Kuo YC, Yu LY, Wang HY, Chen MJ, Wu MS, Liu CJ, Lin YC, Shih SC, Hu KC. Effects of Helicobacter pylori infection in gastrointestinal tract malignant diseases: From the oral cavity to rectum. World J Gastrointest Oncol 2022; 14(1): 55-74 [PMID: 35116103 DOI: 10.4251/wjgo.v14.i1.55]
Corresponding Author of This Article
Kuang-Chun Hu, MD, PhD, Attending Doctor, Department of Internal Medicine, Healthy Evaluation Center, Mackay Memorial Hospital, MacKay Junior College of Medicine, Nursing, and Management, No. 92, Sec. 2, Chung-Shan North Road, Taipei 10038, Taiwan. mimiandbear2001@yahoo.com.tw
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Yang-Che Kuo, Horng-Yuan Wang, Ming-Jen Chen, Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
Lo-Yip Yu, Department of Internal Medicine, Healthy Evaluation Center, Mackay Memorial Hospital, Taipei 10449, Taiwan
Ming-Shiang Wu, Department of Internal Medicine, National Taiwan University Hospital, Taipei 10051, Taiwan
Chun-Jen Liu, Department of Internal Medicine, Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan
Ying-Chun Lin, Department of Anesthesia, MacKay Memorial Hospital, Taipei 10449, Taiwan
Shou-Chuan Shih, Division of Gastroenterology, Department of Internal Medicine, Health Evaluate Center, Mackay Memorial Hospital, Taipei 10449, Taiwan
Kuang-Chun Hu, Department of Internal Medicine, Healthy Evaluation Center, Mackay Memorial Hospital, MacKay Junior College of Medicine, Nursing, and Management, Taipei 10038, Taiwan
Author contributions: Wang HY, Chen MJ, Wu MS, Liu CJ, Lin YC and Shih SC performed literature research; Kuo YC, Yu LY, Lin YC and Hu KC wrote the manuscript and performed the revision and approval of the final version; Hu KC designed research, coordinated and corrected the writing of the paper.
Supported by108DMH0100146 and 108WHK0910031.
Conflict-of-interest statement: The authors deny any conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Kuang-Chun Hu, MD, PhD, Attending Doctor, Department of Internal Medicine, Healthy Evaluation Center, Mackay Memorial Hospital, MacKay Junior College of Medicine, Nursing, and Management, No. 92, Sec. 2, Chung-Shan North Road, Taipei 10038, Taiwan. mimiandbear2001@yahoo.com.tw
Received: March 7, 2021 Peer-review started: March 7, 2021 First decision: April 19, 2021 Revised: May 3, 2021 Accepted: December 9, 2021 Article in press: December 9, 2021 Published online: January 15, 2022
Abstract
Helicobacter pylori (H. pylori) has infected approximately fifty percent of humans for a long period of time. However, improvements in the public health environment have led to a decreased chance of H. pylori infection. However, a high infection rate is noted in populations with a high incidence rate of gastric cancer (GC). The worldwide fraction of GC attributable to H. pylori is greater than 85%, and a high H. pylori prevalence is noted in gastric mucosa-associated lymphoid tissue lymphoma patients. These results indicate that the majority of GC cases can be prevented if H. pylori infection is eliminated. Because H. pylori exhibits oral-oral or fecal-oral transmission, the relationship between this microorganism and other digestive tract malignant diseases has also attracted attention. This review article provides an overview of H. pylori and the condition of the whole gastrointestinal tract environment to further understand the correlation between the pathogen and the host, thus allowing improved realization of disease presentation.
Core Tip: Helicobacter pylori (H. pylori) has infected approximately fifty percent of humans for a long period of time. However, improvements in the public health environment have led to a decreased chance of H. pylori infection. This review article provides an overview of the correlation of H. pylori infection and gastrointestinal tract malignant diseases. Based on data on H. pylori, we believe that the digestive tract microenvironment and H. pylori motility affect the risk of cancer formation by H. pylori infection.
Citation: Kuo YC, Yu LY, Wang HY, Chen MJ, Wu MS, Liu CJ, Lin YC, Shih SC, Hu KC. Effects of Helicobacter pylori infection in gastrointestinal tract malignant diseases: From the oral cavity to rectum. World J Gastrointest Oncol 2022; 14(1): 55-74
According to 2020 Global Cancer Observatory data, seven of the top twenty cancers with the highest cumulative risk of incidence affect the gastrointestinal system, including oral cavity, laryngeal-pharynx, esophagus, stomach, pancreas, liver and colorectal cancers (CRC). In 2020, gastrointestinal oncology diseases accounted for greater than 26% of all cancers worldwide. With the exception of pancreatic cancer and liver cancer, other cancer tracts were interlinked (Figure 1)[1]. Three major risk factors are thought to be related to cancers: Obesity, infection and ultraviolet radiation. Several infections are considered to be related to cancer formation, including infection by Helicobacter pylori (H. pylori), human papillomavirus (HPV), and hepatitis B and C viruses, and these different infectious agents account for greater than 90% of infection-related cancers worldwide[2]. H. pylori was identified as an origin of peptic ulcer disease and has become an important public health issue worldwide since 1982. With different geographic areas, ages, ethnicities and socioeconomic statuses, the prevalence rates of H. pylori infection are also different[3,4]. Approximately 50% of people worldwide are infected by this bacterium. At the beginning of the 21st century, the prevalence was reduced in highly industrialized countries of the Western world. In contrast, the prevalence remains high in developing and newly industrialized countries. The discrepancy in prevalence may result from the degree of urbanization, sanitation, access to clean water, and socioeconomic status[5].
Figure 1 Estimated cumulative risk of incidence and mortality of gastroenterology tract malignancy disease in 2020, both sexes, ages 0-74 (reproduced from http://globocan.iarc.fr/).
According to the International Agency for Research on Cancer, H. pylori is a human carcinogen highly correlated with gastric cancer (GC)[6]. H. pylori also accounted for approximately 810000 infection-related cancer cases, which is greater than that reported for any other microorganism, in 2018[2].
