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Gastritis: a pattern-based approach
GASTROINTESTINAL AND HEPATIC PATHOLOGY
Gastritis: a pattern-based approach
The biopsy with chronic inflammation This general pattern is a common offender and is seen in a myriad of inflammatory (infectious and non-infectious) processes. There are no established criteria for what accounts for “too many” lamina propria lymphocytes and plasma cells. Our approach consists of examining the biopsy at low magnification (4X) searching for increased “dot density” (plasma cells and lymphocytes) in the lamina propria, which separates the glands and imparts a “blue” (hematoxylin) appearance to the biopsy. The next step is to then confirm that the extra “dots” are indeed chronic inflammatory cells at higher magnification (40x) (and not a devious “inflammatory-mimicking” diffuse-type adenocarcinoma). Once we have determined that there is an excess of inflammatory cells, we must pay attention to the distribution of the inflammation in order to narrow the differential diagnosis.
Kevin M Waters Lysandra Voltaggio
Abstract Evaluation of inflammatory gastric biopsies is one of the most common tasks pathologists face on a daily basis. Their analysis requires recognition of inflammatory patterns and their associated differential diagnoses, an especially vital skill in the not-so-uncommon instance when there is little clinical information available. In this review we summarize the most common gastric inflammatory patterns and their clinical associations, ranging from Helicobacter gastritis to autoimmune enteropathy to the biopsy with prominent Russell bodies. Our aim is to add to the readers’ arsenal of tools to narrow the differential diagnosis in these ubiquitous specimens.
“Top heavy” chronic inflammation When the majority of the inflammation resides in the upper half of the biopsy (Figure 1), think Helicobacter gastritis. Helicobacter pylori is a curved flagellated gram negative bacillus strongly associated with gastritis and ulceration. Though Helicobacterassociated inflammation most severely affects the antrum,1 the oxyntic mucosa will display at least mild “top heavy” gastritis.2 This infiltrate will often be accompanied by at least focal active (neutrophilic) inflammation. “Up front” ancillary stains (Warthin Starry, Giemsa, immunostain) are no longer recommended3 and instead should be applied to cases with suspicious morphology but where no organisms are seen on H&E. Some cases of Helicobacter gastritis feature germinal center formation (A.K.A. follicular gastritis), a finding strongly associated with Helicobacter infection.2 Atrophy and intestinal metaplasia (also known as environmental metaplastic atrophic gastritis [EMAG]) may also be seen. A “bottom heavy” infiltrate in the setting of Helicobacter gastritis should trigger suspicion for mucosa associated lymphoid tissue (MALT) lymphoma. These cases will feature dense aggregates of monomorphic lymphocytes with or without perinuclear halos and lymphoepithelial lesions that tend to infiltrate the muscularis mucosae. In these cases, a panel of immunostains is in order; we perform an initial abbreviated version consisting of CD20, CD3, and CD43, and assess for CD20reactive B cells that aberrantly express CD43. CD3 is necessary because it is normal for T cells to express CD43 and the various stains must be compared. In addition to being a source of gastritis and ulcers, Helicobacter gastritis is well-known as a risk factor for the development of gastric carcinoma. Helicobacter heilmannii is a rare (<1% of cases), longer and more tightly coiled variant (Figure 2) that cross-reacts with H. pylori on immunohistochemistry. The gastritis associated with H. heilmannii has the same features as that of H. pylori but the inflammation is typically less severe.
Keywords autoimmune; biopsies; gastritis; patterns of inflammation
Introduction Evaluation of inflammatory gastric biopsies is one of the most common tasks pathologists face on a daily basis. Their analysis requires recognition of inflammatory patterns and their associated differential diagnoses, an especially vital skill in the not-souncommon instance when there is little clinical information available. Pattern recognition is crucial as treatment regimens differ from antibiotics (e.g. Helicobacter gastritis) to vitamin supplementation (e.g. autoimmune metaplastic atrophic gastritis [AMAG]) to immunomodulatory therapy (e.g. autoimmune enteritis [AIE]) to dietary modification (e.g. eosinophilic gastritis). Some gastritides are considered benign incidental findings (e.g. Russell body gastritis) with no clinical or treatment consequence, while others are part of a systemic process (e.g. inflammatory bowel disease), and yet others confer an increased risk of lymphoma (e.g. Helicobacter gastritis) or carcinoma (e.g. AMAG). Yes, sorting through all these inflammatory patterns can be daunting as there are several entities affecting the stomach and many share overlapping histologic features. In this review we hope to provide the reader with some tools to tease out common inflammatory patterns encountered in daily practice. If we examine these specimens in a consistently systematic fashion we will be able, in the majority of cases, to provide at least a narrow differential for the clinician to work with and effectively guide patient management. The inflammatory patterns presented here are summarized in Table 1.
“Bottom heavy” chronic inflammation A number of gastritides may be associated with a “bottom heavy” type of inflammation. The inflammatory pattern associated with AMAG, most commonly seen in females in their 6th decade, is important to identify as it leads to pernicious anemia due to vitamin B12 deficiency and confers a roughly 3 fold increased risk of gastric carcinoma. Patients may present with
Kevin M Waters MD PhD, Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA. Conflicts of interest: none. Lysandra Voltaggio MD, Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA. Conflicts of interest: none.
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Differential diagnosis for each histologic pattern The Biopsy with Chronic Inflammation C “Top Heavy” distribution C Helicobacter gastritis (H. pylori or H. heilmanni) C “Bottom Heavy” Distribution C Autoimmune metaplastic atrophic gastritis C Autoimmune pangastritis C Autoimmune enteritis C Patchy Distribution C Inflammatory bowel disease The Biopsy with Chronic Active Gastritis without Helicobacter pylori C Treated Helicobacter infection (typically no activity) C Inflammatory bowel disease Chemical/Reactive Gastropathy Pattern C Non-steroidal anti-inflammatory drugs C Bile reflux C Antral biopsy of autoimmune metaplastic atrophic gastritis C Gastric antral vascular ectasia (GAVE) The Biopsy with Prominent Eosinophils C Helicobacter Gastritis (H. Pylori or H. Heilmanni) C Autoimmune metaplastic atrophic gastritis C Post-radiation C Parasite C Solid organ transplantation C Collagenous gastritis C Inflammatory bowel disease C Eosinophilic gastritis C Medications The biopsies with Lymphocytic or Collagenous Patterns C Helicobacter Gastritis (H. pylori or H. heilmanni) C Celiac disease C Medications The Biopsy with Prominent Mott Cells C Russell body gastritis The Biopsy with a Prominent Monocytic Reaction C Cytomegalovirus C EpsteineBarr virus
Figure 1 Helicobacter gastritis. Note the superficial (“top heavy”) lamina propria inflammation. This field also shows a prominent lymphoid aggregate with germinal center formation, another clue to the diagnosis.
