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SECTION 3

CHAPTER
Histopathology of Crohn’s
18 Disease and Ulcerative Colitis
K. GEBOES

Goal
Introduction SECTION 3

To review the important histologic features required for the Ulcerative colitis (UC) and Crohn’s disease (CD) are
diagnosis, assessment of disease activity and early chronic inflammatory bowel diseases of unknown cause.
detection of malignancy. The variability of features with Clinically, both conditions usually begin gradually, but
time and treatment and difficult differential diagnostic they can start abruptly and sometimes even present as
problems will be discussed. fulminant disease.The clinical course is characterized by
exacerbations and spontaneous or drug-induced remis-
Key points sions. UC primarily affects the mucosa of the large
• Histopathology can help to solve many diagnostic bowel, while CD is a transmural disease that can affect
problems, especially when multiple biopsies of the colon the whole gastrointestinal tract.The various clinical pat-
and ileum are available. terns are reflected in the microscopic features observed
• Exacerbations and remissions are reflected by mucosal in biopsies obtained from surgical specimens or during
inflammation and activity of variable intensity, including endoscopy. Endoscopic mucosal biopsies will not show
healing. all the characteristic features of CD. Review of biopsies,
• Multiple biopsies are also indicated for the early in combination with clinical, laboratory, radiographic
detection of pre-cancerous lesions and cancer in and endoscopic observations, is used for the diagnosis of
ulcerative colitis and Crohn’s disease. UC and CD and the differentiation from other condi-
tions. Such differentiation is important because a precise
Key references diagnosis is essential for appropriate treatment.1–3 A
• Schumacher G, Kollberg B, Sandstedt B. A prospective correct diagnosis is possible in the large majority of
study of first attacks of inflammatory bowel disease and patients; still, in some patients with acute onset or fulmi-
infectious colitis. Histologic course during the 1st year nant disease, a precise diagnosis may be difficult to reach,
after presentation. Scand J Gastroenterol 1994; resulting in a temporary diagnosis of indeterminate
29:318–332. colitis (IC). Biopsies also allow assessment of disease
• Jenkins D, Balsitis M, Gallivan S et al. Guidelines for the
activity and identification of pre-cancerous lesions and
initial biopsy diagnosis of suspected chronic idiopathic
cancer. In clinical practice, often only rectal biopsies are
inflammatory bowel disease. The British Society of
obtained for diagnosis. However, in contrast with UC,
Gastroenterology Initiative. J Clin Pathol 1997; 50:
the rectum is not always involved in CD and lesions
93–105.
in CD frequently occur in a background of normal
mucosa.Therefore it is more appropriate to take multiple
• Shepherd NA. Pathological mimics of chronic
endoscopic biopsies in different segments of the colon
inflammatory bowel disease. J Clin Pathol 1991;
(and ileum) during the initial work-up of a patient pre-
44:726–733
senting with inflammatory diarrhea or during follow-up
and screening for cancer. Multiple biopsies permit an in-
depth analysis of the distribution of inflammation and 255
are essential for the recognition of dysplasia. It also
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increases diagnostic accuracy by 5–41%. Carcinoma

can occur during the course of the disease as a late
complication.

The Normal Intestine

The gastrointestinal (GI) tract is a hollow tube consisting
of three layers: mucosa, submucosa, muscularis propria
and loose areolar tissue covered by mesothelium where
the tract borders on the body cavity (serosa). In the
colon, the surface of the mucosa is flat and its architec-
ture is characteristic with crypts as straight tubes, in par-
allel alignment. The crypt base rests upon a layer of
smooth muscle cells, the muscularis mucosae, which
Fig. 18.1 Normal colon. Mucosal lymphoid follicle extending
separates the mucosa from the submucosal connective
towards the submucosa. The germinal centre is stimulated
tissue. The distance between the crypts and the internal (H&E × 25).
diameter of the crypts is constant.The crypt architecture
is maintained throughout the colon, except in the pres-
ence of lymphoid collections, in zones of transition to tute the mucosa associated lymphoid tissue (MALT)
small intestinal mucosa (ileocecal valve) or to squamous where the immune response is induced. GALT (gut
epithelium (the anorectum) and in normally occurring associated lymphoid tissue) is especially prominent in
grooves in the surface. In the small intestine, the surface the appendix and terminal ileum where it forms the
is irregular due to the presence of finger-like villi of Peyer’s patches along the anti-mesenteric border. Four
uniform size and shape. In the ileum, the villi are taller compartments are distinguished in Peyer’s patches: the
and the crypts less deep compared with the jejunum. follicle, dome, follicle-associated epithelium and inter-
Surface, villi and crypts are covered with a single-cell follicular regions. The specialized follicle-associated
layer of columnar epithelium, separated from the con- epithelium, overlying lymphoid aggregates is distinct
nective tissue lamina propria by the basement membrane from the surrounding villous epithelial surfaces. It
complex. The epithelial cells form a heterogeneous characteristically has fewer goblet cells and contains
group with mature cells (absorptive enterocytes and membranous cells or M cells.The M cell is a specialized
goblet cells) lining the surface, villi and upper part of the epithelial cell that transports luminal antigens, thus
crypts, immature crypt cells including stem cells in the allowing access to immunocompetent cells. It plays a
base of the crypts and endocrine cells. Paneth cells are key role in mucosal-based immunity and antigen toler-
present in the base of the crypts in the small intestine ance. IELs are present in-between the epithelial cells
and caecum. Epithelial cells have a barrier and secretory lining the surface. They are mainly CD8+ T lympho-
function and are involved in the immune response cytes. LPLs are B cells (15–40%) and T cells (40–90%)
(secretion of SIgA). In the colon they do not constitu- and a limited number of natural killer cells. B cells are
tively express the major histocompatibility class II anti- mainly present as plasma cells with a predominance of
gens (MHC). Epithelial cell turnover ranges between 2 IgA over IgM and IgG containing cells.The majority of
and 8 days.4–6 the T cells are CD4+ cells (65%). A second important
The lamina propria extends from the subepithelial subtype of leukocytes in the lamina propria are the cells
basement membrane complex to the muscularis of the monocyte/macrophage lineage. In the colon they
mucosae. It is composed of extracellular matrix, fibro- are diffusely present in the subepithelial part of the
blasts and various types of leukocytes. The presence of lamina propria. They are a heterogeneous group com-
leukocytes is necessary because the mucosa is continu- posed of cells having more phagocytic properties and
ously challenged by luminal antigens, which results in a cells equipped for antigen presentation. They appear
‘controlled’ or ‘physiologic’ inflammation. Lymphocytes often as foamy histiocytes.7,8 Other myeloid cells that
are the largest subtype. According to the location, they normally reside in the lamina propria are eosinophils
are subdivided into intraepithelial lymphocytes (IEL), and mast cells. Neutrophils should not be present.
lamina propria lymphocytes (LPL) and lymphocytes Fibroblasts are located randomly, distributed throughout
organized in follicles in association with epithelial cells the lamina propria and in the most superficial portion
(lymphoepithelial complexes). The latter may extend and the pericryptal fibroblast sheet, tightly apposed to
256 across the muscularis mucosae (Fig. 18.1). They consti- the subepithelial basement membrane complex.4,5
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ULCERATIVE COLITIS

