Anatomic Pathology / CHRONIC INACTIVE GASTRITIS AND COCCOID H PYLORI

Anatomic Pathology / CHRONIC INACTIVE GASTRITIS AND COCCOID H PYLORI Chronic Inactive Gastritis and Coccoid Helicobacter pylori in Patients Treated for Gastroesophageal Reflux Disease or With H pylori Eradication Therapy Neal S. Goldstein, MD Key Words: Gastritis; Helicobacter pylori; Proton pump inhibitors; Dyspepsia; Inflammation; Pathology; Immunohistochemistry Abstract Gastric biopsy specimens from 105 consecutive adults with persistent dyspepsia who did not have changes due to esophageal reflux disease changes or gastric or duodenal ulcers at endoscopy were scored using the updated Sydney gastritis classification system. The medication history of proton pump inhibitors (PPIs) or Helicobacter pylori eradication therapy during the month before endoscopy was retrieved. Of the patients, 72 (68.6%) had chronic inactive gastritis, and 7 (6.7%) had antral-predominant, chronic mild active gastritis. H pylori infection was present in 36 patients (34.3%), of whom 29 had chronic inactive gastritis. Forty-six patients (43.8%) had a positive medication history, including 40 (56%) of 72 with chronic inactive gastritis. The most common morphologic feature associated with H pylori infection was moderate chronic inactive gastritis, which was found most often in patients who had received recent PPIs or H pylori eradication therapy. Pathologists should be aware of the extensive use of these medications, their association with chronic inactive gastritis, and rare H pylori that frequently are coccoid shaped. Modified Giemsa stain may not be the optimal method to detect H pylori in this group of patients. Helicobacter pylori typically causes antral-predominant, chronic active gastritis. 1-5 It is a well-studied lesion, and most practicing pathologists are familiar with its morphologic features. The yield when identifying H pylori with standard histochemical stains seems low when there is no active gastritis. 2,6-8 Proton pump inhibitors and previous H pylori eradication medications can alter the morphologic features of H pylori associated gastritis. 7,9-15 Both are commonly used empiric therapies offered by primary care physicians to patients with persistent nonlocalized, upper abdominal and lower chest pain and discomfort that often is postprandial and associated with mild bloating. This constellation of symptoms often is termed nonulcer dyspepsia if there are no changes due to esophageal reflux disease, no gastric or duodenal ulcers revealed by endoscopy, and no related biochemical abnormalities. The prevalence of these medications and their effects on the morphologic features of gastric biopsy specimens is not well studied in adults with nonulcer dyspepsia who undergo endoscopy. This study evaluated gastric biopsy specimens from adult dyspeptic patients to shed light on these issues and identify associations among gastric biopsy morphologic features, medication ingestion history, and H pylori. Materials and Methods For the study, 247 consecutively accessioned records of adult patients (older than 18 years) with persistent, nonlocalized, upper abdominal and lower chest pain and discomfort who underwent upper endoscopy at William Beaumont Hospital, Royal Oak, MI; had distinctive antral and oxyntic American Society for Clinical Pathology Am J Clin Pathol 2002;118:719-726 719

Goldstein / CHRONIC INACTIVE GASTRITIS AND COCCOID H PYLORI mucosa biopsy specimens that could be clearly separated; and had detailed endoscopy reports and/or gastroenterologist consultations (including medication history) on the hospital information system were identified from the surgical pathology computer system for the period July 9, 2000, through January 18, 2001. The diagnosis of persistent, nonlocalized, upper abdominal and lower chest pain and discomfort or dyspepsia was made from the constellation of symptoms by the gastroenterologists, usually on referral by a primary care physician. Cases were included in the study if patients had any of the following: persistent dyspepsia, dyspepsia, chronic dyspepsia, or chronic or persistent abdominal pain