Table 1
Figure 2 Helicobacter heilmanii. H. heilmanii is longer and more tightly coiled than H. pylori.
iron deficiency anemia as acid is necessary for iron absorption. The histologic changes of AMAG are limited to the gastric body. Biopsies from the antrum will be normal or present a reactive/ chemical gastropathy pattern (discussed later). Besides “bottom heavy” chronic inflammation, the gastric body will feature atrophy with injured, decreased or absent parietal cells, intestinal metaplasia, and enterochromaffin cell like (ECL) cell hyperplasia (Figures 3 and 4). Roughly half of the cases will show pancreatic metaplasia, a finding rarely seen in the stomach outside the setting of AMAG.4 Interestingly, the amount of inflammation tends to decrease as atrophy develops and the parietal cells are lost (a distinguishing feature with autoimmune pangastritis, discussed later). The findings can be patchy with some areas of the stomach showing full blown atrophy and others showing preserved oxyntic mucosa. Immunohistochemistry can be useful when the specific source of the biopsy (antrum vs. body) is in
question. Atrophic (antralized) oxyntic mucosa will be negative for gastrin (or may have few gastrin-immunoreactive cells) as it lacks G cells (only present in the “true” antrum). In its early stages (“early AMAG”), this process can be challenging to recognize as it can feature mild to severe full thickness or deep chronic inflammation of the gastric body accompanied by subtle or focal findings such as inflammatory destruction of oxyntic glands, intestinal, pyloric, or pancreatic acinar metaplasia, prominent lamina propria eosinophils, and parietal cell pseudohypertrophy.5 The AMAG biopsy (early or fully developed) will feature linear and/or nodular ECL cell hyperplasia, which can occasionally be seen on H&E but is better highlighted on a chromogranin or synaptophysin immunostain. Multiple types of polyps are common in the setting of AMAG including hyperplastic polyps, type 1 gastric neuroendocrine tumors (carcinoid tumor, which are indolent), and intestinal or pyloric
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Figure 3 Autoimmune metaplastic atrophic gastritis (AMAG). These cases are characterized by deep (“bottom heavy”) inflammation, parietal cell destruction, and pyloric and intestinal metaplasia. Paneth cells are seen in this field (the bottom right). This case does not yet show complete atrophy, as evidenced by groups of residual oxyntic mucosa.
Figure 5 Autoimmune metaplastic atrophic gastritis (AMAG). The findings can be patchy with pockets of atrophy (center) in the background of preserved oxyntic mucosa. The residual oxyntic mucosa may appear polypoid to the endoscopist. This is the same case as the one shown in Figures 4 and 5.
Figure 4 Autoimmune metaplastic atrophic gastritis (AMAG), chromogranin immunostain. This is the same case as the one shown in Figure 4. Linear and nodular ECL cell hyperplasia is seen here.
Figure 6 Atrophic autoimmune pangastritis. There is marked inflammatory expansion of the lamina propria throughout the entire thickness of the mucosa accompanied by increased intraepithelial lymphocytes and active inflammation.
type adenomas. Lastly, the residual non atrophic mucosa can appear polypoid in the background of severe atrophy (Figure 5).6 “Bottom heavy” chronic inflammation is seen in both the antrum and body in atrophic autoimmune pangastritis (AAP).7 While more severe in the bottom half of the mucosa, there is inflammatory expansion of the lamina propria throughout the entire thickness, including the muscularis mucosae. Unlike AMAG, the intense “bottom heavy” infiltrate persists even after severe atrophy develops (Figure 6). Neutrophils are present to varying degrees in all cases. Autoimmune pangastritis also features prominent apoptotic bodies (GVHD-like) and increased intraepithelial lymphocytes. A chromogranin immunostain will
show lack of ECL cell hyperplasia, another distinguishing feature from AMAG. Patient presentation is dramatic with abdominal pain, nausea, vomiting, diarrhea, or malnutrition. Most patients have associated systemic autoimmune diseases including systemic lupus erythematosus (SLE), refractory sprue, autoimmune hemolytic anemia, and fibromyalgia. Treatment consists of immunomodulatory medications. The risk of neoplasia in patients with autoimmune pangastritis is uncertain. A “bottom heavy” autoimmune pangastritis-like pattern of inflammation can also be seen in patients with autoimmune enteropathy (AIE). Both children and adults will present with intractable diarrhea. Small intestinal biopsies will show severe
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villous atrophy that is not responsive to the dietary restrictions that typically provide clinical relief and histologic improvement to patients with celiac disease. Gut autoantibodies (anti-goblet cell or anti-enterocyte) can be detected serologically and patients lack severe immunodeficiency. In the stomach, the histologic findings are similar to those seen in the setting of autoimmune pangastritis with both the antrum and body showing marked lymphoplasmacytic lamina propria expansion with or without active inflammation, atrophy with loss of parietal cells, increased apoptotic bodies, increased intraepithelial lymphocytes, intestinal metaplasia, and epithelioid multinucleated giant cells. Some cases may resemble AMAG in that they show ECL cell hyperplasia.7,8 AIE may be seen as part of certain genetic syndromes including IPEX (Immune dysfunction, Polyendocrinopathy, Enteropathy, and X-linked inheritance) and APECED (Autoimmune Polyendocrinopathy, Candidiasis, and Ectodermal dysplasia). Patients with AIE are treated with immunosuppressive therapy and nutritional support. We suspect that, although reported separately, autoimmune pangastritis and AIE may be part of the same disease spectrum as they have nearly identical histologic features and half of the patients in the original description of autoimmune pangastritis also had AIE. An infectious process that deserves brief mention in this section is syphilitic gastritis. Its histologic appearance can be as dramatic as that of AAP and AIE. Biopsies will show overwhelming chronic active inflammation with or without prominent plasma cells, with glandular destruction, crypt abscesses, and lymphoid aggregates with or without granulomas. A syphilis immunostain is available but commonly yields “negative” results in infected patients.9 This diagnosis requires a high index of suspicion and clinical correlation with appropriate laboratory tests (e.g. rapid plasma regain [RPR], fluorescent treponemal antibody absorption test [FTA-ABS]).
Figure 7 Gastritis in a patient with Crohn disease. These cases commonly feature a chronic or chronic focally active gastritis that is at first reminiscent of Helicobacter infection but no organisms are found upon staining. The differential here would include treated Helicobacter gastritis.
