Virchows Arch (2018) 472:3–14

DOI 10.1007/s00428-017-2210-3

ORIGINAL ARTICLE

Granulomas in the gastrointestinal tract: deciphering

the Pandora’s box
Ian Brown 1,2 & Marian Priyanthi Kumarasinghe 3,4

Received: 4 June 2017 / Revised: 17 July 2017 / Accepted: 20 July 2017 / Published online: 4 August 2017
# Springer-Verlag GmbH Deutschland 2017

Abstract Granulomas are organised collection of activated Keywords Crohn’s disease . Sarcoidosis . Chronic
histiocytes induced by a persistent antigen stimulus. A wide granulomatous disease . Drug reaction . Granulomatous
variety of antigens encountered by the gastrointestinal tract are appendicitis . Gastrointestinal infection
of this nature and hence the resulting granulomatous inflam-
mation represents a tissue reaction pattern. The potential
causes can be broadly classified as infections or non- Introduction
infectious immune reactions. There is also a group where a
cause is never identified. Granulomas may be of varying mor- A granuloma is an organised collection of activated macro-
phological appearance, most commonly epithelioid, foreign phages (or histiocytes), the result of a unique chronic inflam-
body type, suppurative and necrotizing. This may provide a matory process to an antigen (or autoantigen) that is persistent
clue as to the aetiology; however, in most cases, the cause or difficult to remove [1]. Many antigens encountered by the
requires further inquiry. Pathologists may need to cut deeper luminal gastrointestinal tract have these qualities, and hence
levels to look for foreign material and apply special stains to granulomas are not infrequently encountered in this organ.
look for microorganisms. Pathologists also need to be certain The histiocytes in a granuloma are organised as a circumscribed
that the process is a true granuloma and not a mimic. The site collection with defined boundaries. Two main types of granu-
of occurrence in the gastrointestinal tract and the clinical set- lomatous reactions are recognised: (1) foreign body type,
ting is often paramount in establishing the aetiology. For in- formed in an attempt to phagocytose relatively inert foreign
stance, infections are more likely the cause in developing material (e.g. suture material) and not involving activation of
countries or when there is immunosuppression. Similarly, the T cell-mediated immune response, and (2) immune granu-
granulomas in the stomach are usually due to Crohn’s disease; lomata, developing as a result of a persistent T cell-mediated
however, it is only rarely the cause of granulomas isolated to immune response and activation of both innate and adaptive
the appendix. immune pathways [1, 2]. The exact pathways and relative effect
of mediating cytokines vary depending on the inciting antigen
and this produces varied morphology. Lymphocytes are a com-
mon accompaniment of the histiocytes in a granuloma.
* Ian Brown Occasionally, other inflammatory cells such as neutrophils
[email protected]
and eosinophils are also present, again dependant on the incit-
ing antigen and consequent immune pathway.
1
Envoi Pathology, 5/38 Bishop Street, Kelvin Grove, Granulomatous inflammation is best viewed as an inflamma-
Brisbane, QLD 4059, Australia tory reaction pattern with the defining morphological marker
2
Royal Brisbane and Women’s Hospital, Brisbane, Australia being an organised arrangement of histiocytes—a ‘granuloma’.
3
School of Pathology and Laboratory Medicine, University of Granulomas may exhibit a variety of patterns which broadly
Western Australia, Perth, Australia reflect the underlying aetiology. General types include foreign
4
PathWest Laboratory Medicine, Queen Elizabeth II Medical Centre, body type, characterised by multinucleate cells with eccentrically
Nedlands, Australia or haphazardly arranged nuclei; epithelioid, characterised by
4 Virchows Arch (2018) 472:3–14

