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Prevalence of benign gastric polyps in a large pathology database
Digestive and Liver Disease 47 (2015) 164–169
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Oncology
Prevalence of benign gastric polyps in a large pathology database Amnon Sonnenberg a,b,∗ , Robert M. Genta a,c a
Miraca Life Sciences, Research Institute, Irving, TX, United States Portland VA Medical Center, Portland, OR, United States c University of Texas Southwestern Medical Center, Dallas, TX, United States b
a r t i c l e
i n f o
Article history: Received 19 August 2014 Accepted 5 October 2014 Available online 8 November 2014 Keywords: Epidemiology Fundic gland polyps Gastric adenomas Gastric atrophy Gastric hyperplastic polyps Gastric neuroendocrine tumours Intestinal metaplasia
a b s t r a c t Aims: The aim of the study was to utilize a large national histopathology database for the analysis of the clinical epidemiology of gastric polyps. Methods: In a case–control study, 71,575 case subjects with gastric polyps were compared to 741,351 control subjects without gastric polyps. Results: Of all patients, 7.72% harboured fundic gland polyps, 1.79% gastric hyperplastic polyps, 0.09% gastric adenomas, and 0.06% type I neuroendocrine tumours. All types showed a clear-cut age-dependent rise. Reflux disease was significantly more common in patients with fundic gland polyps and significantly less common in patients with gastric adenomas or neuroendocrine tumours. Anaemia was more common in patients with gastric hyperplastic polyps, gastric adenomas, or neuroendocrine tumours. Helicobacter pylori was found significantly less frequently in all subjects with gastric polyps than in controls. Intestinal metaplasia and gastric atrophy were both more common in gastric adenoma and neuroendocrine tumours and less common in fundic gland polyps than in controls. Different polyp types tended to coincide in the same patients. Conclusions: Gastric hyperplastic polyps appeared to mark the beginning of a progression from chronic gastritis to intestinal metaplasia and gastric atrophy, which leads to diminished gastric acid output and increased gastrin secretion. Gastric adenoma and neuroendocrine tumours reflect later stages of this process. Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
1. Introduction In the past thirty years, two major factors have altered the pathology of the stomach in the industrialized world and in the emerging economies. The first is the decline of Helicobacter pylori, identified in 1984 and quickly recognized as the main cause of chronic gastritis and peptic ulcer disease, as well as a crucial risk factor for gastric cancer and lymphoma [1,2]. The second factor is the development of proton-pump inhibitors (PPIs), introduced in 1988 in Europe and in 1990 in the United States. In addition to their acid-suppression properties, which have led to widespread use amongst patients with gastroesophageal reflux disease (GERD) and dyspepsia, PPIs also have substantial anti-inflammatory activity [3,4]. As a consequence of these changes, the epidemiology of
∗ Corresponding author at: Gastroenterology, Portland VA Medical Center P3-GI, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239, United States. Tel.: +1 503 220 8262x56679; fax: +1 503 220 3426. E-mail address: [email protected] (A. Sonnenberg).
gastric lesions associated with gastritis, gastric atrophy, and acid imbalance has undergone substantial changes. These changes have been particularly noticeable with respect to gastric polyps, lesions of heterogeneous histogenesis united into a single category only by their common elevated shape. While the overall incidence of polyps appears to have increased, as indicated by a higher prevalence in large series, there has also been a shift in the relative proportion of the different types of polyps: fundic gland polyps, which tend to arise in the normal oxyntic mucosa of subjects on long-term proton-pump therapy, have become the dominant type, while growths traditionally associated with H. pylori gastritis and its sequelae (e.g., hyperplastic and adenomatous polyps) have become less common. Over the years, several studies have attempted to define the relative distribution of gastric polyps, and their clinical and histopathological associations [5–12]. Because of their infrequent occurrence, however, many studies have been hampered by relatively small case numbers. Having access to a national pathology database that contains histopathologic, endoscopic, and clinical data on more than three quarter million patients who have had EGD with gastric biopsies, we designed a study to characterize
http://dx.doi.org/10.1016/j.dld.2014.10.004 1590-8658/Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
A. Sonnenberg, R.M. Genta / Digestive and Liver Disease 47 (2015) 164–169
gastric polyps with respect to their demographic characteristics and clinical associations, as well as their relationships with underlying changes of the gastric mucosa.
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2. Materials and methods
majority of cases. Megaloblastic changes are only rarely reported. For the purpose of this study we have collected data on the following indications: gastroesophageal reflux disease (GERD, as defined by the guidelines of the American College of Gastroenterology) [20], dyspepsia, and anaemia (all types).
2.1. Data source
2.4. Gastric histopathology
The Miraca Life Sciences Database is an electronic repository of histopathologic patient records. Biopsy specimens are submitted to Miraca Life Sciences by approximately 1500 gastroenterologists distributed throughout the United States. The database contains demographic information, a detailed list of all results of surgical pathology reports (current and past, coded in a pre-defined, standardized, and searchable fashion), a summary of the endoscopic report, and a synopsis of the clinical indications that lead to the current procedure. Medication history (including information about current and past use of acid-suppressing agents and previous H. pylori treatment), serology, and results of other laboratory tests are rarely provided. Therefore, they were not extracted for the performance of this study. In the recent past, this database has been utilized for a large variety of histo-epidemiologic studies [13–18]. For the purpose of the present study, the database was searched for all records of patients who underwent an esophagogastro-duodenoscopy (EGD) between January 1, 2008 and August 17, 2013. All data were derived from pre-existing records. No direct contact with either patients or providers was made and no individual patient information was revealed. All patient records were de-identified before being analyzed. For these reasons, the study protocol was exempted from the need for informed consent from its participants.
