REVIEW ARTICLE
Histologic Diagnosis of Inflammatory Bowel Diseases
Bence Kővári, MD, PhD,*† Ágnes Báthori, MD,*†
Mark S. Friedman, MD,‡ and Gregory Y. Lauwers, MD*
Abstract: Inflammatory bowel disease, including ulcerative colitis
and Crohn disease, is an idiopathic chronic inflammatory condition
of the gastrointestinal tract. Since neither the clinical manifestations
nor the morphologic features of inflammatory bowel disease are
pathognomonic alone, the differential diagnosis to consider is rel-
atively broad, and it relies on the synthesis of clinical, endoscopic,
and microscopic features. Long-held histologic diagnostic principles
include recognizing structural and inflammatory features of chron-
icity, that is, architectural distortion, basal plasmacytosis, and
expansion of the lamina propria lymphoplasmacytic infiltrate. In
addition, evaluation of the neutrophilic inflammation and related
crypt and epithelial destruction is essential to gauge the activity of
the disease. Nevertheless, these features can be difficult to confirm in
special settings, including at the inception of the disease or in par-
tially treated cases. This review will explore the classic morphologic
features of ulcerative colitis and Crohn disease, followed by a
detailed discussion of atypical and diagnostically challenging pre-
sentations and a brief review of the clinical aspects necessary for the
daily practice of pathologists.
Key Words: inflammatory bowel disease, Crohn disease, ulcerative
colitis, histopathology, differential diagnosis
(Adv Anat Pathol 2022;29:48–61)
INFLAMMATORY BOWEL DISEASE
Inflammatory bowel disease (IBD), including ulcer-
ative colitis (UC) and Crohn disease (CD), are etiopatho-
genetically poorly understood, partially genetically driven,
chronic inflammatory conditions of the gastrointestinal (GI)
tract that can be associated with inflammatory and neo-
plastic complications. Establishing a diagnosis of IBD can
be difficult. In the absence of specific histologic features,
IBD can often mimic other conditions, and its diagnosis
relies on the synthesis of certain clinical, endoscopic, and
microscopic features.
Histologic evaluation of endoscopic biopsies is critical
to the management of patients with IBD. Its role can be
summarized in 4 steps: (1) establish the diagnosis and
exclude appropriate differential diagnoses; (2) assess the
severity and extent of the disease; (3) exclude complications
From the *Department of Pathology, Henry Lee Moffitt Cancer Center
and Research Institute; ‡Department of Gastroenterology, Gastro-
intestinal Oncology Program, Henry L. Moffitt Cancer Center and
Research Institute, Tampa, FL; and †Department of Pathology,
University of Szeged and Albert Szent-Györgyi Health Center,
Szeged, Hungary.
All authors contributed to the drafting and editing of this manuscript.
G.Y.L. has received consulting fees from Alimentiv Inc. The remaining
authors have no funding or conflicts of interest to disclose.
Reprints: Bence Kővári, MD, PhD, Moffitt Cancer Center, Magnolia
Campus, 12902 USF Magnolia Drive, Tampa, FL 33612 (e-mails:
kovari.bence.p@gmail.com; bence.kovari@moffitt.org).
All figures can be viewed online in color at www.anatomicpathology.com.
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(eg, concomitant cytomegalovirus infection; dysplasia), and
(4) evaluate response to treatment.
This article will review the classic clinical and mor-
phologic features of UC and CD and discuss challenging
aspects of their diagnosis, including atypical endoscopic and
histologic presentations that can contradict certain stereo-
typical rules regarding the differential diagnosis of IBD
types. Specific features of IBD in the pediatric population as
well as manifestations in the upper GI tract and finally, the
issues related to the diagnosis of dysplasia in IBD will be
discussed in other articles of this special issue.
DEFINITION AND CLINICAL ASPECTS
IBD is an idiopathic chronic inflammatory condition of
the GI tract. It comprises 2 disorders: CD and UC both
usually present with distinct clinical and histopathologic
characteristics, although atypical presentations can be seen.
IBDs typically develop in young adulthood and com-
monly persist over a lifetime with relapsing and remitting
episodes.1 Some authors report a second peak between 50
and 80 years of age.2,3 UC is slightly more common in
males, while CD occurs more frequently in females.4–7 The
epidemiologic distribution of IBDs show geographic and
ethnic differences worldwide, with a north-south gradient in
Europe and North America, where IBD is more commonly
observed in Askenazi Jews and Caucasians.1,8 They are less
common in Hispanics and Asians.1,9,10 The incidence of
IBD has been on the rise globally, including newly indus-
trialized countries in Asia and North Africa where it had
previously rarely been reported.11–16
The exact etiopathogenesis of IBD remains unknown,
and an exhaustive review is beyond the scope of this article.
It likely results from a complex interplay of genetic and
environmental factors with various contributions of genetic
susceptibility, dysregulated innate and adaptive immune
responses, bacterial flora, and other environmental
agents.17–19 Several lifestyle factors have been noted to
contribute to the development of IBDs, including diets and
smoking habits. For example, diets rich in fat are associated
with an increased incidence of UC and CD.20–22 Alter-
natively, a diet rich in fibers may be a protective factor for
developing CD but not UC.20,23 Smoking is associated with
an increased risk for CD and its complications.24–26 Alter-
natively, smoking may be a protective factor for developing
UC. Interestingly, appendectomy is suspected to reduce the
risk of developing UC.24,27,28
Numerous observations point toward the role of genetics.
A family history of IBD is a strong risk factor for developing
IBD, somewhat greater for CD than UC.1,29 It has been shown
that first degree relatives of IBD patients are more likely to be
affected by IBD than the general population.30–35 Also, in a
large cohort of twins with IBD, the concordance was the
highest among monozygotic twins36 Finally, it has also been
Adv Anat Pathol  Volume 29, Number 1, January 2022 Histology of IBD

