0016-5107/84/3003-0167$02.

00
GASTROINTESTINAL ENDOSCOPY
Copyright is;) 1984 by the American Society for Gastrointestinal Endoscopy

The value of ileoscopy with biopsy in the

diagnosis of intestinal Crohn's disease
G. Coremans, MD
P. Rutgeerts, MD
K. Geboes, MD
J. Van den Oord, MD
E. Ponette, MD
G. Vantrappen, MD
Leuven, Belgium

Studies to determine the diagnostic value of i1eoscopy and biopsy are not
available. In an attempt to clarify the role of this technique in the diagnosis of
intestinal Crohn's disease, 110 patients with a radiological diagnosis of
inflammatory disease of the terminal ileum were examined in a prospective study.
Suspicion of Crohn's disease was rejected in 28 patients. In 18 patients the
terminal ileum was normal, while 10 patients had lymphoid nodular hyperplasia.
Endoscopic lesions with a predictive value of 0.96 were found in 25 of 48 patients
with the final diagnosis of Crohn's disease. Diagnostic granulomas were only
found in 4 patients, but lesions consistent with Crohn's disease were present in
the pathology sections of 17 patients. It was concluded that ileoscopy with biopsy
is a valuable tool in the diagnosis of inflammatory ileal disease and can provide
useful information about the nature and extent of the inflammation.

It may be difficult to make a definite diagnosis of PATIENTS AND METHODS

intestinal Crohn's disease by roentgen techniques,
especially in the early stages of the disease. 1• 2 Ileos-
copy with biopsy has become a routine procedure in
skilled hands, with a reported successful intubation
rate as high as 80 to 97% in patients in whom the
cecum is reached.:J,4
This prospective study was carried out in order to
determine the value of ileoscopy and biopsy for the
diagnosis of intestinal Crohn's disease. The study was
divided into three parts. In the first part, the endo-
scopic and histological diagnosis was compared with
the final diagnosis in patients with inflammatory ileal
disease diagnosed on the basis of radiological exami-
nations. In the second part, the value of ileoscopy was
determined in patients with a radiological diagnosis
of inflammatory ileal and colonic disease. Finally, the
role of ileoscopy in evaluating radiographically dem-
onstrated narrowing of the terminal ileum was estab-
lished.
From the Department of Medical and Biomedical Research, Univer-
sity Hospital St. Rafael, Leuven, Belgium. Reprint requests: Dr. G.
Coremans, Internal Medicine, A.Z. St. Rafael, Capucienenvoer 33,
B-3000 Leuven, Belgium.
VOLUME 30, NO.3, 1984
Patients
One hundred ten consecutive patients with radio-
logical suspicion of inflammatory ileal disease in
whom the ileum could be reached with a colonoscope
participated in the study. There were 45 men and 65
women. Their ages varied from 14 to 68 years, with a
mean of 32 years.
Techniques
A barium meal with special attention to the terminal
ileum and an examination of the colon by a single
contrast technique were performed. Colonoscopy and
ileoscopy were performed with an Olympus CFIB
colonoscope within 2 weeks following the radiographic
studies. Diazepam, 5 to 10 mg, was given intravenously
immediately before the examination. All patients were
prepared by the whole gut irrigation procedure. 5,6 The
technique for intubation and biopsy of the terminal
ileum has been described previously in detai1. 3,4,7 In
the absence of rigid stenosis, 10 to 30 em of the distal
ileum were inspected.
Biopsies were cut into serial sections and stained by
hematoxylin and eosin, periodic acid-Schiff, and acid-
167
fast techniques. The acid-fast staining was applied on
fresh obtained biopsies. All pathology slides were then
reviewed blindly by a senior staff pathologist.

