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Revista Española de Enfermedades Digestivas
versão impressa ISSN 1130-0108
Rev. esp. enferm. dig. vol.97 no.11 Madrid Nov. 2005
ORIGINAL PAPERS |
Role of Helicobacter pylori in stomach cancer after partial gastrectomy for benign ulcer disease
A. Seoane, X. Bessa, F. Alameda1, A. Munné1, M. Gallen2, S. Navarro3, E. O'Callaghan, A. Panadès, M. Andreu1 and F. Bory
Services of Gastroenterology, 1Pathology, 2Oncology, and 3General Surgery. Hospital del Mar. Universidad Autónoma de Barcelona, Spain
ABSTRACT
Objective: to determine the prevalence of Helicobacter pylori infection in patients having undergone gastrectomy for non-neoplastic disease who later developed gastric stump cancer.
Material and methods: retrospective study of all patients with partial gastrectomy for non-malignant peptic disease who were submitted to an endoscopic exploration between 1995 and 2001. A comparison was made of major clinical and histological characteristics, and the presence of Helicobacter pylori among patients with and without gastric cancer in the stomach remnant.
Results: a total of 73 patients were studied in this period. Fifteen patients (20.5%) had remnant-stump gastric cancer. All but one were adenocarcinomas (71% intestinal and 29% diffuse, respectively). The average time between diagnosis of gastric cancer and previous gastrectomy was 32 (14-48) years. There was a higher detection rate of Helicobacter pylori in patients with cancer in the gastric remnant (100 vs. 81.5%, respectively, p < 0.07). No relationship was seen between type of gastric reconstruction (Billroth I or II) and rate of Helicobacter pylori detection.
Conclusions: Helicobacter pylori infection is frequent in patients with previous gastrectomy for non-neoplastic disease. The results of the study suggest that Helicobacter pylori infection may play a role in gastric stump cancer.
Key words: Gastric stump cancer. Helicobacter pylori.
Seoane A,Bessa X, Alameda F, Munné A, Gallen M, Navarro S, O'Callaghan E, Panadès A, Andreu M, Bory F. Role of Helicobacter pylori in stomach cancer after partial gastrectomy for benign ulcer disease. Rev Esp Enferm Dig 2005; 97: 778-785.
This study has been supported by a grant of Instituto Carlos III C03/02.
Recibido: 21-02-05.
Aceptado: 22-06-05.
Correspondencia: Agustín Seoane Urgorri. Departamento de Gastroenterología. Hospital del Mar. Passeig Maritim, 25-29. 08003 Barcelona. Fax: 93 248 33 76. e-mail: 92847@imas.imim.es
INTRODUCTION
In 1994 the consensus group comprised of the World Health Organization and the International Agency for Research on Cancer stated that there was enough epidemiologic and histologic evidence to classify H. pylori as a definitive carcinogen (1). In that sense, a previous meta-analysis suggests that chronic H. pylori infection induces a two- to three-fold increase in the risk of gastric cancer (2-4), and a recent prospective study found that H. pylori is associated with the development of gastric cancer (5).
In patients submitted to partial gastrectomy for benign ulcer disease, an increased risk of gastric stump cancer after a long latency period has been noted (6,7), and a previous meta-analysis suggests that the risk is higher fifteen years after gastric surgery (8). In contrast to gastric cancer in the intact stomach, where H. pylori has a predominant role in carcinogenesis, bile reflux, an invariable consequence of operations that remove or by-pass the pylorus, is thought to be a major factor in carcinogenesis after gastric surgery (9). The role of H. pylori in gastric stump cancer has been the main topic in several studies, although such role is not absolutely clear yet. There are also studies where H. pylori and biliary reflux to the gastric stump obviously play a synergistic role in cell proliferation. It has been suggested that alkaline intragastric pH as induced by bile reflux produces an unfavorable microambient for H. pylori colonization (10,11). In that sense, it has been proved that bile salts seem to have a bactericidal effect on H. pylori, and following a Billroth resection H. pylori rapidly disappears from the gastric remnant (12). Moreover, the low incidence of H. pylori infection of the gastric stump detected in previous studies determines that the cellular proliferation rate resulting from bile acid reflux has been again implicated as the main factor involved in the pathogenesis of gastric stump cancer (13-15).