shown that children of parents with both IBD have a 33% risk
of being diagnosed with IBD.30 Numerous IBD susceptibility
loci have been reported, some associated with both UC and
CD, and others specific to UC or CD. Gene identification
studies have highlighted the role of 4 critical pathways in the
pathogenesis of IBD susceptibility. These are (a) intracellular
innate immunity pathways; (b) autophagy pathways; (c)
adaptive immunity pathways; and (d) pathways regulating
epithelial functions. In relation to the innate immunity path-
ways, NOD2/CARD15 located on chromosome 16 was the first
gene to be associated with IBD. It encodes for a protein that
leads to activation of NF-kb, which, when deficient, predis-
poses to terminal ileal CD.37–39 As most of these pathways are
related to immunity, the pathogenetic role of an interplay
between host immune response and microbiota has been
proposed.40 Finally, a series of monogenic IBD disorders have
also been reported to affect young children (ie, very early-onset
IBD)41–43 and are discussed in detail in the Review on pediatric
inflammatory bowel disease article of this special issue.

CLINICAL MANIFESTATIONS OF
INFLAMMATORY BOWEL DISEASE
Early in the disease course, the symptoms of IBDs may
be insidious, and the histologic features may also be
immature. Therefore, establishing a chronic disease course
by clinical follow-up is essential since most infectious colitis
resolve within 2 to 3 weeks and rarely last over 30 days.
UC patients frequently present with bloody diarrhea,
colicky abdominal pain, and tenesmus. In contrast, CD
patients report more heterogeneous symptoms, usually
depending on the location of their disease. The common
complaints associated with CD include abdominal pain and
diarrhea. Furthermore, systemic symptoms such as malaise,
anorexia, and fever are more common in CD. Life-threat-
ening complications may develop, including severe bleeding,
bowel obstruction, perforation, fistulae, abscess formation,
as well as fulminant colitis and toxic megacolon.44
Although some endoscopic features are highly suggestive
of a diagnosis of IBD, none are pathognomonic (Fig. 1).45 UC
begins in the rectum and progresses proximally in a con-
tinuous pattern, without apparent skip lesions. In the
untreated patient, the disease is typically worse distally. Loss
of normal vascular markings is an early finding, and as the
inflammation progresses, hyperemia and edema with a fine
mucosal granular appearance are detected. The mucosa is
friable and bleeds easily on contact. In moderate disease,
aphthous and small ulcers are seen; however, in distinction to
CD, the ulcers are surrounded by inflamed mucosa. In severe
disease, larger continuous ulcers may be observed.
In contrast to UC, CD typically affects the proximal
colon or the ileocecal region while sparing the rectum. The
disease distribution is characteristically patchy with skip areas
of normal-appearing mucosa. Early in the course of CD, small
punched-out aphthous ulcers can be seen overlying sub-
mucosal lymphoid hyperplasia. These ulcers can coalesce into
larger ulcers and may appear stellate. “Bear claw” refers to
large linear to serpiginous ulcers (Fig. 1B), while the combi-
nation of linear ulceration and edematous islands of inter-
vening preserved mucosa results in cobblestone appearance.
The presence of ileal involvement favors CD, although back-
wash ileitis can be observed in UC patients with pancolitis.
Ulceration, stenosis, or distortion of the ileocecal valve favors
the former, whereas patchy inflammation without ulceration
extending only a few centimeters into the ileum favors the
FIGURE 1. Example of ulcerative colitis characterized by a coarse
and friable mucosa with fibrinopurulent material and ecchymoses
(A). Endoscopic appearance of a linear bear claw-like ulcers with
intervening uninvolved mucosa in a patient with Crohn
disease (B).
latter. CD can affect any segment of the GI tract from mouth
to anus. Symptomatic upper GI involvement is reported to
occur in 5% of CD; however, ∼ 50% of patients may have
asymptomatic lesions found on endoscopy.46,47 These aspects
of IBD are covered in Upper Gastrointestinal Tract Involve-
ment in Inflammatory Bowel Diseases: Histologic Clues and
Pitfalls article of this special issue. Extraintestinal manifes-
tations are seen in 25% to 40% of IBD, involving the skin,
eyes, hepatobiliary and musculoskeletal systems.
It is worth underscoring that in some cases, although
the clinical evidence is strong enough to support a diagnosis
of IBD, definitive histologic evidence to favor either UC or
CD evades even the most experienced pathologist. By gen-
eral convention, the term IBD unclassified is used for such
cases when only biopsy material is available. The term
“Indeterminate colitis” (IC) is favored for cases for which a
definitive diagnosis of either CD or UC cannot be made
despite examining a colectomy specimen.48
In addition to clinical evaluation, endoscopic examina-
tion, and microscopic assessment, immune markers detected
in the sera of UC and CD patients have been extensively
evaluated. The two most intensively studied antibodies are
atypical anti-Saccharomyces cerevisiae (ASCA) and peri-
nuclear antineutrophil cytoplasmic p-ANCA antibodies, the

