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68. Derikx LAAP, Nissen LHC, Smits LJT et al (2016) Risk of neoplasia after colectomy in
patients with inammatory bowel disease: a systematic review and meta-analysis. Clin
Gastroenterol Hepatol 14(6):798–806
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Mark-Christensen A, Erichsen R, Brandsborg S et al (2018) Long-term risk of cancer
following ileal pouch-anal anastomosis for ulcerative colitis. J Crohns Colitis 12(1):57–62
G. Poggioli et al.
Diagnosis of Ulcerative Colitis: Morphology
and Histopathological Characteristics
Antonietta D’Errico and Deborah Malvi
5.1 Role of Histology
The role of the pathologist in the clinical management of inammatory bowel
disease (IBD) is to diagnose and dene the type of IBD, to dene the status of
the colonic mucosa (active or chronic), to identify the presence of dysplasia and
to exclude complications [1, 2].
Moreover, histology provides information regarding the phase of IBD
and mucosal status, unlike that of the endoscopic examination; endoscopic
evaluation can be different from histological assessment [3] and endoscopic
mucosal healing (MH) does not necessarily correspond to MH at a histological
level [4, 5]. For these reasons, guidelines consider histological evaluation to be
the gold standard for the management of patients [6].
Several studies have conrmed that histology is a better indicator of the inammatory status of the colonic mucosa than endoscopy, for the most part in the
presence of only minimal or mild mucosal inammation; Truelove et al. have
reported that 40–60% of normal endoscopic examinations of ulcerative colitis
(UC) patients had mild to moderate histologically evident mucosal inammation [7]. Thomas et al. reported only low agreement between clinical status,
endoscopy and histology, and the study conducted by Rosenberg et al. showed
that more than 50% of patients in clinical remission had histological evidence of
inammation, independent of the therapeutic regimen used [8, 9]. Of interest, in
the latter study, islands of activity in the right colon were found during complete
endoscopy (i.e., cecal patch) in patients with only distal UC, indicating a key
role for a total and complete endoscopic examination with biopsy [9].
5
A. D’Errico (*)
Department of Experimental Diagnostic and Specialty Medicine, University of Bologna,
S. Orsola-Malpighi Hospital
Bologna, Italy
e-mail: antonietta.derrico@unibo.it
G. Poggioli (Ed), Ulcerative Colitis,
Updates in Surgery
DOI: 10.1007/978-88-470-3977-3_5, © Springer-Verlag Italia 2019
61
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A. D’Errico and D. Malvi
Histologically, the remission of UC is dened by the presence of complete
mucosal healing [10, 11] or by the presence of residual features of chronicity
[12, 13]. The lymphomonocytic inltrate of the lamina propria can be increased
or decreased, and basal cell plasmacytosis is no longer apparent.
Long-term remission, a long relapse-free period, and reduction in
hospitalization and surgical treatment have been proven to be related to MH
[14]. Moreover, MH has been associated with a reduction in cancer risk and
cancer-related mortality [14], indicating that the persistence of inammatory
activity may play a role in IBD-related carcinogenesis [15, 16].
The presence of basal plasmacytosis in an otherwise remission phase of UC
has been associated with a shorter disease-free period [17]. Conversely, the
persistence of an increased inammatory inltrate of the lamina propria and
the presence of other signs of activity are associated with an increased risk of
relapse [9, 17–19] and colectomy [20, 21]. In particular, the study of Tanaka et
al. has proposed ve histological parameters to predict the success or failure
of the medical treatment; moreover, it demonstrated that non-responding UC
patients had a higher number of eosinophils of the lamina propria, suggesting
that they could be a possible sign of the failure of steroid therapy [22–24].
Several studies have analyzed the predictive factors for colectomy in UC
patients: Daperno et al. [25] reported the presence of “slow” and “early” steroid
responders; Molnár et al. 2011 [26] demonstrated that the colectomy rate was
higher in non-responding patients and that approximately 40% of patients
had undergone colectomy the following year despite the good response to the
second-line rescue therapy.
Among pediatric UC patients, there are some interesting articles correlating
the clinical, biological and histological parameters with clinical relapse, starting
with the study of Bitton et al. in 2001 [17], in which basal plasmacytosis and
rectal biopsies had a signicant predictive value.
In spite of the key role of histological evaluation in demonstrating mucosal
alterations in UC patients, some limitations remain, mainly due to the use
of clinical and endoscopic endpoints in routine clinical practice [27] related
to the lack of standard histological reporting and validated histological
scoring systems, and especially to the lack of reproducible criteria for defining
MH [28].