single or multinucleate collections of histiocytes with abundant mimic a granuloma under certain circumstances. for in-
eosinophilic cytoplasm and ‘foot print’-like nuclei; stance the sclerotic germinal centre of a reactive lym-
xanthogranulomatous, characterised by collections of lipid laden phoid follicle and cross-cutting of the pericryptal fibro-
macrophages and multinucleate cells; suppurative, with a central blast sheath. Inflammation may also alter normal struc-
zone of neutrophils; and necrotising, with central necrosis that tures such that they might resemble a granuloma.
may retain the structure of the underlying necrotic tissue or in the Examples include ganglion cells which undergo hyper-
case of tuberculosis related caseous necrosis will be devoid of trophy and become translocated to the mucosa.
any structure. Two important subtypes of epithelioid granulomas Similarly, the muscularis mucosae might be disrupted
are also recognised. Sarcoidal granulomas are a form largely and appear as a rounded collection of smooth muscle
devoid of other inflammatory cells and often containing calcified cells (Fig. 1a), and endothelial cells may enlarge and
bodies (Schaumann bodies and/or asteroid bodies). appear clustered. In addition, lesions such as Schwann
Microgranulomas are smaller than usual granulomas with the cell hamartoma (Fig. 1b), perineurioma and
number of histiocytes averaging 7–18 as against 25–90 [3]. elastofibroma can all resemble granuloma in their early
The inciting antigens are best considered for practical pur- development. Pathologists should be vigilant to the pos-
poses under two headings, infectious and non-infectious. In some sibility of these mimics.
cases, despite extensive investigation, an identifiable cause may Once confirmed, the next step is to determine the
not be found and the term idiopathic granulomatous inflamma- likely cause of the granuloma and therefore the clinical
tion is appropriate. Table 1 lists the major aetiologies of granulo- significance. The clinical setting might already indicate
mas in the gastrointestinal tract. the aetiology and no further inquiry is required, for
example in follow-up biopsies of established Crohn’s
disease or a patient known to have chronic granuloma-
tous disease. The morphology of the granuloma and
Approach to granulomas in the gastrointestinal tract
presence, pattern and type of background inflammation
are important to aid identification when the cause is
The first issue when presented with a ‘granuloma’ in
unknown. Table 2 summarises this morphology-based
the gastrointestinal tract is to confirm that the process
method.
is indeed a true granuloma. Many normal structures can
In all cases where the cause is not known, the following
approach is recommended. Firstly, look for an inciting
Table 1 General aetiological considerations cause in the tissue sections. This might be a foreign mate-
rial (polarise the slide, also consider pneumatosis)
Infectious (Fig. 2a), a parasite (ensure sufficient levels are cut)
Systemic (tuberculosis, histoplasmosis, Whipple disease) (Fig. 2b) or crypt rupture (look for a crypt that is at the
GI specific infections (Salmonella, Yersinia, Campylobacter, edge of the granuloma with mucin extravasation and neu-
Helicobacter)
trophil and eosinophil infiltration) (Fig. 2c). Secondly,
Parasites (schistosoma, enterobius)
look for any additional clues, for instance the brown pig-
Venereal infections (syphilis, lymphogranuloma venereum)
ment laden macrophages in the non-inflamed bowel of
Non-infectious
chronic granulomatous disease (Fig. 3b). Thirdly, all cases
Crohn’s disease
for which an aetiology remains uncertain should have or-
Drugs (non-steroidal anti-inflammatory drugs—diclofenac, biologics)
ganism stains (‘bug stains’) performed, at a minimum PAS,
Foreign material (talc, starch, barium, faecal material including pulse
ZN and Wade-Fite. If infection is favoured clinically and
granuloma, pneumatosis)
organisms are not identified by special stains, additional
Crypt/gland rupture associated granuloma
polymerase chain reaction (PCR) studies on paraffin-
Sarcoidosis
embedded formalin fixed tissue can be performed for tu-
Inherited disorders (chronic granulomatous disease,
Hermansky-Pudlak syndrome, Blau syndrome) berculosis, fungi and Yersinia. Clinical investigations such
Autoinflammatory granulomatous diseases as stool culture or serology are also potentially helpful.
Diverticular colitis Finally, and often most importantly, the clinical setting
Malignancy/neoplasm related
might provide the answer as to the aetiology, and great value
Vasculitis (granulomatosis with polyangitis, Churg-Strauss syndrome,
is often obtained by discussing the case with the referring
Behcet’s disease, giant cell arteritis) clinician. Significant clinical factors that aid in the diagnosis
Common variable immunodeficiency are summarised in Table 3.
Cord colitis syndrome Depending of the aetiology, granulomas may be localised
Idiopathic to a particular site in the gastrointestinal tract or may occur at
several sites.
Virchows Arch (2018) 472:3–14 5

Fig. 1 a Disrupted muscularis mucosae in a chronic ulceroinflammatory process. b Small focus of Schwann cell hamartoma (tactile body-like
appearance)