Final diagnosis
The final diagnosis of Crohn's disease was based on
the presence of granulomas in biopsies or surgical
specimens of the gastrointestinal tract. When no his-
tological proof for Crohn's disease was available, the
final diagnosis was based on a combination of char-
acteristic clinical, radiological, endoscopic, and histo-
logical features of the disease. Only the presence of Figure 1. Nodular lymphoid hyperplasia, grade 3: densely
granulomas was accepted as diagnostic. A granulo- distributed lymph follicles with interfollicular fusions retaining
ileal content.
ma was defined as a nodule consisting of epithelioid
and giant cells with a peripheral rim of lymphocytes.
The presence of three other features of Crohn's dis-
ease, fissure-ulceration, giant cells, and discontinuity (76.3%). In 26 patients (23.6%) there was also a radi-
of the inflammation and epithelial cell follicles in the ological diagnosis of inflammatory colon disease. Mu-
absence of granulomas, was regarded as suggestive of cosal lesions confined to the ileocecal valve, in asso-
or compatible with Crohn's disease. 8 ciation with terminal ileum changes, were never ob-
The diagnosis of acute infectious ileitis was based served. Different degrees of narrowing of the terminal
on a positive stool culture on appropriate media and/ ileum were reported in 49 of 110 patients (44.5%).
or demonstration of changing titers of specific anti- Narrowing was differentiated from hyperkinetic con-
bodies. Reliable tests are now available for detection tractions by the presence of a constant reduction in
of Yersinia enterocolitica serotypes 3 and 9. 9 caliber. The presence of thickened mucosal folds was
Tuberculous enteritis was diagnosed by the presence not interpreted as narrowing.
of acid-fast bacilli in ileal biopsies or, in the case of
lung cavitation, when positive sputum occurred to- lIeoscopy
gether with ileal inflammatory lesions and when ther- The endoscopic lesions observed in the ileum are
apy with tuberculostatic drugs resulted in healing of summarized in Table 1. In 37 patients (33.6%), normal
the lesions. folds or different degrees of nodularity covered by a
Different degrees of nodularity covered by a ma- normal mucosa were observed. Nodularity was char-
croscopically normal mucosa, as well as the presence acterized by the presence of multiple round or oval
of numerous large lymphoid follicles in the lamina tumefactions not exceeding 5 mm in diameter (Fig. 1).
propria on pathology sections, were considered path- In 54 patients, or almost 50%, typical ulcerations were
ognomonic for nodular lymphoid hyperplasia. 4 , 7,10 demonstrated, usually in association with cobbleston-
RESULTS
ing and thickened mucosal folds (Fig. 2). Cobbleston-
ing referred to the presence of hyperemic congested
Radiology mucosa divided by linear ulcerations (Fig. 3). Segmen-
Inflammatory disease limited to the terminal ileum tal narrowing that failed to expand on insufflmion
was radiologically demonstrated in 84 patients and prevented passage of the 'scope was considered as
an organized stenosis and precluded further evaluation
Table 1. of the ileum in 17 patients (15.4%). Inflammatory
Endoscopic findings in the terminal ileum of 110 patients lesions on or surrounding the ileocecal valve were
with a radiological suspicion of inflammatory ileal present in 22 patients.
disease.
N % Pathology
Normal mucosa 22 20.0 Adequate biopsies were obtained in 97 patients
Nodularity only 15 13.6 (88%). The findings are shown in Table 2. Comparing
Cobblestoning 15 13.6 the pathology and endoscopy findings revealed normal
Thickened folds 29 26.3
Ulcerations
mucosa or numerous lymphoid follicles in the lamina
44 40.0
Aphthous ulcers 10 9.1 propria of 28 of 37 patients (75.6%) with endoscopi-
Organized stenosis 17 15.4 cally normal ileal folds or nodularity covered by nor-
Lesions of ileocecal valve 16 14.5 mal looking mucosa. Nonspecific inflammation was a
Lesions surrounding the valve 6 5.4 less common finding in this group (24.4%). In patients
