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versión impresa ISSN 1130-0108
Rev. esp. enferm. dig. vol.98 no.9 sep. 2006
Linfoma MALT gástrico: características clínicas y prevalencia de la infección por H. pylori en una serie de 37 casos
J. P. Gisbert, B. Aguado1, M. Luna, S. Nistal1, L. M. Asenjo, T. Reina2, A. Acevedo2 and R. Arranz1
Services of Gastroenterology, 1Hematology and 2Pathology. Hospital Universitario de La Princesa. Universidad Autónoma. Madrid, Spain
Objective: to perform a retrospective review of the clinical characteristics and prevalence of H. pylori infection in patients with gastric MALT lymphoma diagnosed in our hospital during the last 15 years.
Methods: patients with gastric MALT lymphoma diagnosed in our hospital during the last 15 years were retrospectively included. Demographic, clinic, analytic, endoscopic, and histological variables were reviewed. The extension study, the staging classification, and the presence of H. pylori infection were assessed.
Results: thirty-seven patients with gastric MALT lymphoma were identified. Mean age was 61 years, with 62% of males. The most common presentation symptom was dyspepsia (76%), followed by digestive bleeding (11%) and constitutional syndrome (8%). At endoscopy, erosive lesions were identified in 41%, and proliferative or exophytic lesions in 43%. Most lymphomas were classified as low-grade (68%). The stage distribution was EI for 56%, EII for 13%, EIII for 3%, and EIV for 28%. The prevalence of H. pylori infection (histology in all cases, rapid urease test in 19%, and 13C-urea breath test in 24%) was 46%. When only low-grade lymphomas in stage EI were considered, H. pylori prevalence increased to 55%. When H. pylori infection was evaluated by 13C-urea breath testing (in addition to histology), the prevalence of H. pylori infection increased to 78%.
Conclusions: it is probable that the reduced H. pylori prevalence found in some studies, as in ours, could be explained by false-negative results obtained when only one diagnostic method was used. Therefore, at least two (invasive) diagnostic methods should be performed. Furthermore, the performance of a non-invasive diagnostic method (such as a 13C-urea breath test) before the exclusion of H. pylori infection should be considered.
Key words: MALT. Mucosa-associated lymphoid tissue. Gastric lymphoma. Helicobacter pylori.
Non-Hodgkin's gastric lymphoma is a rare tumor accounting for less than 10% of lymphomas, and 3% of gastric neoplasms (1-5). However, primary gastric lymphoma is the most common extranodal lymphoma (1-5). Histological features of gastric low-grade lymphomas closely resemble mucosa-associated lymphoid tissue (MALT) (1-5). Nevertheless, most MALT lymphoma locations do not contain lymphoid tissue. For example, under normal conditions there is no evidence of organized lymphoid tissue in the gastric mucosa, where only the presence of a few lymphocytes has been described. However, as previously mentioned, this is the most common site for extranodal lymphomas. The clue to correctly explain this paradox is MALT development after H. pylori colonization (6).
Several lines of evidence establish a causal association between H. pylori infection and gastric MALT lymphoma, such as the high prevalence of the microorganism in this type of lymphoma and, particularly, the demonstration of tumor regression after H. pylori eradication. Therefore, the question of MALT lymphoma as an infectious disease has been recently proposed, and the answer was "partly yes' (6,7).
However, nowadays the real prevalence of H. pylori in MALT lymphomas is unknown, as it varies between the various epidemiologic studies performed. Some studies showed that the prevalence of infection depends on the lymphoma's histological grade or the diagnostic method used, among others (8). A knowledge of the true prevalence of H. pylori in patients with MALT lymphoma is clinically relevant, as the detection of his organism will be followed by adequate eradication treatment, with consequent tumor regression in a high number of cases (1-5).
Our objective was to perform a retrospective review of the clinical characteristics and the prevalence of H. pylori infection in patients with gastric MALT lymphoma diagnosed in our hospital during the last 15 years.