The aim of this retrospective study was to determine the prevalence of H. pylori infection in gastric stump cancer for patients surgically treated for benign peptic ulcer disease.
MATERIAL AND METHODS
Model design and patient selection
This study was performed retrospectively. Between January 1995 and December 2001, at the Endoscopy Unit of the Digestive Department, a gastroscopy was performed on 116 patients who had previously undergone partial gastrectomy for benign peptic ulcer. In 73 patients (63%), a sample for histological study was available in the files of Department of Pathology (samples obtained during endoscopy or surgical specimen). It is important to point out that carcinomas from the gastric cardia and patients with less than 10 years of follow-up were excluded. All gastric stump cancers were located near the gastro-enterostoma.
In order to establish the role of H. pylori infection in gastric cancer after previous partial gastrectomy we established two subgroups for the analysis: group 1 (patients with gastric stump cancer) and group 2 (patients without cancer). A comparison of the main clinical (gender, age, reason for gastrectomy, type of gastric reconstruction), and histological variables (gastritis, metaplasia, presence of H. pylori infection) was carried out (9).
Histological assessment and H. pylori identification
Biopsy specimens or samples from gastrectomy were placed in 10% formaline, routinely processed, and then stained with hematoxylin and eosin. A modified Giemsa and Masson Trichromic stain was used to detect H. pylori infection. The histological type of gastric cancer was determined using Lauren's classification, and was then assigned to one of three groups: intestinal, diffuse or mixed (16). The non-neoplastic mucosa was examined for chronic inflammation, glandular atrophy, and intestinal metaplasia according to Sydney's classification. Histological examination and H. pylori status were evaluated independently by two pathologists.
Statistical methods
Continuous variables were expressed as mean ± standard deviation. Qualitative variables were evaluated by means of the χ2 test, applying Yates' correction as required. Continuous variables with parametric and non-parametric distribution were compared by means of Student's t test and Mann-Whitney U test, respectively.
RESULTS
The baseline characteristics of patients studied are depicted in table I. Overall, H. pylori was detected in the gastric remnant of 63 patients (86%). In fifteen patients (20.5%) a gastric stump cancer was diagnosed. H. pylori colonization was detected in all patients (100%) with gastric stump cancer. All but one were gastric adenocarcinomas (71 and 29%, intestinal and diffuse types, respectively). In one patient a gastric T lymphoma was diagnosed. Average time between diagnosis of gastric cancer and previous gastrectomy was 32 (14-48) years, without differences in the time to last endoscopic follow-up in the non-cancer group (Table I).
Although smoking status was more prevalent in the cancer group (93 vs. 69%, p < 0.05), no differences were observed in age, gender, alcohol consumption, etiology for gastrectomy, and type of Billroth reconstruction between groups: patients with or without gastric cancer (Fig. 1, Table II).
Atrophy and intestinal metaplasia were more frequent in the non-neoplastic mucosa of patients with gastric stump cancer than in patients without cancer (29 and 57 vs. 2 and 26%, respectively). Although not reaching statistical significance, H. pylori detection was higher in patients with cancer in the gastric remnant (100 vs. 81,5%, respectively) (p < 0.07) (Fig. 2). No relationship was seen between type of gastric reconstruction (Billroth I or II) and rate of histologic H. pylori detection (Fig. 3).
DISCUSSION
After partial gastrectomy there is an increased risk of gastric cancer, and this risk increases steadily with the duration of the post-operative interval (6-8). Pathogenesis is not clear, but the increased proliferation of mucosal cells associated with chronic bile reflux seems to be a risk factor (17,18), and associations between bile reflux and intestinal metaplasia have been reported following gastric surgery (19). The currently dominant hypothesis is that intestinal metaplasia is a pre-cancerous condition occurring as a result of exposure to mutagens in hypochlorhydric gastric juice. Although in the intact stomach H. pylori infection has been considered a factor increasing the risk of gastric cancer (2-5), its role in the development of gastric stump cancer in patients surgically treated for benign ulcer disease is unclear.