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Kővári et al Adv Anat Pathol  Volume 29, Number 1, January 2022

FIGURE 2. Comparative scanning view of ulcerative colitis (A)

and Crohn disease colitis (B). ulcerative colitis usually demon-
strates a more distinct chronic architectural disarray compared
with Crohn disease. *The crypt abscess present in the Crohn
disease case. Please see this image in color online.

elevation of which may favor CD and UC, respectively. An

exhaustive review is again beyond the scope of the subject
treated herein. However, to date, no single marker has been
shown to be diagnostic of IBD; yet, combinations of markers
have been used to support the diagnosis in challenging cases.
The expectations that a marker or series of markers would
allow predicting the classification of clinical phenotypes and
response to treatment has not been fully met.49

HISTOPATHOLOGIC CHARACTERISTICS OF
INFLAMMATORY BOWEL DISEASE
Although there is no single histologic feature specific
for IBD, long-held diagnostic tenets include recognizing
structural and inflammatory features of chronicity, that is,
architectural distortion, basal plasmacytosis, and expansion
of the lamina propria lymphoplasmacytic infiltrate (Fig. 2).
In addition, evaluation of the neutrophilic inflammation and
related crypt and epithelial destruction is essential for FIGURE 3. High-power features related to chronic mucosal dam-
age, that is, Paneth cell hyperplasia (A), pseudopyloric gland meta-
gauging the disease activity. These microscopic hallmarks
plasia (B), and endocrine (enterochromaffin) cell hyperplasia (C).
are usually best established in treatment-naive IBD and are Please see this image in color online.
subtler in CD. Nevertheless, these features can be difficult to
confirm at the inception of the disease in pediatric UC cases
and patients with primary sclerosing colitis. Finally, a Challenges at the Inception of the Disease
definitive diagnosis can also be challenging in partially Biopsies performed during the early phase of the dis-
treated cases if previous biopsy material is not available for ease can be challenging since the full spectrum of chronicity
review and pertinent clinical information is not provided. features may be missing, while neither the clinical

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Adv Anat Pathol  Volume 29, Number 1, January 2022
FIGURE 4. Features of activity with cryptitis (A) and crypt abscess
(B). In B, observe the pericryptic accumulation of pale-staining
histiocytes secondary to a stromal reaction to crypt rupture and
mucin extravasation. Please see this image in color online.
presentation nor the endoscopic features are fully
diagnostic.50,51 A study evaluating the evolution of histo-
logic features in IBD reported focal basal plasmacytosis as
the earliest sign of IBD. The frequency of basal plasmacy-
tosis increased from 38% in the very early phase (1 to 15 d
after the initial symptoms) to 54% in the 16 to 30 days
period and started to plateau after 30 days in the 80% to
90% range. The presence of crypt architectural distortion
rose from 0% to 23% to 31% and finally to 33% to 78% of
cases in the 1 to 15 days, 16 to 30 days, and 121 to 300 days
intervals, respectively. Crypt shortening (base of crypts not
touching the muscularis mucosae) and villous surface have
been reported to develop relatively earlier than crypt
branching and shape irregularity.51 Establishing the diag-
nosis of chronic colitis may be especially problematic in the
pediatric population, with pediatric patients presenting less
frequently with architectural features of chronicity than
adult patients.52
A differential diagnosis from acute self-limited (infec-
tious) colitis may be especially challenging in this early
phase. Superficial distribution of the lamina propria
inflammatory infiltrate once reported as a feature of an
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Histology of IBD
FIGURE 5. Example of granulomas in inflammatory bowel dis-
ease. Cryptolytic granulomas are characterized by the aggrega-
tion of histiocytes around ruptured crypts with intermingled
neutrophils, mucin, mucinophages, and fragments of damaged
crypt epithelium (A). They can develop in patients with ulcerative
colitis as well as Crohn disease with crypt damage. Crohn disease-
related granulomas are typically located between crypts and tend
to be small (B). Giant cells are frequently absent, while necrosis
always prompts exclusion of tuberculosis. Please see this image in
color online.
infectious etiology has not been confirmed by subsequent
studies. Other authors claimed that the diagnosis should
instead rely on the absence of IBD-specific changes and
clinical follow-up.53,54
ULCERATIVE COLITIS
UC typically affects the rectum and extends proximally
in a continuous and circumferential manner. In the appro-
priate clinical context, the histologic diagnosis of UC relies
on the recognition of chronicity features, that is, crypt
structural alterations and density, quality, and topography
of the lamina propria infiltrate. Depending on the activity of
the disease, various degrees of neutrophilic infiltration
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Kővári et al Adv Anat Pathol  Volume 29, Number 1, January 2022

FIGURE 6. Schematic depiction of the different distribution patterns of ulcerative colitis (UC). Please see this image in color online.