An adequate immune response implies migration of

immune cells, cell recognition and interaction of cells
requiring adhesion and deadhesion. Proteins involved in
leukocyte recruitment and migration belonging to the
large family of ‘adhesion molecules’ are therefore vari-
ably expressed on endothelial cells and leukocytes.
Molecules involved in cell interactions can also be
identified. Examples of these are proteins such as CD40,
CD40 ligand (CD40L), CD28 and CD80 and CD86.
These molecules act as ligand-receptor pairs. They can
be expressed on T cells (CD40L) and monocytes acting
as antigen presenting cells (CD40) and by doing so,
induce cell activation.4,5
In the submucosa, the ganglionated plexuses of
Meissner and Henle of the ENS are found. Ganglia are
Fig. 18.2 Ulcerative colitis. Inflammatory pseudopolyps in
composed of enteroglial cells and neurones.The muscu-
ulcerative colitis are typically multiple. They can have a filiform
laris propria is composed of two layers of smooth configuration (H&E × 1).
muscle separated by a thin layer of connective tissue in SECTION 3
which the ganglionated myenteric plexus (Auerbach’s)
can be observed. Multiple confluent ulcerations provoke denudation of
the mucosa. The serosal side may appear congested,
often to a larger extent than the mucosal lesions.
Ulcerative Colitis Following healing of mucosal ulcers, elevated sessile
reddish nodules – pseudopolyps – appear in an other-
Gross features wise flat surface. They are typically small and multiple,
but may have a filiform configuration (Fig. 18.2).There
UC starts from the rectum, spreads proximally and in is some variability in the prevalence of the lesions
continuity, involving a variable length of the colon. depending upon the colonic segment involved. Pseudo-
Pancolitis normally stops abruptly at the ileocecal valve, polyps are common in the sigmoid and descending
but in some cases a limited distal ileitis, called backwash colon and rare in the rectum where mucosal friability
ileitis, is observed.9 These ileal lesions are in continuity predominates. In the more advanced stages, the entire
with colonic lesions and characterized microscopically bowel becomes fibrotic, narrowed and shortened.
by diffuse inflammatory lesions with regular shortening During remission, the mucosa may become normal
of the villi. In patients with limited UC, the transition again. Healing often occurs in an irregular way leading
from diseased to normal mucosa is usually gradual and to a discontinuous, heterogeneous aspect of the mucosa,
only occasionally abrupt. Atypical presentations can be which can be confused with CD.Treatment may increase
observed. Some patients have left-sided involvement of the heterogeneous nature of the lesions. In children,
the colon and cecal (cecal patch) or appendiceal lesions may initially be heterogeneous.Topical treatment
involvement.10 The affected sites are separated by of the rectum can induce complete rectal healing. UC
normal mucosa. Diffuse duodenitis and extensive with rectal sparing, although rare, must therefore not be
involvement of the upper small bowel can occur in confused with CD.12 In severe, active forms, the entire
severely ill UC patients.11 colon, or a segment, may become dilated (toxic mega-
The gross appearance varies with the activity of the colon). Inflammation may extend towards the submu-
disease. Lesions are usually limited to the mucosa. cosa. In such cases, the wall is thin and perforation can
Stenoses, fistulas and significant thickening of the wall occur.
are rare. In the acute form, the mucosal surface is wet
and glaring from blood and mucus with numerous
petechial hemorrhages. Ulcers of various sizes can
Microscopic features of
appear. They may be small, rounded and superficial or
ulcerative colitis
more irregular and somewhat geographic in configura- Diagnostic features
tion. Fissuring ulcers are not seen, except in some cases The microscopic pattern of UC is characterized by an
of toxic megacolon. Ulcers can become more extensive inflammatory reaction with special distribution and
and undermine the mucosa so that mucosal bridges structural abnormalities of the mucosa (Table 18.1).
with an underlying inflammatory infiltrate develop. Inflammation is characterized by increased intensity of 257
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Table 18.1 Microscopic features suggestive for a

diagnosis of ulcerative colitis

Architecture
Severe crypt architectural distortion
Severe widespread decreased crypt density
Frankly villous surface
Inflammatory
Heavy diffuse transmucosal lamina propria cell increase
Diffuse basal plasmacytosis
Miscellaneous
Increased intensity of the alterations towards the distal colon
Severe mucin depletion
Paneth-cell metaplasia distal to the hepatic flexure

the lamina propria cellular infiltrate with alterations of

the composition and changes in distribution. The
normal lamina propria infiltrate is located in the upper
part of the mucosa and this pattern persists in infectious
colitis. In UC, the infiltrate is more extensive and
extends diffusely towards the deeper part (transmucosal)
(Fig. 18.3). Accumulation of plasma cells near the
mucosal base, in-between the crypt base and the muscu-
laris mucosae (basal plasmacytosis), is common. Focal or
diffuse basal plasmacytosis (combined with crypt distor-
tion) is a strong predictor for the diagnosis of chronic
idiopathic inflammatory bowel disease (IBD) and occurs
in over 70% of the patients.2
The presence of neutrophils, indicating a change in
the composition of the inflammatory infiltrate, is another Fig. 18.3 Ulcerative colitis. The microscopic diagnosis of
important feature. When combined with unequivocal ulcerative colitis is based upon widespread mucosal distortion
epithelial cell damage, it indicates disease activity.13 This (shortened and branching crypts) and transmucosal
feature can be assessed with good reproducibility. inflammation with basal plasmacytosis. Activity can be
Neutrophils within epithelial structures, such as the recognized by the presence of neutrophils infiltrating the wall of
crypt wall (cryptitis), or the crypt lumen and wall (crypt some crypts (H&E × 10).
abscesses) or in association with crypt damage (crypt
destruction) are helpful for the diagnosis, but the predic-
tive value of these features is limited. Cryptitis and crypt cases. Low-power examination is important for the dif-
abscesses can indeed also be seen in infectious colitis, ferential diagnosis with CD where similar architectural
Crohn’s colitis and diversion colitis. In UC however, they alterations are less common (27–71%) and less diffuse.2
are generally more common, being present in 41% of the They can however, also be seen after surgery, in drug-
cases while in CD they are found in 19% of the cases.2 induced lesions and in rare forms of chronic infectious
Eosinophils may be so numerous as to suggest eosi- colitis such as chronic Shigella dysentery. Crypt distor-
nophilic colitis, particularly in chronic disease or when tion includes shortened crypts that become widely
the disease is quiescent. This is partly explained by separated from the underlying muscularis mucosae,
the reduction of other inflammatory cells, induced by crypt drop-out and especially prominent crypt budding
medical treatment. (branching crypts, bifid crypts) (Fig. 18.4). Mucosal
Structural changes include an irregular surface or a atrophy is a combination of crypt drop-out and short-
villiform surface and a disturbed crypt architecture.This ening of crypts. These alterations can be evaluated on
can be assessed with good reproducibility. Overall, an perpendicular sections (preferentially), but also on trans-
irregular surface is present in approximately 60% of verse or tangential sections. For the latter, one can rely
cases with UC.14 Crypt alterations are more common on differences in intercryptal distance and variability of
258
and more widespread; they are observed in 57–100% of the internal crypt diameter (Fig. 18.5).15
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ULCERATIVE COLITIS

Fig. 18.4 Ulcerative colitis. Distortion of the mucosal Fig. 18.6 Ulcerative colitis. Quiescent phase characterized by an
architecture can persist in quiescent ulcerative colitis. The crypts abnormal architecture and diffuse thickening of the muscularis
are widely separated from the underlying muscularis mucosae. mucosae. (H&E × 10)
Some of the crypts are branching. (H&E × 10). SECTION 3

seen. ‘Cryptolytic lesions’ or pericryptal granulomas

present a special diagnostic problem.According to several
authors these granulomas are not reliable for a diagnosis
of CD and occur in UC.2,16 Yet, in a series of 22 patients
with suspected IBD, this lesion was present in colorectal
biopsies in 14 cases. Ten patients were subsequently
found to have CD.17
The diagnostic sensitivity and specificity of the
above-mentioned features has been assessed mainly on
rectal biopsies. UC is also characterized by a special dis-
tribution of inflammation and architectural distortion
with increasing intensity from the proximal towards the
distal colon. For proper assessment of this feature, exam-
ination of multiple biopsies obtained in different seg-
ments is needed.
Fig. 18.5 Ulcerative colitis. Transverse section of the mucosa
showing bifid crypts characterized by the presence of double
Variation in time: evolution
lumina. The diameter of the lumina and the intercryptal space are The pattern of the various microscopic features varies
variable. (H&E × 25) in time and depends upon the severity of the disease.
In the early, acute phase, crypts are often still regular in
shape and size. The most characteristic feature is mucin
Several other features may help to establish a diagno- depletion, associated with neutrophils infiltrating crypt
sis of UC or to evaluate the severity of the condition. and surface epithelium and inducing crypt abscesses and
These include mucosal ulcerations and erosions, mucin secondary crypt destruction.The cellular infiltrate in the
depletion, Paneth-cell metaplasia and diffuse thickening lamina propria is homogeneously increased in intensity
of the muscularis mucosae (Fig. 18.6). Erosions and and mixed in composition. It may show a transmucosal
widespread surface epithelial damage are more common distribution. Crypt architectural abnormalities appear
in UC than in CD. Severe, almost total mucin depletion only during the evolution of the disease. The natural
is another feature that distinguishes UC from CD, history of crypt distortion has been examined in a study
where preserved mucin secretion is more common. comparing the evolution of the histology in patients
Paneth cells in crypts distal to the ascending colon after first attacks of inflammatory bowel disease and
suggest IBD, usually UC. infectious colitis. Biopsies were taken before any treat-
Granulomas are not present in UC but isolated giant ment was given (0–15 days), between 16–30 days,
cells or a histiocytic reaction around a ruptured crypt, between 1–4 months and between 4–10 months. Crypt
259
mimicking granuloma formation, can occasionally be distortion started in the second period being present in
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almost 25% of the patients that eventually had IBD. In