frequently feature a chronic or chronic focally active gastritis that is at first reminiscent of Helicobacter infection (Figure 7) but no organisms are found upon staining. Gastric involvement is less commonly seen in ulcerative colitis (UC) compared to CD, but features include focal intense gastritis with a diffuse superficial pattern rich in plasma cells or a patchy basal pattern.13
The biopsy with a chemical/reactive gastropathy pattern In contrast to the “chronic inflammation pattern”, the “chemical/ reactive pattern” lacks increased blue “dots” and instead the biopsy appears “eosin-rich” (pink) on initial inspection at low magnification. This pattern is typically more dramatic in the antrum and additional histologic features include surface mucin loss, corkscrew-shaped, elongated gastric pits, and fibromuscular stranding (Figure 8). It is essential to recognize this pattern as
The biopsy with chronic active gastritis without Helicobacter pylori In some cases, this pattern of inflammation may still be attributable to Helicobacter gastritis as treated infection will often have residual “top heavy” chronic inflammation (typically without activity) in the absence of microorganisms. The patient’s history may not reflect treated Helicobacter gastritis as patients may receive antibiotic therapy for unrelated reasons. Another possibility when encountering this pattern is Helicobacter in a patient receiving proton pump inhibitor therapy. In this setting, the organisms may be difficult to find as they can become coccoid instead of rod-like and they tend to migrate from the surface into to the deep pits. If no organisms are found despite performing ancillary stains, the culprit may be inflammatory bowel disease. Though inflammation in this setting can certainly be diffuse, a peculiar pattern described in this setting is the “focally enhanced” gastritis (FEG) pattern.10 FEG is characterized by discrete foci of lymphoplasmacytic and histiocytic inflammation with variable numbers eosinophils and neutrophils, with or without granulomas, and separated by relatively normal mucosa. Though the association with IBD is weaker in adults, FEG seems to be more predictive of IBD in children.11,12 In our experience though, patients with upper tract involvement of Crohn disease more
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Figure 8 Chemical gastropathy. These feature elongated, corkscrewshaped glands and fibromuscular stranding. The presence of mild chronic inflammation does not preclude the diagnosis.
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some cases can present striking reactive atypia that may be misinterpreted as dysplasia. Clinical associations include bile acid reflux, use of nonsteroidal anti-inflammatory drugs (NSAIDS), AMAG, and gastric antral vascular ectasia (GAVE), A.K.A. “watermelon stomach”. “Watermelon” refers to its endoscopic appearance, which features erythematous linear streaks (visible reddened vessels) emanating from the pylorus towards the body. These patients often present with anemia due to gastric bleeding. In addition to the endoscopic findings, focal fibrin thrombi can be a histologic clue that the chemical/reactive pattern is to the result of GAVE.
The biopsy with prominent eosinophils What to think of first Gastric eosinophilia may be seen in a variety of settings. The first order of business when one encounters gastric eosinophilia is to search for Helicobacter. Rare cases of Helicobacter-associated gastritis may feature atypical inflammatory patterns, one of which may be gastric eosinophilia. Thankfully these cases will likely also feature the already discussed “top heavy” chronic active inflammation. Eosinophilia in the absence of Helicobacter organisms, should raise suspicion for inflammatory bowel disease, especially if the accompanying inflammation is both active and chronic and distributed throughout the thickness of the mucosa. If the inflammatory backdrop consists mostly of lymphocytes and plasma cells with no or little activity, AMAG should be investigated, especially if the inflammation is “bottom heavy”, and even in the absence of significant parietal loss since early AMAG may show relatively preserved oxyntic mucosa. Collagenous gastritis (discussed in a later section) can incite an exuberant eosinophilic response, which will be accompanied by an expanded irregular collagen table with entrapped capillaries and inflammatory cells. While uncommon in the United States, some parasites are known to elicit an eosinophilic reaction and should be searched for when eosinophils are seen, especially if eosinophilic microabscesses are present. Biopsies with eosinophilic microabscesses that lack parasites should be cut deeper into the block as organisms not uncommonly make their appearance on later sections. Additional clinical settings that may result in a biopsy with prominent eosinophils include solid organ transplantation,14 post-radiation (Figure 9), and medications.15
Figure 9 Prominent eosinophils in a patient post-radiation. Biopsies in patients who have undergone radiation (e.g. lung cancer), may feature pockets of eosinophilic inflammation. The key is to note the background epithelial and stromal atypical cells, which typically feature abundant, vacuolated cytoplasm and large nuclei with prominent nucleoli.
eosinophilic gastritis include eosinophilic infiltration of the gastric epithelium, muscularis mucosae, and submucosa (Figure 10).18 Eosinophilic gastritis is a diagnosis of exclusion and should be considered only after the other possibilities just mentioned in the previous paragraph have been excluded.
The biopsies with lymphocytic or collagenous patterns Lymphocytic gastritis shows increased numbers of intraepithelial lymphocytes within the surface epithelium. How many is too many? We don’t know because we don’t count and we don’t know of anybody who does. The biopsy typically looks “busy” at
After everything else has been excluded Though generally thought of as a pediatric disease, eosinophilic gastritis (EG) can also be seen in adults. It is most commonly associated with food allergy (86% of cases) and can be treated with dietary restriction in the pediatric population or with steroids, antihistamines, or asthma drugs in adults.16 It nearly always effects the antrum, but not always the fundus. Eosinophilic infiltration may occur in other areas of the upper gastrointestinal tract (esophagus, duodenum), but eosinophilic gastritis is typically not associated with eosinophilia in concurrent colon biopsies. There is no established threshold for diagnosis, but one study found that normal controls have less than 32 eosinophils per mm2 and it has proposed that the threshold for diagnosis of eosinophilic gastritis be at least 127 eosinophils per mm2.17 In addition to the sheer number of eosinophils, features of
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Figure 10 Eosinophilic gastritis pattern. These cases typically show dramatic eosinophilia involving the lamina propria, epithelial cells, and muscularis mucosae. All other causes associated with eosinophilia must be excluded.
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Figure 11 Lymphocytic gastritis. These biopsies show prominent intraepithelial lymphocytes, typically associated with mucin loss and inflammatory lamina propria expansion.
Figure 13 Russell body gastritis. These cases are characterized by prominent mucosal accumulation of plasma cells with intracytoplasmic, glassy eosinophilic globules composed of immunoglobulins (Russell bodies). A backdrop of chronic gastritis is seen in this example.
low magnification and closer inspection reveals surface mucin loss and markedly increased intraepithelial lymphocytes (Figure 11). This pattern does not point to a specific etiology but it has a number of associations. When this pattern is the result of Helicobacter gastritis, organisms tend to be few and far between and a long and tedious search may be necessary. This pattern is also seen in the settings of celiac disease and as a result of medication-associated injury. Common offenders include proton pump inhibitors, NSAIDs, selective serotonin reuptake inhibitors, olmesartan,19 and rarely TNF-alpha inhibitors.15 If medication-related, patients usually improve upon withdrawal of the implicated agent. Collagenous gastritis is rare and can be seen in both children and young adults (Figure 12).20,21 In children there is an equal sex distribution while there is a female predominance in adults.
These patients can rarely be asymptomatic but often present with anemia, epigastric or abdominal pain, and nausea and vomiting. In 14e20% of cases it is associated with a systemic autoimmune condition. As with lymphocytic gastritis, olmesartan injury has also been associated with a collagenous gastritis pattern,19,21 with one study finding resolution of the irregular collagen deposition after cessation of treatment.21 Endoscopic findings often include atrophy or nodules. Slides show a thick irregular subepithelial collagen table with trapping of inflammatory cells and capillaries. There is associated surface epithelial injury with mucin loss and epithelial flattening. Additional findings include prominent eosinophils, atrophy of the gastric body mucosa, and prominent intraepithelial lymphocytes. Treatment is difficult, but
Figure 12 Collagenous gastritis. The collagen table is thick and irregular entrapping capillaries and inflammatory cells (typically including eosinophils).