Open valve with dilated ileum 2 1.8
with obvious inflammatory lesions on ileoscopy, non-
168 GASTROINTESTINAL ENDOSCOPY
Figure 2. Typical delineated linear ulcerations with a yellow-
gray base and a hyperemic, slightly friable mucosa in the
terminal ileum of a patient with Grohn's disease.
specific inflammation was frequently observed in the
sections. The classical epithelioid granulomas were
only demonstrated in four patients. Less specific his-
topathological criteria consistent with Crohn's disease
were present in 17 patients (Figs. 4 and 5). Positive
acid-fast staining and central necrosis in a hyperplas-
tic lymph follicle, which is considered a strong indi-
cation for Yersina infection,l1 were rare findings.
Final diagnosis
The various disease entities identified in this group
of patients are summarized in Table 3. As expected,
Crohn's disease accounted for the majority of the
diagnoses (44.5%). The diagnosis was made by pa-
thology on four patients with granulomas in the biopsy
specimen of the terminal ileum. In one of these pa-
tients additional granulomas were found in a resected
specimen. In 10 other patients who underwent intes-
tinal resection after the study was finished, diagnostic
granulomas were found in the resected specimen of
colon and/or ileum. In eight other patients with en-
doscopically demonstrated inflammatory ileal disease,
the diagnosis of Crohn's disease was confirmed by the
presence of granulomas in biopsy specimen of colon
and rectum (five), anus (one), stomach (one), and
esophagus (one). In one of these patients granulomas
were even found in the liver and kidney. In an addi-
tional 17 patients the pathology findings of the spec-
imen of the terminal ileum were "consistent with
Crohn's disease" according to well-defined criteria.8
Only in nine patients (18.7%) was a final diagnosis of
Crohn's disease based on a syndrome diagnosis of
clinical, radiological, endoscopic, and histological
data, after careful elimination of known infectious
etiology. The follow-up of the patients was at least 2
years after the ileoscopy was performed. The diagnosis
did not have to be revised in any of the patients.
A normal ileum or nodular lymphoid hyperplasia
was diagnosed in 25.5% of the patients. A final diag-
nosis of infectious ileitis in 7% of the patients with a
radiological diagnosis of inflammatory ileal disease
VOLUME 30, NO.3, 1984
Figure 3. Gobblestoning: islands of swollen, hyperemic mu-
cosa segmented by deep intersecting ulcers in a patient with
Grohn's disease.
Table 2.
Histopathological findings in the biopsies of 97 patients
with suspected terminal ileum disease.
N %
Normal mucosa 28 25.4
Nonspecific inflammatory infiltration 46 41.8
Epithelioid granulomas 4 3.6
Consistent with Crohn's disease 17 15.4
Acid-fast staining positive 1 0.9
Central necrosis in a hyperplastic lymph- 1 0.9
oid follicle
stresses the importance of careful bacteriological in-
vestigation. In 23 patients with ileitis, no definite
etiology could be demonstrated, even on ileoscopy with
biopsy. Although this number is surprisingly high,
chronic inflammatory colon disease was present in
seven patients, suggesting backwash ileitis or early
Crohn's disease as causes of the nonspecific terminal
ileal changes. Therapy for chronic inflammatory bowel
disease was continued. Likely causes of the endoscopic
findings in eight patients were parasitoses in two
patients, immune reactions in two patients, and a
recent history of Y. enterocolitica infection, irradia-
tion, lymphangiectasia of the small bowel, and carci-
noma of the ileocecal valve in one patient each. No
related disease could be found in the remaining eight
patients showing a normal colon. None of these pa-
tients were treated for Crohn's disease or for a specific
infectious disease.
Endoscopic lesions in patients with a final
diagnosis of Crohn's disease
As shown in Table 4 three groups of lesions fre-
quently found endoscopically in patients with a final
diagnosis of Crohn's disease could be recognized.