Because H. pylori exhibits oral-oral or fecal-oral transmission and the whole gastrointestinal tract is connected, we further surveyed the role of H. pylori in different gastrointestinal malignant diseases to provide a better understanding of the relationship between H. pylori infection and malignant diseases. GC was highly correlated to H. pylori infection, but the relationship between H. pylori and cancer formation in other gastrointestinal tract malignant diseases, such as oral cavity cancer, laryngeal cancer, esophageal cancer, and colon cancer, has not been completely studied. Recent studies have shown some association between GC and H. pylori infection but lack a further overview of H. pylori infection and malignant diseases of the whole gastrointestinal tract. Past studies used the host viewpoint and examined which pathogen could cause disease in the host. This review article used the viewpoint of microorganisms and focused on the effects of H. pylori infection in gastrointestinal tract malignant diseases from the oral cavity to the rectum to further realize the connection between infectious and malignant diseases.
ORAL CANCER
Epidemiology of oral cancer
Oral cancer represents approximately 3% of all cancers worldwide and is the 6th most common cancer globally. As a popular habit in Asian countries, betel quid chewing is associated with periodontal disease, oral submucous fibrosis, and oral cancer[7,8]. Compared with other tumors in the oral cavity, oral squamous cell carcinoma (OSCC) tends to exhibit local invasion and metastasis[9]. In addition, OSCC occurs more frequently in middle-aged and older populations, particularly in men[10].
Pathological differences in oral cancer
Constituting 94% of oral malignancies, OSCC is far more common than the remaining malignancies, including salivary gland cancer, soft tissue sarcoma, jaw osteosarcoma, non-Hodgkin’s lymphoma, melanomas and metastatic tumors, in the oral cavity[11,12].
Role of H. pylori in oral cancer
As a Class I carcinogen, the role of H. pylori in oral cancer is not yet clear. Whether the colonization of H. pylori is facilitated by betel chewing-related lesions or the resulting chemical changes in the oral cavity remains an important issue to be studied. By comparing the prevalence of H. pylori in patients with oral cancer and healthy controls with different betel chewing statuses (Table 1), Fernando et al[13] noticed a significantly higher rate of infection among betel chewers regardless of the cancer status. Thus, betel chewing, not oral cancer, is a potential contributing factor to H. pylori infection.
Table 1 Association with Helicobacter pylori infection and oral squamous cell carcinoma.
Few studies have shown the association between H. pylori and oral cancer. Grandis et al[14] reported a similar seroprevalence of H. pylori in 21 patients with oral cancer and 21 controls; thus, the association could not be proven. Another study adopted polymerase chain reaction (PCR) and culture techniques to identify the existence of H. pylori in serum and tissue samples and reported insignificant differences in the prevalence of H. pylori between patients with oral cancer and controls. Nevertheless, the odds ratio (OR) was 3.0 [95% confidence interval (CI): 0.34-26.4] by culture and 1.5 (95%CI: 0.28-8.0) by PCR[15]. Only a few studies have attempted to examine the presence of H. pylori in OSCC[16]. Due to conflicting results, the relationship between H. pylori and OSCC cannot be concluded. The variable results may be caused by differences in methodology, specifically the disparity in the sensitivity and specificity of diagnostic methods. Using the three detection methods [H. pylori immunoglobin (Ig) G antibodies, PCR, and histochemical staining], Meng et al[17] suggested an inverse association between H. pylori infection and OSCC in the subgroup of individuals over 60 years of age according to the prevalence (35.3% vs 54.8%, P = 0.012), stratification analysis (P = 0.037) and Spearman's correlation (coef. = -0.191, P = 0.012). Regardless of race, lifestyle and habitual risk factors, the absence of H. pylori in the available OSCC cohorts indicates that H. pylori is unlikely to contribute to OSCC pathogenesis[18].
Role of the host effect in oral cancer
It is well known that H. pylori modifies the host’s immune response, resulting in GC. A similar mechanism might contribute to oral carcinoma; however, this relationship has not been revealed to date. To illustrate the potential relationship between H. pylori and oral cancer, a prospective cohort should be conducted in the future. Other risk factors, such as smoking, alcohol consumption, fungi (candidiasis) and viruses (Epstein-Barr virus and HPV), have already been extensively studied[19].
Summary
According to currently available studies, the relationship between H. pylori and oral malignancy cannot be made at present (Tables 1 and 2). Results varied among the studies due to the use of different diagnostic methods (culture, immunohistochemistry, enzyme-linked immunosorbent assay, PCR) adopted for H. pylori identification. Overall, the meta-analysis revealed a nonsignificant association between the bacterium and OSCC.
Pharyngeal-laryngeal cancer is a common malignancy of the upper aerodigestive tract. The prevalence is greater in people over the age of 60 and in males (5.8 cases per 100000 in males vs 1.2 per 100000 in females)[20]. Pharyngeal-laryngeal cancer comprises 2%-3% of the malignancies of the whole body and constitutes 25% of head and neck cancers[21]. In addition, racial differences were noticed with a younger age and a higher incidence and mortality in African Americans than in Caucasians[22,23]. Moreover, the younger (< 40 years old) the patients were diagnosed, the more aggressive and the poorer the survival rate[24]. Major risk factors for pharyngeal-laryngeal cancer include cigarette smoking and alcohol consumption. A study examining the effect of alcohol consumption and smoking in laryngeal cancer reported that the adjusted odds ratios for nonsmoking heavy drinkers (defined as > 8 drinks per day) and for nondrinking smokers were 2.46 and 9.38, respectively[25]. Microbes, viruses, occupational exposures, gastroesophageal reflux, and genetic inheritance, for example, were also linked to malignancy[26].
Pathological differences in pharyngeal-laryngeal cancer
Most of these cancers are squamous cell carcinoma, accounting for 85%-95% of pharyngeal-laryngeal malignancies[27].
Role of H. pylori in pharyngeal-laryngeal cancer
H. pylori has been detected in tooth plaque, saliva, nasal sinuses, and the middle ear[28,29]. The association between H. pylori infection and pharyngeal-laryngeal cancer has been described by Zhou et al[30]. Eleven studies were included in a meta-analysis that demonstrated a significantly higher rate of H. pylori infection in patients with pharyngeal-laryngeal cancer compared with healthy controls (OR = 2.87, 95%CI: 1.71-4.84; P < 0.0001). Furthermore, the ORs for laryngeal carcinoma were greater than those for pharyngeal cancer [(OR: 3.28, 95%CI: 1.91-5.63) vs (OR: 1.35, 95%CI: 0.86-2.12), respectively]. On the basis of the study results, a relationship between H. pylori infection and laryngeal carcinoma but not pharyngeal cancer was suggested. This association may result from the direct exposure of the larynx to known carcinogens (e.g., alcohol and tobacco), whereas mucosal and immune barriers were broken down after H. pylori infected the larynx. In patients with either benign or malignant laryngeal diseases, H. pylori was detected in greater than one-third (38.8%) of the biopsy samples from the larynx. The infection rate of H. pylori was highest in patients with laryngeal cancer (46.2%) and chronic laryngitis (45.5%) and was significantly lower in controls (9.1%)[31]. Based on the results of a meta-analysis, H. pylori infection increases the risk of laryngeal cancer by twofold compared to controls[32].