To carry out the present retrospective study all patients diagnosed with gastric MALT lymphoma in our center during the last 15 years (from January 1991 to December 2005) were initially identified. To this end, a triple search was carried out in the files of the Digestive, Hematology and Pathology units.
Subsequently, all medical records were recovered and a specifically designed questionnaire was completed, where the following variables were included:
1. Demographic variables: age, sex, smoking habit, alcohol intake, and history of neoplasm.
2. Clinical variables: most common reason for consultation (presentation symptom), and presence of B symptoms (fever, night sweats, and weight loss -more than 10% of body mass in the previous 6 months).
3. Physical exploration: presence of adenopathies (and their localization), oropharyngeal exploration, presence of hepatomegaly or splenomegaly.
4. Laboratory variables: human immunodeficiency virus (HIV) serology, Epstein-Barr virus serology, hepatitis B and C virus serology.
5. Endoscopic variables: type of macroscopic lesion (erosive, exophytic, hypertrophic), localization (antrum, body, diffuse), and characteristics of gastric biopsies obtained by the initial endoscopic exploration (number and localization).
6. Histological variables: low-grade and high-grade lymphoma classification.
7. Extension study: ORL exploration, chest X-rays, abdominal ultrasounds, gastrointestinal follow-through, cervical and thoraco-abdominal computerized tomography (CT) scans, and bone marrow citology/biopsy.
8. Staging: according to the Ann Arbor classification as modified by Musshoff, where stage EI indicates disease is confined to the stomach, EII implies the involvement of subdiaphragmatic lymph nodes, EIII means the involvement of lymph nodes on both sides of the diaphragm, and EIV refers to the involvement of distant organs. A differentiation between stages EI1 (confined to the mucosa and submucosa) and EI2 (extended over the submucosa) was only performed in those few cases where an endoscopic ultrasonogram was performed.
9. H. pylori infection: prevalence and diagnostic methods used in its evaluation.
Statistical analysis: for qualitative variables, the percentage was calculated (with its corresponding 95% confidence interval or 95% CI). For quantitative variables, the arithmetic mean (and standard deviation) was provided. Although a comparison of the various variables was initially planned, only a descriptive analysis of variables could be done due to the limited number of patients included (37), resulting in reduced statistical power (that is, an elevated risk for beta errors).
From 1991 to 2005, 37 patients with gastric MALT lymphoma were identified and included in our study.
1. Demographic variables: the mean age of patients was 61 ± 14 years; 62% were males, 30% were smokers, and 16% had a history of alcohol abuse. In 11% a previous history of neoplasm existed.
2. Clinic variables: the most common reason for consultation (presentation symptom) was dyspepsia (76%), followed by digestive bleeding (hematemesis or melena, 11%) and constitutional syndrome (8%); 11% had B symptoms, fever (5%), night sweats (5%), and weight loss (8%).
3. Physical exploration: adenopathies were identified in 22% of cases; of these, the distribution was: submaxillary (0%), cervical (14%), supraclavicular (5%), axillary (14%), and inguinal (8%). The oropharyngeal exploration was normal in 88% of patients, whereas the pharynx was hyperemic in 6%, and a hyperplasia of sublingual salivary glands was observed in 6% of patients. Hepatomegaly and splenomegaly were present in 11% and 5% of patients, respectively.
4. Laboratory variables: Epstein-Barr virus and HIV serology were negative in all cases, while the serology for hepatitis B and C virus was positive in 5 and 3% of cases, respectively.
5. Endoscopic variables: gastroscopy was normal in 16% of cases, whereas erosive lesions were identified in 41%, and proliferative or exophytic lesions in 43%. Endoscopic lesions were most commonly localized in the antrum (60%), were observed in the body in only 35% of cases, and were diffuse in 5%. The site for gastric biopsies obtained during the initial endoscopy was: antrum (89%), body (57%), incisure (16%), and fundus (11%). The mean number of biopsies obtained by endoscopy was 8 ± 3, with a range from 2 to 23.