of dyspeptic type. Cases were excluded if duodenal, gastric, or esophageal masses or Barrett esophagus, esophageal strictures, or submucosal lesions were seen at endoscopy; if previous gastric or duodenal surgery had been performed; if intestinal metaplasia was present in the gastric biopsy specimen; or if there was recent use of nonsteroidal anti-inflammatory drugs, aspirin, ingested steroids, chemotherapy, or colchicine. Cases also were excluded if the endoscopy report did not contain information pertaining to whether the patient had taken proton pump inhibitor medications or received a combination H pylori eradication drug in the month before the endoscopy. The medication and clinical information was extracted from the William Beaumont Hospital Information System. After these exclusions, 105 patients remained in the study group. Pathology Antral and oxyntic mucosa biopsy specimens were submitted in the same specimen container and were embedded in 1 block. The blocks were cut at 3 levels, each separated by 75 to 100 µm. Two slides were made at each level, each containing 3 to 4 tissue sections. One slide at each level was stained with H&E, and the second, charged slide initially was left unstained. A modified Giemsa stain (rapid Romanowsky method) was performed on the level 1 unstained slide, and an H pylori immunohistochemical stain was performed on the level 2 unstained slide. The immunohistochemical staining procedure used EDTA buffer (ph 8.0) as the immersion solution for the heat antigen retrieval pretreatment step, anti H pylori antibody clone CH-20/429 (dilution 1:200, DAKO, Carpinteria, CA), and the Envision (DAKO) polymer detection system using diaminobenzidine as the chromogen. The specificity of this antibody was evaluated before the study. Ten suppurative appendicitis appendectomy specimens were stained with this antibody. One appendix had brown staining of fewer than 10 short bacilli with nodular, spherical ends that were morphologically similar to some H pylori seen in the stomach biopsy specimens. No spurious staining of cytoplasm fragments, mucin globules (intracellular or extracellular), food particles, or unidentified substances was seen on the slides stained with this antibody. Slides of 20 normal gastric antral mucosa and 20 normal duodenal mucosa biopsy specimens also were stained immunohistochemically with this H pylori antibody to evaluate the level of nonspecific bacteria and nonbacterial small particulate staining. All 40 slides were nonreactive. None had spurious staining of extracellular mucin globules or small particulates. I reviewed all slides. The following information was recorded separately for antral and oxyntic mucosa: 1. Number of biopsy fragments. 2. Lymphoplasmacytic inflammation (chronic gastritis) level: scored as normal, mild, moderate or marked, using the updated Sydney gastritis classification system text and visual analogue scale criteria. 3 Image 1 and Image 2. 3. Polymorphonuclear neutrophil inflammation (activity) level: scored as normal, mild, moderate, or marked using the updated Sydney gastritis classification system text and visual analogue scale criteria. 3 4. Presence of H pylori on modified Giemsa (rapid Romanowsky method)-stained slides. Spiral H pylori were predominantly bacilliform on modified Giemsa stained slides. There was a broad range of shapes, including thin and straight, thin and angulated (gull-wing), and short Image 3. Most of the modified Giemsa stained H pylori had a similar diameter. Coccoid H pylori could not be distinguished reliably from extracellular mucin globules and spherical nonbacterial particulates on the modified Giemsa stain. 