More than 90% of gastric biopsies in this laboratory are routinely stained with a specific anti-Helicobacter monoclonal immunochemical stain (Cell Marque, Rocklin, CA, USA); the remainder are stained with a modified Giemsa stain (HP Blue, Anatech, Ltd., Battle Creek, MI); all specimens are also stained with Alcian Blue–Periodic Acid Schiff to enhance the detection of intestinal metaplasia. Gastric biopsy specimens were diagnosed following the guidelines of the Updated Sydney System, and the 2002 International Atrophy Consensus [21,22]. OLGA scores are not routinely used, but the OLGA guidelines for the evaluation of atrophy and metaplasia are followed [23]. Briefly, Helicobacter infection was diagnosed when the characteristic curved organisms were visualized in a gastric biopsy specimen. Intestinal metaplasia was diagnosed in the presence of goblet cells in the gastric mucosa. Chronic inactive gastritis was diagnosed when the lamina propria contained dense populations of lymphocytes and plasma cells. The diagnosis of reactive gastropathy was based on the 2006 guidelines, which includes various combinations of foveolar hyperplasia, regenerative changes in the surface epithelium, oedema or hyperemia of the lamina propria, erosions, and smooth muscle proliferation [24]. Standard criteria were used for the diagnosis of gastric polyps, as previously detailed in Carmack et al. [12] Polyps could be received either as complete or as piecemeal excisions. The extent and location of the gastric mucosa sampled in each case was determined by the endoscopist, and ranged from a Sydney System-compliant set of biopsies to small amounts of tissue available at the base or peduncle of the lesion.
2.2. Patient selection All patients in the database who had gastric biopsies during the study period were included in the analysis. The presence of gastric biopsy specimens was the sole criterion for inclusion. If the database contained multiple entries for identical patients, only the first entry was considered. The presence of any one gastric biopsy containing H. pylori, intestinal metaplasia, or gastric atrophy was considered sufficient for making such diagnosis. Our analysis was restricted to the following types of polyps: fundic gland polyps, gastric hyperplastic polyps (also referred to as “inflammatory gastric polyps”), gastric adenomas, and type I neuroendocrine tumours (NETs, formerly referred to as “carcinoids”). Lipomas, pancreatic heterotopia, gastrointestinal stromal tumours, NETs type II and III, and malignant tumours presenting as polyps (lymphomas or carcinomas, primary or metastatic) are so rare that even in our large database it would be difficult or impossible to detect statistically significant associations. Therefore, they were excluded from the analysis. The diagnoses of fundic gland polyps, hyperplastic gastric polyps, gastric adenoma, and NETs, we used standardized histopathologic criteria as listed in previous publications [12,19].
2.5. Statistical analyses The statistical analyses focused on the comparison of cases (patients with one of the benign gastric polyps listed above) and controls (patients without such diagnosis). The mean ages and their standard deviations among case and control groups were compared using a t-test. The varying distributions of clinical and histopathologic findings among case and control groups were described in terms of odds ratios (OR) and their 95% confidence intervals (CI). In addition to univariate comparisons, multivariate logistic regression analyses were used to adjust the odds ratios for individual predictor variables entered simultaneously into the regression model, that is, age, gender, as well as presence of H. pylori, intestinal metaplasia, gastric atrophy, gastro-esophageal reflux disease (GERD), or anaemia. 3. Results
2.3. Clinical manifestations
3.1. Demographics
As stated above, the clinical information included a synopsis of the clinical indications leading to the current procedure as provided by the clinicians submitting the biopsy specimens. Therefore, we had no control over the definitions they used to determine their patients’ signs and symptoms. Detailed medical histories, including medications, laboratory results, social habits (e.g. smoking), and family history are not available. Therefore, certain indications for endoscopy that could be better defined by the integration of clinical and laboratory information must remain more general. For example, anaemia is listed unqualified or as due to “iron deficiency” in the
The database included 741,351 unique patients, of whom 7.72% harboured fundic gland polyps, 1.79% gastric hyperplastic polyps, 0.09% gastric adenomas, and 0.06% NETs. All types of gastric polyps showed a clear-cut age-dependent rise (Fig. 1). The prevalence of fundic gastric polyps rose steeply between the ages 10–69 years and then again declined in the oldest age groups. In contradistinction, the age specific rise of gastric adenoma was most pronounced in the oldest age groups after age 70 yrs. The prevalence of gastric hyperplastic polyps and NETs also exhibited an age-related increase, but showed a slight decline in the oldest or two oldest
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Fig. 1. Age-specific prevalence of gastric polyps. FGP, fundic gland polyp; GHP, gastric hyperplastic polyp; NET, type I Neuroendocrine tumour.
age-groups, respectively. Overall, women underwent more endoscopies with gastric biopsies than men (Fig. 2). Compared with the control group, female predominance was more pronounced in patients with fundic gastric polyps or NETs. It was less pronounced in patients with gastric adenomas. All these differences were statistically significant (Table 1).
Fig. 2. Sex distribution by gastric polyp type. FGP, fundic gland polyp; GHP, gastric hyperplastic polyp; NET, type I neuroendocrine tumour.