Burduk et al[33] showed a correlation of a high incidence of positivity for the H. pylori cytotoxin-associated gene A (CagA) gene in laryngeal cancer tissue (46.7% to 49.3%) and a reduced survival rate. However, several studies failed to demonstrate the direct correlation between H. pylori and laryngeal cancer. A study found a significantly higher frequency of H. pylori colonization at the antrum compared with the gastric body in patients with laryngeal cancer. It was hypothesized that H. pylori in the antrum reduces gastric acid when colonizing the body and increases by G cell hyperplasia, thus leading to laryngeal cancer through gastric reflux[34]. H. pylori has been identified in some laryngeal diseases. Given the lack of reliable research, the role of H. pylori in the larynx remains unclear.
In addition, acting as confounders, smoking cigarettes and alcohol consumption could mask the true relationship between laryngeal cancer and H. pylori infection, and well examined evidence supports the role of these confounders in the development of laryngeal cancer. Zhou et al[30] declared that no adjustment was made to eliminate the influence of tobacco and alcohol in their study. More concrete evidence is needed to determine whether H. pylori infection is simply associated with or has a causal relation with smoking and drinking among patients with laryngeal-pharyngeal cancer. Furthermore, given the lack of the temporality between laryngeal cancer and H. pylori infection, the causal relation cannot be defined by these studies. Finally, almost all these studies were case-control studies with potential recall and selection biases that potentially influenced the outcomes of the present research.
Summary
Current studies demonstrate the existence of H. pylori in the laryngeal mucosa (Tables 2 and 3) and support a possible connection between H. pylori infection and laryngeal cancer, but this relationship is not noted in pharyngeal cancer. The etiological mechanism of H. pylori-induced laryngeal squamous cell carcinoma is unclear, and related studies are lacking. Further evaluation of the cause-effect of H. pylori infection and pharyngeal-laryngeal cancer is required.
Table 3 Association with Helicobacter pylori infection and pharyngeal-laryngeal cancer.
Esophageal cancer constitutes 5.3% of all global cancer deaths and affects greater than 570000 people worldwide. However, the incidence rate varies across regions and populations[35]. Esophageal cancer can be categorized into two main subtypes: Esophageal squamous-cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). In past years, ESCC accounted for 70% of all esophageal cancer cases, and EAC has observed a significant and sustained rise in Western industrialized countries[36]. ESCC exhibits severe geographic distribution differences: The incidence rate is highest in Eastern to Central Asia followed by the Indian Ocean coast and can exhibit greater than tenfold differences among countries. On the other hand, the prevalence of EAC increased in several regions, such as North America and Europe[36,37]. In addition, the global incidence of esophageal cancer in men is 70%, and the cumulative risk from birth to 74 years of age is also higher in men compared with women (1.15% vs 0.43%, respectively)[35]. Regarding subtypes, men have a higher risk for developing both ESCC and EAC than women with three- to fourfold and seven- to tenfold differences for each type[38]. The incidence of esophageal carcinoma increases with age, peaks in the seventh and eighth decades of life, and is rare in younger people[37].
Pathological and etiological differences in esophageal cancer
ESCC and EAC exhibit very different biological presentations. ESCC is primarily found in the middle third of the esophagus, whereas EAC is located more often in the distal third of the esophagus[39]. Several dietary habits are related to both types of esophageal cancer. For example, a high intake of red meats, fats, and processed foods is linked to an increased risk, whereas a high intake of fiber, fresh fruits, and vegetables is associated with a lower risk[37]. Other major risk factors differ in these two types of esophageal cancer. ESCC is three to five times as likely to occur in people who consume alcohol (three or more drinks daily)[37]. Smoking or betel quid chewing also increase the risk of ESCC. In addition, the combination of alcohol intake and smoking has a synergistic effect in increasing ESCC risk[37,40]. The absolute risk of EAC developing in an individual 50 years of age or older is approximately 0.04% per year, and that risk is approximately twice as high among current smokers as it is among people who have never smoked[37,41]. The first risk factor reported for EAC was gastroesophageal reflux disease (GERD), which was identified in the 1990s[42]. Several significant associations between two of the common GERD symptoms, i.e., heartburn sensation and acid regurgitation, and the risk of EAC have been demonstrated by several studies. When heartburn symptoms presented for at least 30 years, the risk of EAC was 6.2-fold greater than that in individuals without heartburn[43]. The increasing prevalence of GERD combined with the declining prevalence of H. pylori infection has been hypothesized to be related to the increasing incidence of EAC.
Role of H. pylori in esophageal cancer
Rokkas et al[44] showed no consistent association between H. pylori infection and ESCC. Unlike ESCC, several studies have found that H. pylori infection is prevalent and leads to a reduced risk of EAC (OR: 0.50-0.57)[44-46]. Xie et al[47] showed that the risk of adenocarcinoma decreased by 41% among persons with H. pylori infection. Since the middle of the twentieth century, the prevalence of H. pylori infection has decreased in Western populations, and an increasing incidence of EAC has occurred. Scientists have proposed that the elevated incidence of EAC might result from the decreased H. pylori infection rate in these populations[48,49]. The possible mechanism of this bacterial infection effect might involve H. pylori infection-induced host atrophic gastritis formation followed by reduced volume and acidity of gastric juice. Finally, this situation could counteract GERD and thereby reduce the risk of EAC[50]. Further meta-analysis studies also supported the notion of a decreased risk of EAC up to 40%-60% and an OR of 0.56 for H. pylori infection (95%CI: 0.46-0.68, P < 0.05)[46,47].