Figure 14 Epstein Barr Virus gastritis. This case shows dramatic lamina propria expansion by large, monocytic cells in a backdrop of active inflammation, a key to the diagnosis.
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may include a gluten free diet, budesonide, carafate, and steroids.
4 Jhala NC, Montemor M, Jhala D, et al. Pancreatic acinar cell metaplasia in autoimmune gastritis. Arch Pathol Lab Med 2003; 127: 854e7. 5 Pittman ME, Voltaggio L, Bhaijee F, Robertson SA, Montgomery EA. Autoimmune metaplastic atrophic gastritis: recognizing precursor lesions for appropriate patient evaluation. Am J Surg Pathol 2015; 39: 1611e20. 6 Krasinskas AM, Abraham SC, Metz DC, Furth EE. Oxyntic mucosa pseudopolyps: a presentation of atrophic autoimmune gastritis. Am J Surg Pathol 2003; 27: 236e41. 7 Jevremovic D, Torbenson M, Murray JA, Burgart LJ, Abraham SC. Atrophic autoimmune pangastritis: a distinctive form of antral and fundic gastritis associated with systemic autoimmune disease. Am J Surg Pathol 2006; 30: 1412e9. 8 Singhi AD, Goyal A, Davison JM, Regueiro MD, Roche RL, Ranganathan S. Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders. Mod Pathol 2014; 27: 543e53. 9 Arnold CA, Limketkai BN, Illei PB, Montgomery E, Voltaggio L. Syphilitic and lymphogranuloma venereum (LGV) proctocolitis: clues to a frequently missed diagnosis. Am J Surg Pathol 2013; 37: 38e46. 10 Oberhuber G, Puspok A, Oesterreicher C, et al. Focally enhanced gastritis: a frequent type of gastritis in patients with Crohn’s disease. Gastroenterology 1997; 112: 698e706. 11 McHugh JB, Gopal P, Greenson JK. The clinical significance of focally enhanced gastritis in children. Am J Surg Pathol 2013; 37: 295e9. 12 Xin W, Greenson JK. The clinical significance of focally enhanced gastritis. Am J Surg Pathol 2004; 28: 1347e51. 13 Lin J, McKenna BJ, Appelman HD. Morphologic findings in upper gastrointestinal biopsies of patients with ulcerative colitis: a controlled study. Am J Surg Pathol 2010; 34: 1672e7. 14 Romero R, Abramowsky CR, Pillen T, Smallwood GA, Heffron TG. Peripheral eosinophilia and eosinophilic gastroenteritis after pediatric liver transplantation. Pediatr Transpl 2003; 7: 484e8. 15 Muir A, Surrey L, Kriegermeier A, Shaikhkalil A, Piccoli DA. Severe eosinophilic gastroenteritis in a Crohn’s disease patient treated with infliximab and adalimumab. Am J Gastroenterol 2016; 111: 437e8. 16 Ko HM, Morotti RA, Yershov O, Chehade M. Eosinophilic gastritis in children: clinicopathological correlation, disease course, and response to therapy. Am J Gastroenterol 2014; 109: 1277e85. 17 Lwin T, Melton SD, Genta RM. Eosinophilic gastritis: histopathological characterization and quantification of the normal gastric eosinophil content. Mod Pathol 2011; 24: 556e63. 18 Collins MH. Histopathology associated with eosinophilic gastrointestinal diseases. Immunol Allergy Clin North Am 2009; 29: 109e17. x-xi. 19 Rubio-Tapia A, Herman ML, Ludvigsson JF, et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc 2012; 87: 732e8. 20 Arnason T, Brown IS, Goldsmith JD, et al. Collagenous gastritis: a morphologic and immunohistochemical study of 40 patients. Mod Pathol 2015; 28: 533e44.
The biopsy with prominent mott cells Russell body gastritis is the benign and typically incidental finding of prominent mucosal accumulation of plasma cells with intracytoplasmic eosinophilic globules (A.K.A Mott cells) composed of immunoglobulins (Russell bodies) (Figure 13). Biopsies can feature an accompanying chronic inflammatory infiltrate. Helicobacter infection has been a common though not universal association. There are reports and we have seen cases of Russell body esophagogastroenteritis where Mott cells are present in the esophagus, small bowel, and colon.22,23 Most notably, Mott cells should not be confused with the signet ring cells seen in diffuse-type gastric carcinoma. If necessary, immunostains can be employed to demonstrate that the Mott cells are immunoreactive for CD138 and CD79a and negative for cytokeratins.
The biopsy with a prominent monocytic reaction Cytomegalovirus (CMV) and EpsteineBarr virus (EBV) infection may provoke a brisk monocytic response that can be easily mistaken for lymphoma. The telltale sign in these cases (which we invariably share with our hematopathology colleagues) is the backdrop of acute inflammation. Once we identify the neutrophils we initiate an intense search for CMV viral cytopathic inclusions (which can be seen in epithelial, stromal, or endothelial cells) and/or order CMV immunostain and EBV in situ hybridization (Figure 14). The takeaway from this section is: never diagnose lymphoma in a gastric biopsy with a background of acute inflammation without considering CMV and EBV gastritis.
Conclusions It is our belief that simply reporting patterns of inflammation without pointing to potential etiologies is not particularly helpful to clinicians or patients. We hope we provided the reader with some tools to narrow the differential diagnoses in inflammatory gastric biopsies. Of course, some cases remain enigmatic despite thorough chart review and/or discussion with the clinicians. These should be in the minority if one adheres to a consistent and systematic analysis of these biopsies. A REFERENCES 1 Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfil Koch’s postulates for pyloric Campylobacter. Med J Aust 1985; 142: 436e9. 2 Conces MR, Arnold CA, Baker PB, et al. A strategy for Helicobacter immunohistochemistry utilization in pediatric practice: insights from morphologic and cost-benefit analyses. Am J Clin Pathol 2016; 146: 611e7. 3 Batts KP, Ketover S, Kakar S, et al. Appropriate use of special stains for identifying Helicobacter pylori: recommendations from the rodger C. Haggitt gastrointestinal pathology society. Am J Surg Pathol 2013; 37: e12e22.
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21 Ma C, Park JY, Montgomery EA, et al. A comparative clinicopathologic study of collagenous gastritis in children and adults: the same disorder with associated immune-mediated diseases. Am J Surg Pathol 2015; 39: 802e12. 22 Bhaijee F, Brown KA, Long BW, Brown AS. Russell body gastroenteritis: an aberrant manifestation of chronic inflammation in gastrointestinal mucosa. Case Rep Med 2013; 2013: 797264. 23 Muthukumarana V, Segura S, O’Brien M, Siddiqui R, El-Fanek H. “Russell body gastroenterocolitis” in a posttransplant patient: a case report and review of literature. Int J Surg Pathol 2015; 23: 667e72.
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Practice Points C
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A superficial pattern of inflammation should trigger suspicion for H. pylori infection. Autoimmune gastritides associate with deep mucosal inflammation. Gastric eosinophilia can be a useful clue to a diagnosis of infection or iatrogenic/medication-associated injury. Biopsies with a prominent monocytic response in a background of active inflammation must raise suspicion for viral infections.