5. Presence and shape of H pylori on immunohistochemically stained slides. The shape was classified as spiral or coccoid. Included in the spiral group were coiled Image 4, straight or angulated elongate (bacilliform) with tapered ends Image 5, straight or angulated elongate with terminal knobs (barbell-shaped) Image 6, and short, cigar-shaped forms. The diameter of immunohistochemically stained H pylori varied to a greater degree than Giemsa-stained bacteria. Included within the coccoid group were spherical and oval forms (Images 4 and 5) Image 7 and Image 8. Most coccoid H pylori had a diameter of approximately one half to one third the length of the spiral forms. Definitions The following definitions were used: chronic active gastritis, lymphoplasmacytic and neutrophilic inflammation; chronic inactive gastritis, lymphoplasmacytic inflammation without neutrophils; antral-predominant gastritis, lymphoplasmacytic inflammation (of any intensity) greater in antral than in oxyntic mucosa (including cases with mild antral lymphoplasmacytic inflammation and normal oxyntic mucosa); and oxyntic-predominant gastritis, lymphoplasmacytic inflammation (of any intensity) greater in oxyntic than in antral mucosa (including cases with mild oxyntic lymphoplasmacytic inflammation and normal antral mucosa). 720 Am J Clin Pathol 2002;118:719-726 American Society for Clinical Pathology

Anatomic Pathology / ORIGINAL ARTICLE Image 1 Moderate chronic gastritis. This density of lymphocytes and plasma cells is the lower end (least dense) of the spectrum of moderate chronic gastritis. Inflammation that was below this density was classified as mild chronic gastritis (H&E, 12). Image 2 Moderate chronic gastritis, higher magnification of Image 1. Neutrophils are absent. Most of the columnar mucin cells have well-defined apical cytoplasmic membranes (H&E, 48). Image 3 Helicobacter pylori. The bacteria are bacilliform and of uniform diameter (modified Giemsa, original magnification, 96). Inset, Computer-enlarged portion of image shows most bacteria are straight or angulated (gullwing) (modified Giemsa, 192). Image 4 Immunohistochemical stain, Helicobacter pylori. Spiral coiled (upper) and coccoid, round (lower) forms (diaminobenzidine counterstain, original magnification 128 with oil immersion lens). Inset, Computer-enlarged portions of image show the notched outlines of both bacteria (diaminobenzidine counterstain, 256). Results Antral and oxyntic mucosa were normal in 26 cases (24.8%) Table 1. Chronic inactive gastritis was present in 72 cases (68.6%); antral-predominant, chronic inactive gastritis in 42 (40.0%); chronic inactive gastritis that was of similar intensity in the antral and oxyntic mucosa in 16 (15.2%); oxyntic-predominant, chronic inactive gastritis in 14 (13.3%); and antral-predominant, chronic mild active gastritis in 7 (6.7%). American Society for Clinical Pathology Am J Clin Pathol 2002;118:719-726 721

Goldstein / CHRONIC INACTIVE GASTRITIS AND COCCOID H PYLORI Image 5 Immunohistochemical stain, predominantly bacilliform Helicobacter pylori of different shapes. Coccoid bacteria are admixed (diaminobenzidine counterstain, 84). Image 6 Immunohistochemical stain, spiral Helicobacter pylori with terminal knobs, producing a barbell shape (diaminobenzidine counterstain, 192 with oil immersion lens). Inset, Computer-enlarged image (diaminobenzidine counterstain, 768). Image 7 Immunohistochemical stain, single coccoid Helicobacter pylori (diaminobenzidine counterstain, 64). Inset, Computer-enlarged image (diaminobenzidine counterstain, 192). Image 8 Immunohistochemical stain, coccoid Helicobacter pylori (diaminobenzidine counterstain, 224 with oil immersion lens). Inset, Computer-enlarged image (diaminobenzidine counterstain, 448). H pylori Infection and Morphologic Features of Gastritis H pylori was identified in the biopsy specimens of 36 (34.3%) patients Table 2. H pylori was identified in biopsy specimens from only the antral mucosa in 24 cases (22.9%), antral and oxyntic mucosa in 4 cases (3.8%), and only the oxyntic mucosa in 8 cases (7.6%). Of the 36 patients with H pylori infection, 29 (81%) had chronic inactive gastritis, and 7 (19%) had antral-predominant, chronic mild active gastritis. In the 72 cases of chronic inactive gastritis, the prevalence of H pylori increased with the density of the lymphoplasmacytic inflammation. H pylori was identified in 3 (12%) of 25 biopsy specimens with mild, chronic inactive antral gastritis and in 18 (49%) of 37 biopsy specimens with moderate or 722 Am J Clin Pathol 2002;118:719-726 American Society for Clinical Pathology