Specific aetiologies and diseases However, not all studies have found granulomatous Crohn’s
disease to be prognostically significant [8].
Crohn’s disease Granulomas in Crohn’s disease may occur in all layers of
the gastrointestinal tract wall. They may become intimately
Although considered to be a hallmark of this disease, the re- associated with the mural vasculature [10, 11]. Similarly, they
ported frequency of granulomas in Crohn’s disease varies may reside within the muscularis mucosae. A wide variety of
from only 15 to 60%, with an average detection of 45% [4, patterns including microgranulomas (with limited numbers of
5]. Granulomas are present in 25–40% of Crohn’s disease histiocytes) [3], sarcoidal type epithelioid granulomas without
biopsies at first presentation [6, 7]. Detection is higher in chil- associated inflammation and sometimes exhibiting
dren than adults [7, 8], and the likelihood of finding granulo- Schaumann bodies (Fig. 4a) [12] and epithelioid type with
mas increases with the more biopsies taken [4, 6]. Granulomas prominent multinucleate histiocytes may be seen. Rarely,
are more commonly found in resection specimens than muco- there may be focal necrosis or suppuration (see Fig. 4b).
sal biopsies [4]. It is also recognised that granulomas are more
likely to be detected as the length of disease increases [6]. Tuberculosis
Granulomas developing in Crohn’s disease are in a constant
state of development and resolution [8, 9] depending on the Infection by mycobacterium tuberculosis (tuberculosis) re-
immunological state. The findings of a recent meta-analysis mains an important treatable aetiology of granulomatous dis-
conclude that the presence of granulomas in Crohn’s disease is ease of the gastrointestinal tract with the combined impact of
associated with a higher number of recurrences and immigration from high risk areas, HIV infection, bacterial mul-
reoperations and a shorter time to recurrence and reoperation tidrug resistance [13] and increasing use of immunomodulators
compared to Crohn’s disease without granulomas [5]. [14] altering the epidemiology. Clinically, radiologically,

Table 2 Histological pattern and

potential aetiology Granuloma type Potential aetiology

Epithelioid granuloma with background active Crohn’s disease, crypt rupture-associated granuloma in
chronic inflammation ulcerative colitis
Epithelioid granuloma, no inflammation Sarcoidosis, inactive Crohn’s disease, medication
Granuloma with background eosinophils Parasites, Churg-Strauss vasculitis, pneumatosis,
resolving Crohn’s disease
Granuloma with background necrosis Polyangitis granulomatosis, intravascular fungal
infection
Granuloma with background vasculitis Behcet’s, polyangitis, Churg-Strauss, rarely Crohn’s
disease
Necrotising granuloma Tuberculosis, Yersinia, fungal infection
Foreign body type granuloma Foreign material, parasites
Xanthogranulomatous Chronic infection
6 Virchows Arch (2018) 472:3–14

Fig. 2 a Pulse granuloma. Foreign body giant cells associated with hyaline apparent in deeper levels. c Crypt rupture-associated granuloma. Note the
ribbons and rings and dystrophic calcification. b Schistosomiasis parasite close association to the ruptured crypt
with surrounding granulomatous inflammation. The parasite was only

endoscopically and histologically, this infection may closely investigation is serological examination for specific interferon
resemble Crohn’s disease [15]. Histological features that serve gamma release (QuantiFERON tuberculosis) [20].
as clues to the possibility of tuberculosis include large coalesc-
ing granulomas, the presence of caseous necrosis and tendency Inherited disorders
for the inflammation to be focal and have submucosal accentu-
ation [16–18]. Basal plasmacytosis and presence of Several inherited conditions produce granulomas in the
microgranuloma are more typical of Crohn’s disease cases gastrointestinal tract. The most common of these is chron-
[16, 17]. In general, granulomata of tuberculosis are more read- ic granulomatous disease which can be inherited in both
ily found compared to Crohn’s disease [16]. Unfortunately, X-linked and autosomal recessive fashion [21]. The for-
while caseous necrosis is quite specific for gastrointestinal tract mer is more common and hence males are more likely
tuberculosis, it is found in a minority of cases on biopsy and affected. Granulomas develop from defective neutrophil
only about half of cases overall [2, 16, 18]. Furthermore, the function resulting from dysfunction of NADPH oxidase
sensitivity of Ziehl-Neelsen stain is only approximately 20.5% required for the generation of superoxide essential to kill
[19] and formal culture is notoriously slow to yield a result ingested bacterial organisms [21]. The condition typically
when oftentimes diagnosis and treatment need to be established presents within the first two decades of life and 55–61%
quickly. PCR performed on paraffin material to confirm the of patients with chronic granulomatous disease have gran-
mycobacterium tuberculosis organism is more rapid and has a ulomas in the gastrointestinal tract [22, 23]. These are
reported sensitivity of 64.1% [19]. The most useful often associated with focal inflammation and this occurs