Table 18.2 Example of a scoring system for the
the period from 4–10 months, almost 75% of these assessment of severity in ulcerative colitis.
showed crypt distortion.1 Treatment may induce some Subgrades are defined for each grade.
reversibility. Examples are given for grade 0 and 1
Basal plasmacytosis also becomes more prominent in
the course of the disease, mainly after two weeks of Grade 0 Structural (architectural change)
symptom duration. It is seen in 54% of biopsies Subgrades 0.0 No abnormality
obtained two weeks after the start of the symptoms and 0.1 Mild abnormality
in more than 80% in samples obtained after 4 weeks. 0.2 Mild or moderate diffuse or
During the first attack of IBD, it is commonly the only multifocal abnormalities
0.3 Severe diffuse or multifocal
finding. It can start as focal plasmacytosis. From 16 days abnormalities
onwards, focal plasmacytosis develops into diffuse
Grade 1 Chronic inflammatory infiltrate
plasmacytosis. This feature is usually also present in Subgrades 1.0 No increase
biopsies obtained during a flare-up and may predict 1.1 Mild but unequivocal increase
relapse.18 During the natural course, the cellular lamina 1.2 Moderate increase
propria infiltrate can remain homogeneously increased 1.3 Marked increase
and mixed in composition with a predominance of Grade 2 Lamina propria neutrophils and eosinophils
lymphocytes and plasma cells. The distribution pattern 2A Eosinophils
2B Neutrophils
may, however, become patchy.19 These data show that it
Grade 3 Neutrophils in epithelium
may be important to obtain further biopsies one month
following the start of symptoms and treatment, if the Grade 4 Crypt destruction
diagnosis is not clear during the initial examination. Grade 5 Erosion or ulceration
The inactive, quiescent phase of UC is characterized
by the presence or persistence of more severe crypt archi-
tectural abnormalities, while mucin secretion returns to
normal.The lamina propria infiltrate is mononuclear and
may be moderately increased in intensity. In a more
chronic phase, lymphoid aggregates and follicles, mainly
situated in the deeper part of the mucosa, will develop or
increase in number.

Disease activity
Histology as a tool for the measurement of disease
activity of UC was introduced in the 1950s.The altera-
tions in intensity and composition of the lamina propria
infiltrate, which can be observed in routinely processed
sections stained with hematoxylin and eosin, allow a dis-
tinction between active, inactive and quiescent disease.
Active disease is defined by the presence of neutrophils
Fig. 18.7 Ulcerative colitis. Mucosal atrophy with loss of crypts.
in association with epithelial cell damage.13 Inactive
Neutrophils are still present in the lumen and wall of one of the
chronic disease is defined as the presence of architec- crypts indicating persistent activity. (H&E × 10). (With permission
tural changes and an increase of lamina propria mono- from Geboes et al. Gut 2000; 47: 404–409.)
nuclear cells. Quiescent disease means the presence of
structural changes without alterations in intensity and
composition of the lamina propria infiltrate. Over the scores may be used to either document disease evolu-
years, several microscopic scores for the assessment of tion, or to assess clinical efficacy in therapeutic trials.
disease activity in UC have been developed, generally Histological assessment of disease activity could be
for study purposes (Table 18.2).20,21 The reproducibility important for the prediction of relapse. Clinical trials
of activity scores has not been studied extensively, but have indeed shown that persistent active inflammation
the limited data available show good agreement between and basal plasmacytosis are associated with an increased
different observers.22 The microscopic pattern of activity frequency of relapse (Fig. 18.7).23
generally correlates well with endoscopic features of In fulminant disease, mucosal inflammation may
severity, although in endoscopically inactive disease, extend towards the submucosa and focally even towards
260 the muscularis propria (proportionate inflammation).
microscopic features of activity may persist.The activity
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CROHN’S DISEASE

sies of pouches suggest that villous atrophy and chronic

inflammation of the small intestinal mucosa may be fol-
lowed by colonic metaplasia, so that pouchitis ultimately
represents a form of ulcerative colitis in metaplastic ileal
mucosa. Granulomas and transmural inflammation,
which are considered to be diagnostic for CD, can be
observed in pouchitis, following surgery for ulcerative
colitis. Review of the original surgical specimen and of
any other material available is essential before consider-
ing changing a diagnosis of ulcerative colitis into
Crohn’s disease.27

Crohn’s Disease
Fig. 18.8 Ulcerative colitis. Mucosal biopsy obtained 6 weeks
after the start of medical treatment with 5-ASA showing limited Gross features
mucosal distortion and disappearance of activity. (H&E × 10)
CD can affect different segments of the GI tract. The SECTION 3
appearances are similar at all levels. The terminal ileum
Transmural lymphoid hyperplasia is however highly and proximal colon are the most common sites, fol-
unusual. lowed by the anorectum and colon. Perianal disease
A significant association between disease activity and varies between 14–76%. Involvement of the upper
numbers of immunoglobulin-containing cells in the gastrointestinal tract is uncommon. The length of the
lamina propria has been demonstrated.24 Upregulation segments involved is variable and the lesions are sepa-
of adhesion molecules and other markers is also related rated by uninvolved ‘skip areas’. Macroscopic lesions
with disease activity. Several studies have shown are apparent on the mucosal and serosal side of the
increased or aberrant colonic epithelial cell expression bowel wall. In the Vienna classification proposed by an
of HLA-DR, MHC class II molecules and reduction or International Working Party for the World Congress of
disappearance with different types of treatment. The Gastroenterology in 1998, a distinction is made between
expression of activation markers and the assessment of inflammatory disease, stricturing disease – defined as
immunoglobulin-containing cells are however not constant luminal narrowing – and penetrating disease,
useful in routine practice. defined by the occurrence of intra-abdominal or peri-
anal fistulas, inflammatory masses and/or abscesses.
Medical treatment Fistulas are commonly associated with strictures and
Topical and systemic medical treatments have a major therefore the clinical distinction is often limited to
impact upon histology in UC. Mucosal injury and neu- two types: the perforating type and non-perforating
trophils can diminish substantially within 4 weeks, or type with predominantly mucosal lesions. The mucosal
even disappear. Normalization with disappearance of appearance is usually heterogeneous. Lesions of different
architectural alterations of the crypts and surface size are simultaneously present.The mucosa may appear
together with reduction of the cellular lamina propria normal or may show multiple small (1–2 mm in size)
infiltrate takes more time, but can occur (Fig. 18.8).25 punctiform, rounded nodules or superficial erosions
In many cases, the inflammatory features become dis- known as ‘aphthoid lesions’. Over a period of time, the
continuous and heterogeneous. This may make a differ- erosions become confluent and give rise to larger longi-
ential diagnosis between UC and CD difficult. It is tudinal ulcers, known as serpiginous ulcers.28 The com-
therefore important to know treatment and its effects bination of longitudinal and transverse ulceration in an
upon histology when analysing a biopsy.26 edematous mucosa induces a characteristic ‘cobblestone’
aspect. Ulcerations are more common on the mesen-
Pouchitis teric border of the small intestine. They can become
Treatment of ulcerative colitis with total colectomy and deeply situated fissuring ulcers reaching the muscularis
creation of a continent ileoanal anastomosis is not propria or pass through the muscularis and give rise to
uncommonly accompanied by inflammation of the ileal abcesses or fistulas between involved segments and
pouch. Histologically there is normally slight mucosal adjacent organs or nearby uninvolved loops. Fistulas are
inflammation, but occasionally crypt abscesses, ulcera- defined as abnormal communications between the
tion and blunting of the villi are seen. Sequential biop- lumen of the gut and the mesentery and/or another 261
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Being a transmural disease, the bowel wall is thick-