Multiple studies have evaluated the prevalence of H. pylori in patients with gastric cancer (2-5). In few previous studies, the prevalence of H. pylori infection in patients with stump gastric cancer has been estimated at around 38% (14,20-24). Only one study (25), using polymerase chain reaction (PCR)-based methods to detect H. pylori DNA in the gastric juice, observed a higher prevalence (62.4%); however, this study included patients with partial gastrectomy for gastric cancer.
It has been advocated that the increase of bile acid reflux seen after a partial gastrectomy, more prevalent in patients with a Billroth II reconstruction, produces an unfavorable microenvironment for H. pylori infection and colonization, and could explain the low H. pylori detection in these patients. As previously indicated, it has been proved that bile salts seem to have a bactericidal effect on H. pylori, and after a Billroth resection H. pylori disappears rapidly from the gastro-enterostoma (12,27). Moreover, the low incidence of H. pylori infection in the gastric stump as detected in previous studies reveals that the cellular proliferation rate resulting from bile acid reflux has been again implicated as the main factor involved in the pathogenesis of gastric stump cancer (13-15). Due to the retrospective nature of our study, it has not been possible to quantitate bile reflux in our patients, but as in all patients with operations that remove or by-pass the pylorus, our patients would have a high intragastric pH (9).
Our results, with a noteworthy high prevalence of H. pylori infection in the gastric remnant, argue against the deletereous effect of an intragastric alkaline microenvironment in H. pylori colonization. It may be reasonable to think that H. pylori infection was acquired before gastrectomy, and all patients were operated on for untractable or complicated ulcer disease. In addition, differences in H. pylori prevalence may be due to the fact that the size of fragments studied were much larger in the stump cancer group. So, as infection may be sparse and irregular, larger samples could allow a more detailed study, thus giving a higher chance of detecting patchy H. pylori infection.
As previously described (10,21,27), although not reaching statistical significance in our study, perhaps due to the low number of cases, patients with Billroth I reconstructions had a higher prevalence of H. pylori infection than those with Billroth II reconstructions. H. pylori colonization in the gastric stump has not been correlated with any one of the evaluated variables (age, gender, reason for gastrectomy, type of anastomosis or interval between surgery and H. pylori status).
In our study, chronic gastritis was detected in 70% of patients without gastric cancer. Although H. pylori infection has not been implied in ulcer relapse in gastrectomized patients for benign peptic disease (23), persistent infection produces residual gastritis in the gastric stump and epithelial cell proliferation in the corpus (20). One study suggests that H. pylori eradication induces a regression of gastritis in the remnant (28), and H. pylori-induced gastritis has a synergic effect with bile reflux in stimulating cellular proliferation in the gastric stump (20,21). Moreover, a study of cell proliferation in patients with previous gastrectomy has shown that those positive for H. pylori had higher levels of cell proliferation than those who tested negative for this organism (22), suggesting that both may be implicated in gastric carcinogenesis in these patients.
Although, in the present study, the differential prevalence of H. pylori infection between both groups (with and without gastric cancer) did not reach statistical significance, the high prevalence of H. pylori infection in patients with gastric cancer (100% of patients) deserves some attention. Probably, with a greater number of patients, differences would reach statistical significance. And secondly, the high prevalence of H. pylori infection in both groups and the high efficacy of various treatments (29) reinforce the need for H. pylori eradication in patients with partial gastrectomy for benign ulcer disease, not only for the ulcerous antecedent but also as a measure to prevent gastric cancer.
In conclusion, H. pylori colonization in patients undergoing partial gastrectomy for benign ulcer disease does not seem to be influenced by bile reflux, and the results of the present study suggest that H. pylori may have a role in gastric carcinogenesis in gastrectomized patients.
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