Fig. 3 a Granulomatous and chronic inflammatory process typical of chronic granulomatous disease. b Characteristic brown pigment laden
macrophages in the non-inflamed mucosa
Virchows Arch (2018) 472:3–14 7

Table 3 Clinical setting and

potential aetiology Clinical finding Potential aetiology

Significant past history Crohn’s disease, chronic granulomatous disease, common variable
immunodeficiency, vasculitis
Extraintestinal granulomas Crohn’s disease, tuberculosis, sarcoidosis, Blau syndrome, chronic
granulomatous disease
History of Infectious causes
immunosuppression
Travel history/geographic Potential exposure to parasitic infection, tuberculosis
location
Medication history Recent introduction of a new medication
Sexual practices Anal intercourse and the risk of lymphogranuloma venereum
Patient’s age Young patients—considered an inherited condition

throughout the gas intestinal tract but is more commonly although gastrointestinal tract involvement is relatively
seen in the colorectum (Fig. 3a) [22, 23]. The histological uncommon [25].
pattern may be strikingly similar to Crohn’s disease [23].
A very useful diagnostic pointer is the presence of Sarcoidosis
pigmented macrophages in the mucosa which is seen in
up to 75% of patients (Fig. 3b) [22]. This common cause of systemic granulomatosis only af-
Other rare inherited conditions include Hermansky- fects the luminal gastrointestinal tract in 0.1–1.6% of
Pudlak syndrome, an autosomal recessive condition cases [26]. The stomach, in particular the antrum, is most
characterised by albinism, skin hyperpigmentation and commonly affected with 96% of all digestive tract sar-
platelet deficiency. Fewer than 10% of patients develop coidosis involving this site [26, 27]. This is followed by
colonic inflammation; however, this may closely resem- the colon which is involved in approximately in one third
ble Crohn’s disease by the presence of granulomas and/ of cases [26]. Endoscopic features include ulceration, pol-
or fistulas [24]. Similar to chronic granulomatous dis- yp formation and occasionally stricturing [26, 27]. The
ease, pigment laden (ceroid) macrophage may be seen granulomas are tight non-necrotising collections of histio-
in the adjacent mucosa [24]. Blau syndrome is an auto- cytes typically with minimal or no inflammation (Fig. 5b)
somal dominant condition with multiorgan granuloma unless there is accompanying ulceration. Calcified struc-
formation. Similar to some forms of Crohn’s disease, tures (Schaumann bodies) may be seen within the granu-
the immunopathogenesis is via mutation in NOD2 gene, lomas and represent a minor clue to diagnosis; however,

Fig. 4 a Crohn’s disease with

Schaumann-like body. b Crohn’s
disease resection with a focus of
suppurative inflammation in one
granuloma
8 Virchows Arch (2018) 472:3–14

Fig. 5 a Crohn’s disease of the stomach. The granulomas are epithelioid and often indistinct. Background focal inflammation is typical. b Sarcoidosis of
the stomach. A large epithelioid granuloma with minimal associated inflammation

