Granulomatous gastritis

INTRODUCTION — A granuloma is an organized aggregation of combined histiocytic, lymphocytic, and plasmacytic infiltrates (granulomatous inflammation). When this organized collection of cells is identified in the stomach, it is referred to as granulomatous gastritis.

This topic review will discuss the epidemiology, etiology, histopathology, and diagnosis of granulomatous gastritis. The classification of gastritis and causes of acute and chronic gastritis are presented separately. (See "Gastritis: Etiology and diagnosis" and "Acute and chronic gastritis due to Helicobacter pylori".)

EPIDEMIOLOGY — Granulomatous gastritis is rare, with an incidence in gastric biopsies of approximately 0.35 percent [1-5]. In one large series, only 56 cases were diagnosed after review of 15,947 biopsies/resections [5].

ETIOLOGY — Granulomatous gastritis is a type of chronic gastritis and can be subclassified based on the etiology into infectious, noninfectious, and idiopathic granulomatous gastritis [5].

A specific cause can be identified in most patients found to have granulomatous gastritis [2,6]. The most likely causes vary by geography and ethnicity. Most cases of granulomatous gastritis in resource-abundant countries are noninfectious with the most common causes being Crohn disease and sarcoidosis [2,3,7]. In contrast, in resource-limited countries, infections, particularly tuberculosis, are the most common cause of granulomatous gastritis [8].

In a Belgian cohort in which biopsies from 71 patients with granulomatous gastritis were reviewed, the most common causes of granulomatous gastritis were [2]:

●Crohn disease (55 percent) or possible Crohn disease (2 percent)

●Sarcoidosis (21 percent)

●Distal esophageal adenocarcinoma with chronic active gastritis (5 percent)

●Mucosa-associated lymphoid tissue (MALT) lymphoma (5 percent)

●Peptic ulcer complications (5 percent)

●Hypertrophic gastropathy and chronic active gastritis (2 percent)

In a study from Korea, 18 of 22,643 patients (0.08 percent) biopsied were diagnosed with granulomatous gastritis over a six-year period (1997 to 2002) [4]. Of those, 14 had chronic Helicobacter pylori gastritis, two had gastric adenocarcinoma, one had chronic gastritis without H. pylori, and one had Crohn disease.

A retrospective review of 23 children and 23 adults with granulomatous gastritis in a southern United States medical center demonstrated age- and race-related differences in the etiologies of granulomatous gastritis [9]. In the children (average age 12 years), the most common diagnosis was Crohn disease. In the adults (average age 49 years), who were most often African American, the leading diagnoses were sarcoidosis and idiopathic granulomatous gastritis.

Noninfectious causes

Crohn disease — Although granulomatous gastritis is rare in Crohn disease, this is the most common etiology of granulomatous gastritis in resource-abundant countries. While clinically apparent gastritis is seen in only 2 to 7 percent of patients with Crohn disease, microscopic involvement may be detected in up to 75 percent of patients with Crohn disease and endoscopically normal mucosa [9-12].

In a retrospective study of 269 cases of granulomatous gastritis of which 185 (68.8 percent) were due to Crohn disease, patients with Crohn disease were more likely to be younger and male, relative to other etiologies of granulomatous gastritis [7]. The granulomas tended to be single or located in the gastric antrum. Upper gastrointestinal symptoms were often present.

Individuals with Crohn disease of the stomach may have focally enhanced gastritis (FEG), a focal inflammatory lesion composed of lymphocytes, histiocytes, and admixed granulocytes (which involve either one or a few adjacent foveolae) in a background of normal gastric mucosa. FEG is more frequent in the gastric antrum than in the gastric body [13] and is more commonly seen with Crohn disease when compared with other causes of granulomatous gastritis [7]. Lymphocytic gastritis may also be present [6]. Approximately 10 to 33 percent of these patients will have H. pylori infection with chronic active gastritis [6].

Granulomatous gastritis is present in approximately one-third of individuals with Crohn disease and a normal microscopic exam. The rate may be higher with increased tissue sampling [14]. These granulomas are mucosal but are sharply separated from the foveolar epithelium and often poorly formed (picture 1) [4].