Role of host genetic effects in esophageal cancer
Past studies have shown that esophageal cancer might not be associated with family history. However, in China, studies have demonstrated an approximately two-fold increased risk of ESCC in patients with first-degree relatives who have ESCC[51,52]. This situation might be explained by family members sharing some habitual factors, such as diet, obesity, alcohol and smoking. Several genetic disorders have been thought to be related to ESCC. For example, the concentrations of acetaldehyde after alcohol consumption are higher in persons with particular variants in the acetaldehyde dehydrogenase gene and the aldehyde dehydrogenase 2 family gene. If patients had these polymorphic variants, the risk of ESCC was increased up to 43- to 73-fold[53]. In all ESCC individuals, 83% had TP53 mutations, 76% exhibited EGFR overexpression, 46% harbored CCND1 mutations and 24% had CDK4/CDK6 mutations[40]. In EAC patients, 19% exhibited CCNE1 amplification, and 17% harbored cyclin E and MGST1 mutations[40]. These genetic studies might help us to detect esophageal cancer in earlier stages[54]. In addition to the above description, there are several known risk factors related to esophageal cancer. Excess intake of processed foods, hot foods and red meat was associated with an increased risk of both ESCC and EAC, and an increased intake of fresh fruits, vegetables and fiber was associated with a lower risk[37]. Obesity and increased body mass index (BMI) were also thought to be associated with EAC. In particular, if the increase in BMI began in childhood or adolescence, the EAC risk seemed to be stronger than if the increase in BMI began in adulthood[55].
Summary
Unlike other gastrointestinal tract malignancy diseases, H. pylori infection might indicate a decreased risk of EAC and be unrelated to ESCC. The OR of EAC in H. pylori-infected participants was 0.56 (95%CI: 0.46-0.68, P < 0.05) (Tables 2 and 4). H. pylori infection might increase atrophic gastritis in the host and decrease gastric acid formation, leading to a decrease in GERD and the probability of EAC. To prevent esophageal cancer, the elimination of smoking and alcohol and very hot food or drink consumption and the practice of healthy dietary habits are beneficial.
Table 4 Association with Helicobacter pylori infection and Esophageal cancer.
Although it is steadily decreasing in incidence, GC remains one of the most common malignant diseases worldwide[35]. According to GLOBOCAN 2020 data, GC is the sixth most commonly diagnosed cancer and the fifth leading cause of cancer mortality in the world, following lung, breast, colorectal and liver cancer. A Global Cancer Observatory report in 2018 noted that the cumulative risk of GC was higher in men than in women (1.87% and 0.79%)[1]. Compared to North and East Africa and North America, the incidence of GC was higher in East and Central Asia. In East Asia, the average incidence of GC for men and women is 3.21 and 1.32 per individual, respectively, whereas the incidence is 0.56 per million individuals in North America. The risk varies from six- to fifteen-fold between areas with the highest and the lowest incidence. The cause of this difference might be related to region and culture[56]. Ninety-five percent of GCs are adenocarcinomas followed by primary gastric lymphoma, and we focus on reviewing adenocarcinoma in this section. According to the anatomical site, gastric adenocarcinomas can be classified into cardia GCs and non-cardia GCs. The pathogenesis of cardia GCs might be related to GERD or EAC. Non-cardia GCs are caused by H. pylori-related atrophic gastritis and a variety of environmental factors, such as diet, alcohol, and smoking[57].
In the past fifty years, the incidence of GC has steadily declined. This trend was more significant in East Asia and might be due to a successful reduction in the number of H. pylori infections. Approximately 90% of cases of non-cardia GCs are attributable to H. pylori infection. Given H. pylori eradication and reduced infection rates, the incidence of non-cardia GCs is also declining[58]. In addition to H. pylori eradication, improved food conservation, higher standards of hygiene, and high intake of fresh fruits and vegetables could explain the reduced incidence of GCs[59].
Role of H. pylori in GC
In 1982, Warren and Marshal[60] found a connection between H. pylori and gastric ulcer disease, and since then, this bacterium has become a topic of study in the gastroenterology field. Twelve years later, the International Agency for Research on Cancer recognized H. pylori as a class I carcinogen[61]. For general microorganisms, the stomach environment is not suitable for survival because the gastric acid and pH level is less than 0.3-2.9[62]. However, with the assistance of urease-derived ammonia, H. pylori can buffer cytosolic, periplasmic and surface acidity in such an extreme environment of the stomach[63]. This environment might induce H. pylori to become the predominant microorganism in the stomach. In addition, the gastric transit time was greater than 2-4 h (Table 2), giving H. pylori more chances to attach to the stomach. When H. pylori strains carry the cag pathogenicity island (cagPAI), the risk of peptic ulcer disease or GC increases. With a size of 40 kb, cagPAI contains 30 genes, including cagA[64]. A previous study showed that H. pylori-infected people had an approximately sixfold increased risk of developing non-cardia GCs (OR: 5.9; 95%CI: 3.4-10.3) compared with uninfected individuals[65]. Furthermore, compared to infection with cagA-negative strains, a 1.64-fold (95%CI: 1.21-2.24) increased risk of GC was found for cagA-positive strains[66]. In gastric epithelial cells, a cell scattering effect caused by cytoskeletal modifications and proinflammatory responses triggered by the transcription factor NF-κB were observed when a functional cagPAI was present in H. pylori[67,68]. Activation of growth factor receptors, cell proliferation, inhibition of apoptosis, invasion and angiogenesis occurred through cagA[69].
The connection between H. pylori infection and GC was most significant in whole gastrointestinal tract cancer. H. pylori infection increases GC incidence, but GC incidence is decreased after H. pylori eradication. Lee et al[70] demonstrated an association of H. pylori infection eradication with a reduced incidence of GC in a meta-analysis study. After adjustment for baseline GC incidence, the pooled incidence rate for individuals receiving H. pylori eradication treatment was 0.53 (95%CI: 0.44-0.64). Recently, the long-term benefits of eradication were confirmed by Chiang et al[71], revealing a significant reduction in the occurrence of GC by 53% for a high-risk Taiwanese population. From 2004 to 2018, a mass eradication program was conducted in patients older than 30 years old on the Matsu Islands, where H. pylori infection was prevalent. After H. pylori eradication, the infection rates declined from 64% to 15%. GC incidence and mortality after the chemoprevention period were reduced to 53% (95%CI: 0.3-0.69) and 25% (95%CI: 0.14-0.51), respectively. The 2020 Taipei global consensus supported that “eradication therapy should be offered to all individuals infected with H. pylori” and suggested that screen-and-treat is a cost-effective strategy for young adults in GC high incidence areas at the general population level[72].