3.2. Clinical manifestations We analyzed the clinical information provided with the tissue specimen; in most cases this included the immediate indications
Table 1 Associations between 4 types of benign gastric polyps and various demographic, histopathologic, and clinical patient characteristics. Cases, % Fundic gland polyp Grand total Average age, SD Male Female H. pylori Intestinal metaplasia Gastric atrophy GERD Anaemia
57,214 59.5, 13.1 18,050 39,146 162 851 47 31,972 3985
7.86%
Gastric hyperplastic polyp Grand total Average age, SD Male Female H. pylori Intestinal metaplasia Gastric atrophy GERD Anaemia
13,288 64.9, 13.1 5131 8156 754 546 308 5586 2007
1.94%
Gastric adenoma Grand total Average age, SD Male Female H. pylori Intestinal metaplasia Gastric atrophy GERD Anaemia
661 68.8, 13.9 297 364 38 66 47 202 163
0.10%
Gastric neuroendocrine tumour Grand total 412 63.5, 13.2 Average age, SD 127 Male 285 Female 7 H. pylori 50 Intestinal metaplasia 117 Gastric atrophy 100 GERD 81 Anaemia
6.53% 8.67% 0.22% 2.98% 1.23% 9.32% 7.31%
1.95% 1.94% 1.02% 1.93% 7.52% 1.76% 3.82%
0.11% 0.09% 0.05% 0.24% 1.23% 0.06% 0.32% 0.06% 0.05% 0.07% 0.01% 0.18% 3.00% 0.03% 0.16%
Controls
Odds ratio
95% CI
671,042 55.7, 16.4 258,187 412,561 72,902 27,704 3787 311,079 50,539
t = 64.154 1 1.36 0.02 0.35 0.14 1.47 0.92
p = 0.000
671,042 55.7, 16.4 258,187 412,561 72,902 27,704 3787 311,079 50,539
t = 79.6 1 0.99 0.49 1.00 4.18 0.84 2.18
p = 0.000
671,042 55.7, 16.4 258,187 412,561 72,902 27,704 3787 311,079 50,539
t = 24.2 1 0.77 0.50 2.58 13.49 0.51 4.02
p = 0.000
671,042 55.7, 16.4 258,187 412,561 72,902 27,704 3787 311,079 50,539
t = 11.9 1 1.40 0.14 3.21 69.88 0.37 3.00
p = 0.000
OR, odds ratio; CI, confidence interval; SD, standard deviation; GERD, gastroesophageal reflux disease. a Adjusted for age and sex.
(1.33–1.38) (0.02–0.03) (0.33–0.38) (0.11–0.19) (1.44–1.49) (0.89–0.95)
(0.96–1.03) (0.46–0.53) (0.91–1.08) (3.72–4.70) (0.81–0.87) (2.08–2.29)
(0.66–0.89) (0.36–0.69) (2.00–3.32) (10.01–18.18) (0.43–0.60) (3.37–4.80)
(1.14–1.73) (0.07–0.30) (2.39–4.31) (56.28–86.77) (0.30–0.46) (2.36–3.83)
Adjusted ORa
95% CI
1.36 0.02 0.36 0.14 1.47 0.94
(1.33–1.38) (0.02–0.03) (0.34–0.39) (0.10–0.18) (1.44–1.49) (0.90–0.97)
0.98 0.55 0.76 2.97 0.91 1.65
(0.95–1.02) (0.51–0.59) (0.69–0.83) (2.63–3.35) (0.88–0.94) (1.57–1.74)
0.76 0.54 1.49 5.89 0.63 2.39
(0.65–0.89) (0.38–0.74) (1.12–1.94) (4.22–8.03) (0.53–0.75) (1.98–2.86)
1.28 0.19 0.89 47.32 0.45 1.56
(1.04–1.58) (0.08–0.37) (0.63–1.22) (36.73–60.55) (0.36–0.57) (1.20–2.00)
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Fig. 3. Prevalence of gastro-esophageal reflux disease and anaemia by polyp type.
for the endoscopy and a brief summary of the past clinical history. With the notable exception of anaemia and GERD, no striking associations were found between the presence of gastric polyps and any other clinical manifestations. Compared with controls, GERD was significantly more common in patients with fundic gland polyps and significantly less common in patients with gastric adenomas or NETs. Compared with controls, anaemia was more common in patients with gastric hyperplastic polyps, gastric adenomas, or NETs (Fig. 3, Table 1). 3.3. Associations with gastric histopathology Fig. 4. Prevalence of mucosal histopathology by polyp type.
Histologic evidence for H. pylori was found significantly less frequently in all subjects with gastric polyps than in controls (Fig. 4). The difference was most striking with respect to fundic gland polyps and gastric carcinoids. Intestinal metaplasia was more common in gastric adenoma and carcinoid and less common in fundic gland polyps than in controls. A similar distribution applied to gastric atrophy, which was also more common in gastric adenoma and carcinoid, and less common in fundic gland polyps than in controls. Table 2 compares the joint associations among various types of gastric polyps. The odds ratios were adjusted for age, sex, clinical manifestations, and gastric mucosal changes. In general, the presence of any one type of gastric polyp tended to be associated with the presence of other types. For instance, the presence of gastric hyperplastic polyps was significantly associated with fundic gland polyp, gastric adenoma, and NET. The strongest association was found between gastric adenoma and NET. Fundic gland polyps were associated with hyperplastic polyps, but not with gastric adenoma and inversely associated with gastric NETs. 4. Discussion Using a national database of histopathology reports, the present study analyzed the epidemiology of the four most common types of benign gastric polyps in a large patient population from the United States. Fundic gland polyps (80%) and gastric hyperplastic polyps (19%) comprised the majority of all gastric polyps. Adenomas and neuroendocrine tumours both comprised less than 1% of all gastric
polyps. The distinctive demographic and clinical patterns of different gastric polypoid lesions and their varying associations with H. pylori, intestinal metaplasia or gastric atrophy point at varying influences in their underlying pathophysiology. Comparing the prevalence of polyps reported in different studies is complicated by several factors. Studies that include sufficient numbers of patients were conducted in different populations, the methods were widely different (with both prospective and retrospective studies included), the histopathologic criteria were not always detailed, and the background phenotype of the gastric mucosa was not evaluated. Older studies described gastric hyperplastic polyps as the most common type of gastric polyps, a more recent US study found fundic gland polyps to be the most common type of benign gastric polyp [12]. Fundic gland polyps are particularly common in patients with GERD and appear related to long-term suppression of gastric acid secretion with proton pump inhibitors [25,26]. Their presence is inversely associated with the presence of gastric H. pylori infection, as demonstrated by the present analysis, as well as previously published data [27]. This negative association lends itself to at least two possible explanations. H. pylori infection, or the associated inflammatory responses, could exert a direct (protective) influence on the formation of fundic gland polyps. This scenario appears unlikely in light of the finding that the oxyntic mucosa of patients with H. pylori gastritis have a prevalence of parietal cell protrusions and oxyntic gland dilatations similar to that of non-infected patients on proton-pump inhibitors
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Table 2 Associations among different types of benign gastric polyp.
