AIM: To investigate the factors influencing the occurrence of gastric varioliform lesions (GVLs) and their possible link with gastric cancer.

METHODS: A 1:1 matched case-control study was performed to retrospectively analyze data from 1638 chronic gastritis patients who had undergone gastroscopy at one of two Chinese hospitals between 2009 and 2014. Patients with GVLs (cases) were compared to those without such lesions (controls). Endoscopic and pathological findings were recorded, along with interview information on Helicobacter pylori (H. pylori) infection, medical, drug and family histories, lifestyle and eating habits. The association between each factor and the occurrence of GVLs was estimated, and then multivariate conditional logistic regression was used to evaluate the independent factors.

RESULTS: The frequency and severity of glandular atrophy, intestinal metaplasia (IM) and low-grade intraepithelial neoplasia were significantly increased in the GVL group (P < 0.01). Overall analysis showed that H. pylori infection [3.051 (2.157, 4.317), P <0.001], allergic respiratory diseases [3.636 (2.183, 6.055), P < 0.001], work-related stress [2.019 (1.568, 2.600), P < 0.001], irregular meals [2.300 (1.462, 3.619), P < 0.001], high intake of spicy food [1.754 (1.227, 2.507), P = 0.002] and high intake of fresh fruit [0.231 (0.101, 0.529), P = 0.001] were significantly correlated with the occurrence of GVLs (positively, except for the latter). Stratified analyses indicated that pickled food consumption in patients over 50 years old [7.224 (2.360, 22.115), P = 0.001] and excessive smoking in men [2.013 (1.282, 3.163), P = 0.002] were also positively correlated, and that, for antral GVLs, vegetable consumption [0.491 (0.311, 0.776), P = 0.002] was negatively correlated.

CONCLUSION: Seven risk factors and two protective factors are determined for GVLs, which were found to be associated with premalignant abnormalities.

Varioliform gastritis (VG), or “octopus sucker” gastritis in the foreign literature and verrucous gastritis in the national literature, is a disease with a characteristic endoscopic manifestation but no specific clinical symptoms. The major endoscopic feature is the presence of gastric varioliform lesions (GVLs), namely, widespread small lesions, manifesting as round, oval or irregularly shaped elevations, often possessing a central umbilical-like depression covered in gray-colored secretion or tiny bleeds. In 1947, Moutier and Martin[1] first described two cases of this distinctive gastric mucosal disease, and then in 1978, Lambert et al[2] classified the disease, according to its site of occurrence, into “diffuse” VG when spread throughout the stomach, and “antral” VG when restricted to the antrum. These two forms of VG are thought to have different etiopathogenesis and histological manifestations[3]. VG has been recognized as a protruded type of chronic erosive gastritis in the Consensus on Chronic Gastritis in China (2012)[4], but endoscopists more often present the diagnosis as chronic gastritis with varioliform lesions.

Until recently, very little was known about the etiopathogenesis of GVLs. Malfertheiner et al[5] reported that the Helicobacter pylori (H. pylori) infection rate was 89% among 37 patients with GVLs, and their clinical symptoms and mucosal inflammation were substantially improved after effective eradication of the infection. In the national literature, most authors support this point of view and regard H. pylori as the main cause of GVLs. On the other hand, several studies have provided compelling evidence that type I hypersensitivity may play a role[6]. Andre et al[7] found a large number of IgE-containing cells in the affected gastric mucosa and a significantly increased incidence of allergic diseases in patients with GVLs, as compared with the normal population. Furthermore, they performed a randomized double-blind placebo-controlled trial to compare clinical and endoscopic outcomes in patients treated with sodium cromoglycate, cimetidine or placebo[8]. The result stated that treatment with sodium cromoglycate greatly improved both sets of outcomes, whereas treatment with cimetidine or placebo showed no appreciable effect. Other previously reported pathogenic factors include hyperacid[9] and viral infection[10].