ened with involvement of the submucosa, the muscu-
laris propria, the subserosa and mesenteric fat. The
serosal surface reveals prominent distended blood vessels
and may show fibrinous exudate with or without adhe-
sions to adjacent loops. Mesenteric fat partially sur-
rounds the intestine, extending from the mesenteric
attachment anteriorly and posteriorly corresponding to
the involved segment. This phenomenon, known as ‘fat
wrapping’, is specific for CD. It is observed in 75% of
the surgical specimens (Fig. 18.10). Fat wrapping is
defined on a transverse section of the intestine and
defined as being present when more than 50% of the
intestinal circumference is affected. The corresponding
Fig. 18.9 Crohn’s disease. Small intestine: high-grade stenosis.
mesentery is usually thickened and retracted. Fibrous
The mucosa is ulcerated. Lymphoid hyperplasia is present in the strands are present in the mesenteric fat, irradiating from
deeper parts of the bowel wall. (H&E × 1) the intestine and surrounding thickened, hypertrophied
fat lobules.31 The mesenteric lymph nodes are com-
monly swollen, but the number and size of the swollen
lymph nodes in CD is not different from that observed
in UC.32
Inflammatory pseudopolyps of the colon and small
intestine (in approximately 20% of the cases), identical
to those described in UC can be observed in CD.These
are usually tall mucosal outgrowths measuring a few
millimeters in length, but giant forms have been
described. Such giant forms are more common in CD
than in UC. In extinguished cases, the characteristic
lesions may no longer be present. The specimen shows
merely neuromuscular and vascular lesions and a proper
diagnosis may be difficult.

Microscopic features
Fig. 18.10 Crohn’s disease. Small intestine: fat wrapping is a Granuloma
characteristic feature of Crohn’s disease. It is characterized by the Granulomas in histological sections are a key feature of
overgrowth of mesenteric fat. CD.33 It should however be remembered that granulo-
mas can occur in other conditions, especially infectious
diseases, such as tuberculosis and Yersinia pseudo-
hollow organ or the abdominal wall and skin. Histo- tuberculosis and occasionally in drug-induced colitis. A
logically, they are composed of granulation tissue, sur- granuloma is defined as a collection of monocyte/
rounding a lumen, which is mostly filled up by nuclear macrophage cells and other inflammatory cells with or
debris and inflammatory cells, in particular neu- without giant cells (Fig. 18.11).The macrophages appear
trophils.29 Granulomas are present in approximately 25% as large cells with abundant pale eosinophilic cytoplasm
of the perianal fistulas or abscesses. Fistulas are often and large oval nucleus. They are arranged in clusters.
associated with strictures. Strictures are characterized by Because of this epithelial cell-like morphology, they
luminal narrowing and bowel wall thickening with or are called epithelioid cells. The cells can be closely
without prestenotic dilatation. In high-grade stenosis, packed together, and have a sarcoid-like aspect but a
the luminal diameter is less than 0.5 cm.They are often ‘loose’ expanded form of granuloma is more common
associated with severe ulcerations with complete cir- in CD (Fig. 18. 12). Central necrosis and caseation are
cumferential loss of the mucosa (Fig. 18.9). In rare cases, rare findings and should raise suspicion of tuberculosis.
CD can present a macroscopic picture of the left colon Giant cells may contain calcified conchoid bodies.27,34
with continuous involvement, reminiscent of UC, in Associated inflammatory cells are lymphocytes, usually
262
association with ileal disease.30 CD4+ T cells, showing expression of CD28, the ligand
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CROHN’S DISEASE

for the B7-related cell surface proteins CD80 (B7-1)

and CD86 (B7-2).
The granuloma has to be distinguished from the
microgranuloma, which is smaller and composed of his-
tiocytes.They are smaller than the epithelioid cells in the
genuine granuloma. The number of histiocytes in the
microgranuloma is also smaller than in the granuloma
(7–18 versus 25–90) while the number of lymphocytes is
comparable (4–11 versus 2–15). Microgranulomas are
usually situated in the upper part of the mucosa.The fre-
quency in CD is not well established, but seems to vary
between 12% and 24% of endoscopic biopsies obtained
in patients with CD. The exact meaning of the micro-
granuloma is still unclear. They seem more common in
inactive disease.35 Granulomas must also be distinguished
from granulomatous crypt abscesses, a crypt abscess with
a giant cell and with or without an excess of histiocytes,
and from cryptolytic granulomas. The latter are defined SECTION 3
by the rupture of the epithelial lining and the presence
of histiocytes with or without giant cells. While this
lesion seems more common in CD it has also been
reported in genuine UC.
Granulomas can be detected in otherwise healthy
mucosa or in inflamed tissue. They develop in all layers
of the intestines from the mucosa to the serosa but are
most frequent in the submucosa.They are also common
in draining lymph nodes being present in approximately
20–50% of the cases. Rarely does the granulomatous
inflammation affect extraintestinal sites, such as the skin,
liver, lungs, eyes and ovaries.
Fig. 18.11 Crohn’s disease. Rectal biopsy: a granuloma, so The frequency of finding granulomas in CD varies
called because of the round appearance, is a collection of between 15% and 85%, but is rarely higher than
epithelioid cells with giant cells as in the picture or without. 50–60%. The results depend highly on tissue sampling
(H&E × 10)
(number of biopsies, number of sections examined,
endoscopic or surgical samples). For surgical samples the
frequency varies between 15–82% and for endoscopic
samples between 3–56%. The highest numbers are
observed in children, both in surgical series (82%) and
in endoscopic series. In pediatric CD, the incidence of
granulomas is two-fold compared with adults but it is
reduced after the second year of the disease and after
the age of 16 years. The lowest number comes from a
surgical series composed of older patients. In general,
granulomas are more common in the distal colon and
rectum. Granulomas are as common in CD of the upper
gastrointestinal tract as in the ileum and colon.The fre-
quency of detection for the stomach and duodenum
varies between 3% and 58% and is higher when biopsy
samples are taken in macroscopic lesions.
The number of examinations can influence the fre-
quency of detection of granulomas. A granuloma was
Fig. 18.12 Crohn’s disease. In Crohn’s disease the granulomas found in 23% and 47% respectively, of the patients in
have often a loose aspect as illustrated by this lesion laying close whom one (2.5 ± 1.4 biopsy samples) and four colono-
263
to a ganglion of the myenteric plexus. (H&E × 25) scopies were performed (8.0 ± 1.8 samples). Increasing
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the number of biopsies increased the diagnostic yield.

For 1–6 biopsy samples, the diagnostic frequency varies
between 11–47%. Six biopsy samples seems an optimal
number. When multiple serial sections are examined in
the pathology laboratory the frequency of detection
further increases with 50%.
While the diagnostic value of the granuloma in CD
is generally accepted, its clinical and prognostic
significance remain unclear. Several studies have exam-
ined the relation between the presence of granulomas
and prognosis looking at the recurrence rate, either clin-
ically or the risk of a new surgical intervention. The
results are conflicting. In 8 of 14 studies the presence of
granulomas had no influence upon the outcome. In
three series recurrence was diminished and in three
other series recurrence rate was increased.34