Gastric hyperplastic polyp Gastric adenoma Neuroendocrine tumour
Fundic gland polyp
Gastric hyperplastic polyp
Gastric adenoma
1.12 (1.05–1.19) 0.85 (0.63–1.16) 0.27 (0.14–0.52)
– 2.79 (1.95–3.98) 5.89 (4.25–8.17)
– – 19.37 (9.14–41.05)
Table shows odds ratios and their 95% confidence intervals, adjusted for age, gender, as well as presence of H. pylori, intestinal metaplasia, gastric atrophy, gastro-esophageal reflux disease (GERD), and anaemia.
[28]. H. pylori infection is also inversely associated with GERD; thus, the negative association between H. pylori gastritis and fundic gland polyps seems more likely to reflect on the underlying indirect influence of GERD in H. pylori-free patients with well-maintained acid secretion, who are frequently treated with antisecretory medications [29,30]. Similarly to the present data, previous studies have also shown gastric hyperplastic polyps to be the second most common type of gastric polyps, being equally common in men and women [12]. Previous studies have also shown a positive association between gastric atrophy and the occurrence of hyperplastic polyps [8,31]. Consistent with these earlier reports, the present study found an increased prevalence of anaemia (a possible epiphenomenon of atrophic gastritis) and gastric atrophy in patients with gastric hyperplastic polyps. Gastric adenomas are considered true premalignant conditions of the gastric mucosa, which can lead from dysplasia to carcinoma. Type I neuroendocrine tumours derive from the enterochromaffin-like cells of the gastric mucosa. They are associated with hypergastrinemia resulting from atrophic gastritis. In the present study, adenomas were relatively more common in men, whereas NETs were strikingly more common in women. Although both polyp types showed an age-dependent rise, this rise was more pronounced in adenomas than NETs. Apart from these demographic differences, however, adenomas and NETs were also characterized by some striking resemblance in their epidemiologic patterns. The presence of gastric adenomas was strongly associated with the simultaneous presence gastric NETs. Both types of polyp were negatively associated with clinical symptoms of GERD and positively associated with anaemia. With respect to gastric histopathology, both types were also negatively associated with H. pylori and positively associated with presence of intestinal metaplasia and gastric atrophy. The negative association with H. pylori may be partly influenced by the presence of intestinal metaplasia and gastric atrophy, which in by themselves negatively influence the presence of H. pylori in the stomach. It might also be related, at least in part, to previous H. pylori treatment. This study must be interpreted in light of a number of limitations. First, it reflects the prevalence of polyps as biopsied or excised by a diverse group of practicing endoscopists across the United States. Therefore, the extent of the accompanying gastric mucosa varied greatly: while in a small percentage of cases the polyps were accompanied by a Sydney System-compliant set of biopsies, many included only one sample from the non-polypoid mucosa. The most common combination was a fundic gland polyp and a sample from the antral mucosa. In cases where only the polyp was submitted, pathologists used the tissue available at the base or peduncle to estimate the status of the gastric mucosa. While the variability of the source is partially offset by the uniformity of the process from tissue to diagnosis and the standardized histopathologic criteria applied, it is still possible that the acquisition of the biopsies was influenced by several types of bias. Gastroenterologists who removed a polyp from an endoscopically normal stomach may have been less inclined to sample other areas of the gastric mucosa because of the assumption that it would be unremarkable. Since less than 4% of US endoscopists regularly follow the Sydney
System biopsy protocol, it is unlikely that the presence of a polyp may have swayed many of those who do not to expand their biopsy sampling [32]. Furthermore financial considerations related to patients’ insurance coverage may have limited some endoscopists’ ability to collect more than a certain number of samples. The ideal study to determine the prevalence of gastric polyps and the background of the gastric mucosa associated with each type would be straightforward to design: patients should be prospectively recruited; a Sydney System compliant protocol should be performed, with biopsies read by a single pathologist; serology for H. pylori should be performed in all patients, and those who are histologically Helicobacter-negative but have active gastritis should undergo a urea breath test or a stool antigen test. In a European or North American population, such study would require approximately 10 endoscopy procedures to detect one fundic gland polyp, 30 for each inflammatory polyp, and 100 each for carcinoids and adenomas. Since such a study is clearly unfeasible, we have to accept that a large body or retrospective data is the best alternative to answer the questions we posed. In summary, our study suggests that the observed demographic, clinical, and histopathologic patterns stem from the underlying pathophysiology that affects the development of the various types of gastric polyps, ranging from fundic gland polyps to gastric hyperplastic polyps and ultimately gastric NETs or adenomas. The varying age difference between case and control subjects and among patients harbouring different polypoid lesions reflects on the time it takes for such changes to develop in the gastric mucosa. The main driving force of the observed changes is probably the stage-wise development of gastritis and its effect on acid secretion. Over a prolonged time period, chronic gastritis can result in the development of intestinal metaplasia and gastric atrophy, which leads to diminished gastric acid output and increased gastrin secretion. Gastric hyperplastic polyps may mark the beginning of this process, while gastric adenoma and carcinoid may reflect on its later stages. Gastritis and partial atrophy would be protective against GERD but promote the development of anaemia. Besides gender differences and age, other additional environmental risk factors may be responsible for the different pathways taken by gastric adenoma versus carcinoids. Conflict of interest A Sonnenberg declares no relevant conflicts of interest. RM Genta is employed by Miraca Life Sciences, Irving, TX. References [1] Marshall BJ. Campylobacter pyloridis and gastritis. Journal of Infectious Diseases 1986;153:650–7. [2] Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. New England Journal of Medicine 1991;325:1127–31. [3] Vakil N. Prescribing proton pump inhibitors: is it time to pause and rethink. Drugs 2012;72:437–45. [4] Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. Digestive Diseases and Sciences 2009;54:2312–7. [5] Laxen F, Sipponen P, Ihamaki T, et al. Gastric polyps; their morphological and endoscopical characteristics and relation to gastric carcinoma. Acta