Granulomatous gastritis may be present in patients with known Crohn colitis or ileitis or may be the first manifestation of Crohn disease, particularly in children. In patients with the histopathologic findings of FEG or granulomatous gastritis, or with symptoms suggestive of inflammatory bowel disease, a search for intestinal Crohn disease should be undertaken [2,3]. (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)

Sarcoidosis — Within the gastrointestinal (GI) tract, the stomach is the most commonly affected site in sarcoidosis [15]. Gastric granulomas found in patients with systemic sarcoidosis are usually asymptomatic. Subclinical GI tract involvement has been identified in 5 to 10 percent of patients with systemic sarcoidosis, while symptomatic granulomatous gastritis has been reported in less than 1 percent [16]. Symptomatic forms are dependent on the site of involvement in the stomach and range from ulcerative lesions to lesions that are polypoid with gastric outlet obstruction. Infiltrative and hyperplastic patterns of involvement may mimic Ménétrier's disease or linitis plastica carcinoma [17]. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)

Other causes — Rare noninfectious causes of granulomatous gastritis include tumors (upper GI tract adenocarcinoma and MALT lymphoma), vasculitides (eg, granulomatosis with polyangiitis [GPA] and eosinophilic granulomatosis with polyangiitis [EGPA]), drugs (eg, cocaine, carbimazole, and interferon), xanthogranulomatous gastritis, foreign body reactions to stomach contents within an ulcer repair zone or to surgical material (eg, suture), crystalline drugs (eg, antacids containing magnesium, aluminium, and silicon), reaction to endogenous materials (mucin, lipid, or crystalline material), Langerhans cell histiocytosis (which is more common in childhood), and chronic granulomatous disease (which is also more common in childhood and adolescence) [18]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis" and "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)

Infectious causes — An association with granulomatous gastritis and H. pylori has been described [3,4,19,20], although evidence does not support H. pylori as an etiologic agent in most cases of granulomatous gastritis [18,21]. In a review of 18,000 gastric biopsies, H. pylori was only identified in 6 of 16 granulomatous biopsies [22]. In a subsequent series of 71 patients, 92 percent of biopsies contained H. pylori; however, many diverse etiologies for the associated granulomatous gastritis were also found [2].

Isolated granulomatous gastritis associated with H. pylori has reportedly shown improvement after eradication therapy for the H. pylori, although persistence of granulomas after 12 to 17 months was noted [23].

While H. pylori infection with related chronic active gastritis may be responsible for rare cases of granulomatous gastritis, a search for other causes of granulomata must be undertaken when H. pylori is present [1,22]. It is currently not known whether granulomatous gastritis responds to H. pylori eradication [24].

Other infections that can cause granulomatous gastritis include tuberculosis, syphilis, Whipple disease, a variety of fungal infections including cryptococcosis, as well as anisakidosis, taeniasis, and infestations with other parasitic worms and schistosomes. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis" and "Syphilis: Treatment and monitoring" and "Whipple's disease" and "Tapeworm infections" and "Schistosomiasis: Epidemiology and clinical manifestations" and "Schistosomiasis: Diagnosis".)

Idiopathic granulomatous gastritis — In up to 25 percent of cases a cause of granulomatous gastritis cannot be identified [2]. These patients are considered to have idiopathic or isolated granulomatous gastritis [18,25]. The clinical importance of idiopathic granulomatous gastritis and its existence as a distinctive condition are uncertain [25,26]. It is possible that "idiopathic" granulomatous gastritis represents a nonspecific inflammatory reaction to an as yet unknown or undiscovered agent [2,4]. Some of these patients may also eventually be diagnosed with a known cause (eg, sarcoidosis or Crohn disease). Therefore the use of the descriptive terminology granulomatous gastritis of uncertain etiology rather than the term idiopathic or isolated granulomatous gastritis as a specific diagnosis has been suggested [21].

HISTOPATHOLOGIC FEATURES — Granulomatous gastritis encompasses a broad spectrum of histopathologic features ranging from vague, ill-defined collections of mucosal/submucosal macrophages to fully formed granulomas with giant cells and palisading histiocytes.