leading to epithelial damage can also be noted. However,
the morphology may vary since the duration of the disease,
the presence of superimposed complications (eg, cytome-
galovirus infection), and potential therapy can alter any of
these features.
After 30 days of activity, histologic features of chronicity
will become evident.51 Classic signs of chronicity include the
presence of a deep lymphoplasmacytic infiltrate and archi-
tectural distortion (Fig. 2A). The parallel organization of the
crypts will be altered with a variable degree of structural
alterations (ie, branching, irregular shape, size, lumen dia-
meter, orientation, and distance of crypts, and villous trans-
formation of the surface). The mucosa may become atrophic
with shortened crypts and reduced crypt density (crypt drop-
out) if medical therapy is unsuccessful. Another feature of
chronicity is the appearance of Paneth cell metaplasia that
may take place in the left colon. Although Paneth cells are
normally present in the small bowel and right colon, an
increased number of Paneth cells (ie, Paneth cell hyperplasia)
may also suggest chronicity in these segments. Pyloric

TABLE 1. Features of Ulcerative Colitis Versus Crohn Disease

Classic Less Common but Compatible Incompatible
UC Chronic active colitis Deeper or transmural inflammation in fulminant True nonpericryptic
colitis granulomas
Architectural disarray Discontinuous chronic active colitis and relative Chronic ileitis (excluding
rectal sparing (eg, post-therapy) backwash ileitis)
Basal lymphoplasmacytosis Cecal/appendiceal and right-sided skip lesion Transmural lymphoid
aggregates
Distal Paneth cell metaplasia Backwash ileitis Disproportionate
submucosal inflammation
Inflammation limited to mucosa Duodenitis or gastritis
Continuous involvement, including rectum Stenosis (UC-associated neoplasia)
No extracolonic involvement
CD Discontinuous chronic active colitis Continuous mucosal inflammation and limited
submucosal inflammation in older patients with
isolated CD colitis
Intervening zones of normal bowel
Chronic active ileitis, villous blunting and
crypt distortion, pyloric metaplasia
Granulomas
Fissuring ulceration, stricture and fistula
formation
CD indicates Crohn disease; UC, ulcerative colitis.

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Adv Anat Pathol  Volume 29, Number 1, January 2022
FIGURE 7. Example of complete mucosal healing after successful
therapy for ulcerative colitis. Please see this image in color online.
metaplasia may also be detected, although it is more often
noted in the terminal ileum of CD patients (Fig. 3).55
The diffuse expansion of the lamina propria by a mixed
lymphoplasmacytic infiltrate extending deep in the mucosa
with loss of the normal superficial-deep inflammatory gra-
dient is another classic feature of chronicity. So is the so-
called basal plasmacytosis, a band-like infiltrate developing
between the base of shortened crypts and the muscularis
mucosae.
FIGURE 8. Schematic depiction of the different endoscopic dis-
tribution patterns of Crohn disease. UC indicates ulcerative colitis.
Please see this image in color online.
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Histology of IBD
In this active phase of the disease, the inflammation is
distributed diffusely with no or limited skip areas. In prac-
tice, it translates to every biopsy fragment showing a
somewhat similar degree of inflammation. This inflamma-
tion is characteristically limited to the mucosa. Nevertheless,
focal submucosal spillage of the inflammation can be
observed in severe cases. It is especially the case with ful-
minant colitis, which presents with transmural inflamma-
tion. Occasionally, in such cases, a definitive diagnosis
regarding the type of the IBD cannot be reached, and the
diagnosis of IC is applied56
Active inflammatory features of an unabated disease
include cryptitis (ie, epithelial neutrophilic infiltrate of the
crypts) and crypt abscesses (ie, intraluminal collection of
neutrophils). Cryptitis can range from scant to florid and
affect the entire length of the crypts (Fig. 4A). In contrast,
the neutrophilic infiltrate noted in infectious colitis tends to
be more superficial.57 Neutrophils can also be detected in
the lamina propria independently of erosion. Mucin deple-
tion secondary to a decrease in the number of goblet cells is
FIGURE 9. Crohn disease is characterized by a discontinuous
inflammatory infiltrate with patches of chronic active colitis
interspersed by less inflamed mucosa (A). Example of aphthous
ulceration (arrow) associated with prominent lymphoid
hyperplasia (B). Please see this image in color online.
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Kővári et al
TABLE 2. Differential Diagnosis of Inflammatory Bowel Disease
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Antimetabolite
(chemotherapy or
Infectious Colitis immunosuppression) Diversion
[ASLC] ICI Colitis Colitis Colitis SCAD Ischemia Radiation MP/SRUS
Structural Absent Variable Variable Limited Limited Variable, if chronic Variable Absent or limited
alterations
Epithelial Mucin depletion Mucin Mucin depletion Mucin Mucin depletion Mucin depletion, withering crypts, Nuclear atypia Mucin depletion,
alterations depletion Apoptosis Crypt depletion degeneration/necrosis of superficial epithelial
Apoptosis attenuation/withering crypts and surface with serration or
Crypt pseudomembrane withering crypts
attenuation/
withering
Paneth cell — — — May be seen May be seen May be seen —
metaplasia
LP Neutrophils Variable Variable with Diffuse with Mixed inflammation Limited Typically not Not typical;
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inflammation chronic numerous eosinophils prominent increased inflammation

inflammation may follicular unless with
be seen late hyperplasia surface erosion
Cryptitis/crypt Cryptitis, often Variable Variable Variable Variable Absent Typically absent Absent; unless
abscesses superficial; associated with
crypt abscesses may ulceration