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Oncology
Prevalence of benign gastric polyps in a large pathology database Amnon Sonnenberg a,b,∗ , Robert M. Genta a,c a
Miraca Life Sciences, Research Institute, Irving, TX, United States Portland VA Medical Center, Portland, OR, United States c University of Texas Southwestern Medical Center, Dallas, TX, United States b
a r t i c l e
i n f o
Article history: Received 19 August 2014 Accepted 5 October 2014 Available online 8 November 2014 Keywords: Epidemiology Fundic gland polyps Gastric adenomas Gastric atrophy Gastric hyperplastic polyps Gastric neuroendocrine tumours Intestinal metaplasia
a b s t r a c t Aims: The aim of the study was to utilize a large national histopathology database for the analysis of the clinical epidemiology of gastric polyps. Methods: In a case–control study, 71,575 case subjects with gastric polyps were compared to 741,351 control subjects without gastric polyps. Results: Of all patients, 7.72% harboured fundic gland polyps, 1.79% gastric hyperplastic polyps, 0.09% gastric adenomas, and 0.06% type I neuroendocrine tumours. All types showed a clear-cut age-dependent rise. Reflux disease was significantly more common in patients with fundic gland polyps and significantly less common in patients with gastric adenomas or neuroendocrine tumours. Anaemia was more common in patients with gastric hyperplastic polyps, gastric adenomas, or neuroendocrine tumours. Helicobacter pylori was found significantly less frequently in all subjects with gastric polyps than in controls. Intestinal metaplasia and gastric atrophy were both more common in gastric adenoma and neuroendocrine tumours and less common in fundic gland polyps than in controls. Different polyp types tended to coincide in the same patients. Conclusions: Gastric hyperplastic polyps appeared to mark the beginning of a progression from chronic gastritis to intestinal metaplasia and gastric atrophy, which leads to diminished gastric acid output and increased gastrin secretion. Gastric adenoma and neuroendocrine tumours reflect later stages of this process. Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
1. Introduction In the past thirty years, two major factors have altered the pathology of the stomach in the industrialized world and in the emerging economies. The first is the decline of Helicobacter pylori, identified in 1984 and quickly recognized as the main cause of chronic gastritis and peptic ulcer disease, as well as a crucial risk factor for gastric cancer and lymphoma [1,2]. The second factor is the development of proton-pump inhibitors (PPIs), introduced in 1988 in Europe and in 1990 in the United States. In addition to their acid-suppression properties, which have led to widespread use amongst patients with gastroesophageal reflux disease (GERD) and dyspepsia, PPIs also have substantial anti-inflammatory activity [3,4]. As a consequence of these changes, the epidemiology of
∗ Corresponding author at: Gastroenterology, Portland VA Medical Center P3-GI, 3710 SW U.S. Veterans Hospital Road, Portland, OR 97239, United States. Tel.: +1 503 220 8262x56679; fax: +1 503 220 3426. E-mail address: [email protected] (A. Sonnenberg).
gastric lesions associated with gastritis, gastric atrophy, and acid imbalance has undergone substantial changes. These changes have been particularly noticeable with respect to gastric polyps, lesions of heterogeneous histogenesis united into a single category only by their common elevated shape. While the overall incidence of polyps appears to have increased, as indicated by a higher prevalence in large series, there has also been a shift in the relative proportion of the different types of polyps: fundic gland polyps, which tend to arise in the normal oxyntic mucosa of subjects on long-term proton-pump therapy, have become the dominant type, while growths traditionally associated with H. pylori gastritis and its sequelae (e.g., hyperplastic and adenomatous polyps) have become less common. Over the years, several studies have attempted to define the relative distribution of gastric polyps, and their clinical and histopathological associations [5–12]. Because of their infrequent occurrence, however, many studies have been hampered by relatively small case numbers. Having access to a national pathology database that contains histopathologic, endoscopic, and clinical data on more than three quarter million patients who have had EGD with gastric biopsies, we designed a study to characterize
http://dx.doi.org/10.1016/j.dld.2014.10.004 1590-8658/Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
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gastric polyps with respect to their demographic characteristics and clinical associations, as well as their relationships with underlying changes of the gastric mucosa.
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2. Materials and methods
majority of cases. Megaloblastic changes are only rarely reported. For the purpose of this study we have collected data on the following indications: gastroesophageal reflux disease (GERD, as defined by the guidelines of the American College of Gastroenterology) [20], dyspepsia, and anaemia (all types).
2.1. Data source
2.4. Gastric histopathology
The Miraca Life Sciences Database is an electronic repository of histopathologic patient records. Biopsy specimens are submitted to Miraca Life Sciences by approximately 1500 gastroenterologists distributed throughout the United States. The database contains demographic information, a detailed list of all results of surgical pathology reports (current and past, coded in a pre-defined, standardized, and searchable fashion), a summary of the endoscopic report, and a synopsis of the clinical indications that lead to the current procedure. Medication history (including information about current and past use of acid-suppressing agents and previous H. pylori treatment), serology, and results of other laboratory tests are rarely provided. Therefore, they were not extracted for the performance of this study. In the recent past, this database has been utilized for a large variety of histo-epidemiologic studies [13–18]. For the purpose of the present study, the database was searched for all records of patients who underwent an esophagogastro-duodenoscopy (EGD) between January 1, 2008 and August 17, 2013. All data were derived from pre-existing records. No direct contact with either patients or providers was made and no individual patient information was revealed. All patient records were de-identified before being analyzed. For these reasons, the study protocol was exempted from the need for informed consent from its participants.
