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Autoimmune Gastritis: Distinct Histological and Immunohistochemical Findings Before Complete Loss of Oxyntic Glands Michael Torbenson, M.D., Susan C

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Autoimmune Gastritis: Distinct Histological and Immunohistochemical Findings Before Complete Loss of Oxyntic Glands Michael Torbenson, M.D., Susan C Autoimmune Gastritis: Distinct Histological and Immunohistochemical Findings Before Complete Loss of Oxyntic Glands Michael Torbenson, M.D., Susan C. Abraham M.D., John Boitnott M.D., John H. Yardley, M.D., Tsung-Teh Wu, M.D., Ph.D. Division of Gastrointestinal/Liver Pathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland phoplasmacytic infiltrates within the lamina pro- Autoimmune gastritis (AG) can be easily recognized pria with foci of gland infiltration and damage, when the histological features are fully developed, epithelial metaplasia, parietal cell pseudohypertro- but recognizing AG before the complete loss of the phy, and ECL cell hyperplasia at the linear or oxyntic mucosa is more challenging. One feature of greater level. fully developed AG is enterochromaffin cell-like (ECL) hyperplasia, but its presence or absence in KEY WORDS: Autoimmune gastritis, Chromo- earlier stages of AG has not been fully evaluated. A granin, ECL-cell hyperplasia, Gastrin, Metaplasia, retrospective study of biopsy specimens from 40 Stomach. patients was performed; all of the patients were Mod Pathol 2002;15(2):102–109 originally diagnosed with possible AG based on the presence of lymphocytic infiltration and damage to oxyntic glands and/or the presence of metaplastic Autoimmune gastritis (AG) is an inflammatory con- epithelium that disproportionately involved the dition of the stomach that is associated with auto- body mucosa. Nineteen cases had follow-up sero- antibodies to parietal cells and intrinsic factor and logical studies for anti–parietal cells and/or anti– can lead in a small percentage of patients to de- intrinsic factor antibodies: 13 were positive and 6 struction of the oxyntic mucosa, pernicious ane- negative. The remaining 21 cases were indetermi- mia, and the development of carcinoid tumors that nate because of incomplete testing. The histological are typically indolent. AG is also referred to as Type findings were similar in the patients who were se- A gastritis and is recognized as a corpus-restricted rologically positive and those who were indetermi- atrophic gastritis in the updated Sydney classifica- nate for AG. In all of these cases, the oxyntic mucosa tion system (1). In fully established AG, the body showed lymphoplasmacytic infiltrates within the mucosa is inflamed and shows extensive atrophy lamina propria with focal gland infiltration and with replacement of the oxyntic glands by intestinal damage. Sixty-five percent (22/34) of the cases and pyloric metaplastic epithelium, whereas the showed intestinal and/or pyloric metaplasia, and antral mucosa is relatively spared. Autoimmune 85% (29/34) showed parietal cell pseudohypertro- gastritis is often easily recognized when these phy. Chromogranin stains were performed in 11 of changes are fully developed and adequately sam- 13 cases with positive serological markers for AG, pled, but earlier manifestations of AG are more and all showed at least linear ECL cell hyperplasia. challenging to recognize. The following histological In contrast, none of the six cases with negative se- features of AG have recently been described in rological studies had linear ECL cell hyperplasia, P cases without total loss of the oxyntic mucosa (2, 3): < .001. In conclusion, the following constellation of (1) a mononuclear infiltrate within the lamina pro- findings supports a diagnosis of AG before the com- pria that was often heavier in the deep, glandular plete loss of oxyntic mucosa: deep or diffuse lym- portions, (2) foci of lymphocytic infiltration and destruction of oxyntic glands, (3) intestinal and/or Copyright © 2002 by The United States and Canadian Academy of pyloric gland metaplasia, and (4) pseudohypertro- Pathology, Inc. phy of the remaining parietal cells with parietal cell VOL. 15, NO. 2, P. 102, 2002 Printed in the U.S.A. Date of acceptance: October 30, 2001. snouting similar to that seen in patients on proton- Address reprint requests to: Tsung-Teh Wu, M.D., Ph.D., Department of Pathol- pump inhibitors (PPI). Finally, one third of cases ogy, Box 85, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Hous- ton, TX 77030; e-mail: [email protected]; fax: 713-792-4049. also showed hyperplasia of the enterochromaffin- 102 like (ECL) cells using hematoxylin and eosin (H&E) riodic acid–Schiff/Alcian blue at pH 2.5, gastrin (1: stains alone (2). 