Some reports suggest a possible association between GVLs and gastric neoplasia. In 1960, Munoz Monteavaro et al[11] observed “in situ” carcinomatous transformation in a patient with VG, and other groups have reported similar findings more recently[12,13]. The elevated lesions can persist and transform into sessile polyps and appear as a gastric carcinoma several years later; as a result, the disease was classified as a precursor to gastric cancer at the World Congress of Gastroenterology (WCOG) in 1994. Diverse risk factors are involved in gastric carcinogenesis, including bacterial, environmental, dietary and genetic variables[14]. Numerous epidemiological studies have attempted to shed light on the factors impacting gastric neoplasia and precancerous lesions; these include a history of diabetes[15], aspirin consumption[16], excessive smoking[17] and drinking[18], pickled food consumption[19], tea consumption[20], amongst others. However, the results are somewhat inconsistent due to the ethnic diversity and limited sample size. A recent systematic review concluded that smoking, drinking, red meat and pickled food were risk factors, and that fresh vegetables and fruit may be protective; there was insufficient evidence to draw conclusions regarding coffee, tea or seafood[21]. GVLs may share some of these risk factors, and clarifying the matter should provide a better understanding of this potentially premalignant condition, allowing physicians to better identify at-risk patients and to devise more effective treatment strategies. Therefore, we carried out a retrospective 1:1 matched bi-center case-control study, analyzing endoscopic and pathological data from 1638 patients with chronic gastritis. The association between potentially relevant variables and the occurrence of GVLs was systematically evaluated, with an aim to find independent risk factors and protective factors.

The systematic database search yielded 268538 man-hours of gastroscopy over the five-year period of interest. Following the inclusion/exclusion criteria and the 1:1 matched design, 1638 subjects were selected to populate the case and control groups. A flow chart of the selection process is presented in Figure 1. There were 448 men and 371 women in the case group, with a mean age of 53.40 ± 11.41 years (ranging from 18 to 87 years old). The basic, endoscopic and pathological characteristics of the case group are shown in Table 1.

Open in New Tab   Full Size Figure   Download Figure

Figure 1 Flow chart of participant selection in the case-control study.

As is widely accepted, intestinal-type gastric carcinogenesis is a multi-stage process, developing from chronic gastritis through a series of precancerous abnormalities to gastric carcinoma[26,27]. In addition, H. pylori infection is thought to be the key promoter[28,29]. These precursor conditions include chronic atrophic gastritis with or without IM, with a reported malignancy rate of 0.5%-1%[30,31], and intraepithelial neoplasia[32], which is classified from low to high grade according to WHO specifications. It is reported that 0%-15% of low-grade intraepithelial neoplasia could progress to high-grade, which has an extremely high malignancy rate of 25%-85%[33]. In the present study, the frequency and severity of glandular atrophy, IM and low-grade intraepithelial neoplasia were significantly elevated in the case group, indicating that the presence of GVLs is a potential risk factor for cancer. Nevertheless, no high-grade intraepithelial neoplasia was observed, and the results were inconsistent when analysis was restricted to antral varioliform lesions. Thus, this malignancy risk should be further investigated via a large-scale prospective study.

In view of the association between GVLs and H. pylori infection status, the literature is somewhat inconclusive[34]. Our analysis showed a statistically significant difference in infection rates between GVL patients (32.1%) and controls (17.2%). The adjusted analysis of the interview data indicated that H. pylori infection, especially chronic persistent infection, was a pathogenic factor. In contrast, no correlation existed where infections had been successfully treated. Thus, H. pylori eradication and regular endoscopic follow-ups should be key components of the treatment for GVLs.