More than 90% of gastric biopsies in this laboratory are routinely stained with a specific anti-Helicobacter monoclonal immunochemical stain (Cell Marque, Rocklin, CA, USA); the remainder are stained with a modified Giemsa stain (HP Blue, Anatech, Ltd., Battle Creek, MI); all specimens are also stained with Alcian Blue–Periodic Acid Schiff to enhance the detection of intestinal metaplasia. Gastric biopsy specimens were diagnosed following the guidelines of the Updated Sydney System, and the 2002 International Atrophy Consensus [21,22]. OLGA scores are not routinely used, but the OLGA guidelines for the evaluation of atrophy and metaplasia are followed [23]. Briefly, Helicobacter infection was diagnosed when the characteristic curved organisms were visualized in a gastric biopsy specimen. Intestinal metaplasia was diagnosed in the presence of goblet cells in the gastric mucosa. Chronic inactive gastritis was diagnosed when the lamina propria contained dense populations of lymphocytes and plasma cells. The diagnosis of reactive gastropathy was based on the 2006 guidelines, which includes various combinations of foveolar hyperplasia, regenerative changes in the surface epithelium, oedema or hyperemia of the lamina propria, erosions, and smooth muscle proliferation [24]. Standard criteria were used for the diagnosis of gastric polyps, as previously detailed in Carmack et al. [12] Polyps could be received either as complete or as piecemeal excisions. The extent and location of the gastric mucosa sampled in each case was determined by the endoscopist, and ranged from a Sydney System-compliant set of biopsies to small amounts of tissue available at the base or peduncle of the lesion.
2.2. Patient selection All patients in the database who had gastric biopsies during the study period were included in the analysis. The presence of gastric biopsy specimens was the sole criterion for inclusion. If the database contained multiple entries for identical patients, only the first entry was considered. The presence of any one gastric biopsy containing H. pylori, intestinal metaplasia, or gastric atrophy was considered sufficient for making such diagnosis. Our analysis was restricted to the following types of polyps: fundic gland polyps, gastric hyperplastic polyps (also referred to as “inflammatory gastric polyps”), gastric adenomas, and type I neuroendocrine tumours (NETs, formerly referred to as “carcinoids”). Lipomas, pancreatic heterotopia, gastrointestinal stromal tumours, NETs type II and III, and malignant tumours presenting as polyps (lymphomas or carcinomas, primary or metastatic) are so rare that even in our large database it would be difficult or impossible to detect statistically significant associations. Therefore, they were excluded from the analysis. The diagnoses of fundic gland polyps, hyperplastic gastric polyps, gastric adenoma, and NETs, we used standardized histopathologic criteria as listed in previous publications [12,19].
2.5. Statistical analyses The statistical analyses focused on the comparison of cases (patients with one of the benign gastric polyps listed above) and controls (patients without such diagnosis). The mean ages and their standard deviations among case and control groups were compared using a t-test. The varying distributions of clinical and histopathologic findings among case and control groups were described in terms of odds ratios (OR) and their 95% confidence intervals (CI). In addition to univariate comparisons, multivariate logistic regression analyses were used to adjust the odds ratios for individual predictor variables entered simultaneously into the regression model, that is, age, gender, as well as presence of H. pylori, intestinal metaplasia, gastric atrophy, gastro-esophageal reflux disease (GERD), or anaemia. 3. Results
2.3. Clinical manifestations
3.1. Demographics
As stated above, the clinical information included a synopsis of the clinical indications leading to the current procedure as provided by the clinicians submitting the biopsy specimens. Therefore, we had no control over the definitions they used to determine their patients’ signs and symptoms. Detailed medical histories, including medications, laboratory results, social habits (e.g. smoking), and family history are not available. Therefore, certain indications for endoscopy that could be better defined by the integration of clinical and laboratory information must remain more general. For example, anaemia is listed unqualified or as due to “iron deficiency” in the
The database included 741,351 unique patients, of whom 7.72% harboured fundic gland polyps, 1.79% gastric hyperplastic polyps, 0.09% gastric adenomas, and 0.06% NETs. All types of gastric polyps showed a clear-cut age-dependent rise (Fig. 1). The prevalence of fundic gastric polyps rose steeply between the ages 10–69 years and then again declined in the oldest age groups. In contradistinction, the age specific rise of gastric adenoma was most pronounced in the oldest age groups after age 70 yrs. The prevalence of gastric hyperplastic polyps and NETs also exhibited an age-related increase, but showed a slight decline in the oldest or two oldest
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Fig. 1. Age-specific prevalence of gastric polyps. FGP, fundic gland polyp; GHP, gastric hyperplastic polyp; NET, type I Neuroendocrine tumour.
age-groups, respectively. Overall, women underwent more endoscopies with gastric biopsies than men (Fig. 2). Compared with the control group, female predominance was more pronounced in patients with fundic gastric polyps or NETs. It was less pronounced in patients with gastric adenomas. All these differences were statistically significant (Table 1).
Fig. 2. Sex distribution by gastric polyp type. FGP, fundic gland polyp; GHP, gastric hyperplastic polyp; NET, type I neuroendocrine tumour.