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Gastritis: a pattern-based approach
The biopsy with chronic inflammation This general pattern is a common offender and is seen in a myriad of inflammatory (infectious and non-infectious) processes. There are no established criteria for what accounts for “too many” lamina propria lymphocytes and plasma cells. Our approach consists of examining the biopsy at low magnification (4X) searching for increased “dot density” (plasma cells and lymphocytes) in the lamina propria, which separates the glands and imparts a “blue” (hematoxylin) appearance to the biopsy. The next step is to then confirm that the extra “dots” are indeed chronic inflammatory cells at higher magnification (40x) (and not a devious “inflammatory-mimicking” diffuse-type adenocarcinoma). Once we have determined that there is an excess of inflammatory cells, we must pay attention to the distribution of the inflammation in order to narrow the differential diagnosis.
Kevin M Waters Lysandra Voltaggio
Abstract Evaluation of inflammatory gastric biopsies is one of the most common tasks pathologists face on a daily basis. Their analysis requires recognition of inflammatory patterns and their associated differential diagnoses, an especially vital skill in the not-so-uncommon instance when there is little clinical information available. In this review we summarize the most common gastric inflammatory patterns and their clinical associations, ranging from Helicobacter gastritis to autoimmune enteropathy to the biopsy with prominent Russell bodies. Our aim is to add to the readers’ arsenal of tools to narrow the differential diagnosis in these ubiquitous specimens.
“Top heavy” chronic inflammation When the majority of the inflammation resides in the upper half of the biopsy (Figure 1), think Helicobacter gastritis. Helicobacter pylori is a curved flagellated gram negative bacillus strongly associated with gastritis and ulceration. Though Helicobacterassociated inflammation most severely affects the antrum,1 the oxyntic mucosa will display at least mild “top heavy” gastritis.2 This infiltrate will often be accompanied by at least focal active (neutrophilic) inflammation. “Up front” ancillary stains (Warthin Starry, Giemsa, immunostain) are no longer recommended3 and instead should be applied to cases with suspicious morphology but where no organisms are seen on H&E. Some cases of Helicobacter gastritis feature germinal center formation (A.K.A. follicular gastritis), a finding strongly associated with Helicobacter infection.2 Atrophy and intestinal metaplasia (also known as environmental metaplastic atrophic gastritis [EMAG]) may also be seen. A “bottom heavy” infiltrate in the setting of Helicobacter gastritis should trigger suspicion for mucosa associated lymphoid tissue (MALT) lymphoma. These cases will feature dense aggregates of monomorphic lymphocytes with or without perinuclear halos and lymphoepithelial lesions that tend to infiltrate the muscularis mucosae. In these cases, a panel of immunostains is in order; we perform an initial abbreviated version consisting of CD20, CD3, and CD43, and assess for CD20reactive B cells that aberrantly express CD43. CD3 is necessary because it is normal for T cells to express CD43 and the various stains must be compared. In addition to being a source of gastritis and ulcers, Helicobacter gastritis is well-known as a risk factor for the development of gastric carcinoma. Helicobacter heilmannii is a rare (<1% of cases), longer and more tightly coiled variant (Figure 2) that cross-reacts with H. pylori on immunohistochemistry. The gastritis associated with H. heilmannii has the same features as that of H. pylori but the inflammation is typically less severe.
Keywords autoimmune; biopsies; gastritis; patterns of inflammation
Introduction Evaluation of inflammatory gastric biopsies is one of the most common tasks pathologists face on a daily basis. Their analysis requires recognition of inflammatory patterns and their associated differential diagnoses, an especially vital skill in the not-souncommon instance when there is little clinical information available. Pattern recognition is crucial as treatment regimens differ from antibiotics (e.g. Helicobacter gastritis) to vitamin supplementation (e.g. autoimmune metaplastic atrophic gastritis [AMAG]) to immunomodulatory therapy (e.g. autoimmune enteritis [AIE]) to dietary modification (e.g. eosinophilic gastritis). Some gastritides are considered benign incidental findings (e.g. Russell body gastritis) with no clinical or treatment consequence, while others are part of a systemic process (e.g. inflammatory bowel disease), and yet others confer an increased risk of lymphoma (e.g. Helicobacter gastritis) or carcinoma (e.g. AMAG). Yes, sorting through all these inflammatory patterns can be daunting as there are several entities affecting the stomach and many share overlapping histologic features. In this review we hope to provide the reader with some tools to tease out common inflammatory patterns encountered in daily practice. If we examine these specimens in a consistently systematic fashion we will be able, in the majority of cases, to provide at least a narrow differential for the clinician to work with and effectively guide patient management. The inflammatory patterns presented here are summarized in Table 1.
“Bottom heavy” chronic inflammation A number of gastritides may be associated with a “bottom heavy” type of inflammation. The inflammatory pattern associated with AMAG, most commonly seen in females in their 6th decade, is important to identify as it leads to pernicious anemia due to vitamin B12 deficiency and confers a roughly 3 fold increased risk of gastric carcinoma. Patients may present with
Kevin M Waters MD PhD, Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA. Conflicts of interest: none. Lysandra Voltaggio MD, Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA. Conflicts of interest: none.
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Differential diagnosis for each histologic pattern The Biopsy with Chronic Inflammation C “Top Heavy” distribution C Helicobacter gastritis (H. pylori or H. heilmanni) C “Bottom Heavy” Distribution C Autoimmune metaplastic atrophic gastritis C Autoimmune pangastritis C Autoimmune enteritis C Patchy Distribution C Inflammatory bowel disease The Biopsy with Chronic Active Gastritis without Helicobacter pylori C Treated Helicobacter infection (typically no activity) C Inflammatory bowel disease Chemical/Reactive Gastropathy Pattern C Non-steroidal anti-inflammatory drugs C Bile reflux C Antral biopsy of autoimmune metaplastic atrophic gastritis C Gastric antral vascular ectasia (GAVE) The Biopsy with Prominent Eosinophils C Helicobacter Gastritis (H. Pylori or H. Heilmanni) C Autoimmune metaplastic atrophic gastritis C Post-radiation C Parasite C Solid organ transplantation C Collagenous gastritis C Inflammatory bowel disease C Eosinophilic gastritis C Medications The biopsies with Lymphocytic or Collagenous Patterns C Helicobacter Gastritis (H. pylori or H. heilmanni) C Celiac disease C Medications The Biopsy with Prominent Mott Cells C Russell body gastritis The Biopsy with a Prominent Monocytic Reaction C Cytomegalovirus C EpsteineBarr virus
Figure 1 Helicobacter gastritis. Note the superficial (“top heavy”) lamina propria inflammation. This field also shows a prominent lymphoid aggregate with germinal center formation, another clue to the diagnosis.