this feature is not specific (see Crohn’s disease above). A foreign body giant cell reaction may occur around the
Foreign material may also mimic the calcific bodies. gas pockets of pneumatosis in the gastrointestinal tract. In
The diagnosis of sarcoidosis is usually established by mucosal biopsies, this often occurs in the deep aspect of the
identification of thoracic or other extraintestinal disease specimen, where the inciting gas pocket may not be appreci-
and by elevated level of angiotensin-converting enzyme. ated. Variable inflammation and crypt disarray can produce a
resemblance to Crohn’s disease [36]. Eosinophils can be
Foreign material prominent and further confuse the diagnosis but serve as a
clue when the pathologist is cognisant of this condition.
The gastrointestinal tract encounters large number foreign
bodies both via ingestion and by iatrogenic means (i.e. post- Medications
surgical). A characteristic feature is the foreign body giant cell
reaction containing multinucleate giant cells with nuclei that A medication reaction producing granulomatous inflamma-
are randomly distributed through eosinophilic cytoplasm. The tion is surprisingly infrequently reported in the luminal gas-
inciting foreign material may be evident in the H&E stain, trointestinal tract in contrast to examples in the liver, skin and
sometimes after cutting multiple deeper levels, or may become lung. There exist sparse case reports [36]; however, our per-
apparent upon polarisation. Well-described foreign materials sonal experience is that medications are responsible for some
encountered in the gastrointestinal tract include talc and starch cases of either localised or diffuse gastrointestinal tract gran-
(often in the subserosal region in a post-operative setting) ulomatosis. In particular, we have seen cases associated with
[28], barium [29], suture material [30] and faecal material. A several new immune modulatory drugs (see Fig. 6a, b), al-
particular form of the latter is the pulse granuloma, most often though it is unclear whether the granulomas result from an
encountered in the rectum and sometimes forming a mass aberrant immune reaction, florid crypt destruction or an infec-
(‘pseudotumour’) [31]. Histological features include foreign tion due to the induced immunodeficiency. Recent reports
body giant cells with variable amounts of hyaline ribbons and have affirmed this impression with colonic granulomas being
rings, inflammation, calcifications and food particles (see Fig. associated with PD1 inhibitor-induced colitis [37].
2a) [32]. A foreign body giant cell reaction often surrounds
parasites and their eggs that invade the stomach or intestinal Vasculitis
wall. Most commonly encountered are schistosomiasis [33],
enterobius [34] and strongyloides [35] (see Fig. 2b). All may Four forms of vasculitis affecting the gastrointestinal tract can
be accompanied by an intense eosinophil reaction sometimes be associated with granulomata. Eosinophilic granulomatosis
masking the causative organism; hence, multiple deeper levels with polyangiitis (Churg Strauss syndrome) is a triad of asth-
are always recommended when granulomas and focal eosino- ma, hypereosinophilia and vasculitis which involves the gas-
phil infiltration are encountered. Parasite-related granuloma- trointestinal tract in approximately one third to one half of
tous inflammation may be so marked as to cause a polyp or patients [2, 38]. The associated vasculitis and eosinophilic
mass lesion [33]. This is often in the rectum with enterobius infiltrate are a clue to the diagnosis; however, it is the clinical
and schistosomiasis. Serological testing is available to assist in background that establishes the diagnosis. Despite the name
the diagnosis of strongyloides and schistosomiasis [33]. granulomata are infrequent [38]. Granulomatosis with
Virchows Arch (2018) 472:3–14 9

Fig. 6 a Granulomatous
vasculitis in the intestinal wall in a
patient taking a PD1 inhibitor
drug. b Diffuse granulomatous
colitis in a patient taking an anti-
CD20 medication for multiple
sclerosis

polyangitis (Wegener’s granulomatosis) most commonly af- mucin admixed with neutrophils and eosinophils associated with
fects the respiratory tract. Unusually, there is involvement of the granuloma [8, 44, 45]. Deeper levels are very useful in
the gastrointestinal tract. Granulomatous inflammation, vas- documenting the association with a ruptured crypt [46].
culitis, extensive ulceration and necrosis are the main histo- Finally, there is an expanding interest in so-called
logical findings [2, 39]. Behcet’s disease is a multiorgan in- autoinflammatory granulomatous diseases, which result
flammatory process of presumed immune aetiology that is from dysfunction, often inherited, of genes involved in
characterised by recurrent oral and genital ulcerations and certain inflammatory pathways, the end result being
manifestations of vasculitis. Intestinal involvement is seen in granulomatous inflammation [47]. Blau syndrome
between 3 and 60% of patients depending on geographic lo- (discussed above) and early onset sarcoidosis are exam-
cation [40]. The ileocaecal valve is the most involved site and ples, with mutations existing in the NOD2 gene.
punched out ulcers that appear aphthoid or round are present.
Histologically, there is relatively non-specific active chronic Idiopathic
inflammation. Characteristic vasculitis is not often identified
on mucosal biopsies. Epithelioid granulomata are only rarely Despite the investigation, some cases of gastrointestinal tract
encountered, but when seen, the already difficult separation granulomatosis defy explanation. Infection for which the or-
from Crohn’s disease is further exacerbated. Finally, giant cell ganism cannot be identified is often blamed. Immune dysreg-
arteritis may very rarely involve the gastrointestinal tract. The ulation syndromes such as common variable immunodeficien-
intimate association of the giant cells with a medium-sized cy should always be considered, because other clinical mani-
muscular artery helps with the diagnosis, although Crohn’s festations may be underappreciated. In some cases, only long-
disease is a far more common cause of this pattern in the term follow-up can exclude Crohn’s disease.
gastrointestinal tract [41].