Anatomic Pathology / ORIGINAL ARTICLE Table 1 Morphologic Features of Antral and Oxyntic Mucosa * Antral Mucosa Mild Chronic Moderate or Marked Normal Inactive Chronic Inactive Chronic Active Total (n = 105) 36 (34.3) 25 (23.8) 37 (35.2) 7 (6.7) Oxyntic mucosa Normal 26 (24.8) 16 (15.2) 17 (16.2) 5 (4.8) Mild chronic inactive 10 (9.5) 5 (4.8) 9 (8.6) 1 (1.0) Moderate or marked chronic inactive 4 (3.8) 11 (10.5) Chronic active 1 (1.0) * Data are given as number (percentage). Moderate chronic with mild to moderate activity. Table 2 Helicobacter pylori Identification in Antral and Oxyntic Mucosa * H pylori Shape (Stain) Spiral Coccoid Morphologic Feature Spiral (Giemsa) (Immunohistochemical) (Immunohistochemical) Antral mucosa No. of specimens 11 2 15 Normal (n = 36) 0 (0) 0 (0) 0 (0) Mild chronic inactive (n = 25) 0 (0) 0 (0) 3 (12) Moderate or marked chronic inactive (n = 37) 4 (11) 2 (5) 12 (32) Chronic with mild or moderate activity (n = 7) 7 (100) 0 (0) 0 (0) Oxyntic mucosa No. of specimens 2 0 10 Normal (n = 64) 0 (0) 0 (0) 0 (0) Mild chronic inactive (n = 25) 0 (0) 0 (0) 6 (24) Moderate or marked chronic inactive (n = 15) 1 (7) 0 (0) 4 (27) Chronic with mild activity (n = 1) 1 (100) 0 (0) 0 (0) * Data are given as number (percentage). marked chronic inactive antral gastritis. In oxyntic mucosa, H pylori was identified in 6 (24%) of 25 biopsy specimens with mild chronic gastritis and in 5 (33%) of 15 biopsy specimens with moderate or marked chronic gastritis. The predominant shape of H pylori varied according to the morphologic features of the associated gastritis. In general, the percentage of spiral H pylori decreased with decreased activity level and less dense lymphoplasmacytic inflammation. In the antral biopsy specimens, spiral H pylori were present in all 7 (100%) with chronic active gastritis, 6 (33%) of 18 with moderate or marked chronic inactive gastritis, and none (0%) of 25 with mild chronic inactive gastritis. In the oxyntic biopsy specimens, spiral H pylori were present in 1 (100%) with chronic mild active gastritis, 1 (7%) of 15 with moderate or marked chronic inactive gastritis, and in none (0%) of 25 with mild chronic inactive gastritis. In contrast, coccoid H pylori were seen in biopsy specimens with inactive chronic gastritis on immunohistochemical stains, including in 3 (12%) of 25 antral specimens with mild chronic inactive gastritis, 6 (24%) of 25 of oxyntic specimens with mild chronic inactive gastritis, 12 (32%) of 37 antral specimens with moderate or marked chronic inactive gastritis, and 4 (27%) of 15 oxyntic specimens with moderate or marked chronic inactive gastritis, but in none of the antral specimens with chronic active gastritis (Table 2). Giemsa staining of H pylori was a reflection of the number of spiral bacteria. Giemsa stains identified H pylori in 13 (87%) of 15 antral and oxyntic biopsy specimens with spiral H pylori. The other 2 specimens had rare spiral H pylori (seen on immunohistochemical stains) that were overlooked on the initial review of the Giemsa-stained slides. These 2 Giemsa-stained slides were reviewed after examining the immunohistochemically stained slides. The H pylori were identified during the second review of the Giemsa-stained slides after careful inspection at high magnification. Of the 105 patients, 46 (43.8%) had positive medication histories Table 3. Five (19%) of 26 with normal antral and oxyntic mucosa biopsy specimens and only 1 (14%) of 7 with antral chronic active gastritis had a positive medication history. In contrast, 26 (62%) of 42 patients with antralpredominant, chronic inactive gastritis, 6 (38%) of 16 with American Society for Clinical Pathology Am J Clin Pathol 2002;118:719-726 723