Granuloma type — Granulomas may be non-caseating, caseating, or necrotizing. Caseation is usually associated with an infectious etiology that may be bacterial or fungal (eg, Mycobacterium tuberculosis, atypical mycobacteria, histoplasmosis). Well-defined, non-caseating epithelioid granulomas with a circumscribed solid appearance are commonly seen in sarcoidosis. Non-caseating granulomas are also seen in Crohn disease and occasionally in association with H. pylori. Necrotizing granulomas, especially if associated with vasculitis, suggest eosinophilic granulomatosis with polyangiitis (EGPA) or granulomatosis with polyangiitis (GPA).

Whereas the morphologic features of the granulomas may yield a clue to the etiology, in many cases the granulomas are morphologically nonspecific. Special stains are needed to rule out infectious etiologies (acid-fast stains and silver impregnation stains, or specific immunohistochemical stains for designated microorganisms).

Granuloma environment — The tissue surrounding the granulomas may also contain a clue to the etiology of the granulomatous gastritis. In Crohn disease, the gastric mucosa may demonstrate focally enhanced gastritis, and in granulomatous disease associated with H. pylori, a chronic active gastritis or chronic atrophic gastritis may be present [21]. An infiltrate rich in eosinophils is suggestive of a parasitic infection, drug-induced mucosal injury, or EGPA. The presence of isolated compact granulomas sometimes surrounded by lymphocytes in otherwise normal-appearing mucosa is suggestive of sarcoidosis [21]. Gastric involvement in syphilis is characterized by a dense lymphoplasmacytic and granulomatous infiltrate often in a perivascular distribution [27-29].

Other features — Diseases with granulomatous infiltrates, instead of having well-formed granulomas, may have specific morphologic features, such as Langerhans cell histiocytosis, in which the macrophages are reniform and are CD1a-positive. The presence of necrotizing granulomatous vasculitis is consistent with GPA. EGPA (Churg-Strauss syndrome) is characterized by extravascular granulomatous inflammation with eosinophils comprising the predominant cell type in the inflammatory infiltrate. Xanthogranulomatous gastritis (XGG), a specific subtype of granulomatous gastritis, can present as a mass lesion, mimicking a gastrointestinal stromal tumor or other gastric tumor when it involves the muscularis propria of the gastric wall [30-32]. A case of XGG associated with gastric actinomycosis has been described [33].

CLINICAL FEATURES — Patients may be asymptomatic or present with epigastric abdominal pain. Nausea, vomiting, and weight loss may result from gastric outlet obstruction. Patients with concomitant intestinal involvement (eg, from Crohn disease) may have diarrhea. Upper gastrointestinal bleeding, although rare, has been reported in patients with sarcoidosis and may occasionally be massive and fatal [34,35]. Other clinical features vary based on the underlying etiology. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis" and "Sarcoid myopathy" and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults" and "Whipple's disease".)

DIAGNOSIS — The diagnosis of granulomatous gastritis is based on the histopathologic evaluation of gastric tissue. Granulomatous gastritis is considered to be present when there is a nodular, fairly circumscribed collection of epithelioid histiocytes, often mixed with a lymphocytic and plasmacytic infiltrate in the stomach. (See 'Histopathologic features' above.)

An approach to the diagnosis of granulomatous gastritis is outlined in the algorithm (algorithm 1) [17].

Evaluation to determine the underlying etiology — The following approach may be used to determine the underlying cause of granulomatous gastritis:

●A clinical history should include a history of residence in or travel to areas endemic for certain infectious diseases (eg, Mycobacterium tuberculosis, atypical mycobacteria, histoplasmosis, H. pylori, schistosomiasis, teniasis), high-risk behaviors (eg, cocaine, syphilis), medications (eg, antacids), pulmonary or systemic symptoms (eg, sarcoidosis, eosinophilic granulomatosis with polyangiitis, Whipple's disease, mucosa-associated lymphoid tissue lymphoma), and/or evidence of lower gastrointestinal symptoms (eg, Crohn disease, Whipple's disease).