Miscellaneous
Specific sites
A small subset of common variable immunodeficiency presents
an endoscopic and histological pattern identical to Crohn’s dis- Granulomatous gastritis
ease with focal inflammation and granulomas [42]. The clinical
association of recurrent infections and abnormality in gamma
globulin is helpful in establishing the diagnosis. Cord colitis Aetiology common to granulomatous gastritis
syndrome develops in recipients of umbilical cord blood trans-
plant and is reported to show diffuse gastrointestinal tract gran-
ulomata [43]. A variety of neoplasms of the gastrointestinal tract
may be associated with granulomatous inflammation generally • Crohn’s disease
as an immune reaction to the tumour. A commonly encountered • Sarcoidosis
example of this occurs in microsatellite instability—high colo- • Helicobacter pylori
rectal carcinoma. Granuloma formation may occur when crypts • Non-H. pylori infections
or glands rupture as a result of any inflammatory process. The
• Neoplasm-related gastric adenocarcinomas and mucosa-associated
best characterised situation is in ulcerative colitis. The main clue lymphoid tissue (MALT) lymphomas
to this process is the finding of the granuloma centred on the • Idiopathic
residual crypt or gland and the presence of some extravasated
10 Virchows Arch (2018) 472:3–14

Granulomatous gastritis is the term given for the presence that become impacted in an ulcer or due to suture material
of granulomas occurring in the stomach. Most cases are asso- [59]. Granulomatous inflammation has been reported in asso-
ciated with chronic inflammation, but the term is still applica- ciation with several tumours including gastric adenocarci-
ble without it. This finding is uncommon, with a reported nomas, Langerhans cell histiocytosis and MALT lymphomas
incidence between 0.08 and 0.35% in gastric biopsies [59].
[48–50]. Granulomas may be numerous and dominate the Finally, gastric granulomas develop without obvious
histological pattern. However, more often than not, granulo- aetiology in up to 25% of cases. The term idiopathic
mas are accompanied by other patterns of inflammation, com- granulomatous gastritis is appropriate for these cases that
monly active chronic inflammation, that appear to be the ma- remain of uncertain cause after extensive investigation
jor abnormality. both clinically and pathologically. Long-term follow-up
Granulomatous gastritis is a reaction pattern that has both is important as idiopathic granulomatous gastritis may
infective and non-infective causes. The aetiology varies ac- precede the full spectrum of a specific disease, sarcoidosis
cording to geography and ethnicity. For instance in developed or Crohn’s disease in particular, sometimes by many years
countries, the majority of cases are of non-infectious aetiology [59]. Therefore, an initial ‘diagnosis’ of idiopathic granu-
with the most common cause being Crohn’s disease [49, 50]. lomatous gastritis should not be regarded as a distinct
This is almost always the cause in children [51]. Meanwhile, entity.
worldwide, the most common aetiology of granulomatous
gastritis is infection, of which tuberculosis is the most impor- Granulomatous ileitis
tant cause to consider [52].
Crohn’s disease is associated with granulomatous inflam- Aetiology common to granulomatous ileitis
mation in the stomach in between 8 and 75% of patients [53,
54]. Up to half of all cases of granulomatous gastritis in de-
veloped countries are related to Crohn’s disease [48]. The
prevalence appears to be higher in the paediatric age group Infectious
[51]. Within the stomach, a sub-pattern of focally enhanced • Tuberculosis
gastritis may provide a clue to the diagnosis (Fig. 5a); howev- • Yersinia
er, a diffuse pattern with granulomas is occasionally encoun- Non-infectious
tered in limited biopsies [7]. Gastric Crohn’s disease is often • Crohn’s disease
accompanied by involvement of the other sites of the GI tract;
• Vasculitis—Behcet’s
therefore, an important step is to correlate with the finding of
• Neoplasm related—lymphoma, adenocarcinoma, neuroendocrine
biopsies of other sites [7]. tumour
Granulomas are found in a variable percentage of
H. pylori-infected stomachs. In one study, which accords with Crohn’s disease is by far the most common cause of
our experience, they were identified in 1.1% of H. pylori-con- granulomas in the ileum in developed countries, whereas
taining gastric biopsies [55]. This is in contrast to a Korean in underdeveloped countries, the main cause is tuberculo-
study where H. pylori were present in 78% of cases [49]. The sis. The ileum is a preferential site for intestinal tubercu-
granulomas were single and located in the antrum [49]. It is losis because of the high densities of lymphoid aggre-
unclear whether H. pylori can be regarded as the aetiology or gates, neutral pH environment and ready absorption of
an incidental finding; however, eradication of H. pylori has the organisms at this site [61]. Approximately 90% of
been associated with regression of the granulomas [56, 57]. all intestinal tuberculosis involves the ileum [62].
Practically, if a patient has ileal or ileocolonic Crohn’s disease, Distinction from Crohn’s disease is extremely problematic
then any granulomatous gastritis can be regarded as evidence in regions where tuberculosis is endemic. Features that
of upper gastrointestinal tract Crohn’s disease regardless of the favour Crohn’s disease include the presence of anorectal
presence of Helicobacter infection. disease, a longitudinal pattern of ulceration and a cobble-
In addition to mycobacteria and Helicobacter infection, stone appearance to the mucosa [13, 15, 18, 62].
other infections have been associated with gastric granuloma Histologically large confluent granuloma and necrosis
formation but are quite rare. These include syphilis (tertiary within the granulomas are rare for Crohn’s disease and
form ‘gumma’), Whipple disease, parasitic infections, such as should always prompt investigation for tuberculosis.
anisakiasis, schistosomiasis and taeniasis, and invasive fungal PCR from paraffin-embedded material can aid in the
infections [58, 59]. diagnosis.
Rare causes of granulomas gastritis include sarcoidosis Yersinia infection is a common mimic of both Crohn’s
(discussed above; Fig. 5b), medications, e.g. carbimazole disease and tuberculosis in the ileum. Yersinia enterocolitica
[60], and foreign body granulomas due to food or antacids and Yersinia pseudotuberculosis are the most commonly
Virchows Arch (2018) 472:3–14 11