Goldstein / CHRONIC INACTIVE GASTRITIS AND COCCOID H PYLORI Table 3 Morphologic Features of Gastritis Biopsy Specimens and Medication History * Morphologic Feature Positive Medication History Normal (n = 26) 5 (19) Antral-predominant, chronic inactive gastritis (n = 42) 26 (62) Antral and oxyntic chronic inactive gastritis of similar intensity (n = 16) 6 (38) Oxyntic-predominant, chronic inactive gastritis (n = 14) 8 (57) Antral-predominant, chronic active gastritis (n = 7) 1 (14) * Data are given as number (percentage). antral and oxyntic chronic inactive gastritis of similar intensity, and 8 (57%) of 14 patients with oxyntic-predominant, chronic inactive gastritis had positive medication histories. Five (11%) of 46 patients with a positive medication history had normal antral and oxyntic biopsy specimens; 26 (57%) had antral-predominant, chronic inactive gastritis; 6 (13%) had antral and oxyntic chronic inactive gastritis of similar intensity; 8 (17%) had oxyntic-predominant, chronic inactive gastritis; and 1 (2%) had chronic active antral gastritis. Overall, 40 (87%) of 46 patients with a positive medication history had chronic inactive gastritis compared with 32 (54%) of 59 patients with a negative medication history. The chronic inactive gastritis was of moderate or marked intensity in 33 (82%) of 40 patients with a positive medication history compared with 8 (14%) of 59 patients with a negative medication history. A greater percentage of patients with chronic inactive gastritis with a positive medication history had H pylori infection than patients with a negative medication history Table 4. Eighteen (69%) of 26 patients with antral-predominant, chronic inactive gastritis and a positive medication history had H pylori compared with 1 (6%) of 16 patients with a negative medication history. The percentages were similar among patients with antral and oxyntic chronic inactive gastritis of similar intensity and oxyntic-predominant, chronic inactive gastritis. Discussion This study found that proton-pump inhibitors and H pylori eradication therapy regimens were commonly used to treat adults with nonulcer dyspepsia before endoscopy. Of 105 cases studied, 46 (43.8%) of the patients had a positive medication history. The extent to which these medications are used in adults with nonulcer dyspepsia may not be well known to pathologists. In this vein, pathologists may be unaware of the level to which the morphologic features of H pylori associated gastritis may be altered by these medications. Untreated H pylori associated gastritis usually is an antral-predominant, chronic active gastritis. 1-5 Proton pump inhibitors and H pylori eradication regimens rapidly result in lower or absent activity of antral gastritis and a slower paced decrease of lymphoplasmacytic inflammation in this region. 7,9-15 In this study, 40 (87%) of 46 patients with a positive medication history had chronic inactive gastritis compared with 32 (54%) of 59 patients with a negative medication history. In addition, the chronic inactive gastritis was of moderate or marked intensity in 38 (83%) patients with a positive medication history compared with 8 (14%) patients with a negative medication history. These results are similar to those of a study that found a previous H pylori eradication regimen in 43.8% of the patients with minimal chronic inactive gastritis. 16 The disproportionate representation of biopsy specimens with chronic inactive gastritis and the greater percentage of biopsy specimens with gastritis of moderate or marked intensity among patients with a positive medication history suggests, similar to the changes described by other authors, 16 that chronic inactive gastritis is associated commonly with medications to eradicate H pylori or with proton pump inhibitors. Additional terms associated with this gastritis pattern include ex-h pylori gastritis 3 and inactive superficial gastritis. 17 The most common morphologic feature of gastric mucosa associated with H pylori infection in this study was moderate chronic inactive gastritis, which was seen in 29 (81%) of 36 patients with H pylori infection. Overall, H Table 4 Helicobacter pylori Infection and Medication History * Patients With H pylori Morphologic Feature Negative Medication History Positive Medication History Normal 0/31 0/5 Antral-predominant, chronic inactive gastritis 1/16 (6) 18/26 (69) Antral and oxyntic, chronic inactive gastritis of similar intensity 0/10 (0) 4/6 (67) Oxyntic-predominant, chronic inactive gastritis 0/6 (0) 6/8 (75) Antral-predominant, chronic active gastritis 6/6 (100) 1/1 (100) * Data are given as number with H pylori/number with negative or positive medication history (percentage). 724 Am J Clin Pathol 2002;118:719-726 American Society for Clinical Pathology