Group 1 included diffusely or nodularly thickened ileal
mucosal folds containing typical ulcerations in asso-
ciation with similar lesions around the ileocecal valve
or an organized stenosis of the valve, perhaps in
169
Figure 4. Human ileal mucosa (H & E): pseudopyloric gland
metaplasia can be seen in the base of the crypts. This finding
is an indication of a chronic inflammatory process and is
usually seen in Crohn's disease (original magnification, x25).
Table 3.
Final diagnosis in 110 patients with a radiological
diagnosis of inflammatory ileal disease.
N %
Crohn's disease 48 44.5
Backwash ileitis 2 1.8
Acute infectious ileitis 7 6.3
Yersinia enterocolitica 5 remaining four patients, showing typical ulcerations
Escherichia coli 1 and thickened mucosal folds without narrowing,
Shigella flexneri 1
Tuberculosis 2 1.8
Ileitis without etiology 23 21.0
Normal terminal ileum 18 16.4
Nodular lymphoid hyperplasia 10 9.1
association with segmental colitis. Only round, oval,
linear, or serpiginous ulcers with a yellow-gray base
were regarded as typical for Crohn's disease. Group 2
lesions were similar to the lesions of group 1 but were
confined to the ileum. Group 3 demonstrated hypere-
mia and friability of diffusely or nodularly thickened
folds, large or aphthous ulcers, or an association of
the fold changes with one type of these ulcers.
Predictive value of group 1, 2, and 3 lesions in
patients with inflammatory ileal disease
Twenty-six (23%) of the patients showed group 1
lesions at endoscopy. Twenty-five of them had a final
diagnosis of Crohn's disease, resulting in a predictive
value of 0.96. (The predictive value of a positive test
is the proportion of patients with the disease in all
patients with a positive test.) The other patient (one
of 26), who had longitudinal ulcerations of the ascend-
ing colon and terminal ileum in association with thick-
ened mucosal folds, inflammatory nodules, and ileal
170
Figure 5. Human ileal mucosa (H & E): a fissure-ulcer can be
seen in the lamina propria (original magnification, x25).
stenosis, met the visual criteria of Crohn's disease but
turned out to have a final diagnosis of tuberculosis
based on biopsy specimen of the ileum showing gran-
ulomas and positive acid-fast staining.
The predictive value of group 2 lesions, which are
similar to group 1 but have none of the associated
colonic pathology, was present in 20 patients. Sixteen
patients of this group had a final diagnosis of Crohn's
disease, resulting in a predictive value of 0.8. The
turned out to have a Y. enterocolitica infection that
was demonstrated by positive stool cultures and/or
the presence of Yersinia antibodies. In none of these
16 patients with a final diagnosis of Crohn's disease
was there radiological or endoscopic evidence of heal-
ing of the terminal ileum lesions during a 2-year
follow-up. The predictive value of group 3 was 0.78
(Table 5).
lIeoscopy in patients with inflammatory disease of
colon and ileum
Twenty-six patients had a radiological diagnosis of
inflammatory disease of the small bowel and colon.
Endoscopy demonstrated involvement of colon and
ileum in 12 patients. Pathological examination con-
firmed the presence of an inflammatory infiltrate,
suggesting Crohn's disease. In another 12 patients, the
disease was limited to the colon. Backwash ileitis
accompanying ulcerative colitis was diagnosed in two
patients. A wide ileocecal valve and a slightly dilated
terminal ileum containing atrophic mucosa with hy-
peremia or friability or both were characteristic. Small
superficial ulcers were present in one patient. Acute
and chronic inflammation, ulceration, lymphoid hy-
perplasia, and groups of epithelioid cells were found
on the pathology slides.
GASTROINTESTINAL ENDOSCOPY
Table 4.
Groups of endoscopic lesions frequently encountered in patients with Crohn's disease.
Terminal ileuma
Mucosal changes b
Ileocecal valve Colon
Superficial Ulcers
Folds
aspect
Group 1 Diffusely or nodularly Hyperemia Round Stenosis Segmental colitis
thickened Friability Oval Ulceration
Linear
Serpiginous