6. Histological variables: most lymphomas were classified as low-grade (25 patients, that is 68%), whereas the remaining 12 patients (32%) had a high-grade lymphoma. Patient characteristics by histological grade are summarized in table I.
7. Staging: stage distribution was: EI in 56%, EII in 13%, EIII in 3%, and EIV in 28%. Differentiation between stages EI1 and EI2 was only possible in 2 patients (both were EI1).
8. H. pylori infection: the microorganism was initially detected in only 15 of 37 patients; therefore, all histological paraffin sections of H. pylori-negative patients were reviewed, and infection was identified in 2 further patients. Thus, H. pylori prevalence finally was 46% (31-62, 95% CI). H. pylori prevalence in high-grade lymphomas was 58% (28-85, 95% CI), but in low-grade lymphomas it was 40% (23-59, 95% CI). When only low-grade lymphomas in stage EI were considered (11 patients), H. pylori prevalence was 55% (23-83, 95% CI). The diagnosis of H. pylori infection was determined by histology (hematoxylin-eosin stain) in all cases. In 19 and 24% a rapid urease test and a 13C-urea breath test, respectively, were performed besides histology. When H. pylori infection was detected both by histology and 13C-urea breath testing (9 patients), the prevalence increased to 78%.
In the present retrospective study, 37 patients with gastric MALT lymphoma were included for the last 15 years. Gastric MALT lymphoma is an uncommon neoplasm, with an incidence of 0.4-0.9 cases per 100,000 persons (9). This tumor has been more frequently diagnosed during the last 50 years, with a mean age of 60-65 years, and is 2-3 times more common in males (10,11), as our results show (mean age 61 years, 62% males).
Gastric MALT lymphomas are often asymptomatic, and when symptoms are present, they are generally nonspecific, predominantly dyspeptic (1-5,12,13). Therefore, the diagnosis of early gastric MALT lymphoma is difficult. In our patients the most common presentation symptom was dyspepsia (76%). In patients with advanced-stage lymphoma, anemia or a constitutional syndrome was present in 88% of our patients, these symptoms raising the possible diagnosis of gastric carcinoma (1-5,12,13). Finally, gastric MALT lymphoma may present with upper gastrointestinal bleeding in 20-30% of cases (1-5,12-14). In our experience, the presentation symptom was hematemesis or melena in 11% of patients.
Physical exploration in patients with gastric MALT lymphoma does not usually reveal any alterations (1-5,15), as was the case in most of our patients. Nonetheless, in high-grade lymphomas, clinical manifestations may be more evident. Thus, in advanced-stage lymphoma, hepatomegaly and splenomegaly can be detected (in 11 and 5% of our cases, respectively), or peripheral adenopathies can be found (in 22% of our patients).
A higher incidence of gastric MALT lymphoma in patients with hepatitis B virus has been described (16), as well as in patients with HIV (17,18). All our patients were HIV-negative, whereas 3% were infected by hepatitis B virus. Although this figure is higher than that reported for the general population, the small-size sample does not permit reliable conclusions to be drawn.
Endoscopic exploration may show a completely normal mucosa (this happened in 16% of our patients) or several endoscopic lesions. Three endoscopic patterns of gastric lymphoma have been described (ulcerative, exophytic and hypertrophic) (19). No hypertrophic pattern was found in our patients. Endoscopic lesions were more often localized in the antrum, as described in previous studies (1-5).
Gastric MALT lymphomas are divided up into high- and low-grade lymphomas according to the percentage of blast cells in gastric biopsy samples. At the time of diagnosis, 75-80% of lymphomas are classified as low grade (1-5) (as happened in 75% of our patients). It is very common to find both types of lymphoma in the same lesion, and it has been reported that up to one third of low-grade lymphomas progress to high-grade lymphomas (20), suggesting that both lesions represent the same tumoral process.