Table 1
Figure 2 Helicobacter heilmanii. H. heilmanii is longer and more tightly coiled than H. pylori.
iron deficiency anemia as acid is necessary for iron absorption. The histologic changes of AMAG are limited to the gastric body. Biopsies from the antrum will be normal or present a reactive/ chemical gastropathy pattern (discussed later). Besides “bottom heavy” chronic inflammation, the gastric body will feature atrophy with injured, decreased or absent parietal cells, intestinal metaplasia, and enterochromaffin cell like (ECL) cell hyperplasia (Figures 3 and 4). Roughly half of the cases will show pancreatic metaplasia, a finding rarely seen in the stomach outside the setting of AMAG.4 Interestingly, the amount of inflammation tends to decrease as atrophy develops and the parietal cells are lost (a distinguishing feature with autoimmune pangastritis, discussed later). The findings can be patchy with some areas of the stomach showing full blown atrophy and others showing preserved oxyntic mucosa. Immunohistochemistry can be useful when the specific source of the biopsy (antrum vs. body) is in
question. Atrophic (antralized) oxyntic mucosa will be negative for gastrin (or may have few gastrin-immunoreactive cells) as it lacks G cells (only present in the “true” antrum). In its early stages (“early AMAG”), this process can be challenging to recognize as it can feature mild to severe full thickness or deep chronic inflammation of the gastric body accompanied by subtle or focal findings such as inflammatory destruction of oxyntic glands, intestinal, pyloric, or pancreatic acinar metaplasia, prominent lamina propria eosinophils, and parietal cell pseudohypertrophy.5 The AMAG biopsy (early or fully developed) will feature linear and/or nodular ECL cell hyperplasia, which can occasionally be seen on H&E but is better highlighted on a chromogranin or synaptophysin immunostain. Multiple types of polyps are common in the setting of AMAG including hyperplastic polyps, type 1 gastric neuroendocrine tumors (carcinoid tumor, which are indolent), and intestinal or pyloric
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Figure 3 Autoimmune metaplastic atrophic gastritis (AMAG). These cases are characterized by deep (“bottom heavy”) inflammation, parietal cell destruction, and pyloric and intestinal metaplasia. Paneth cells are seen in this field (the bottom right). This case does not yet show complete atrophy, as evidenced by groups of residual oxyntic mucosa.
Figure 5 Autoimmune metaplastic atrophic gastritis (AMAG). The findings can be patchy with pockets of atrophy (center) in the background of preserved oxyntic mucosa. The residual oxyntic mucosa may appear polypoid to the endoscopist. This is the same case as the one shown in Figures 4 and 5.
Figure 4 Autoimmune metaplastic atrophic gastritis (AMAG), chromogranin immunostain. This is the same case as the one shown in Figure 4. Linear and nodular ECL cell hyperplasia is seen here.
Figure 6 Atrophic autoimmune pangastritis. There is marked inflammatory expansion of the lamina propria throughout the entire thickness of the mucosa accompanied by increased intraepithelial lymphocytes and active inflammation.
type adenomas. Lastly, the residual non atrophic mucosa can appear polypoid in the background of severe atrophy (Figure 5).6 “Bottom heavy” chronic inflammation is seen in both the antrum and body in atrophic autoimmune pangastritis (AAP).7 While more severe in the bottom half of the mucosa, there is inflammatory expansion of the lamina propria throughout the entire thickness, including the muscularis mucosae. Unlike AMAG, the intense “bottom heavy” infiltrate persists even after severe atrophy develops (Figure 6). Neutrophils are present to varying degrees in all cases. Autoimmune pangastritis also features prominent apoptotic bodies (GVHD-like) and increased intraepithelial lymphocytes. A chromogranin immunostain will
show lack of ECL cell hyperplasia, another distinguishing feature from AMAG. Patient presentation is dramatic with abdominal pain, nausea, vomiting, diarrhea, or malnutrition. Most patients have associated systemic autoimmune diseases including systemic lupus erythematosus (SLE), refractory sprue, autoimmune hemolytic anemia, and fibromyalgia. Treatment consists of immunomodulatory medications. The risk of neoplasia in patients with autoimmune pangastritis is uncertain. A “bottom heavy” autoimmune pangastritis-like pattern of inflammation can also be seen in patients with autoimmune enteropathy (AIE). Both children and adults will present with intractable diarrhea. Small intestinal biopsies will show severe
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villous atrophy that is not responsive to the dietary restrictions that typically provide clinical relief and histologic improvement to patients with celiac disease. Gut autoantibodies (anti-goblet cell or anti-enterocyte) can be detected serologically and patients lack severe immunodeficiency. In the stomach, the histologic findings are similar to those seen in the setting of autoimmune pangastritis with both the antrum and body showing marked lymphoplasmacytic lamina propria expansion with or without active inflammation, atrophy with loss of parietal cells, increased apoptotic bodies, increased intraepithelial lymphocytes, intestinal metaplasia, and epithelioid multinucleated giant cells. Some cases may resemble AMAG in that they show ECL cell hyperplasia.7,8 AIE may be seen as part of certain genetic syndromes including IPEX (Immune dysfunction, Polyendocrinopathy, Enteropathy, and X-linked inheritance) and APECED (Autoimmune Polyendocrinopathy, Candidiasis, and Ectodermal dysplasia). Patients with AIE are treated with immunosuppressive therapy and nutritional support. We suspect that, although reported separately, autoimmune pangastritis and AIE may be part of the same disease spectrum as they have nearly identical histologic features and half of the patients in the original description of autoimmune pangastritis also had AIE. An infectious process that deserves brief mention in this section is syphilitic gastritis. Its histologic appearance can be as dramatic as that of AAP and AIE. Biopsies will show overwhelming chronic active inflammation with or without prominent plasma cells, with glandular destruction, crypt abscesses, and lymphoid aggregates with or without granulomas. A syphilis immunostain is available but commonly yields “negative” results in infected patients.9 This diagnosis requires a high index of suspicion and clinical correlation with appropriate laboratory tests (e.g. rapid plasma regain [RPR], fluorescent treponemal antibody absorption test [FTA-ABS]).
Figure 7 Gastritis in a patient with Crohn disease. These cases commonly feature a chronic or chronic focally active gastritis that is at first reminiscent of Helicobacter infection but no organisms are found upon staining. The differential here would include treated Helicobacter gastritis.
frequently feature a chronic or chronic focally active gastritis that is at first reminiscent of Helicobacter infection (Figure 7) but no organisms are found upon staining. Gastric involvement is less commonly seen in ulcerative colitis (UC) compared to CD, but features include focal intense gastritis with a diffuse superficial pattern rich in plasma cells or a patchy basal pattern.13
The biopsy with a chemical/reactive gastropathy pattern In contrast to the “chronic inflammation pattern”, the “chemical/ reactive pattern” lacks increased blue “dots” and instead the biopsy appears “eosin-rich” (pink) on initial inspection at low magnification. This pattern is typically more dramatic in the antrum and additional histologic features include surface mucin loss, corkscrew-shaped, elongated gastric pits, and fibromuscular stranding (Figure 8). It is essential to recognize this pattern as
The biopsy with chronic active gastritis without Helicobacter pylori In some cases, this pattern of inflammation may still be attributable to Helicobacter gastritis as treated infection will often have residual “top heavy” chronic inflammation (typically without activity) in the absence of microorganisms. The patient’s history may not reflect treated Helicobacter gastritis as patients may receive antibiotic therapy for unrelated reasons. Another possibility when encountering this pattern is Helicobacter in a patient receiving proton pump inhibitor therapy. In this setting, the organisms may be difficult to find as they can become coccoid instead of rod-like and they tend to migrate from the surface into to the deep pits. If no organisms are found despite performing ancillary stains, the culprit may be inflammatory bowel disease. Though inflammation in this setting can certainly be diffuse, a peculiar pattern described in this setting is the “focally enhanced” gastritis (FEG) pattern.10 FEG is characterized by discrete foci of lymphoplasmacytic and histiocytic inflammation with variable numbers eosinophils and neutrophils, with or without granulomas, and separated by relatively normal mucosa. Though the association with IBD is weaker in adults, FEG seems to be more predictive of IBD in children.11,12 In our experience though, patients with upper tract involvement of Crohn disease more
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Figure 8 Chemical gastropathy. These feature elongated, corkscrewshaped glands and fibromuscular stranding. The presence of mild chronic inflammation does not preclude the diagnosis.