Mucosal lesions
E A R LY M U C O S A L L E S I O N S
Various types of early microscopic lesions have been
described in CD.They occur as focal lesions, in a back-
ground of normal mucosa in contrast with UC where
diffuse epithelial necrosis is seen. Early lesions in CD
include epithelial patchy necrosis, the aphthoid ulcer or
mucosal microulcerations (loss of 1–6 cells). Other fea-
tures include the occurrence of a naked surface of the
dome area overlying a mucosal lymph follicle and loss of
M cells. Ulcers at the base of crypts with neutrophils
streaming into the bowel lumen, which leads in a later
phase to mountain peak ulcers, villous abnormalities
and damage of small capillaries (including capillary Fig. 18.13 Crohn’s disease. Aphthoid ulcer in the ileum: early
thrombi) with subsequent loss of surface epithelial cells mucosal ulcer, centrally located and appearing as a mountain top
(summit lesion) have been reported (Figs 18.13 and ulcer. (H&E × 4)
18.14).35–39 In general, limited necrosis of surface
epithelial cells is common while crypt epithelial cells are
rarely involved (an exception is the ulcer at the crypt of IBD. It has been suggested that the diagnosis of CD
base). Overall, biopsies of early lesions do not yield should be based upon the presence of an epithelioid
essential diagnostic information. An exception to this granuloma with one other feature suggestive or diagnos-
may be the aphthoid ulcer.This ulcer has a predilection tic for IBD, or the presence of three other features in the
for the epithelium overlying the lymphoid follicles, absence of granulomas, provided that specific infection
although it can occur in other sites too. According to has been excluded.40 The mucosal lesions of IBD consist
some studies, biopsies of aphthoid ulcers show more of epithelial alterations and a cellular inflammatory
commonly the characteristic granulomas, which are response.The former include cytological and architectural
diagnostic for CD.34 changes, indicative of damage and repair. The cellular
inflammatory response consists of changes in intensity of
D I AG N O S T I C F E AT U R E S the infiltrate, alterations in composition and changes in
Although the degree of mimicry with UC can be high, the distribution pattern. These features have been exam-
the presence of aphthoid ulcers, fissure ulcers, transmural ined in a number of studies of rectal and colorectal biop-
inflammation, fistulas, lymphangiectasia, fibrous strictur- sies and surgical specimens. Only a limited number have
ing and neural changes is predominantly a feature of CD. acceptable sensitivity, specificity and predictive value
Six of these features proposed cannot, however, be reli- and are sufficiently reproducible (Table 18.3). Features
ably detected on endoscopic samples. A diagnosis of CD that favor CD are epithelioid granulomas, relatively
on endoscopic samples of the colon therefore relies unchanged crypts or segmental distribution of crypt
264 heavily on the identification of the microscopic features atrophy and crypt distortion together with discontinuous
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CROHN’S DISEASE

Table 18.3 Microscopic features with sufficient

reproducibility, discriminative and predictive
value, useful for the differential diagnosis
between normal and IBD, acute infectious
colitis (AIC) and IBD and CD, and UC

Mucosal architecture
Mucosal surface, normal, irregular, villous
Crypt atrophy (shortened, widely spaced crypts)
Distorted, dilated, branching crypts
Inflammatory changes
Basal plasmacytosis, increase in cells in basal third of lamina
propria
Increased lamina propria cellularity (round cells and
neutrophils)
Basal lymphoid aggregates
Specific features
Epithelioid granuloma
Basal giant cells
Excess histiocytes in lamina propria SECTION 3
Features related with activity (separating IBD from normal)
Neutrophils in surface epithelium
Neutrophils in crypt epithelium
Ulceration

Fig. 18.14 Crohn’s disease. Early mucosal lesions in CD can be

associated with damage of small capillaries as illustrated here by
the presence of a fibrin plug in the lumen of a small vessel
(immunohistochemistry × 40).

focal or patchy inflammation and mucin preservation in

the epithelium at an ulcer edge, and the presence of a
mixture of normal samples (skip lesions) and inflamed
Fig. 18.15 Crohn’s disease. Crohn’s disease is characterized by
samples in a set of biopsies obtained in the same the presence of granulomas and by hyperplasia of the
area.1,2,14,41–43 Focal inflammation is defined as a small submucosal nerves, sometimes called ‘neuromatous lesion’.
collection of inflammatory cells in otherwise normal (H&E × 10)
mucosa. It can present as a focal aggregation of neutrophil
polymorphs in a pericryptal position, a lesion which is
suggestive for CD but not pathognomonic. Patchy Most of the studies examining the features of IBD have
inflammation is diagnosed when the mucosal background been performed in adults. Separating CD and UC might
shows inflammation of varying intensity. The diagnostic be different in children and adolescents. Discontinuous
value of patchy inflammation is limited because a similar inflammation and density of infiltration prevail in chil-
pattern can be seen in UC in long-standing disease or dren while the diffuse type of infiltration is more
following treatment.Another reliable feature which helps common in CD in adults. However, granulomas are more
to distinguish CD from UC in favor of CD is the pres- common in children, being present in 26% of the biop-
ence of neuronal changes (Fig. 18.15).42 These are sies and 42% of the patients.
however only rarely observed in endoscopic biopsy Ileal biopsies have rarely been included in studies
samples because of the superficial nature of the latter. examining the microscopic features of CD.The presence 265
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of ileal lesions is however another key lesion, which The value of multiple, multi-step biopsies
allows to discriminate between UC and CD. Important The importance of stepwise biopsies for the diagnosis of
diagnostic microscopic features of CD are architectural either CD or UC has received little attention in the
abnormalities of the villi (irregularity and blunting or literature. Most studies have focused on single rectal
broadening), preserved mucin secretion or increased biopsies. Discontinuous inflammation in stepwise biop-
mucin production (hypercrinia) by epithelial cells, sies does not distinguish CD from UC in adults. It can
mucoid or pseudopyloric metaplasia, active chronic be found in approximately 30% of patients with long-
inflammation and the presence of granulomas.44 Pseudo- standing UC but it discriminates in children and in
pyloric gland metaplasia is however a non-specific feature patients with a short history of the disease.The presence
related with ulceration, healing and the ulcer associated of an inflammatory infiltration with decreasing intensity
cell lineage (Fig. 18.16).45 from caecum to rectum favors a diagnosis of CD.12,46 In
Immunohistochemical analysis of mucosal biopsies combination with ileal biopsies, multiple colonic biop-
reveals expression of various cytokines and other media- sies are useful for the diagnosis.
tors, such as interleukin-10, interleukin-12, interleukin-
15 and tumor necrosis factor alfa (TNFα ). Some markers Disease activity: effect of treatment
may be more specific for CD but increased expression Microscopic assessment of disease activity in CD is
indicates mainly ongoing immune response and has no difficult because of the segmental and transmural char-
diagnostic value at present. acter of the disease. Yet, several scoring systems have
been designed and even used in clinical trials. These
scores are usually based on the microscopic analysis of
multiple biopsies from different segments. The correla-
tion between endoscopic findings, clinical indices of
disease activity and microscopic scores is variable.47 This
reflects the fact that mucosal biopsies are not representa-
tive of the transmural inflammation and that clinical fea-
tures are not always reliable indicators of disease activity
at the tissue level. Mucosal biopsies however do reflect
mucosal inflammation. Monotherapy with corticos-
teroids or 5-ASA has only a limited influence upon
mucosal lesions in CD, although long-term combina-
tion treatment may induce normalization. Reduction of
epithelioid granulomas with persistent chronic inflamma-
tion has been reported following long-term treatment
with prednisolone, sulfasalazine and 6-mercaptopurine.
In contrast, polymeric diet and immunomodulatory
therapy with azathioprine and infliximab can pro-
foundly influence the histologic lesions and induce
healing.48–50

The submucosa, muscularis propria and serosa

L E S I O N S O F T H E E N T E R I C N E RVO U S S YS T E M
Abnormalities of the enteric nervous system (ENS) are
common in CD. The major structural abnormalities are
irregular hypertrophy and hyperplasia of nerve fibers
and alterations of neuronal cell bodies and enteric glial
cells in ganglia of the submucosa and plexus myenteri-
cus. The abnormalities of the nerve fibers are most
prominent in the submucosa, mainly in involved areas.
They have been called ‘neuromatous lesions’. Mucosal
nerve fiber hypertrophy is only seen in areas overlying
Fig. 18.16 Crohn’s disease. Ileal biopsies can help to establish
submucosal fiber hypertrophy and cannot reliably be
the diagnosis of Crohn’s disease. The villi are irregular. Mucoid assessed on routinely hematoxylin and eosin-stained
or pseudopyloric metaplasia indicates previous ulceration. slides. Nerve fiber hypertrophy is commonly associated
266
(H&E × 10) with inflammation and granulomas in the plexus
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CROHN’S DISEASE