●A careful endoscopic inspection of the stomach with biopsies to map the extent of the disease process should be undertaken. The endoscopic appearance of granulomatous gastritis may reveal erythema, erosions, ulcers, rugal hypertrophy or luminal obstruction simulating malignancy or be completely normal [22,36]. Note should be made of the presence of suture material. Multiple biopsies of the gastric mucosa should be obtained to increase diagnostic yield, as granulomas may be present in endoscopically normal mucosa. If endoscopic inspection is unrevealing, additional studies may be indicated (eg, endoscopic ultrasound, computed tomography scan) if malignancy is suspected.

●Histopathologic examination should include hematoxylin and eosin stains to evaluate the number of granulomas, location of the granulomas, and the nature of the inflammatory background of surrounding gastric mucosa. Certain histopathologic features may be suggestive of the underlying etiology. For example, the presence of caseating necrosis may be due to mycobacterial or fungal infections (Mycobacterium tuberculosis, atypical mycobacteria, histoplasmosis). The presence of well-defined epithelioid granulomas surrounded by normal-appearing mucosa is suggestive of sarcoidosis. Non-caseating granulomas are seen with Crohn disease and occasionally in association with H. pylori. In Crohn disease, the gastric mucosa may demonstrate focally enhanced gastritis. Necrotizing granulomas, especially if associated with vasculitis, suggest granulomatosis with polyangiitis. Special stains should be performed for specific bacteria/fungi (acid-fast stains and silver impregnation stains, or specific immunohistochemical stains for designated microorganisms). Polarization microscopy should be performed to look for birefringent material (foreign body).

●Laboratory testing, colonoscopy, and imaging studies should be based on clinical suspicion (eg, chest radiography for tuberculosis and sarcoidosis, angiotensin-converting enzyme level for sarcoidosis, serum antineutrophil cytoplasmic antibodies for GPA, and serologic tests for syphilis). (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis" and "Clinical manifestations and diagnosis of sarcoidosis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Syphilis: Screening and diagnostic testing".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Granulomatous gastritis is a type of chronic gastritis that may be infectious, noninfectious, or idiopathic in etiology. Granulomatous gastritis is rare, with an incidence in gastric biopsies of approximately 0.35 percent. Granulomatous gastritis encompasses a broad spectrum of histopathologic features ranging from vague, ill-defined collections of mucosal/submucosal macrophages to fully formed granulomas with giant cells and palisades of histiocytes. (See 'Epidemiology' above.)

●Etiology – In resource-abundant countries, the most common causes of granulomatous gastritis are Crohn disease and sarcoidosis, while in resource-limited countries, infectious causes are more common. The cause of granulomatous gastritis cannot be identified in up to 25 percent of patients. These individuals are considered to have "granulomatous gastritis of uncertain etiology." Some of these patients will eventually present with an identifiable etiology for the granulomatous gastritis. (See 'Etiology' above.)

●Clinical features – Patients may be asymptomatic or present with epigastric abdominal pain. Nausea, vomiting, and weight loss may result from gastric outlet obstruction. Patients with concomitant intestinal involvement (eg, from Crohn disease) may have diarrhea. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of granulomatous gastritis is based on the histopathologic evaluation of gastric tissue. Granulomatous gastritis is considered to be present when there is a nodular, fairly circumscribed collection of epithelioid histiocytes, often mixed with a lymphocytic and plasmacytic infiltrate in the stomach. (See 'Histopathologic features' above.)

●Determining the etiology – Evaluation of patients to determine the underlying etiology of granulomatous gastritis requires a detailed clinical history and endoscopic evaluation including biopsies for histopathologic examination that includes hematoxylin and eosin stains (algorithm 1). Special stains should be performed for designated organisms/fungi (acid-fast stains and silver impregnation stains, or specific immunohistochemical stains) and polarization. (See 'Histopathologic features' above.)

Additional laboratory testing, colonoscopy, and imaging studies should be performed to establish the etiology of granulomatous gastritis, based on the clinical setting. (See 'Diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Beverly Dickson, MD, who contributed to an earlier version of this topic review.