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some cases can present striking reactive atypia that may be misinterpreted as dysplasia. Clinical associations include bile acid reflux, use of nonsteroidal anti-inflammatory drugs (NSAIDS), AMAG, and gastric antral vascular ectasia (GAVE), A.K.A. “watermelon stomach”. “Watermelon” refers to its endoscopic appearance, which features erythematous linear streaks (visible reddened vessels) emanating from the pylorus towards the body. These patients often present with anemia due to gastric bleeding. In addition to the endoscopic findings, focal fibrin thrombi can be a histologic clue that the chemical/reactive pattern is to the result of GAVE.
The biopsy with prominent eosinophils What to think of first Gastric eosinophilia may be seen in a variety of settings. The first order of business when one encounters gastric eosinophilia is to search for Helicobacter. Rare cases of Helicobacter-associated gastritis may feature atypical inflammatory patterns, one of which may be gastric eosinophilia. Thankfully these cases will likely also feature the already discussed “top heavy” chronic active inflammation. Eosinophilia in the absence of Helicobacter organisms, should raise suspicion for inflammatory bowel disease, especially if the accompanying inflammation is both active and chronic and distributed throughout the thickness of the mucosa. If the inflammatory backdrop consists mostly of lymphocytes and plasma cells with no or little activity, AMAG should be investigated, especially if the inflammation is “bottom heavy”, and even in the absence of significant parietal loss since early AMAG may show relatively preserved oxyntic mucosa. Collagenous gastritis (discussed in a later section) can incite an exuberant eosinophilic response, which will be accompanied by an expanded irregular collagen table with entrapped capillaries and inflammatory cells. While uncommon in the United States, some parasites are known to elicit an eosinophilic reaction and should be searched for when eosinophils are seen, especially if eosinophilic microabscesses are present. Biopsies with eosinophilic microabscesses that lack parasites should be cut deeper into the block as organisms not uncommonly make their appearance on later sections. Additional clinical settings that may result in a biopsy with prominent eosinophils include solid organ transplantation,14 post-radiation (Figure 9), and medications.15
Figure 9 Prominent eosinophils in a patient post-radiation. Biopsies in patients who have undergone radiation (e.g. lung cancer), may feature pockets of eosinophilic inflammation. The key is to note the background epithelial and stromal atypical cells, which typically feature abundant, vacuolated cytoplasm and large nuclei with prominent nucleoli.
eosinophilic gastritis include eosinophilic infiltration of the gastric epithelium, muscularis mucosae, and submucosa (Figure 10).18 Eosinophilic gastritis is a diagnosis of exclusion and should be considered only after the other possibilities just mentioned in the previous paragraph have been excluded.
The biopsies with lymphocytic or collagenous patterns Lymphocytic gastritis shows increased numbers of intraepithelial lymphocytes within the surface epithelium. How many is too many? We don’t know because we don’t count and we don’t know of anybody who does. The biopsy typically looks “busy” at
After everything else has been excluded Though generally thought of as a pediatric disease, eosinophilic gastritis (EG) can also be seen in adults. It is most commonly associated with food allergy (86% of cases) and can be treated with dietary restriction in the pediatric population or with steroids, antihistamines, or asthma drugs in adults.16 It nearly always effects the antrum, but not always the fundus. Eosinophilic infiltration may occur in other areas of the upper gastrointestinal tract (esophagus, duodenum), but eosinophilic gastritis is typically not associated with eosinophilia in concurrent colon biopsies. There is no established threshold for diagnosis, but one study found that normal controls have less than 32 eosinophils per mm2 and it has proposed that the threshold for diagnosis of eosinophilic gastritis be at least 127 eosinophils per mm2.17 In addition to the sheer number of eosinophils, features of
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Figure 10 Eosinophilic gastritis pattern. These cases typically show dramatic eosinophilia involving the lamina propria, epithelial cells, and muscularis mucosae. All other causes associated with eosinophilia must be excluded.
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Figure 11 Lymphocytic gastritis. These biopsies show prominent intraepithelial lymphocytes, typically associated with mucin loss and inflammatory lamina propria expansion.
Figure 13 Russell body gastritis. These cases are characterized by prominent mucosal accumulation of plasma cells with intracytoplasmic, glassy eosinophilic globules composed of immunoglobulins (Russell bodies). A backdrop of chronic gastritis is seen in this example.
low magnification and closer inspection reveals surface mucin loss and markedly increased intraepithelial lymphocytes (Figure 11). This pattern does not point to a specific etiology but it has a number of associations. When this pattern is the result of Helicobacter gastritis, organisms tend to be few and far between and a long and tedious search may be necessary. This pattern is also seen in the settings of celiac disease and as a result of medication-associated injury. Common offenders include proton pump inhibitors, NSAIDs, selective serotonin reuptake inhibitors, olmesartan,19 and rarely TNF-alpha inhibitors.15 If medication-related, patients usually improve upon withdrawal of the implicated agent. Collagenous gastritis is rare and can be seen in both children and young adults (Figure 12).20,21 In children there is an equal sex distribution while there is a female predominance in adults.
These patients can rarely be asymptomatic but often present with anemia, epigastric or abdominal pain, and nausea and vomiting. In 14e20% of cases it is associated with a systemic autoimmune condition. As with lymphocytic gastritis, olmesartan injury has also been associated with a collagenous gastritis pattern,19,21 with one study finding resolution of the irregular collagen deposition after cessation of treatment.21 Endoscopic findings often include atrophy or nodules. Slides show a thick irregular subepithelial collagen table with trapping of inflammatory cells and capillaries. There is associated surface epithelial injury with mucin loss and epithelial flattening. Additional findings include prominent eosinophils, atrophy of the gastric body mucosa, and prominent intraepithelial lymphocytes. Treatment is difficult, but
Figure 12 Collagenous gastritis. The collagen table is thick and irregular entrapping capillaries and inflammatory cells (typically including eosinophils).
Figure 14 Epstein Barr Virus gastritis. This case shows dramatic lamina propria expansion by large, monocytic cells in a backdrop of active inflammation, a key to the diagnosis.