myentericus are not uncommon. A three-fold increase significance are unquestionable. Lymphangiectasia in the
in the number of ganglion cells of the ileal myenteric submucosa is another common finding in CD in addi-
plexus was recorded in a series of 24 cases with CD. All tion to granulomatous vasculitis.55
these features were shown to be highly suggestive for a
diagnosis of CD with a significant difference between LY M P H O I D H Y P E R P L A S I A
UC and CD and they can be detected with great Lymphoid aggregates and nodules with or without ger-
reliability.51 minal centres are common in the mucosa and even
Ultrastructural studies have shown that nerve fibers more numerous in the submucosa in CD. They occur
or axons appear as swollen, empty structures.52 The also in the muscularis propria, in the vicinity of the
specificity of this lesion for CD has however not been myenteric plexus and in the subserosa. This transmural
confirmed. A relative increase in myenteric neurones lymphoid hyperplasia is believed to be characteristic for
containing nitric oxide synthase (NOS), vasoactive CD and is not observed in UC or IC.56
intestinal peptide (VIP) and pituitary adenylate cyclase
activating peptide (PACAP) and an abnormal pattern E D E M A , F I B RO S I S, F I B RO M U S C U L A R
of VIP containing fibers have been recognized in CD.53 O B L I T E R AT I O N S, S T R I C T U R E S
Immunohistochemistry revealed also increased MHC Widening of the submucosa by edema is common in
class II (HLA-DR) membranous expression on enteric CD and probably a sign of active disease. Strictures are
glial cells in macroscopically involved and uninvolved a common complication of CD and an indication for SECTION 3
areas. The enhanced expression is positively correlated surgery in approximately 50% of all CD patients.
with the local intensity of the cellular inflammatory Histological studies of strictures show marked expan-
infiltrate. Induction of HLA-DP and DQ antigens on sion of the muscularis mucosae by an irregular increase
glial cells is restricted to areas of moderate and high in the number of smooth muscle cells in this layer and
inflammatory activity.51 the presence of large amounts of collagen, laminin and
tenascin. Types V and III collagen can be abundantly
VA S C U L A R L E S I O N S present (Fig. 18.18). Mast cells can be numerous. In
Inflammatory cell infiltration of blood vessels and oblit- addition to the expansion of the muscularis mucosae
erative lesions have been observed with microscopy in per se, islands of smooth muscle cells and myofibroblasts
surgical samples from patients with CD in a number of are noted in disorganized fashion in the adjacent sub-
studies. The frequency varies between 3% and 85%. mucosa. Smooth muscle cell fibers may interconnect
The frequency of vascular granulomatous inflamma- the muscularis mucosae and propria. The submucosa
tion varies between 3–100% of the cases examined contains dense masses of large amounts of collagenous
(Fig. 18.17).54 Granulomas are not only found in associ- material and the luminal margin of the muscularis
ation with blood vessels. They may even be more propria is disorganized with numerous collagenous
common in lymphatic channels. While the nature and
the exact frequency of granulomatous vasculitis in CD
remain to be determined, its occurrence and diagnostic

Fig. 18.18 Crohn’s disease. Small intestine. Fibrosis is a common

complication of Crohn’s disease. It is characterized by abnormal
deposition of collagens, illustrated here by the presence of
Fig. 18.17 Crohn’s disease. Granulomatous vasculitis is another collagen V in the edges of a mucosal ulceration
(immunohistochemistry × 10).
267
lesion, which is not uncommon in Crohn’s disease. (H&E × 10)
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septae invaginating its ragged edges and extending into

the muscularis. In general the muscularis propria is also
greatly increased in thickness, although it may be inter-
rupted in certain areas.57,58

Upper gastrointestinal disease

Upper GI disease is present in approximately 8–40% of
the cases.The variability is explained by the methods of
examination such as symptomatology, endoscopy with
biopsy or radiology, used to evaluate upper GI involve-
ment. Of all the sites within the GI tract, which may be
affected by CD, the esophagus has been suggested as the
one least likely involved. Early changes include micro-
scopic disease or aphthous ulcerations.The latter should
not be confused with other conditions, such as herpetic
esophagitis. Biopsies are the method of choice for the
differential diagnosis and the finding of granulomas
implies CD. More extensive disease includes ulceration
and stricture formation. Fissuring ulceration or fistula
formation is uncommon. Most cases of esophageal CD
are associated with CD elsewhere in the gut, but there
are a few reports of cases in which CD initially pre-
sented in the oesophagus.59
In the stomach, three major patterns may be distin-
guished. First, reactive gastritis or Helicobacter pylori-
associated gastritis not related with CD, minor but
characteristic lesions known as focally enhanced gastri-
tis, and CD of the stomach with histological evidence of
granulomatous infiltration.3 Focally enhanced gastritis is
characterized by a focal infiltration of CD3+ lympho- Fig. 18.19 Crohn’s disease. Stomach. Gastric mucosal biopsy
cytes and CD68+ histiocytes with granulocytes. It was containing two characteristic granulomas. (H&E × 10)
found in 48% of a series of 75 CD patients and in only
0.8% of the controls.60 Granulomatous infiltration is
observed in 2–10% of CD patients (Fig. 18.19). Besides tous’ inflammation in the appendix is however not nec-
typical granulomas, the gastric wall may also show trans- essarily CD. It may be the result of a number of diverse
mural, often focal lymphoid infiltrates, lymphangiec- and unrelated causes such as parasites, foreign body
tasias, submucosal and subserosal fibrosis, fissures and reaction and bacterial infections.
ulceration. Generally, CD of the stomach is associated
with disease in more typical sites. More than 80% of
patients with gastric CD have duodenal bulb involve- Indeterminate Colitis
ment. The finding of a granuloma in a gastric biopsy
should not automatically be considered as CD. Granulo- The term ‘colitis indeterminate’ was initially proposed
matous gastritis can have many other causes, as shown in for a small group of cases in which there was difficulty
a study of 71 patients in which CD was finally diag- in distinguishing CD from UC (and even infectious
nosed in only 52%.61 diseases) in the excised specimen. The difficulty was
due to the fact that features of both conditions were
Granulomatous appendicitis present in the same specimen. Most of the cases had
Crohn’s disease affecting the appendix is well docu- fulminant disease and the classification was essentially
mented and is present in up to 25% of cases.The disease temporary before a final diagnosis was established.56
is also reported as being isolated to the appendix. The Later, ‘indeterminate colitis’ (IC) was applied as a tem-
histological features of CD in the appendix include porary classification to cases where a definite diagnosis
thickening of the wall, transmural inflammation, patchy was not possible with endoscopic samples because of
lymphoid aggregates throughout the wall, fissured ulcer- absence of diagnostic features discriminating between
268 ation and epithelioid granulomas. Isolated ‘granuloma- CD and UC. The diagnostic accuracy of a single rectal
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DIFFERENTIAL DIAGNOSIS

biopsy is estimated to be 37–77% for CD patients and

67–70% for UC patients. Multiple endoscopic biopsies
of the colon can already solve many problems for CD.
In difficult cases with pancolitis, the differential diagno-
sis can sometimes be solved by analysis of ileal biopsies
or gastric biopsies. A special type of focal gastritis has
been observed in CD. Indeterminate colitis is by
definition a disease limited to the colon. The morpho-
logic features of ‘indeterminate colitis’ diagnosed on
endoscopic samples include lesions suggestive or diag-
nostic for IBD such as (minimal) architectural distor-
tion, inflammatory features (usually transmucosal
inflammation) which do not allow a firm distinction
between UC and CD because of their patchy nature,
and absence of small bowel involvement. While only a
minority of patients have a diagnosis of IC, it is impor-
tant to realize that such a diagnosis has certain conse-
quences. It means that the patient has IBD and that SECTION 3
other conditions, especially infections, are less likely or
indeed excluded. Relapse of symptoms due to compli-
cations, such as cytomegalovirus (CMV) infection is
equally excluded (Fig. 18.20). A diagnosis of IC also
means that the patient needs careful follow-up in order
to reach a definite diagnosis.