Adv Anat Pathol

be seen
Granulomas May occur Cryptic Cryptic granuloma Absent Absent Absent Absent Absent
(Yersinia, TB, granuloma can be seen
Campylobacter, can be seen
fungal, parasitic)
Other LP Edema — Prolapse; thickening Hyalinization of LP Telangiectasia, LP Muscular
alterations of subepithelial Fibrin thrombi fibrosis; thickening splaying


Volume 29, Number 1, January 2022
collagen and Cholesterol emboli; vasculitis subepithelial collagen
muscularis mucosa Hemosiderin and vessels
ASLC indicates acute self-limiting colitis; ICI, immune checkpoint inhibitor; LP, lamina propria; MP/SRUS, mucosal prolapse/solitary rectal ulcer syndrome; SCAD, segmental colitis associated with diverticular
disease.
Adv Anat Pathol  Volume 29, Number 1, January 2022
also observed secondary to the active inflammation. With
increasing intensity of active inflammation, crypt damage
ranging from attenuation to destruction with breaking down
to the epithelial contour also develops (Fig. 4B). Epithelial
regenerative changes can also be observed with various
degrees of cytologic atypia. Mucin granulomas representing
stromal reaction secondary to crypt rupture and mucin
extravasation may be detected (Figs. 4B and 5A). Their
location, adjacent to remnants of a damaged crypt, neu-
trophils, mucin, or a combination of all 3, are key differ-
entiating features from Crohn granulomas (Fig. 5B).
Eventually, mucosal erosion and ulceration may be seen in
severe disease. Rare patterns of mucosal injury that can be
seen include pseudomembrane formation58 and intra-
epithelial lymphocytosis.59 However, they are rarely in iso-
lation and shall not distract from rendering the diagnosis of
UC.
More commonly in the elderly population,60 some
patients present with a morphologically similar disease
limited to the rectum, that is, Ulcerative proctitis. In such
cases, prominent hyperplasia of mucosal lymphoid follicles
(follicular proctitis) can be seen. Approximately 10% of
these patients will develop more extensive ulcerative
proctocolitis,61 whereas 15% will have recurrent bouts of
active proctitis, and 75% will enter permanent remission.
Progression of the disease usually occurs within 2 years and
seldom after 5 years.62
In routine practice, the degree of active inflammatory
changes is graded into mild (cryptitis and crypt abscesses
involving < 50% of crypts), moderate (cryptitis and crypt
abscesses involving ≥ 50% of crypts), and severe (presence
of ulceration). However, driven by the recognition that
histologic assessment of activity is a crucial indicator of
clinical course (eg, risk of relapse and need for corticosteroid
use, among others), numerous grading systems have been
developed. This subject is discussed in Review on activity
grading in IBD article of this special issue.
Atypical Manifestations
Classically, UC is a distal colonic disease, starting in
the rectum, from where it can spread continuously orally
and evolve to pancolitis in some patients. Another key
feature of the diagnosis is the exclusively colonic distribution
of the disease. Nevertheless, atypical presentations of UC
can be seen and may confuse the unwary pathologists (Fig. 6
and Table 1). In patients with severe pancolitis, backwash
ileitis, an inflammatory process involving no more than a
10 cm long segment can be detected. Another possible pitfall
that can affect several groups of patients is the non-
continuous nature of the disease. The discontinuity can
result in endoscopically detectable skip lesions (eg, “Cecal
patch”) or represent histologically patchy inflammation.63
It worth emphasizing that in some cases, an endo-
scopically normal-looking segment can still show patchy
inflammation if biopsied. In the case of the rectum, this
phenomenon is referred to as relative rectal sparing. Patients
with primary sclerosing cholangitis (PSC)-associated IBD
are more likely to develop mild patchy inflammation, rela-
tive rectal sparing, and backwash ileitis.64–67 Absolute rectal
sparing is used to describe the histologic absence of proctitis,
a highly atypical finding in patients with UC. Some authors
claim, these cases may represent patchy proctitis with a
biopsy accidentally sampling the intervening noninflamed
mucosa.67–70 Pediatric manifestation of UC (exhaustively
discussed in Review on pediatric inflammatory bowel
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Histology of IBD
disease article of this special issue) may also include partial
or absolute rectal sparing that usually occurs in young
children under the age of 10 and possibly in children with
associated PSC.52,71–73 In addition, the biopsies may display
milder and patchy structural anomalies and inflammation.52
“Cecal patch” or “periappendiceal red patch” refers to
skip lesions detected in the ascending colon around the
appendiceal ostium in individuals with either subtotal or
left-sided colitis. This finding is not uncommon, reported in
up to 75% of UC patients. The right-sided patch of chronic
active inflammation shall not be falsely interpreted as
CD.63,74–76 Ulcerative appendicitis as a “skip” lesion of UC
has also been reported in 15% to 86% of patients in surgical
series.77–82
Discontinuous disease can also be detected in the setting
of fulminant UC. In these patients, relative or complete rectal
sparing, patchy ulceration, fissuring ulceration extending into
the inner half of muscularis propria, and transmural lym-
phocytic inflammation can be detected.56,83–85 However,
studies have shown that the natural history of fulminant colitis
usually mimics that of UC.83 However, the presence of
superficial fissuring ulcers may herald an increased risk of
postoperative pouchitis in patients undergoing total procto-
colectomy with ileal pouch anal anastomosis.85
Ileal inflammation may occur in UC as “backwash ilei-
tis.” Endoscopically, the small bowel involvement is recog-
nized by ileal erythema and granularity extending into a short
segment (< 10 cm) of the very distal terminal ileum. Backwash
ileitis classically arises in continuity with cecal inflammation in
patients with severe pancolitis, but rare cases have been
reported in association UC limited to the left colon.86 The
mechanism underlying this phenomenon is unclear but may
results from the retrograde flow of colonic contents into the
ileum, as well as stasis of luminal contents. Inflammation-
induced colonic hypomotility and incompetence of the ileoce-
cal valve may represent the initial insult.87 Morphologically,
mild villous atrophy, increased mononuclear cells within the
lamina propria, and scattered cryptitis/crypt abscesses are
observed. Pseudopyloric metaplasia, a feature usually asso-
ciated with CD,55,88 has been reported in rare cases of alleged
Backwash ileitis in the setting of UC. However, the clin-