3.2. Clinical manifestations We analyzed the clinical information provided with the tissue specimen; in most cases this included the immediate indications
Table 1 Associations between 4 types of benign gastric polyps and various demographic, histopathologic, and clinical patient characteristics. Cases, % Fundic gland polyp Grand total Average age, SD Male Female H. pylori Intestinal metaplasia Gastric atrophy GERD Anaemia
57,214 59.5, 13.1 18,050 39,146 162 851 47 31,972 3985
7.86%
Gastric hyperplastic polyp Grand total Average age, SD Male Female H. pylori Intestinal metaplasia Gastric atrophy GERD Anaemia
13,288 64.9, 13.1 5131 8156 754 546 308 5586 2007
1.94%
Gastric adenoma Grand total Average age, SD Male Female H. pylori Intestinal metaplasia Gastric atrophy GERD Anaemia
661 68.8, 13.9 297 364 38 66 47 202 163
0.10%
Gastric neuroendocrine tumour Grand total 412 63.5, 13.2 Average age, SD 127 Male 285 Female 7 H. pylori 50 Intestinal metaplasia 117 Gastric atrophy 100 GERD 81 Anaemia
6.53% 8.67% 0.22% 2.98% 1.23% 9.32% 7.31%
1.95% 1.94% 1.02% 1.93% 7.52% 1.76% 3.82%
0.11% 0.09% 0.05% 0.24% 1.23% 0.06% 0.32% 0.06% 0.05% 0.07% 0.01% 0.18% 3.00% 0.03% 0.16%
Controls
Odds ratio
95% CI
671,042 55.7, 16.4 258,187 412,561 72,902 27,704 3787 311,079 50,539
t = 64.154 1 1.36 0.02 0.35 0.14 1.47 0.92
p = 0.000
671,042 55.7, 16.4 258,187 412,561 72,902 27,704 3787 311,079 50,539
t = 79.6 1 0.99 0.49 1.00 4.18 0.84 2.18
p = 0.000
671,042 55.7, 16.4 258,187 412,561 72,902 27,704 3787 311,079 50,539
t = 24.2 1 0.77 0.50 2.58 13.49 0.51 4.02
p = 0.000
671,042 55.7, 16.4 258,187 412,561 72,902 27,704 3787 311,079 50,539
t = 11.9 1 1.40 0.14 3.21 69.88 0.37 3.00
p = 0.000
OR, odds ratio; CI, confidence interval; SD, standard deviation; GERD, gastroesophageal reflux disease. a Adjusted for age and sex.
(1.33–1.38) (0.02–0.03) (0.33–0.38) (0.11–0.19) (1.44–1.49) (0.89–0.95)
(0.96–1.03) (0.46–0.53) (0.91–1.08) (3.72–4.70) (0.81–0.87) (2.08–2.29)
(0.66–0.89) (0.36–0.69) (2.00–3.32) (10.01–18.18) (0.43–0.60) (3.37–4.80)
(1.14–1.73) (0.07–0.30) (2.39–4.31) (56.28–86.77) (0.30–0.46) (2.36–3.83)
Adjusted ORa
95% CI
1.36 0.02 0.36 0.14 1.47 0.94
(1.33–1.38) (0.02–0.03) (0.34–0.39) (0.10–0.18) (1.44–1.49) (0.90–0.97)
0.98 0.55 0.76 2.97 0.91 1.65
(0.95–1.02) (0.51–0.59) (0.69–0.83) (2.63–3.35) (0.88–0.94) (1.57–1.74)
0.76 0.54 1.49 5.89 0.63 2.39
(0.65–0.89) (0.38–0.74) (1.12–1.94) (4.22–8.03) (0.53–0.75) (1.98–2.86)
1.28 0.19 0.89 47.32 0.45 1.56
(1.04–1.58) (0.08–0.37) (0.63–1.22) (36.73–60.55) (0.36–0.57) (1.20–2.00)
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Fig. 3. Prevalence of gastro-esophageal reflux disease and anaemia by polyp type.
for the endoscopy and a brief summary of the past clinical history. With the notable exception of anaemia and GERD, no striking associations were found between the presence of gastric polyps and any other clinical manifestations. Compared with controls, GERD was significantly more common in patients with fundic gland polyps and significantly less common in patients with gastric adenomas or NETs. Compared with controls, anaemia was more common in patients with gastric hyperplastic polyps, gastric adenomas, or NETs (Fig. 3, Table 1). 3.3. Associations with gastric histopathology Fig. 4. Prevalence of mucosal histopathology by polyp type.
Histologic evidence for H. pylori was found significantly less frequently in all subjects with gastric polyps than in controls (Fig. 4). The difference was most striking with respect to fundic gland polyps and gastric carcinoids. Intestinal metaplasia was more common in gastric adenoma and carcinoid and less common in fundic gland polyps than in controls. A similar distribution applied to gastric atrophy, which was also more common in gastric adenoma and carcinoid, and less common in fundic gland polyps than in controls. Table 2 compares the joint associations among various types of gastric polyps. The odds ratios were adjusted for age, sex, clinical manifestations, and gastric mucosal changes. In general, the presence of any one type of gastric polyp tended to be associated with the presence of other types. For instance, the presence of gastric hyperplastic polyps was significantly associated with fundic gland polyp, gastric adenoma, and NET. The strongest association was found between gastric adenoma and NET. Fundic gland polyps were associated with hyperplastic polyps, but not with gastric adenoma and inversely associated with gastric NETs. 4. Discussion Using a national database of histopathology reports, the present study analyzed the epidemiology of the four most common types of benign gastric polyps in a large patient population from the United States. Fundic gland polyps (80%) and gastric hyperplastic polyps (19%) comprised the majority of all gastric polyps. Adenomas and neuroendocrine tumours both comprised less than 1% of all gastric
polyps. The distinctive demographic and clinical patterns of different gastric polypoid lesions and their varying associations with H. pylori, intestinal metaplasia or gastric atrophy point at varying influences in their underlying pathophysiology. Comparing the prevalence of polyps reported in different studies is complicated by several factors. Studies that include sufficient numbers of patients were conducted in different populations, the methods were widely different (with both prospective and retrospective studies included), the histopathologic criteria were not always detailed, and the background phenotype of the gastric mucosa was not evaluated. Older studies described gastric hyperplastic polyps as the most common type of gastric polyps, a more recent US study found fundic gland polyps to be the most common type of benign gastric polyp [12]. Fundic gland polyps are particularly common in patients with GERD and appear related to long-term suppression of gastric acid secretion with proton pump inhibitors [25,26]. Their presence is inversely associated with the presence of gastric H. pylori infection, as demonstrated by the present analysis, as well as previously published data [27]. This negative association lends itself to at least two possible explanations. H. pylori infection, or the associated inflammatory responses, could exert a direct (protective) influence on the formation of fundic gland polyps. This scenario appears unlikely in light of the finding that the oxyntic mucosa of patients with H. pylori gastritis have a prevalence of parietal cell protrusions and oxyntic gland dilatations similar to that of non-infected patients on proton-pump inhibitors
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Table 2 Associations among different types of benign gastric polyp.