encountered species. They are gram-negative coccobacilli ac- Granulomatous appendicitis

quired by ingestion of contaminated food. Infection is often
self-limited but chronic infections can develop [62]. Infection Aetiological common to granulomatous appendicitis
risk is increased in patients with iron overload disorders.
Table 4 provides helpful diagnostic clues.

Infectious
Granulomatous colitis - Tuberculosis, Yersinia, parasites (enterobius, schistosomiasis)
Non-infectious
Aetiology common to granulomatous colitis - Interval appendicitis
- Crohn’s disease
- Idiopathic

Infectious
• Systemic forms (tuberculosis, histoplasmosis)
• GI infections (Salmonella, Yersinia, Campylobacter, parasites)
• Venereal infections in rectum (syphilis, lymphogranuloma venereum)
Non-infectious
Granulomatous appendicitis is an uncommon finding iden-
• Crohn’s disease
tified in 0.1 to 2.0% of appendicectomy specimens [67, 68].
Cases may present with symptoms and signs of acute appen-
• Ulcerative colitis (mucin granuloma)
dicitis or the process may be asymptomatic and identified in
• Diverticular colitis (syn. diverticular disease-associated colitis)
the appendix removed for other reasons. Granulomatous ap-
• Pneumatosis coli
pendicitis was originally believed, at least in developed coun-
• Malignancy related—e.g. granulomatous reaction to microsatellite
instability high colorectal carcinoma tries, to represent an isolated organ manifestation of Crohn’s
disease; however, it is now recognised that Crohn’s disease
accounts for only about 5–10% of granulomatous appendicitis
[68] and that Crohn’s disease involving only the appendix is
exceptional.
The large intestine is the most common site in which While previously a common diagnosis, idiopathic
granulomas are identified within the gastrointestinal tract. (primary) granulomatous appendicitis is in fact rare. Two ae-
Crohn’s disease is the most common aetiology. However, tiologies now account for the majority of these cases, namely,
a high index of suspicion of other possibilities should Yersinia infection and interval appendicectomy-related in-
always be maintained before making this diagnosis, par- flammation (see Fig. 7a, b) [68–70]. The relative contribution
ticularly if the inflammatory changes and granulomata are of interval appendectomy depends upon local surgical man-
limited to the large intestine. In particular, granuloma lim- agement but may represent more than half of all granulomas
ited to the sigmoid colon can represent an idiosyncratic appendicitis cases encountered [70]. Other infections, mainly
reaction to the diverticular disease [63]. Furthermore, tuberculosis and parasitic infestations, are more commonly the
granulomata limited to the distal rectum, while common cause of granulomatous appendicitis in tropical and subtropi-
in Crohn’s disease, can also be seen with venereal infec- cal countries. In a recent review of 13 cases drawn mainly
tions in particular syphilis and lymphogranuloma from underdeveloped countries, infectious and non-
venereum [64]. Patchy active chronic inflammation with infectious causes were responsible for 62 and 38% of granu-
granulomata, sometimes numerous, may represent resolv- lomatous appendicitis, respectively [67]. Parasites were re-
ing stage ulcerative colitis. Attention should be paid to the sponsible for 38.5% of the cases [67]. Infrequent causes in-
association of granulomas to crypts [45]. clude sarcoidosis, fungal infection and foreign body reaction
Foreign body type granulomata occurring at the base to impacted faeces [68].
of the mucosa in biopsy specimens may represent The appendix can be normal sized or enlarged. An impor-
pneumatosis coli. Associated gas pockets and eosinophil tant histological feature is the number of granulomas which
infiltrate are helpful clues for the latter [65]. Bacterial are more numerous with both idiopathic granulomatous ap-
infection by Salmonella or Campylobacter may very pendicitis and infection, than with Crohn’s disease [71]. The
rarely produce scattered microgranulomata typically in latter may even be devoid of granulomas. The presence of
the setting of an acute inflammatory process with necrosis in the granulomata should always suggest an infec-
marked cryptitis, crypt abscess formation and mucosal tious aetiology, while fistula or fissure formation is more com-
oedema [66]. mon with Crohn’s disease [71, 72].
12 Virchows Arch (2018) 472:3–14