icopathologic features of these cases do not allow unsuspected
cases of CD to be completely excluded.89,90 Microscopically,
the key to differentiate CD from backwash ileitis is the
detection of granulomas, transmural lymphoid aggregates, and
fissuring ulcers. In challenging cases, endoscopic features of
CD such as length of involvement ( > 10 cm), the presence of
skip lesions, sinus tracts, ulceration and stenosis of the ileocecal
valve, cobblestoning, and fissuring or linear ulcerations in the
ileum will help to establish the correct diagnosis.86,91
Treated Ulcerative Colitis
IBD treatment targets mucosal healing, which can pre-
vent inflammatory and neoplastic complications.92,93 In suc-
cessfully treated cases, various degrees of restitution can be
observed, but a consensus is not yet reached whether the
response should be measured by endoscopy or histology.
Nevertheless, an emerging body of literature suggests a supe-
rior predictive value of histologic remission.94 In some patients,
the microscopic architecture and goblet cell population can
reverse to normal,68,95–98 yet, in most cases, subtle changes
remain (Fig. 7). The treatment can affect both the active and
chronic features of the inflammation. Neutrophils will dis-
appear relatively rapidly from the lamina propria, which
appears to be less cellular. However, rare focal cryptitis/crypt
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Kővári et al
FIGURE 10. Common differential diagnoses in a colitic patient.
Infectious colitis demonstrates various degrees of active inflam-
mation, including neutrophilic infiltration of the lamina propria,
cryptitis, and crypt abscesses but retained mucosal architecture
(A). Diverticular colitis can mimic inflammatory bowel disease
with active chronic colitis features, including basal plasmacytosis.
A key diagnostic feature is a distribution limited to the bowel
segment harboring diverticulosis (B). Radiation colitis can also
induce both chronic colitis-like and ischemic-like changes with
marked stromal expansion (C). Please see this image in color
online.
abscesses can remain as well as focal chronic inflammatory
patches. Crypt architectural distortion, including unevenly
sized crypts with an altered number of goblet cells, shortening,
Paneth cell and pyloric metaplasia, as well as endocrine cell
hyperplasia and reduced crypt density, may persist for a pro-
longed period (usually several months).99,100 Quiescent or
inactive colitis refers to persisting architectural abnormalities
(features of chronicity) in the absence of significant neu-
trophilic crypt injury. It is essential to underscore that the
uneven mucosal restitution may transform the naturally con-
tinuous inflammation in UC to a patchy phenotype. Therefore,
the evaluation of disease “continuity” by biopsies is not helpful
to distinguish UC from CD in previously treated IBD patients.
56 | www.anatomicpathology.com Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
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Adv Anat Pathol  Volume 29, Number 1, January 2022
Other challenging aspects of UC include the growing
recognition of upper GI involvement in adult and pediatric
UC patients.101 Those include focally enhanced gastritis and
the rarely recognized diffuse active duodenitis.102,103 These
specific aspects are discussed in Upper Gastrointestinal
Tract Involvement in Inflammatory Bowel Diseases: His-
tologic Clues and Pitfalls article of this special issue. Finally,
dysplasia will also be discussed separately in The Sig-
nificance of Flat/Invisible Dysplasia and Nonconventional
Dysplastic Subtypes in Inflammatory Bowel Disease: A
Review of Their Morphologic, Clinicopathologic, and
Molecular Characteristics article of this special issue.
CROHN DISEASE
Since some of the more characteristic features of CD
(eg, transmural inflammation with lymphoid aggregates and
submucosal fibrosis) affect the deeper layers of the bowel, it
can be challenging to differentiate it from UC on endoscopic
mucosal biopsies. However, in addition to clinical evidence,
several helpful morphologic pointers can steer the diagnosis
in the right direction. First, it is essential to consider the
endoscopic distribution of the disease with a predilection for
the proximal colon/ileocecal region, often with rectal spar-
ing. Second, the patchiness and segmental nature of CD is a
differentiating feature from treatment-naive UC (Fig. 8).
Nevertheless, as pointed out previously, in special subsets of
patients (ie, in the pediatric population or patients with
PSC52,67) or following therapy,68 some UC cases may
present similar characteristics (Fig. 7 and Table 1). Rectal
sparing in these cases is often “relative” with endoscopically
normal mucosa, but with patchy inflammation still detect-
able microscopically. If resection specimens are carefully
examined, absolute rectal sparing is rare, and absolute rectal
sparing reported in biopsy studies is likely the reflection of
patchy inflammation of the rectum.67–70 Finally, the pres-
ence of a cecal patch is a well-characterized exception under
the rule of UC being a continuous disease and should not be
interpreted as a feature in favor of CD.82
Similar to UC, endoscopic biopsies of CD demonstrate
evidence of chronicity. However, in general, the architectural
changes are more subtle (eg, crypt branching is less marked)
and focal (Fig. 2B). Mucin depletion is also less pronounced
with relative preservation of the number of goblet cells. Con-
versely, the presence of gastric metaplasia, commonly repre-
sented by clusters of pseudopyloric glands at the basal part of
the mucosa, is more common in CD, especially in the terminal
ileum. It has been recently described that, less frequently, the
surface epithelium can also adopt a gastric phenotype, result-
ing in foveolar metaplasia (Fig. 3B).55,104
Microscopically, the lamina propria inflammatory infil-
trate is also patchy in CD, with variability among the biopsies,
and within a single fragment (Fig. 9A). The inflammatory
infiltrate is composed of lymphocytes, plasma cells, and neu-
trophils. However, cryptitis and crypt abscesses are usually less
prominent than in UC. A pattern of “focal active colitis,” in
which a dense cluster of chronic and acute inflammation target
a single crypt or cluster of crypts, while the surrounding
mucosa displays a much decreased inflammation is highly
characteristic of CD once distinguished from “isolated” focal
active colitis (when there is no background chronic inflam-
mation) which may represent resolving infectious colitis.105,106
The detection of granulomas is a key diagnostic feature
of CD (Fig. 5B). The frequency of granulomas depends on
various factors, including the type of specimen (resection vs.
Adv Anat Pathol  Volume 29, Number 1, January 2022 Histology of IBD