Gastric hyperplastic polyp Gastric adenoma Neuroendocrine tumour
Fundic gland polyp
Gastric hyperplastic polyp
Gastric adenoma
1.12 (1.05–1.19) 0.85 (0.63–1.16) 0.27 (0.14–0.52)
– 2.79 (1.95–3.98) 5.89 (4.25–8.17)
– – 19.37 (9.14–41.05)
Table shows odds ratios and their 95% confidence intervals, adjusted for age, gender, as well as presence of H. pylori, intestinal metaplasia, gastric atrophy, gastro-esophageal reflux disease (GERD), and anaemia.
[28]. H. pylori infection is also inversely associated with GERD; thus, the negative association between H. pylori gastritis and fundic gland polyps seems more likely to reflect on the underlying indirect influence of GERD in H. pylori-free patients with well-maintained acid secretion, who are frequently treated with antisecretory medications [29,30]. Similarly to the present data, previous studies have also shown gastric hyperplastic polyps to be the second most common type of gastric polyps, being equally common in men and women [12]. Previous studies have also shown a positive association between gastric atrophy and the occurrence of hyperplastic polyps [8,31]. Consistent with these earlier reports, the present study found an increased prevalence of anaemia (a possible epiphenomenon of atrophic gastritis) and gastric atrophy in patients with gastric hyperplastic polyps. Gastric adenomas are considered true premalignant conditions of the gastric mucosa, which can lead from dysplasia to carcinoma. Type I neuroendocrine tumours derive from the enterochromaffin-like cells of the gastric mucosa. They are associated with hypergastrinemia resulting from atrophic gastritis. In the present study, adenomas were relatively more common in men, whereas NETs were strikingly more common in women. Although both polyp types showed an age-dependent rise, this rise was more pronounced in adenomas than NETs. Apart from these demographic differences, however, adenomas and NETs were also characterized by some striking resemblance in their epidemiologic patterns. The presence of gastric adenomas was strongly associated with the simultaneous presence gastric NETs. Both types of polyp were negatively associated with clinical symptoms of GERD and positively associated with anaemia. With respect to gastric histopathology, both types were also negatively associated with H. pylori and positively associated with presence of intestinal metaplasia and gastric atrophy. The negative association with H. pylori may be partly influenced by the presence of intestinal metaplasia and gastric atrophy, which in by themselves negatively influence the presence of H. pylori in the stomach. It might also be related, at least in part, to previous H. pylori treatment. This study must be interpreted in light of a number of limitations. First, it reflects the prevalence of polyps as biopsied or excised by a diverse group of practicing endoscopists across the United States. Therefore, the extent of the accompanying gastric mucosa varied greatly: while in a small percentage of cases the polyps were accompanied by a Sydney System-compliant set of biopsies, many included only one sample from the non-polypoid mucosa. The most common combination was a fundic gland polyp and a sample from the antral mucosa. In cases where only the polyp was submitted, pathologists used the tissue available at the base or peduncle to estimate the status of the gastric mucosa. While the variability of the source is partially offset by the uniformity of the process from tissue to diagnosis and the standardized histopathologic criteria applied, it is still possible that the acquisition of the biopsies was influenced by several types of bias. Gastroenterologists who removed a polyp from an endoscopically normal stomach may have been less inclined to sample other areas of the gastric mucosa because of the assumption that it would be unremarkable. Since less than 4% of US endoscopists regularly follow the Sydney
System biopsy protocol, it is unlikely that the presence of a polyp may have swayed many of those who do not to expand their biopsy sampling [32]. Furthermore financial considerations related to patients’ insurance coverage may have limited some endoscopists’ ability to collect more than a certain number of samples. The ideal study to determine the prevalence of gastric polyps and the background of the gastric mucosa associated with each type would be straightforward to design: patients should be prospectively recruited; a Sydney System compliant protocol should be performed, with biopsies read by a single pathologist; serology for H. pylori should be performed in all patients, and those who are histologically Helicobacter-negative but have active gastritis should undergo a urea breath test or a stool antigen test. In a European or North American population, such study would require approximately 10 endoscopy procedures to detect one fundic gland polyp, 30 for each inflammatory polyp, and 100 each for carcinoids and adenomas. Since such a study is clearly unfeasible, we have to accept that a large body or retrospective data is the best alternative to answer the questions we posed. In summary, our study suggests that the observed demographic, clinical, and histopathologic patterns stem from the underlying pathophysiology that affects the development of the various types of gastric polyps, ranging from fundic gland polyps to gastric hyperplastic polyps and ultimately gastric NETs or adenomas. The varying age difference between case and control subjects and among patients harbouring different polypoid lesions reflects on the time it takes for such changes to develop in the gastric mucosa. The main driving force of the observed changes is probably the stage-wise development of gastritis and its effect on acid secretion. Over a prolonged time period, chronic gastritis can result in the development of intestinal metaplasia and gastric atrophy, which leads to diminished gastric acid output and increased gastrin secretion. Gastric hyperplastic polyps may mark the beginning of this process, while gastric adenoma and carcinoid may reflect on its later stages. Gastritis and partial atrophy would be protective against GERD but promote the development of anaemia. Besides gender differences and age, other additional environmental risk factors may be responsible for the different pathways taken by gastric adenoma versus carcinoids. Conflict of interest A Sonnenberg declares no relevant conflicts of interest. RM Genta is employed by Miraca Life Sciences, Irving, TX. References [1] Marshall BJ. Campylobacter pyloridis and gastritis. Journal of Infectious Diseases 1986;153:650–7. [2] Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. New England Journal of Medicine 1991;325:1127–31. [3] Vakil N. Prescribing proton pump inhibitors: is it time to pause and rethink. Drugs 2012;72:437–45. [4] Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. Digestive Diseases and Sciences 2009;54:2312–7. [5] Laxen F, Sipponen P, Ihamaki T, et al. Gastric polyps; their morphological and endoscopical characteristics and relation to gastric carcinoma. Acta
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