4000 dilution, Zymed Laboratories Inc, San Despite these careful initial descriptions of AG Francisco, CA), and chromogranin (1:4000 dilution, before the complete loss of the oxyntic mucosa, this Boehringer Mannheim, Indianapolis, IN). All sec- pattern of gastric injury is frequently underrecog- tions of the antrum and body were evaluated for nized on endoscopic biopsy specimens. Further- Helicobacter pylori on Diff-Quik stains. The follow- more, several difficulties can arise when evaluating ing histological features were scored on a scale of 0 biopsy specimens for AG. First, none of the above to3(0ϭ none, 1 ϭ mild, 2 ϭ moderate, and 3 ϭ histological features alone are diagnostic. Second, marked): degree of active inflammation, chronic inflamed and partially atrophic mucosa from the inflammation, and intestinal and pyloric metapla- antral–oxyntic transitional zone can mimic the sia. Pancreatic acinar-type cells were considered to patchy atrophy and pyloric metaplasia seen in AG. be metaplastic in origin, although others have sug- Third, ECL cell hyperplasia can be difficult to rec- gested that they may also represent developmental ognize on H&E stains alone. Therefore, this study abnormalities (6). Periodic acid–Schiff/Alcian blue was undertaken to evaluate the diagnosis of AG on stains were also available and confirmed the pres- endoscopic biopsy specimens of body mucosa that ence of intestinal metaplasia. ECL cell hyperplasia still had oxyntic glands. We also employed immu- in the gastric body was evaluated using chromo- nostains for gastrin (a negative stain indicates that granin stains in 35 available cases and was scored the biopsy specimen is truly from the body and not as normal, simple, linear, or nodular hyperplasia from the antrum or antral–oxyntic transitional zone using the modified Solcia classification schema (7, (4, 5)) and chromogranin to evaluate for ECL cell 8). Briefly, simple hyperplasia showed a mild in- hyperplasia. crease over normal that did not reach the level of linear hyperplasia. Linear hyperplasia was charac- terized by glands with five or more adjacent MATERIALS AND METHODS chromogranin-positive cells. Nodular hyperplasia was diagnosed when nodular aggregates of at least Forty stomach biopsy specimens were retrospec- five chromogranin-positive cells were seen. In the tively collected from the time period of January human stomach, gastrin cells are absent from the 1991 to August 2000 from the Johns Hopkins Hos- body mucosa (4, 5), and gastrin immunostains were pital surgical pathology files. All cases still had re- performed in 33 available cases to ensure that the sidual oxyntic mucosa. By customary practice dur- biopsied tissue was from the body. ing this time interval, a diagnosis of AG when oxyntic glands were still present was suggested when biopsy specimens showed foci of lymphocytic RESULTS destruction of oxyntic glands, often accompanied by intestinal and pyloric metaplasia. When the Clinical Features above histological findings were identified, the pa- A total of 40 cases were reviewed, including 27 thology reports recommended that serological women and 13 men, with an average age at biopsy studies be performed for antibodies to parietal cell of 61 Ϯ 16 years (range, 29–84; median, 64), with no and intrinsic factor. significant difference in ages between men and Follow-up gastric biopsies were also available for women (P ϭ .9; Student’s t test). Twenty-six pa- examination in nine patients. The patients’ medical tients were Caucasian, 11 were African-American, 2 records were reviewed for relevant medical history. were Asian, and 1 was Arabic. Patients were classified as positive for AG if sero- Serological studies allowed classification of pa- logical studies were positive for either anti–parietal tients in 19 cases (Table 1). Of these, 11 patients cell or anti–intrinsic factor antibodies and negative were positive for parietal cell antibodies and 2 for if both serologies were negative. When neither se- intrinsic factor antibodies. In one patient, anti–pa- rological study was available, or when only partial rietal cell antibodies were negative after the index testing was available and was negative, the patients biopsy, but a subsequent biopsy 8 months later were classified as indeterminate for AG. Serum gas- again showed changes suspicious for AG, and re- trin levels were also available in a subset of patients peat testing was positive at a titer of 1:640. Serum and are correlated with the serological status and gastrin levels were measured in 15 patients and the chromogranin immunostaining results but were elevated in 14, ranging from 165 to 2963 were not used to classify individuals as positive or pg/mL (normal, Ͻ100). Seven of these patients negative for AG were positive for AG based on serology and had a Histological sections were obtained from median serum gastrin level of 581 (range, 212–2963 formalin-fixed, paraffin-embedded tissues. The fol- pg/mL) versus a median serum gastrin level of 120 lowing stains were performed: H&E, Diff-Quik, pe- in two patients classified as negative for AG. The Autoimmune Gastritis (M. Torbenson et al.) 103 remaining six patients were classified as indetermi- or somewhat heavier in the deeper portions of the nate for AG and had a median gastrin level of 809 mucosa (Fig. 1A; Table 2). Second, all cases showed pg/mL (range, 231–1488 pg/mL; Table 1). patchy oxyntic gland infiltration and damage by Two patients classified as positive for AG had lymphocytes (Fig. 1B). The remaining histological macrocytic anemia at presentation, and two more findings were present in most but not all cases. patients were Vitamin B12 deficient, including one Parietal cell pseudohypertrophy was seen in 29 classified as positive and one as indeterminate for (85%) patients (Fig.
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