Differential Diagnosis
Ulcerative colitis or Crohn’s disease
Several studies have examined a large variety of mucosal Fig. 18.20 Ulcerative colitis. Relapse of disease symptoms in
biopsy criteria for the distinction between UC and CD ulcerative colitis can be due to infection with cytomegalovirus.
and shown wide overlap.2 The situation is different The virus can be recognized by typical nuclear inclusions.
when surgical specimens are involved, because CD is (H&E × 25)
characterized by transmural inflammation, whereas UC
is a mucosal disease. In most studies examining endo- crypt abscesses have no significant discriminative value
scopic mucosal biopsies, the criteria, which discriminate (Table 18.4).
between UC and CD, have a sensitivity and specificity
exceeding only 75%.The histological diagnosis is largely
based on the finding of granulomas in addition to the
Infectious and drug-related colitis
presence of criteria for the diagnosis of IBD, especially A variety of infectious or drug-related colitides may clin-
mucosal distortion. Segmental distribution of crypts or ically mimic CD or UC, especially those cases with
crypt atrophy, segmental distribution of mucin deple- abrupt clinical onset. Acute inflammatory diarrhea
tion, mucin preservation at the edge of an ulcer or in accompanied by fever and evidence in stool of an
crypts with surrounding neutrophils, the occurrence of inflammatory process such as pus, mucus and blood, and
focal inflammation simultaneously with severe diffuse or dysentery, a more severe manifestation of inflammatory
patchy inflammation in a set of biopsies, have a signifi- diarrhea with, in addition, abdominal pain cramps and
cant discriminative value in favor of CD. Furthermore, rectal tenesmus, are indeed often due to infectious agents.
in contrast to UC, typical CD shows a segmental or These can be divided into two subgroups – organisms
focal distribution of the disease in the bowel and focal that elicit an inflammatory process by penetrating the
or patchy inflammation within a biopsy specimen.These mucosa, and those that elaborate cytotoxins without
features can reliably be assessed with good agreement invading the cells. Worldwide, invasive bacterial agents
between observers. In contrast, Paneth-cell metaplasia constitute the most important subgroup of etiologic
has only limited discriminative value while cryptitis and agents. A precise diagnosis is essential for a proper treat- 269
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Table 18.4 Frequency of detection (%) of the reproducible features for different diagnoses

Normal Infective IBD UC CD

Architecture
Irregular surface 0–5 0–7 39 63 24
Branched crypts 0–5 75 63–83 39–67
Crypt shortening 0–5 0 29–78 12–37
Chronic inflammation
Increased basal cellularity 0 0 63 62
Increased lamina propria cellularity 0–19 30 89–93 76–92 72–81
Granulomas 0 0–2 25–27 0–5 21–100
Discontinuous inflammation 7 10 26
Epithelial alterations
Mucin depletion 17 35–69 5–57
Mucin preservation at ulcer edge – +++
Neuronal changes 2 75

IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn’s disease.

ment. Histology, in collaboration with other methods of infection with Clostridium difficile. The differential
plays an important role in establishing a correct diagno- diagnosis of CD includes mainly bacterial diseases due to
sis.41 The histology of infectious-type colitis is variable, Yersinia enterocolitica and Campylobacter jejuni, which can
due to the natural course of the disease and to differences both affect the ileum and proximal colon (Fig. 18.21).
in the virulence of the bacterial strain and the reaction of Special attention is required for tuberculosis and amoebi-
the host, but in general it shows a picture of active asis because of the indolent nature of these infections and
inflammation with normal mucosal architecture. A the negative effect of a treatment with corticosteroids or
normal biopsy or mild edema can be seen when bacteria immunosuppressants.Tuberculosis is commonly found in
are non-invasive. Active inflammation may be mild or the terminal ileum and ileocecal region but, in contrast to
severe with extensive necrosis. In mild or moderate CD, it is rare in the large intestine. Unlike the longitudi-
disease, neutrophils are found in the upper part of nal serpiginous ulcers of CD, tuberculous ulcers tend to
the lamina propria. Cryptitis, with neutrophils usually in be circumferential or transverse. Examination of ileal or
the upper, more luminal part, superficial crypt abscesses colonic biopsies can reveal specific features. Granulomas
and erosions are common. The lesions show a focal or
patchy distribution. Neutrophils are more common in the
early phase of the disease. Residual lesions appear later.
An increase of plasma cells is observed 7–10 days after
the initial onset of the disease. Increased numbers of IgA-
and IgM-containing plasma cells are found in the mucosa
in patients with Campylobacter colitis, in contrast with
patients with active UC, who show increases of IgA and
IgG.The crypts remain parallel, but they are often smaller
at the upper part. The distinction between IBD and
infective type colitis relies mainly on the absence of fea-
tures (architectural and basal plasmacytosis) which direct
towards a diagnosis of chronic idiopathic inflammatory
bowel disease. In rare occasions, such as Entamoeba his-
tolytica or CMV infection, the pathogen can be identified.
CMV infection constitutes a special situation. It may be
present in the early stage of the disease of UC but it can Fig. 18.21 Yersinia pseudotuberculosis infection. Ileal biopsy
also be responsible for relapse of symptoms or cause pou- showing a characteristic granuloma with central necrosis. The
270
chitis. Histology is the best method for identification of lesion must be differentiated from tuberculosis and Crohn’s
this infection. Relapse of symptoms can also be the result disease. (H&E × 10)
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DIFFERENTIAL DIAGNOSIS

are usually multiple and large and can be confluent. a distorted crypt architecture and basal plasmacytosis.
Positive Ziehl staining suggests intestinal tuberculosis. Colonic mucosa both proximal and distal is usually
Central necrosis of a lymph follicle is suggestive of normal. The inflammatory features can mimic UC or
Yersinia infection. Salmonella, Shigella and Campylobacter CD. The relation of the inflammatory reaction with
infections can mimic UC. genuine IBD is unclear. Overall, it seems that diverticular
A medication history is indispensable in the investiga- disease-associated chronic colitis will precede the onset
tion of patients with diarrhea. A variety of drugs given of conventional ulcerative proctitis and colitis or genuine
either topically or systematically can cause colitis, ileo- CD in only a minority of cases.63
colitis or proctitis. Some of these may mimic UC. Non-
steroidal anti-inflammatory drug (NSAID)-induced Diversion colitis
lesions present a significant clinical problem. Usually the
Diversion colitis is an inflammatory process that occurs
patients are elderly. NSAIDs can induce small bowel and
in the bypassed colonic segment after surgical diver-
colonic lesions. Colitis induced by NSAIDs can present
sion of the fecal stream. In a defunctioned, previously
as non-specific colitis, de novo colitis, reactivation of
normal rectum, mild inflammation is already apparent
quiescent inflammatory bowel disease, allergic colitis
at 3 months. When continuity is restored, the changes
(with eosinophils), constipation with perforation (ster-
disappear. Histologic abnormalities show a spectrum of
coral ulcer), non-specific ulceration and fistulas related
changes ranging from mild colitis to those seen in severe
to diverticulosis. The microscopic distinction between SECTION 3
active ulcerative colitis. Lesions include aphthous ulcers,
active UC and drug-induced colitis is usually not so
crypt distortion, atrophy and abscesses, a villous colonic
difficult because NSAID-induced lesions lack major
surface, mucin granulomas and a mixed inflammatory
inflammation although architectural alterations of the
infiltrate with patchy lymphoid hyperplasia.The latter is
mucosa are common. The distinction with inactive UC
a particular feature of this condition. All these findings
is therefore more difficult (Fig. 18.22). In NSAID-
may mimic IBD. When the original process leading to
induced pathology, apoptosis of epithelial cells may be
diversion of the fecal stream is not an inflammatory
common in the crypts (as in graft-versus-host disease).62
bowel disease the histological diagnosis of diversion
Other drugs that can cause colitis or proctitis are penicil-
colitis is easy. However, when there is underlying UC,
lamine, gold salts, isotretinoin and methyldopa. Oral con-
the differential diagnosis is difficult. Features favoring
traceptives and cocaine tend to mimic ischemic colitis.
diversion colitis are variation in severity of the lesions
seen on multiple biopsies taken from one single area and
Diverticular disease-associated colitis the absence of morphologic changes in the proximal
A clinical syndrome of chronic colitis, localized to the (not bypassed) segment.
sigmoid colon and occurring in association with diver- It has been shown that the defunctioned rectum
ticular disease, has been recognized repeatedly. Mucosal from patients suffering from unequivocal ulcerative
biopsies of this condition show features of IBD including colitis who have undergone proximal colonic resection
may show transmural inflammation, fissures and epithe-
lioid granulomas.3 While these features would suggest a
diagnosis of CD, the temptation to change the underly-
ing diagnosis must be resisted, because the changes may
represent further manifestations of diversion colitis.
Only follow-up of the patient and the eventual appear-
ance of lesions in the small intestine may force a change
of diagnosis. In general, it seems that the condition
worsens in UC, while diversion is favorable in CD.