Role of host genetic effects in GC
In addition to H. pylori infection, dietary habits, lifestyle, family history and occupational exposure are also risk factors for GC. Fresh fruits and vegetables are protective against GC. Compared to individuals who intake less than one serving fruit and vegetable per day, participants who ate 2-5 servings had a hazard ratio (HR) of 0.56 (95%CI: 0.34-0.93)[73]. Some scientists have suggested that this might be related to an increase in vitamin C in fresh fruits and vegetables[74]. On the other hand, pickled vegetables, dried fish, and salted fish were associated with an increased incidence of GC[75]. High dietary salt intake was also associated with an increased risk of GC when salt intake was more than 10 g per day[76]. Regarding lifestyle, alcohol intake and smoking were thought to increase GC incidence. Duellet al[77] found that modest alcohol intake of greater 60 grams per day would increase the risk of GC to 1.65 (95%CI: 1.06-2.58). The meta-analysis conducted by Ladeiras-Lopes et al[78] included 42 studies from Asia, Europe and the United States and reported a relative risk of 1.53 for smokers (1.62 males and 1.2 females). Smoking not only increased GC risk but also affected GC recurrence and survival. As an independent risk factor, smokers had a significantly worse 5-year disease-free survival (HR: 1.46, P = 0.007) and overall survival (HR: 1.48, P = 0.003) than nonsmokers[79]. The GC risk was increased two- to threefold in first-degree relatives of patients with this disease. This finding might be due to the familial clustering trend of H. pylori infection[80]. Occupational exposures to dust and heat, such as those experienced by chefs, wood processing plant operators, food processing and related trade workers, and machine operators, was linked to a significantly raising risk of diffuse GC[67].
Summary
In the whole gastrointestinal tract, GC was most related to H. pylori infection, especially in non-cardia GCs. The OR of GC in H. pylori-infected participants was 5.9 (95%CI: 3.4-10.3, P < 0.05) (Tables 2 and 5). The host organ environment and pathogen characteristics might explain this result. The very low pH level in the stomach allows H. pylori to predominate in this niche, and adequate gastric transit time provides this bacterium with a greater chance of colonization in the stomach. H. pylori strains with a functional cagPAI further increased the risk for GC by 1.64-fold. Based on the 2020 Taipei global consensus, mass screening and eradication of H. pylori are necessary to prevent GC in high-risk populations.
Table 5 Association with Helicobacter pylori infection and gastric cancer.
As the most frequent location for extranodal lymphoma, the gastrointestinal tract represents 5%-20% of all cases[81]. However, primary gastrointestinal lymphoma is very rare. It only constitutes approximately 1%-4% of all gastrointestinal cancers. It is slightly male predominant with a men-women ratio of 3:2. Lymphoma incidence exhibits a double peak: One in patients younger than 10 years old and another in those with a mean age of 53 years[82].
The prevalence of lymphoma among different gastrointestinal locations is highest for the stomach (60%-75%) followed by the small intestine, ileocecal region and rectum[83]. With an elevated incidence worldwide, non-Hodgkin’s lymphomas (NHLs) are the most common primary gastric lymphomas, accounting for 5% of gastric malignancies[84]. Primary small intestinal lymphoma occurrence is comparatively rare, constituting 19%-38% of small intestine cancers[85], 20%-30% of primary gut lymphomas[86], and 4%-12% of all NHLs[87]. The most frequent location of small intestine lymphoma involvement is the ileum (60%-65%) followed by the jejunum (20%-25%) and duodenum (6%-8%)[88].
Colorectal lymphoma constitutes 6%-12% of all gastrointestinal lymphomas. Simply contributing 0.2% of all cancers, it is very rare for primary colorectal lymphoma[89]. The most common sites of tumor growth are the cecum (71.5%), rectum (16.9%), and ascending colon (6.2%), whereas the sigmoid colon is rarely involved[90]. Primarily occurring from the fourth to the seventh decades of life, primary colorectal lymphomas are diagnosed at an average age of 50 years. Males are affected approximately twofold more frequently than females[91].
Pathological differences in gastrointestinal tract lymphoma
Histopathologically, approximately 90% of primary gastrointestinal lymphomas are of the B cell lineage. Among them, over 90% are mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma (DLBCL). Notably, MALT lymphoma constitutes half of all primary lymphomas with gastric involvement[92].
Primary small intestine lymphomas that are more heterogeneous than those in the stomach include MALT lymphoma, DLBCL, enteropathy-associated T-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma and immunoproliferative lymphoma[93].
Primary colorectal lymphomas include MALT-related low-grade B-cell lymphoma, MCL, and peripheral T-cell lymphoma. Manifesting as multiple polyps, MCL is aggressive. In contrast, low-grade B-cell lymphoma derived from MALT is indolent and occasionally appears as multiple polyps. Colonic peripheral T-cell lymphoma expresses as either a diffuse or a focal segmental lesion with extensive mucosal ulceration[94].
Role of H. pylori in gastrointestinal tract lymphoma
A previous large population-based study, in which the seroprevalence of H. pylori was higher in patients with gastric lymphoma than in matched controls, confirmed the relationship between H. pylori-related chronic gastritis and MALT lymphoma[95]. Gastric MALT lymphoma is highly correlated with H. pylori in 72%-98% of low-grade cases[96]. In a retrospective study conducted by Parsonnet et al[95], H. pylori seropositivity preceded the diagnosis of gastric NHL for years (OR: 6.3; 95%CI: 2.0-19.9). MALT lymphoma was positively correlated with H. pylori infection (OR: 1.96; 95%CI: 1.0-3.9)[97]. The regression of low-grade gastric MALT lymphoma after the eradication of H. pylori has been described by some recent studies[98]. Epidemiological and experimental data support the hypothesis that H. pylori can serve as an antigenic stimulus supporting the growth of gastric lymphoma. Polymorphisms in host genes regulating the inflammatory response and antioxidative mechanisms in gastric MALT lymphoma patients suggest a correlation with the capacity to neutralize free radicals, and individual variations in the inflammatory response to H. pylori have been observed in recent research[99]. Expression of the CagA protein by H. pylori strains induced severe gastritis or even peptic ulcerations. The hypothesis that CagA+ H. pylori strains are linked to the development of gastric MALT lymphomas is observed in nearly all cases of patients in whom anti-CagA antibodies are present at a higher rate compared with inactive gastritis cases[100].