The Ann Arbor classification as modified by Musshoff is probably the most widely used staging method (1-5) -56% of our patients had stage EI. MALT lymphomas may invade not only other MALT tissues, but also lymph nodes and the bone narrow. In one Spanish study, 12% of low-grade MALT lymphomas were diagnosed in stages III-IV, and there was bone narrow infiltration in 15% of patients (21). This conclusion was confirmed by other authors (22). In our experience, 31% of patients were in stages III-IV.
To carry out a correct classification of gastric MALT lymphoma the following is required: a minute physical exploration, paying special attention to: presence of adenopathies, splenomegaly, oropharyngeal lesions; laboratory studies, with hemogram and biochemical tests including proteinogram, immunoglobulins, and lactate dehydrogenase; chest X-rays; cervical and thoracoabdominal computerized tomography (CT) scans; and bone marrow citology/biopsy.
Finally, endoscopic ultrasounds constitute a fundamental exploration to accurately evaluate not only the lesion's extent (infiltration of gastric wall) but also the presence of perigastric adenopathies (1-5). Furthermore, response to H. pylori eradication treatment can be predicted with this technique (23).
The prevalence of H. pylori infection in our patients was only 46%, a figure lower than that generally described in the literature. In this respect, we recently carried out a systematic review of all 38 studies (including a total of 1,844 patients) that evaluate H. pylori prevalence in patients with gastric MALT lymphoma (24-61), and the overall prevalence was 79% (8) (although the results varied between 100% (34,38,59) and less than 50% (55,56). Explanations for this diversity may be multiple and seem to depend, at least partly, on the number and type of techniques used to detect the infection, the histological grade of lymphoma, and the depth of tumor invasion. Thus, if appropriate diagnostic methods (in number and characteristics) are used, and if only low-grade lymphomas are considered, the prevalence of H. pylori infection increases to nearly 90%, which reinforces the causal role of these bacteria in gastric MALT lymphoma (8). Nevertheless, in our study, when only low-grade lymphomas in stage EI were considered, H. pylori prevalence was still low (55%).
The number of diagnostic methods used in our study was probably insufficient, as most patients were only evaluated by histology. A higher H. pylori prevalence has been described when serologic rather than histological methods were used (8). This probably could be explained by a decrease in bacterial colonization due to gastric atrophy and hypochlorhydria; however, antibodies against bacteria can be detected even years after mucosal clearance (38,54). On the other hand, H. pylori gastric mucosa colonization is not uniform; thus, even in the presence of infection, microorganisms may not be detected if the biopsy is taken from a non-colonized mucosal area. Therefore, H. pylori detection by histology is highly dependent on the number of gastric biopsies (38,51).
From the aforementioned results, we can deduce that in the presence of a negative result obtained by histology, a non-invasive diagnostic method such as the 13C-urea breath test or serology should be performed after definitely excluding H. pylori infection (27,38). In this respect, when H. pylori infection was evaluated by 13C-urea breath testing as well as by histology (this happened in the last 9 patients), the prevalence of infection increased to 78%. Thus, in our daily practice we usually use two biopsy-based methods (histology and a rapid urease test), and always perform a 13C-urea breath test to confirm negative cases.
To summarize, the accurately identification of H. pylori infection in patients with gastric MALT lymphoma is very relevant, as lymphoma regression has been demonstrated after H. pylori eradication. It is probable that the reduced H. pylori prevalence found in some studies, as in ours, could be explained by false-negative results obtained when only one diagnostic method was used. Therefore, one negative result obtained by histology (or rapid urease testing) should be followed by the use of a non-invasive diagnostic method before the exclusion of H. pylori infection.
Supported in part by grants from the "Instituto de Salud Carlos III" (C03/02 and PI050109).
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Javier P. Gisbert.
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Fax: 914 022 299.