European researchers have suggested that there may be an allergic component in the pathogenesis of the disease, specifically that excessive histamine release could play a central role[7,35]; however, no evidence for this has been reported for Chinese patients. Interestingly, we found that the frequency of allergic diseases was increased in patients with varioliform lesions, in particular bronchial asthma and allergic rhinitis. There were 112 GVL patients (16.6%) with at least one allergic disease, and the multivariate analysis confirmed that allergic respiratory disease was an independent risk factor. Family history of gastric carcinoma has been reported as a risk factor for gastric carcinogenesis[36,37], but it was not associated with GVLs in our study. Diffuse form appeared to have a more positive association with allergic diseases and family history of gastric cancer, yet the results were not conclusive owing to the limited sample size, and will thus need to be verified by larger studies in the future.

In the pooled multivariate analysis, the independent risk factors were high work-related stress, irregular meals, and high intake of spicy food, and the one potentially protective factor was high intake of fresh fruit. The stratified analyses indicated that pickled food consumption in people over 50 years old and excessive smoking in men were also risk factors. Intake of vegetable side dishes was found to be negatively correlated with the antral form of GVLs. Indeed, certain habits of daily life could serve as important risk factors for gastric cancer. Previous studies revealed a close association between negative psychological factors like nervousness or anxiety and susceptibility to neoplasia[38,39]. Our participants with high work-related stress could have an increased risk of gastric malignancy, which may be related to constant anxiety-induced stimulation of the sympathetic system. Smoking is also considered a pathogenic factor for multiple cancers. A 50-year observational study of 34439 British doctors indicated that cigarette smoking was a risk factor in the progression of 14 different cancers including gastric carcinoma[40]. In the present study, excessive smoking in men contributed significantly to the risk of GVLs, but not in women, indicating possible male predominance in the morbidity of the disease. Concerning food consumption, pickled foods have been associated with the development of esophageal and gastric cancers, which can damage gastric mucosa and exacerbate the inflammation caused by H. pylori[41]. In recent times, Chinese dietary habits have changed dramatically. Pickled food may now be less popular in younger sections of the population, whereas spicy foods have greatly increased in popularity. Although capsaicin in spicy food has been shown to help counter the growth of H. pylori[42], we found that high intake of spicy food was a risk factor for varioliform lesions. The reason could be related to oncogene exposure or a chemical process during production. Meanwhile, the present study also provided factors that potentially offer some protection against GVLs. Intake of fresh vegetables and fruit has been reported to beneficial for avoidance of gastric neoplasia[43], which is consistent with the corresponding reduction in the frequency of GVLs seen in our study.

Several limitations of the present study must be taken into account. First, it is a retrospective analysis, for which recall bias and selection bias cannot be completely removed; a prospective study would be required to establish a convincing causal relationship between the factors and the disease. Second, the conclusions of the stratified analyses may be of limited value because of the small sample size, especially in the diffuse form group. Thus, some of the results in our study should be interpreted cautiously. Third, other relevant variables such as body mass index (BMI), hyperlipidemia, ABO blood group, consumption of coffee, carbonated drinks and bean products were not included; in addition, several factors such as the type of cigarette or alcohol consumed, medication dose and professional mental scale were not precisely classified. If the above factors were included in the multivariate regression equation, our results could have been very different. Future studies should therefore use a more complete set of variables.

To the best of our knowledge, this is the first case-control study investigating the factors influencing the formation of GVLs. The results suggest a potentially increased cancer risk for the affected patients, and that H. pylori infection, allergic respiratory diseases, high work-related stress, irregular meals, high intake of spicy food, pickled food consumption in older people, and excessive smoking in men were all positively correlated with the occurrence of GVLs. In contrast, consumption of vegetables and high intake of fresh fruit were found to be negatively correlated and therefore potentially protective. In summary, our results suggest that formation of GVLs can be reduced by maintaining a healthy lifestyle and positive attitude, while ensuring that allergic diseases and H. pylori infection are treated effectively. We suggest that a prospective study should be carried out in the future to examine the morphological and pathological evolution of GVLs, and thereby clarify their relationship with gastric malignancy. A large-scale, well-designed clinical trial is also warranted to provide more precise and robust conclusions on this matter.