Parsonnet et al[95] failed to demonstrate a correlation between non-gastric NHL and prior H. pylori infection (OR: 1.2; 95%CI: 0.5-3.0). Several cases of colorectal MALT lymphoma that disappeared completely after H. pylori eradication were presented in 1998[101]. Unlike gastric MALT lymphomas, which can be successfully treated by H. pylori eradication alone, colorectal MALT lymphomas, which have different relationships with H. pylori infection, act and are viewed as a distinct clinical entity. However, antibiotic treatment against H. pylori is effective for colonic MALT lymphoma, and this treatment even influences H. pylori-negative patients[102].
Role of the host effect in gastrointestinal tract lymphoma
Sixty-five percent of gastric MALT lymphomas present with chromosomal translocations, including the t(14;18)(q32;q21) translocation, which causes deregulation of MALT1; the t(11;18)(q21;q21) translocation, which causes the formation of the chimeric fusion gene AP12-MALT1; and the t(1;14)(p22;q32) translocation, which causes deregulation of BCL10. Through the regulation of different genes, these translocations are involved in immunity, inflammation and apoptosis[103].
Polymorphisms of specific cytokines have been researched in the context of MALT lymphoma. Upregulation of IL-1 production is typically noted in the presence of H. pylori[104]. High IL-1 levels favor a proinflammatory response. In combination with the inhibition of gastric acid, extensive H. pylori colonization is facilitated, and MALT growth is promoted[99].
Acting on the signaling pathway, tumor necrosis factor (TNF) and its receptors greatly influence the immune response. TNF may accelerate the growth of lymphoid cells in vitro, and high concentrations of TNF were detected in patients with malignant lymphoma[105].
A well-known oncogene, Bcl-6, which is located on the long arm of chromosome 3, is found in most extranodal high-grade lymphomas. Its overexpression was also reported in gastric DLBCL[106].
Summary
Gastrointestinal lymphoma is a relatively rare disease with a diverse clinical presentation. The epidemiology and histopathologic subtypes as well as their relationship with H. pylori infection, are highlighted in this review. For gastric MALT lymphoma, a positive association with H. pylori infection was found (OR: 1.96; 95%CI: 1.0-3.9, P < 0.05) (Tables 2 and 6). Other non-gastric MALT lymphomas did not show this association.
Table 6 Association with Helicobacter pylori infection and gastrointestinal tract lymphoma.
CRC is the third most commonly diagnosed cancer in males and the second most commonly diagnosed cancer in females worldwide[107]. In the United States, CRC ranks as the second leading cause of cancer mortality in the population. This trend was similar in Europe, Australia and New Zealand, and these countries showed higher CRC incidence rates[108]. Japan, Thailand, Saudi Arabia and Iran have suffered rapid increases in CRC incidence over the past 30 years[109-111]. However, the age-standardized incidence rates vary in different countries. The country with the highest incidence rate was hungary, which had 51.2 cases per 100000 persons per year, and the country with the lowest incidence rate was Gambia with 1.1 cases per 100000 persons per year. The cause of this variation might be due to several factors, such as lifestyle, genetics, economic status (for example, meat consumption) and life expectancy (for example, some underdeveloped countries had lower CRC incidence rates because fewer people reach ages over 65 years, when most CRC is diagnosed)[107,112]. It is worth noting that some countries had a low CRC risk regardless of a high prevalence of H. pylori. This finding challenges the connection between H. pylori and CRC development.
This result might be explained by the fact that CRC has multiple contributing factors and H. pylori infection is one of them. For example, together with hyperglycemia, H. pylori infection has a synergistic effect on the risk of colon adenoma[113]. Areas with a higher prevalence of H. pylori infection but lower incidence of CRC, including Asia, some eastern European countries, and specific countries in South America, exhibit a lower diabetes prevalence[114]. This finding indicates that if the DM prevalence increases, the CRC prevalence might be elevated, which leads to areas with a higher prevalence of H. pylori infection but lower CRC incidence rates.
Pathological differences in CRC
There are three major pathologic pathways of CRC: The adenoma-carcinoma sequence, the serrated pathway and the inflammatory pathway. An estimated 85%-90% of sporadic CRC cases are derived from the adenoma-carcinoma sequence. In this pathway, several stepwise accumulations of genetic and epigenetic alterations drive the transformation of normal colon mucosal cells into an adenoma. First, the inactivated tumor suppressor gene APC is regarded as the gatekeeper against colorectal neoplasms. Second, KRAS, an oncogene mutation, facilitates adenoma growth. Then, inactivation of the tumor suppressor gene (i.e., TP53) promotes CRC progression[115,116]. Approximately 10%-15% of sporadic CRC is caused by the serrated pathway. This pathway includes several gene mutations. Oncogene BRAF mutations induce uncontrolled cell proliferation and contribute to the formation of hyperplastic polyps through constitutive activation of the MAPK pathway[117]. Then, hypermethylation at repetitive CG dinucleotides CpG island methylator phenotype (CIMP) results in mutations in the promoter regions of tumor suppressor genes. CIMP presents cell progression to sessile serrated adenoma and CRC. Approximately 75% of sessile serrated adenomas and 90% of serrated adenocarcinomas had CIMP-positive presentations[118,119]. Less than 2% of all CRC is caused by the inflammatory pathway. In this pathway, normal colon mucosal cells progress from indefinite dysplasia to low-grade dysplasia, high-grade dysplasia and cancer due to chronic inflammation[107].
Role of H. pylori in CRC
Since the 1990s, the connection between H. pylori and colorectal neoplasm formation has been widely discussed by scientists. Most reports demonstrated that H. pylori was linked to both benign and malignant colon lesions. For instance, H. pylori contributes to an elevated risk of 1.3- to 1.97-fold for colon adenoma with or without high-grade dysplasia[113,120-123]. Some scientists did not agree because their data revealed an insignificant increase in colon adenoma in combination with H. pylori infection[124,125]. Nonetheless, two recent meta-analysis studies uncovered a significant and positive correlation between H. pylori infection and the risk of colorectal adenoma (OR: 1.49, 95%CI: 1.37-1.62)[126] and CRC (OR: 1.70; 95%CI: 1.64-1.76, I2 = 97%)[127]. The potential mechanisms for H. pylori-induced colorectal neoplasms might include direct and/or indirect effects. However, a few studies have shown positive H. pylori PCR histology in colon tumors and found H. pylori in 22%-27% of colorectal polyps or cancers[128,129]. Recent studies favored the associations between CRC and bloodstream infections caused by Streptococcus gallolyticus (S. gallolyticus), Bacteroides fragilis (B. fragilis) and Fusobacterium nucleatum (F. nucleatum)[130]. Thus, S. gallolyticus, B. fragilis and F. nucleatum could have direct effects on the formation of colon neoplasms or cancer.