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may include a gluten free diet, budesonide, carafate, and steroids.
4 Jhala NC, Montemor M, Jhala D, et al. Pancreatic acinar cell metaplasia in autoimmune gastritis. Arch Pathol Lab Med 2003; 127: 854e7. 5 Pittman ME, Voltaggio L, Bhaijee F, Robertson SA, Montgomery EA. Autoimmune metaplastic atrophic gastritis: recognizing precursor lesions for appropriate patient evaluation. Am J Surg Pathol 2015; 39: 1611e20. 6 Krasinskas AM, Abraham SC, Metz DC, Furth EE. Oxyntic mucosa pseudopolyps: a presentation of atrophic autoimmune gastritis. Am J Surg Pathol 2003; 27: 236e41. 7 Jevremovic D, Torbenson M, Murray JA, Burgart LJ, Abraham SC. Atrophic autoimmune pangastritis: a distinctive form of antral and fundic gastritis associated with systemic autoimmune disease. Am J Surg Pathol 2006; 30: 1412e9. 8 Singhi AD, Goyal A, Davison JM, Regueiro MD, Roche RL, Ranganathan S. Pediatric autoimmune enteropathy: an entity frequently associated with immunodeficiency disorders. Mod Pathol 2014; 27: 543e53. 9 Arnold CA, Limketkai BN, Illei PB, Montgomery E, Voltaggio L. Syphilitic and lymphogranuloma venereum (LGV) proctocolitis: clues to a frequently missed diagnosis. Am J Surg Pathol 2013; 37: 38e46. 10 Oberhuber G, Puspok A, Oesterreicher C, et al. Focally enhanced gastritis: a frequent type of gastritis in patients with Crohn’s disease. Gastroenterology 1997; 112: 698e706. 11 McHugh JB, Gopal P, Greenson JK. The clinical significance of focally enhanced gastritis in children. Am J Surg Pathol 2013; 37: 295e9. 12 Xin W, Greenson JK. The clinical significance of focally enhanced gastritis. Am J Surg Pathol 2004; 28: 1347e51. 13 Lin J, McKenna BJ, Appelman HD. Morphologic findings in upper gastrointestinal biopsies of patients with ulcerative colitis: a controlled study. Am J Surg Pathol 2010; 34: 1672e7. 14 Romero R, Abramowsky CR, Pillen T, Smallwood GA, Heffron TG. Peripheral eosinophilia and eosinophilic gastroenteritis after pediatric liver transplantation. Pediatr Transpl 2003; 7: 484e8. 15 Muir A, Surrey L, Kriegermeier A, Shaikhkalil A, Piccoli DA. Severe eosinophilic gastroenteritis in a Crohn’s disease patient treated with infliximab and adalimumab. Am J Gastroenterol 2016; 111: 437e8. 16 Ko HM, Morotti RA, Yershov O, Chehade M. Eosinophilic gastritis in children: clinicopathological correlation, disease course, and response to therapy. Am J Gastroenterol 2014; 109: 1277e85. 17 Lwin T, Melton SD, Genta RM. Eosinophilic gastritis: histopathological characterization and quantification of the normal gastric eosinophil content. Mod Pathol 2011; 24: 556e63. 18 Collins MH. Histopathology associated with eosinophilic gastrointestinal diseases. Immunol Allergy Clin North Am 2009; 29: 109e17. x-xi. 19 Rubio-Tapia A, Herman ML, Ludvigsson JF, et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc 2012; 87: 732e8. 20 Arnason T, Brown IS, Goldsmith JD, et al. Collagenous gastritis: a morphologic and immunohistochemical study of 40 patients. Mod Pathol 2015; 28: 533e44.
The biopsy with prominent mott cells Russell body gastritis is the benign and typically incidental finding of prominent mucosal accumulation of plasma cells with intracytoplasmic eosinophilic globules (A.K.A Mott cells) composed of immunoglobulins (Russell bodies) (Figure 13). Biopsies can feature an accompanying chronic inflammatory infiltrate. Helicobacter infection has been a common though not universal association. There are reports and we have seen cases of Russell body esophagogastroenteritis where Mott cells are present in the esophagus, small bowel, and colon.22,23 Most notably, Mott cells should not be confused with the signet ring cells seen in diffuse-type gastric carcinoma. If necessary, immunostains can be employed to demonstrate that the Mott cells are immunoreactive for CD138 and CD79a and negative for cytokeratins.
The biopsy with a prominent monocytic reaction Cytomegalovirus (CMV) and EpsteineBarr virus (EBV) infection may provoke a brisk monocytic response that can be easily mistaken for lymphoma. The telltale sign in these cases (which we invariably share with our hematopathology colleagues) is the backdrop of acute inflammation. Once we identify the neutrophils we initiate an intense search for CMV viral cytopathic inclusions (which can be seen in epithelial, stromal, or endothelial cells) and/or order CMV immunostain and EBV in situ hybridization (Figure 14). The takeaway from this section is: never diagnose lymphoma in a gastric biopsy with a background of acute inflammation without considering CMV and EBV gastritis.
Conclusions It is our belief that simply reporting patterns of inflammation without pointing to potential etiologies is not particularly helpful to clinicians or patients. We hope we provided the reader with some tools to narrow the differential diagnoses in inflammatory gastric biopsies. Of course, some cases remain enigmatic despite thorough chart review and/or discussion with the clinicians. These should be in the minority if one adheres to a consistent and systematic analysis of these biopsies. A REFERENCES 1 Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfil Koch’s postulates for pyloric Campylobacter. Med J Aust 1985; 142: 436e9. 2 Conces MR, Arnold CA, Baker PB, et al. A strategy for Helicobacter immunohistochemistry utilization in pediatric practice: insights from morphologic and cost-benefit analyses. Am J Clin Pathol 2016; 146: 611e7. 3 Batts KP, Ketover S, Kakar S, et al. Appropriate use of special stains for identifying Helicobacter pylori: recommendations from the rodger C. Haggitt gastrointestinal pathology society. Am J Surg Pathol 2013; 37: e12e22.
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21 Ma C, Park JY, Montgomery EA, et al. A comparative clinicopathologic study of collagenous gastritis in children and adults: the same disorder with associated immune-mediated diseases. Am J Surg Pathol 2015; 39: 802e12. 22 Bhaijee F, Brown KA, Long BW, Brown AS. Russell body gastroenteritis: an aberrant manifestation of chronic inflammation in gastrointestinal mucosa. Case Rep Med 2013; 2013: 797264. 23 Muthukumarana V, Segura S, O’Brien M, Siddiqui R, El-Fanek H. “Russell body gastroenterocolitis” in a posttransplant patient: a case report and review of literature. Int J Surg Pathol 2015; 23: 667e72.
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Practice Points C
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A superficial pattern of inflammation should trigger suspicion for H. pylori infection. Autoimmune gastritides associate with deep mucosal inflammation. Gastric eosinophilia can be a useful clue to a diagnosis of infection or iatrogenic/medication-associated injury. Biopsies with a prominent monocytic response in a background of active inflammation must raise suspicion for viral infections.
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