Table 4 Distinguishing features between TB, Yersinia and Crohn’s disease

Feature Crohn’s disease Yersinia Tuberculosis

Clinical/gross
Predisposition Family history −/+ Iron overload disorder High prevalence area
Ulcers Linear (longitudinal) and Linear and aphthoid Tend to be in
aphthoid transverse axis or circumferential
Oedema + + +
Pseudopolyps + + +
Fistulae + +/− +
Transverse fissures + − +
Cobble stoning + −/+ −/+
Strictures Generally long +/− Usually <3 cm
Anal lesions Frequent No Rare
Serology − Yersinia specific QuantiFERON tuberculosis
Stool culture − Often positive 30% positive
Specific PCR on paraffin − + +
material
Microscopy
Granulomas
Number Multiple Few Many and may
be confluent
Size Small (<200 μm) Large Large (90% over 200 μm)
Nature Compact sarcoid-like Epithelioid granulomas Epithelioid
Poorly organised, discrete or without foreign body giant granulomas with Langhans giant
isolated cells with central necrosis cells and central caseation
and prominent lymphoid
cuffing; stellate abscesses
Location Mucosal location more Mucosa but also submucosa Granulomas in
common than in other sites. and deeper in bowel wall submucosa (if present in biopsy) or in
Granulomas may be associated granulation tissue favours tuberculosis
with lymphatics
Microgranulomas/histiocytic + −/+ −/+
aggregates
Crypt-centred + −/+ −/+
inflammation/pericryptal
granuloma

Fig. 7 a Granulomatous appendicitis in confirmed Yersinia infection. b Granulomatous appendicitis in interval appendicectomy with numerous
granulomas evident
Virchows Arch (2018) 472:3–14 13

Other sites 4. Molnár T, Tiszlavicz L, Gyulai C et al (2005) Clinical significance

of granuloma in Crohn’s disease. World J Gastroenterol 11(20):
3118–3121
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include much submucosa. Crohn’s disease is the most com- rectum 53(2):177–185
mon association in developed countries with the granulomata 6. Heresbach D, Alexandre JL, Branger B et al (2005) Frequency and
significance of granulomas in a cohort of incident cases of Crohn’s
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heavy chronic inflammatory cell infiltrate and lymphocytic 7. Brown IS, Miller GC, Bettington ML, Rosty C (2016)
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sophageal involvement could represent either local infection
distinction of Crohn’s disease from ulcerative colitis.
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clinicopathological correlation is required to establish the final 17. Ye Z, Lin Y, Cao Q et al (2015) Granulomas as the most useful
diagnosis. histopathological feature in distinguishing between Crohn’s disease
and intestinal tuberculosis in endoscopic biopsy specimens.
Medicine (Baltimore) 94(49):e2157
18. Makharia GK, Srivastava S, Das P et al (2010) Clinical, endoscop-
Compliance with ethical standards This manuscript complies with ic, and histological differentiations between Crohn’s disease and
local ethics guidelines. intestinal tuberculosis. Am J Gastroenterol 105(3):642–651
19. Gan HT, Chen YQ, Ouyang Q et al (2002) Differentiation between
Funding No funding was required for this manuscript. intestinal tuberculosis and Crohn’s disease in endoscopic biopsy
specimens by polymerase chain reaction. Am J Gastroenterol
97(6):1446–1451
Conflict of interest The authors state no conflicts of interest.
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the immunodiagnosis of tuberculosis: a systematic review. Lancet
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