H. pylori might affect colorectal tumors through indirect effects. In the whole gastrointestinal tract, the colonic transit time is the longest[131] (Table 2). The long transit time offers more opportunities for H. pylori to alter the colonization of the colon, in which other bacteria might promote the development of neoplasms. Additionally, H. pylori enhances the release of gastrin, which contributes to colorectal carcinogenesis, possibly through its mitogen activity. H. pylori also appears to be associated with metabolic diseases with established connections with CRC. Finally, systemic inflammatory responses triggered by H. pylori-induced chronic inflammation of the gastric epithelium may increase the risk of CRC[132]. Although the possible mechanism of H. pylori-induced CRC was indirect, our previous study demonstrated a reduced risk of colorectal adenoma after successful eradication therapy[133]. This result implies that H. pylori is related to colon neoplasm formation by being a “biomarker” or “indicator organism”, reflecting exposure to immune-stimulating carcinogenic bacteria or antigens.
Role of the host effect in CRC
In addition to H. pylori, several host factors and other environmental factors potentially contribute to the pathogenesis of CRC. Risk factors for colorectal neoplasms included age 60 years or older, male sex, obesity, diet, dyslipidemia, impaired glucose tolerance, a family history of CRC, alcohol intake, tobacco use, and sedentary lifestyle[134-136]. Most of these risk factors were associated with metabolic syndrome. Compared with healthy individuals, patients with hyperglycemia have a higher prevalence of colonic neoplasms (26.6% vs 16.5%, P < 0.001)[137]. Waist circumference, one of the components of metabolic syndrome, was an independent risk factor for colorectal adenoma, and diabetes mellitus type 2 had an OR of 1.38 for CRC[138]. Compared to non- or occasional drinkers, people who consume four more drinks per day have a 72% increased risk of developing CRC. Cigarette smoking increased the risk of CRC approximately two- to threefold compared with nonsmokers[139].
Summary
H. pylori infection might indicate an increased risk of CRC. The OR of CRC in H. pylori-infected participants was 1.70 (95%CI: 1.64-1.76, P < 0.05) (Tables 2 and 7)[127]. Although H. pylori infection might have an indirect effect on the formation of CRC, the presence or absence of this bacterium could remind clinicians of the possibility of CRC. H. pylori eradication therapy benefits both gastric malignancies and colorectal neoplasms by reducing their occurrence.
Table 7 Association with Helicobacter pylori infection and colorectal adenoma/ cancer.
Given that H. pylori infection is an important infectious disease worldwide and affects human health through correlation with several diseases, such as gastric ulcers, GC and gastric MALT lymphoma, further realization of the effects of this bacterium in other gastrointestinal tract diseases is necessary. H. pylori infection induces chronic inflammatory changes in the human body and then increases GC, gastric MALT lymphoma and colorectal adenoma formation. In addition, an inverse relationship between H. pylori infection and EAC formation was observed due to atrophic gastritis and decreased gastric acid formation. From a microorganism viewpoint, the host gastroenterological microenvironment and motility status might play an important role in deciding which bacteria could colonize organs and subsequently induce chronic inflammatory and malignant changes in host organs. Further evaluation of human and bacterial interactions might allow us to better understand disease treatment.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Ferlay J, Ervik M, Lam F, et al Global Cancer Observatory: Cancer Today.
Lyon, France: International Agency for Research on Cancer. [cited 28 January 2021]. Available from: https://gco.iarc.fr/today.
[PubMed] [DOI][Cited in This Article: ]
Tobacco habits other than smoking; betel-quid and areca-nut chewing; and some related nitrosamines. IARC Working Group. Lyon, 23-30 October 1984.IARC Monogr Eval Carcinog Risk Chem Hum. 1985;37:1-268.
[PubMed] [DOI][Cited in This Article: ]
van der Waal R, van der Waal I. Oral non-squamous malignant tumors; diagnosis and treatment.Med Oral Patol Oral Cir Bucal. 2007;12:E486-E491.
[PubMed] [DOI][Cited in This Article: ]
Dayama A, Srivastava V, Shukla M, Singh R, Pandey M. Helicobacter pylori and oral cancer: possible association in a preliminary case control study.Asian Pac J Cancer Prev. 2011;12:1333-1336.
[PubMed] [DOI][Cited in This Article: ]
Pandey S, Follin-Arbelet B, Pun CB, Gautam DK, Johannessen AC, Petersen FC, Costea DE, Sapkota D. Helicobacter pylori was not detected in oral squamous cell carcinomas from cohorts of Norwegian and Nepalese patients.Sci Rep. 2020;10:8737.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 3][Cited by in F6Publishing: 3][Article Influence: 0.8][Reference Citation Analysis (0)]
Koufman JA, Burke AJ. The etiology and pathogenesis of laryngeal carcinoma.Otolaryngol Clin North Am. 1997;30:1-19.
[PubMed] [DOI][Cited in This Article: ]
Pirzadeh A, Doustmohammadian N, Khoshbaten M, Doustmohammadion S. Is there any association between Helicobacter Pylori infection and laryngeal carcinoma?Asian Pac J Cancer Prev. 2011;12:897-900.
[PubMed] [DOI][Cited in This Article: ]
Chow WH, Finkle WD, McLaughlin JK, Frankl H, Ziel HK, Fraumeni JF Jr. The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia.JAMA. 1995;274:474-477.
[PubMed] [DOI][Cited in This Article: ]
Cook MB, Corley DA, Murray LJ, Liao LM, Kamangar F, Ye W, Gammon MD, Risch HA, Casson AG, Freedman ND, Chow WH, Wu AH, Bernstein L, Nyrén O, Pandeya N, Whiteman DC, Vaughan TL. Gastroesophageal reflux in relation to adenocarcinomas of the esophagus: a pooled analysis from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON).PLoS One. 2014;9:e103508.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 105][Cited by in F6Publishing: 111][Article Influence: 11.1][Reference Citation Analysis (0)]
Rehnberg-Laiho L, Rautelin H, Koskela P, Sarna S, Pukkala E, Aromaa A, Knekt P, Kosunen TU. Decreasing prevalence of helicobacter antibodies in Finland, with reference to the decreasing incidence of gastric cancer.Epidemiol Infect. 2001;126:37-42.