Lymphoid hyperplasia
Lymphoid hyperplasia is observed in chronic ulcerative
colitis per se, in a separate entity, described as lymphoid
follicular proctitis and in diversion colitis.

Microscopic colitis: collagenous

Fig. 18.22 Colitis caused by non-steroidal anti-inflammatory and lymphocytic colitis
drugs. There is mucosal ulceration and distortion of the crypt 271
architecture. The lesions are however discontinuous and Collagenous colitis is a disease of the large intestine,
inflammation is moderate. (H&E × 4) characterized by the presence of a thickened collagen
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layer underneath the intercryptal surface epithelium and morphologically different from IBD. Yet, in some
and, circumferentially, around the upper part of the cases, collagenous or lymphocytic colitis can precede (or
crypts and by increased mucosal inflammation. For a follow) genuine UC or CD.
proper diagnosis, it is necessary to obtain several (at least
three) colonic biopsies, because the thickness of the Endometriosis
subepithelial collagen table varies throughout the colon.
To reduce false positivity a minimal value of 10 µm Ileal endometriosis may present with acute, chronic or
has been proposed. Plasma cells and lymphocytes are recurrent distal small bowel obstruction, in the same
increased in the lamina propria and eosinophils may be way as Crohn’s ileitis.The differential diagnosis with CD
focally numerous. Neutrophils are occasionally seen may be very difficult and is mostly not possible pre-
and crypt abscesses are rare. Surface epithelial cells are operatively. Intestinal endometriosis may mimic CD, but
flattened or cuboidal and sometimes desquamated and can also be associated with CD. Endometriotic deposits
goblet cells are reduced in number and size.Yet overall, in the bowel can induce microscopic mucosal lesions
the colonic mucosa has a preserved or only minimally resembling inflammatory bowel disease.
distorted crypt architecture. It should not be confused
with rare forms of amyloid colitis, where the sub- Miscellaneous
epithelial thickening is due to deposition of amyloid
(Fig. 18.23). Microscopic lesions similar to CD have been reported
The microscopic picture of lymphocytic colitis is in ileal and colonic biopsies from patients with reactive
characterized by diffuse lesions with an increase of arthritis and ankylosing spondylitis. Only a minority
inflammatory cells in the epithelium and lamina propria. of these patients developed genuine CD. Less common
The infiltrate is mixed in composition with eosinophils, diseases, such as the colitis of Behçet’s disease and
neutrophils (cryptitis and crypt abscesses), lymphocytes, other vasculitides can mimic CD. Endoscopic biopsies
plasma cells and mast cells.The number of intraepithelial are often inconclusive, except when small vessels
lymphocytes is significantly increased (24.6 ± 3 for 100 are involved. In chronic granulomatous disease and
epithelial cells; normal value 4.6 ± 1.5), whereas a non- Hermansky–Pudlak syndrome, a colitis complete with
significant increase of interepithelial lymphocytes is granulomas, which is indistinguishable from CD, can
noted in UC and CD. Epithelial mucin depletion is occur. The diagnostic feature is the presence of charac-
common in lymphocytic colitis. teristic histiocytes in both mucosa and submucosa.
Microscopic colitis may be associated with primary Occasionally, malignancies may simulate CD on radio-
ileal villous atrophy (PIVA), without alterations in the logical examinations. The most common examples of
upper small intestine. Microscopic colitis is clinically these are in the colon: the poorly differentiated signet-
ring cell carcinoma and metastases in the wall, and
in the small intestine: a neuroendocrine cancer of
the terminal ileum. Mucosal biopsies may show mild
inflammatory features and architectural alterations. The
finding of such features must be interpreted cautiously
and, as always, histology has to be combined with the
clinical history and other data in order to reach a
definite diagnosis and to solve the differential diagnostic
problem.

Dysplasia and Cancer

Endoscopy with multiple biopsies is used for second-
ary prevention and in surveillance programmes for the
early detection of colorectal cancer in patients with
long-standing UC. This is based on the finding that
precancerous lesions can be identified in biopsies.
Fig. 18.23 Amyloid colitis. Collagenous colitis, one of the These lesions are called ‘dysplasia’. More recently, the
subtypes of microscopic colitis is characterized by thickening of
the subepithelial collagen table. The lesion can be mimicked in
term ‘intraepithelial neoplasia’ has been proposed.
amyloid colitis as illustrated in this figure of a colonic biopsy Dysplasia was defined by an international Inflammatory
stained with Congo red and showing the red color of the Bowel Disease–Dysplasia Morphology Study Group as
272
subepithelial amyloid band. (Congo red × 10) ‘unequivocal, non-invasive (confined within the base-
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DYSPLASIA AND CANCER

ment membrane), neoplastic transformation of the epi- Table 18.5 Biopsy classification of dysplasia
thelium excluding all reactive changes’.64 This definition (intraepithelial neoplasia) in inflammatory
stresses the nature and origin of the lesion, but its bowel disease
identification relies upon the recognition of morpho-
logical features resulting from cytological and architec- Negative
tural changes in routinely processed and hematoxylin Indefinite
and eosin-stained sections. Accumulated experience Positive
from several prospective studies shows that 6–10 differ- Low-grade dysplasia
High-grade dysplasia
ent biopsies from different sites might be sufficient to
detect significant dysplasia. Generally, the histological
features of dysplasia in IBD are comparable with those
seen in colonic adenomas in non-colitic patients and monly used classification, proposed by the International
include cytological criteria, such as variations in nuclear Study Group, two grades are distinguished.The category
position, size and chromatin pattern combined with ‘low-grade dysplasia’ includes cases of mild and
architectural distortion (Fig. 18.24). Although the mor- moderate dysplasia. The category ‘high-grade dysplasia’
phological spectrum forms a continuum, dysplasia is includes some cases of moderate dysplasia (particularly
divided into different categories according to the sever- those with prominent architectural alteration) and all
ity of the alterations, because of different implications cases of severe dysplasia and carcinoma in situ. The SECTION 3
for patient management (Table 18.5). In the most com- grade of dysplasia is always determined by the features
of the most dysplastic portion. The distinction between
high- and low-grade dysplasia is dependent primarily
on the degree of cytologic alterations. This classifica-
tion appears to be reproducible, although in general, it
appears that interobserver agreement is better for high-
grade dysplasia.
Surveillance studies have shown that a distinction has
to be made between IBD-related dysplasia, especially the
polypoid or raised type also known as dysplasia associ-
ated lesion or mass (DALM) and sporadic adenoma
occurring in IBD. While the latter is unequivocally a
neoplastic and hence a dysplastic lesion, its development
is unrelated to the underlying IBD. Furthermore, recent
evidence suggests that the molecular pathogenesis of
IBD-associated dysplasia is different in terms of order
and timing of genetic events. DALM in IBD should in
fact be defined as a poorly circumscribed protruding
lesion surrounded by dysplastic flat mucosa. It should
also be distinguished from ALM (adenoma-like mass),
when there is no surrounding dysplasia.65 The differential
diagnosis between polypoid IBD-associated dysplasia and
inflammatory pseudopolyps or dysplasia in inflammatory
pseudopolyps is another problem. Dysplasia in inflamma-
tory polyps is rare. The major problem is that these
polyps frequently contain areas of residual regenera-
tion and it may be difficult to make a clear distinction
between unequivocally neoplastic changes and regenera-
tion.The differential diagnosis between reparative lesions
and ‘genuine’ dysplasia in general may be difficult.
Whereas high-grade dysplasia can usually reliably be dis-
tinguished, the distinction between repair and low-grade
dysplasia may present a serious problem. Reparative
Fig. 18.24 Ulcerative colitis. Low-grade dysplasia, on the right
panel of the figure is characterized by the presence of tall cells of the surface may be distinguished from ‘genuine’
columnar cells with increased staining of the cytoplasm and dysplastic cells because of their shape (cuboidal or low
273
elongated nucleus. (H&E × 10) columnar versus crowded and high columnar) and
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SECTION 3. DIAGNOSIS: A CLINICIAN’S PERSPECTIVE CHAPTER 18. HISTOPATHOLOGY OF CROHN’S DISEASE AND ULCERATIVE COLITIS

ment of perianal squamous carcinoma and both UC and

CD appear more than usually susceptible to malignant
lymphoma.

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