.
The potential effect of H. pylori infection on EC in Spain
López-Gómez et al[13] conducted a retrospective study that included 89 patients with EC in a Spanish hospital from February 2008 to December 2023. Among these patients, 47 (52.8%) had EAC and 37 (41.6%) had ESCC. The results revealed that there were a total of 4 cases of H. pylori infection in EC, including 3 cases in EAC (accounting for 6.3% of all EAC cases), and 1 case in ESCC (accounting for 2.7% of all ESCC cases). It is obvious that the infection rate of H. pylori in this cohort was much lower than that in the general population, whether it was EAC or ESCC. In summary, these results suggest that H. pylori may have a protective effect on EAC and ESCC in Madrid, Spain.
The role of PPIs in EC
There are many kinds of PPIs commonly used, including lansoprazole, pantoprazole, rabeprazole, omeprazole, esomeprazole and so on. In recent years, PPIs have become one of the most commonly used drugs because of their good effects. Although short-term use is often considered safe, long-term use is associated with risks such as cancer and osteoporosis[12,16,17]. Previous studies have shown that long-term use of PPIs can increase the risk of gastric cancer and colorectal cancer while reducing the risk of cervical cancer, breast cancer, and ovarian cancer[17-19]. However, whether the use of PPIs affects the occurrence of EC remains unclear. Considering that PPI drugs can inhibit the growth of H. pylori and that H. pylori is associated with a low risk of EAC, the use of PPIs may be associated with the risk of EAC. In the study of López-Gómez et al[13], 86 (96.6%) of 89 patients with EC had used or were using PPIs, suggesting a possible correlation between PPIs and EC.
Clinical significance and future research directions
The study of López-Gómez et al[13] provided new evidence for the relationship between H. pylori infection and esophageal cancer in Spain. The abuse of PPIs may be one of the factors leading to EC. Therefore, long-term clinical use of PPIs should be treated with caution. Although many previous studies and meta-analyses have concluded that H. pylori can reduce the risk of EAC, there are no relatively reliable prospective studies. In addition, international consensus recommendations advocate for PPI therapy in patients with BE because high-quality evidence derived from randomized controlled trials indicates that PPIs play a chemo-preventative role in developing Barrett’s associated neoplasia. Considering that PPIs are commonly used drugs for BE, it is still unclear whether PPIs are the cause or result of EC. Therefore, in the future, we can use Mendelian randomization analysis or perform prospective studies to obtain more reliable conclusions. In addition, we can explore the mechanism by which H. pylori affects EC through additional animal and cell tests. Moreover, we can identify relevant targets through multi-omics analysis, providing new ideas to prevent EC in the future.