[PubMed] [DOI][Cited in This Article: ]
Turati F, Edefonti V, Bosetti C, Ferraroni M, Malvezzi M, Franceschi S, Talamini R, Montella M, Levi F, Dal Maso L, Serraino D, Polesel J, Negri E, Decarli A, La Vecchia C. Family history of cancer and the risk of cancer: a network of case-control studies.Ann Oncol. 2013;24:2651-2656.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 52][Cited by in F6Publishing: 57][Article Influence: 5.2][Reference Citation Analysis (0)]
Yokoyama T, Yokoyama A, Kato H, Tsujinaka T, Muto M, Omori T, Haneda T, Kumagai Y, Igaki H, Yokoyama M, Watanabe H, Yoshimizu H. Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes, and risk for esophageal squamous cell carcinoma in Japanese men.Cancer Epidemiol Biomarkers Prev. 2003;12:1227-1233.
[PubMed] [DOI][Cited in This Article: ]
Warren JR, Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis.Lancet. 1983;1:1273-1275.
[PubMed] [DOI][Cited in This Article: ]
Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, Stemmermann GN, Nomura A. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach.Cancer Res. 1995;55:2111-2115.
[PubMed] [DOI][Cited in This Article: ]
Chiang TH, Chang WJ, Chen SL, Yen AM, Fann JC, Chiu SY, Chen YR, Chuang SL, Shieh CF, Liu CY, Chiu HM, Chiang H, Shun CT, Lin MW, Wu MS, Lin JT, Chan CC, Graham DY, Chen HH, Lee YC. Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands.Gut. 2021;70:243-250.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 33][Cited by in F6Publishing: 61][Article Influence: 20.3][Reference Citation Analysis (0)]
Liou JM, Malfertheiner P, Lee YC, Sheu BS, Sugano K, Cheng HC, Yeoh KG, Hsu PI, Goh KL, Mahachai V, Gotoda T, Chang WL, Chen MJ, Chiang TH, Chen CC, Wu CY, Leow AH, Wu JY, Wu DC, Hong TC, Lu H, Yamaoka Y, Megraud F, Chan FKL, Sung JJ, Lin JT, Graham DY, Wu MS, El-Omar EM; Asian Pacific Alliance on Helicobacter and Microbiota (APAHAM). Screening and eradication of Helicobacter pylori for gastric cancer prevention: the Taipei global consensus.Gut. 2020;69:2093-2112.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 135][Cited by in F6Publishing: 203][Article Influence: 50.8][Reference Citation Analysis (0)]
Shikata K, Kiyohara Y, Kubo M, Yonemoto K, Ninomiya T, Shirota T, Tanizaki Y, Doi Y, Tanaka K, Oishi Y, Matsumoto T, Iida M. A prospective study of dietary salt intake and gastric cancer incidence in a defined Japanese population: the Hisayama study.Int J Cancer. 2006;119:196-201.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 165][Cited by in F6Publishing: 170][Article Influence: 9.4][Reference Citation Analysis (0)]
Duell EJ, Travier N, Lujan-Barroso L, Clavel-Chapelon F, Boutron-Ruault MC, Morois S, Palli D, Krogh V, Panico S, Tumino R, Sacerdote C, Quirós JR, Sánchez-Cantalejo E, Navarro C, Gurrea AB, Dorronsoro M, Khaw KT, Allen NE, Key TJ, Bueno-de-Mesquita HB, Ros MM, Numans ME, Peeters PH, Trichopoulou A, Naska A, Dilis V, Teucher B, Kaaks R, Boeing H, Schütze M, Regner S, Lindkvist B, Johansson I, Hallmans G, Overvad K, Egeberg R, Tjønneland A, Lund E, Weiderpass E, Braaten T, Romieu I, Ferrari P, Jenab M, Stenling R, Aune D, Norat T, Riboli E, González CA. Alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.Am J Clin Nutr. 2011;94:1266-1275.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 73][Cited by in F6Publishing: 72][Article Influence: 5.5][Reference Citation Analysis (0)]
Kim YH, Lee JH, Yang SK, Kim TI, Kim JS, Kim HJ, Kim JI, Kim SW, Kim JO, Jung IK, Jung SA, Jung MK, Kim HS, Myung SJ, Kim WH, Rhee JC, Choi KY, Song IS, Hyun JH, Min YI. Primary colon lymphoma in Korea: a KASID (Korean Association for the Study of Intestinal Diseases) Study.Dig Dis Sci. 2005;50:2243-2247.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 48][Cited by in F6Publishing: 49][Article Influence: 2.6][Reference Citation Analysis (0)]
Ishikura N, Usui Y, Ito H, Kasugai Y, Oze I, Kato S, Yatabe Y, Nakamura S, Matsuo K. Helicobacter pylori (HP) infection alone, but not HP-induced atrophic gastritis, increases the risk of gastric lymphoma: a case-control study in Japan.Ann Hematol. 2019;98:1981-1987.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 9][Cited by in F6Publishing: 10][Article Influence: 2.0][Reference Citation Analysis (0)]
Rollinson S, Levene AP, Mensah FK, Roddam PL, Allan JM, Diss TC, Roman E, Jack A, MacLennan K, Dixon MF, Morgan GJ. Gastric marginal zone lymphoma is associated with polymorphisms in genes involved in inflammatory response and antioxidative capacity.Blood. 2003;102:1007-1011.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 61][Cited by in F6Publishing: 69][Article Influence: 3.3][Reference Citation Analysis (0)]
Grünberger B, Wöhrer S, Streubel B, Formanek M, Petkov V, Puespoek A, Haefner M, Hejna M, Jaeger U, Chott A, Raderer M. Antibiotic treatment is not effective in patients infected with Helicobacter pylori suffering from extragastric MALT lymphoma.J Clin Oncol. 2006;24:1370-1375.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 63][Cited by in F6Publishing: 68][Article Influence: 3.8][Reference Citation Analysis (0)]
Armaghany T, Wilson JD, Chu Q, Mills G. Genetic alterations in colorectal cancer.Gastrointest Cancer Res. 2012;5:19-27.
[PubMed] [DOI][Cited in This Article: ]
O'Brien MJ, Yang S, Mack C, Xu H, Huang CS, Mulcahy E, Amorosino M, Farraye FA. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points.Am J Surg Pathol. 2006;30:1491-1501.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 368][Cited by in F6Publishing: 399][Article Influence: 23.5][Reference Citation Analysis (0)]