Anatomic Pathology / ORIGINAL ARTICLE pylori was found in 29 (40%) of 72 patients with chronic inactive gastritis. This percentage is similar to the 50% incidence of serologic evidence of H pylori infection in patients with minimal chronic inactive gastritis 16 but seems to be disproportionately greater than those reported in most studies in which active gastritis was more common than inactive gastritis. 7,9-15 Several factors may explain the differences between the results of the present study and those of the studies by the latter group of authors. Most of these studies used histochemical stains to identify H pylori, which may be a less sensitive method than immunohistochemical analysis to detect rare microorganisms. In addition, these studies used controlled time intervals between completion of therapy and biopsy, most of which were longer than the 1-month interval used in the present study. It is possible that many of the patients with chronic inactive gastritis and H pylori infection in the present study would be bacteria-free if they had undergone biopsy at a later date. 18 These points do not detract from the conclusions of the present study: H pylori can be identified in some biopsy specimens with moderate chronic inactive gastritis, and an absence of activity may not be a reliable indicator of the absence of H pylori in this group of patients. Last, proton pump inhibitors and medications to eradicate H pylori decrease the density of H pylori organisms and alter their shape from spiral to coccoid, thus hampering their identification. 19-29 Coccoid H pylori can be difficult to distinguish from small mucin globules or extracellular debris on modified Giemsa histochemical stains, and the ability of this stain to help identify sparse numbers of coccoid H pylori seems limited. Immunohistochemical analysis seems to be a more reliable detection method in these situations. 6-8,13,27,30-37 Several points pertaining to the results and methods of the present study require comment. This study did not evaluate other histochemical stains such as silver stains because this was not the focus of the study and these stains were not performed routinely by the histology laboratory. The results of this study should not be interpreted as offering support for immunohistochemical analysis as a routine or reflex procedure or as the primary detection method for H pylori. Empiric H pylori eradication in patients with nonulcer dyspepsia is currently a clinical debate, and there is no support for the routine search for rare H pylori in this group of patients. 38-45 This study also is not a reflection of the incidence of H pylori infection among adults with nonulcer dyspepsia. The underlying reasons that led to endoscopy and the medications used by the patients before endoscopy were not controlled factors. Substantial biases undoubtedly are introduced by these factors. Statistics were not used in this study for this reason. From the Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI. Address reprint requests to Dr Goldstein: Dept of Anatomic Pathology, William Beaumont Hospital, 3601 W Thirteen Mile Rd, Royal Oak, MI 48073. References 1. Genta RM, Graham DY. Comparison of biopsy sites for the histopathologic diagnosis of Helicobacter pylori: a topographic study of H pylori density and distribution. Gastrointest Endosc. 1994;40:342-345. 2. Genta RM, Robason GO, Graham DY. Simultaneous visualization of Helicobacter pylori and gastric morphology: a new stain. Hum Pathol. 1994;25:221-226. 3. Dixon MF, Genta RM, Yardley JH, et al. 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Blum AL, Talley NJ, O Morain C, et al, for the Omeprazole Plus Clarithromycin and Amoxicillin Effect One Year After Treatment (OCAY) Study Group. Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med. 1998;339:1875-1881. 726 Am J Clin Pathol 2002;118:719-726 American Society for Clinical Pathology