FIGURE 11. Other microscopic differential diagnoses of inflammatory bowel disease. Ischemic colitis shows characteristic withering crypts
and stromal hyalinization (A). Solitary rectal ulcer syndrome may manifest various patterns. This example shows marked architectural disarray
with pseudomembrane formation (B). Mycophenolate mofetil-associated colitis. This example demonstrates combined architectural disarray
and lamina propria inflammatory expansion (C) and marked cryptic apoptosis (D). Please see this image in color online.

biopsy), the number of fragments evaluated, and the review
of serial sections or deeper levels.107,108 Conversely, most
studies reported a highly variable but comparable rate of
granuloma detection in the various segments of the GI tract,
including the upper GI tract, and they may occur in all
concentric layers of the wall.109,110 Granulomas are more
frequently detected in children than adults. However, the
cumulative likelihood of detection increases with the extent
of the disease and the number of samplings.109,111 The
reported prevalence ranges from 15% to 60%, with an

TABLE 3. Differential Diagnosis of Colonic Mucosal Granulomatous Inflammation

Disease Typical Granuloma Type
Crohn disease Small intercryptic non-necrotizing; giant cells uncommon*
Ulcerative colitis Cryptolytic with residual epithelial fragments†
Other infections (eg, Yersiniosis, LGV, fungi) Confluent histiocytes to granuloma with central neutrophils or microabscesses
Tuberculosis Caseous necrotizing granuloma‡
Mycobacterium avium complex Xanthogranulomatous reaction§
Sarcoidosis Well-formed intercryptic non-necrotizing with giant cells∥
Eosinophilic granulomatosis with polyangiitis Perivascular granuloma with numerous eosinophils
Tissue invasive parasites (eg, Schistosomiasis) Foreign body type with numerous eosinophils¶
Drug-induced (eg, immune checkpoint inhibitors) Usually cryptolytic with residual epithelial fragments, sometimes true epithelioid
granulomas
Foreign material (eg, Orise gel) Foreign body type with exogenous material
*Usually single or a few and may lie close together, May be seen in inflamed mucosa or in endoscopically normal mucosa.
†Representing stromal reaction secondary to crypt rupture and mucin extravasation they are. Their adjacent to remnants of a damaged crypt, with
neutrophils and mucin.
‡Caseation may not be present. These granulomas are usually large, confluent, and located on the right side.
§Usually presents as confluent sheets of histiocytes.
∥Usually not associated with symptoms.
¶Residual ova (sometimes calcified) can be detected.
LGV indicates lymphogranuloma venereum.