Group 2 Diffusely or nodularly Hyperemia Round No lesions No lesions

thickened Friability Oval
Linear
Serpiginous

Group 3 Diffusely or nodularly Hyperemia Either aphthous or No lesions No lesions

thickened Friability giant ulcers
a In group 1, terminal ileum lesions are associated with ulcerations around the valve and/or stenosis of the valve with or without segmental

colitis.
b In group 3, mucosal changes can occur isolated or in association with one type of these ulcers.

Table 5. ence of normal mucosa or of multiple lymphoid folli-

Predictive value of group 1, 2, and 3 lesions in Crohn's
disease with the final diagnosis as reference.
N Predictive value
Group 1 26 25/26:0.96
Group 2 20 16/20:0.80
Group 3 9 7/9:0.78
lIeoscopy and radiological narrowing of the
terminal ileum
An organized stenosis was found in 12 of 49 patients
(24.5%) with a radiological diagnosis of narrowing of
the terminal ileum. Normal distention or a functional
stenosis occurred in 37 patients (75.5%).
DISCUSSION
The primary goal of this study was to evaluate the
role of ileoscopy and biopsy in the diagnosis of intes-
tinal Crohn's disease.
Radiologically, it may be impossible to differentiate
lymphoid nodular hyperplasia from Crohn's disease or
infectious enteritis. 1 Ileoscopy with biopsy excluded
the presence of Crohn's disease in 25.5% of the pa-
tients studied, indicating that the radiological limits
of normality in the terminal ileum are not yet well-
defined. Nodular lymphoid hyperplasia must always
be considered in the presence of nodular changes in
the terminal ileum. However, a nodular pattern is
frequently found in the absence of disturbed physiol-
ogy and necessitates no therapy.7.10 We feel, therefore,
that in the presence of atypical radiological lesions,
ileoscopy with biopsy should be carried out after ex-
clusion of infectious disease by negative stool cultures
and serology. Histological confirmation of the pres-
VOLUME 30, NO.3, 1984
cles is of great diagnostic importance.
Besides documenting a normal terminal ileum in
presumed radiological inflammatory changes, ileos-
copy can further provide very specific data indicating
Crohn's disease. The predictive value of inflammatory
changes described as group 1 lesions in this study is
high (0.96). The observation of small ulcerations on
the ileocecal valve or cecum is very helpful in the
diagnosis of Crohn's disease. This study indicates that
routinely performed examination of the colon by sin-
gle contrast technique is not a reliable means of de-
tection of these usually superficial lesions. It may be
stressed that endoscopic biopsies of the terminal ileum
contain epithelioid granulomas only in four of 48
patients with Crohn's disease. However, since Crohn's
disease is still a syndrome diagnosis, we believe that
additional diagnostic information is often provided by
histological findings consistent with Crohn's disease,
as was the case in 17 of 48 patients included in this
study.
The diagnostic importance of group 2 and group 3
lesions is limited because of the possibility of an
infectious ileitis, particularly Y. enterocolitica infec-
tion. This study stresses the importance of repetitive
stool cultures in the presence of inflammatory changes
of the small bowel and colon since acute and subacute
infectious ileitis accounted for 7% of the final diag-
noses. Recently it became evident that Y. enterocoli-
tica, Campylobacter, and autochthonous shigellae and
salmonellae can cause subacute forms of ileocolitis in
Western Europe. 12
The value of ileoscopy and ileal biopsies in the
diagnosis of tuberculosis is not yet well-defined. As a
rule, ileocecal tuberculosis cannot be endoscopically
differentiated from Crohn's disease. 13 Ileal biopsies,
171
however, can provide fresh specimens for acid-fast
staining and tissue culture. Positive cultures and acid-
fast staining of tissue specimens have been reported. 14
Ileal biopsies provided a definite diagnosis in one of
two patients included in this study who were suffering
from tuberculosis. A positive finding for tuberculosis
is of great clinical importance. Because of the low
incidence of tuberculosis in Western Europe, late di-
agnosis and inadequate treatment has become a real
danger. In contrast to the histological method, applied
on fixed material, which is time consuming and diffi-
cult to interpret, acid-fast staining on fresh biopsies
can be performed routinely.
The value of colonoscopy in the diagnosis of chronic
inflammatory bowel disease is generally accepted. IS
Our study demonstrates that ileoscopy provides useful
additional information about the nature and extent of
chronic inflammatory bowel disease, possibly to the
point of influencing therapy. Ulcerative colitis be-
comes likely when a normal ileum or backwash ileitis
is found together with a granular surface and ulcera-
tions of the entire colon. The diagnosis of Crohn's
ileocolitis is based on the presence of segmental find-
ings with cobblestone relief in the large bowel in
continuity with terminal ileal lesions. As demonstra-
ted previously, ileoscopy with biopsy is more accurate
than radiological examination to evaluate the terminal
ileum.
Finally, this study clearly indicates that in the pres-
ence of radiological narrowing of the terminal ileum,
ileoscopy can differentiate between a rigid and a func-
tional stenosis. In the presence of an organized ste-
nosis, an acute infectious etiology of the ileitis can be
ruled out. In Western Europe, the presence of a rigid
stenosis together with ulcerations makes the diagnosis
of Crohn's disease very likely. However, one should be
aware of the rare possibility of tuberculosis. The pres-
ent study also shows that ileoscopy with biopsy per-
mits exclusion of the presumed diagnosis of Crohn's
disease in a number of patients with atypical radio-
logic ileal lesions. The therapeutic consequences of
this observation are obvious. Unjustified use of sulfas-
alazine, a drug with well-known toxicity and adverse
172
reactions,16 can be avoided. In patients with atypical
terminal ileitis in the absence of well-defined colonic
disease or likely causes of the endoscopic finding, one
can assume an attitude of expectation. In our experi-
ence the majority of these patients show spontaneous
healing of the lesions within months, suggesting an
unknown infectious etiology. Ileoscopy should be re-
peated after 3 months. Persistence of the inflam-
mation makes the diagnosis of an early stage of
Crohn's disease very likely.
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GASTROINTESTINAL ENDOSCOPY