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Kővári et al
average detection rate of 45%.107,109 Typical CD gran-
ulomas are composed of a collection of epithelioid histio-
cytes and a cuff of lymphocytes with or without Langerhans
cells. In addition, ill-formed clusters of histiocytes or epi-
thelioid cells and microgranulomas can also be observed.
Granulomas may be seen in inflamed mucosa or endo-
scopically normal mucosa.112 They are usually single or a
few (ie, 2 to 3) may lie close together; however, confluent
granulomas should raise concern, particularly regarding a
differential diagnosis of tuberculosis. Focal central necrosis
may rarely be seen, but caseating necrosis is not a feature of
CD granulomas. A classic differential diagnosis is a “rup-
ture granuloma” or cryptolytic granuloma representing a
stromal reaction to extravasated mucin secondary to rup-
tured crypts and observed in 30% to 50% of UC
(Fig. 5A).113 The use of serial sections can be helpful in
confirming a rupture granuloma by detecting residual crypt
epithelial fragments. Alternatively, the detection of sub-
mucosal lesions secures a diagnosis of CD. Another finding
that can be detected in CD is the presence of aphthous
ulcers, that is, small and usually shallow areas of ulceration
overlying lymphoid follicles (Fig. 9B). However, it is worth
underscoring that aphthous ulcers can be detected in infec-
tious colitides (Campylobacter, Salmonella, Yersinia),
Behcet disease, drugs, diverticular disease, diversion colitis,
or even with bowel preparation.85 In one series, aphthous
ulcers were detected in up to 17% of UC cases.114
When available, deep biopsies may allow submucosal
evaluation, and one may observe inflammation underlying
intact overlying mucosa. This is another valuable feature for
diagnosing CD. Other hallmarks of the transmural nature of
CD that cannot be observed on mucosal biopsies include
submucosal fibrosis, neural hyperplasia, submucosal and
myenteric plexitis, lymphangiectasia, as well as the rarely
reported granulomatous vasculitis.115,116 It is worth under-
scoring that submucosal inflammation is not completely
FIGURE 12. Immune checkpoint inhibitor colitis. Different patterns,
including infectious colitis-like (A and B) or a chronic colitis pattern (C),
can be seen. Image A and B represent an anti-CTLA4 induced colitis
with retained architecture, mild to moderate active inflammation, and
focal cryptitis. Image C depicts colitis in a patient on sequential therapy
with ipilimumab-nivolumab showing architectural distortion, basal
plasmacytosis, and severe active inflammation with focal surface ero-
sion and severe crypt destruction. Please see this image in color online.
58 | www.anatomicpathology.com Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
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Adv Anat Pathol  Volume 29, Number 1, January 2022
specific for CD, as cases of fulminant colitis in patients with
UC can also present with such a feature.56
Atypical Manifestations
Atypical manifestations of CD presenting with a UC-
like pattern of injury involving the colon diffusely with
minimal or no submucosal inflammation and an absence of
upper GI involvement are well reported, with follow-up
confirming a course typical for CD in most cases.91,117,118
The diagnosis in such cases will require the detection of
typical granulomas or transmural lymphoid aggregates on
resection specimens.
Despite optimal clinical and pathologic evaluation and
exhaustive analysis, some cases are stubbornly resistant to a
final categorization. In such cases, the term IBD, unclassified, is
favored when a diagnosis of UC or CD cannot be made
because of overlapping features on biopsy material. The term
IC refers to surgical resection cases (frequently with fulminant
colitis) for which a diagnosis of IBD could be reached, but a
definitive categorization based on macroscopic and microscopic
features of either UC or CD is not possible.119
DIFFERENTIAL DIAGNOSIS
Since neither the clinical manifestations nor the indi-
vidual morphologic features of IBD are pathognomonic, the
differential diagnoses to consider are relatively broad. A full
review of the various entities to consider is beyond the scope
of this article. So instead, we highlight herein the most
common (or challenging) entities in the form of tables pre-
senting the critical features to evaluate.
Whether UC or CD is considered, a distinct set of
morphologic characteristics ought to be evaluated (Table 2).
Although the differential diagnosis typically relies on the
combination of multiple changes rather than a single fea-
ture, each item must be carefully assessed as they will
eventually contribute to whether a diagnosis of UC or CD
should be preferred over non-IBD colitis. However, it shall
be emphasized that a histologic diagnosis shall not be made
in a vacuum. Ultimately, the morphologic conclusion
should be integrated with and reviewed in light of the clin-
ical presentation as well as laboratory, endoscopic, and
imaging findings before arriving at a final diagnosis.
Conditions that may mimic UC histologically include
infectious, ischemic, diverticular, and iatrogenic (partic-
ularly NSAIDs, chemotherapy-related, and radiation) col-
itis, and solitary rectal ulcer syndrome (Figs. 10 and 11).
Each of these entities will show various degrees of alteration
in the mucosal structure (architecture), the quality of the
epithelium, as well as the density and quality of the lamina
propria infiltrate. When granulomas are detected, CD
should also be distinguished from other granulomatous
processes, both infectious (particularly tuberculosis) and
noninfectious (Table 3).
Immune checkpoint inhibitor (ICI) colitis is an area of
intense interest since ICI therapy is a novel and effective
treatment approach for an increasing list of advanced malig-
nancies. In such cases, the patient’s immune system is stimu-
lated to elicit a robust antitumor response. However, in some
patients, the unleashed immune system can induce an auto-
immune disease-like injury on non-neoplastic tissues. GI side
effects, including diarrhea, represent the most common cause of
therapy cessation. Diarrhea and ICI colitis develop in 30% to
40% of patients with anti-CTLA4 therapy, in contrast to only
~15% with anti-PD1 monotherapy.120 Colitis can manifest in
Adv Anat Pathol  Volume 29, Number 1, January 2022
various histologic patterns, including acute colitis (resembling
infectious colitis), chronic active colitis (resembling IBD), and
lymphocytic colitis patterns. IBD-like chronic colitis pattern is
noted in 40% to 60% of cases;121–123 therefore, ICI colitis
should always be considered when examining chronic colitis in
a patient with a history of recently diagnosed malignancy
(Fig. 12). Nevertheless, crypt apoptosis beyond the level usually
observed in IBD is noted in 20% to 50% of ICI colitis cases;
and together with scattered ischemic-like withering crypts,
serves as very useful distinguishing features.
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