5.2 Histological Features
Ulcerative colitis is dened as an idiopathic inammatory process of the large
bowel and rectum, and diagnosis is based on medical history, clinical evaluation
together with endoscopic and histological conrmation of typical signs, and
evaluation of the serological markers [29].
5 Diagnosis of Ulcerative Colitis: Morphology and Histopathological Characteristics
Fig. 5.1 Colectomy specimen, left-
sided colon: the typical presentation
of ulcerative colitis showing a
cobblestone and granular appearance
of the mucosa with supercial
ulcerations
Fig. 5.2 Left-sided colectomy
showing pseudopolyps in the context
of widespread mucosal ulceration
63
Macroscopic examination of the resected specimen classically shows the
presence of a continuous alteration of the mucosa from the rectum to the
proximal colon, with a gradual decrease in the severity of the disease and a
sharp demarcation between the uninvolved and the diseased mucosa. The
typical presentation of UC consists of a friable and granular appearance of the
mucosal surface, with the presence of supercial ulcerations (Fig. 5.1). In the
more severe cases, these can undermine the adjacent mucosa and penetrate deep
through the muscularis mucosae [30, 31] producing deep ssures and stulas in
cases of fulminant colitis which can give rise to the so-called Crohn-like colitis
appearance [32, 33].
The appearance of pseudopolyps (Fig. 5.2) is due to the presence of an island
of normal/healed mucosa in the context of extensive ulceration; this presentation
is typical in the left colon except for the rectum.
Chronic inactive UC is characterized by the presence of atrophic and at
mucosa with the disappearance of the typical haustration.
64
A. D’Errico and D. Malvi
The unusual macroscopic presentation of UC shows rectal sparing (especially
in adults with fulminant colitis or in patients receiving topical treatments)
[32, 34–37], a cecal patch (left-sided colon involvement associated with the
presence of active colitis in the cecum, around the appendiceal orice) [36–40]
and backwash ileitis. Backwash ileitis can be found in 20% of patients with
diffuse UC without a cecal involvement [41–43]. In a minority of cases, UC
can produce strictures due to the presence of marked mucosal and submucosal
brosis [44].
Histology is a key step in the management of clinical patient care; it is
therefore not only used to conrm the endoscopic/clinical suspicion, but it is
also helpful in the patient follow-up to determine the grade of inammatory
activity and the grade of MH, thus helping to predict the risk of relapse [4, 17,
45]. For a correct histological interpretation, clinicians should send an adequate
number of well-oriented biopsies from at least ve sites including the terminal
ileum and rectum, each in a separate biopsy-box, and a clinical report including
the onset and duration of the disease, the therapy carried out and the status of
the patient at the time of the procedure [46].
Studies have demonstrated that histology is a better predictor of MH than
endoscopy [47, 48] demonstrating that complete MH during UC is associated
with a lower rate of immunosuppressive therapy, lower rates of hospitalization
and a lower risk of colectomy and malignancy [21, 49]. Mucosal architecture
distortion with gland branching and deformation, and diffuse transmucosal
inammation with basal crypt plasmacytosis are the typical histological features
of UC. The presence of an active inammatory component causing cryptitis and
crypt abscesses with mucin depletion [50–52] and gland regeneration denes
the active phase of the inammatory process. Typically, the inammatory
inltrate is diffuse and continuous [44, 53, 54] without “skip lesions” and with
the highest grade of severity in the rectum (Fig. 5.3).
The presence of mucosal atrophy characterizes the quiescent phase of the
disease together with Paneth cell metaplasia, inammatory pseudopolyps and
hypertrophy of the muscularis mucosae [55]. Granulomas are not generally
considered features diagnostic of UC (Fig. 5.4); they are rarely found related to
mucin extravasation in active UC with cryptitis and ruptured glands [56].
The histological spectrum of UC can be very variable, depending not only on
the phase of the disease (i.e., chronic active, chronic inactive or simply active
colitis) but also on disease duration and the type of treatment received.
At the very beginning of the disease, histology may not show the typically
expected alterations since only 20% of patients have crypt distortion. Basal cell
plasmacytosis (one of the strongest predictors of IBD together with an increase
in lymphocytes and plasma cells, and gland distortion is found in only fewer than
50% of patients and when present, it can be very focal [18]. On the other hand,
the diagnosis of long-standing UC, is commonly characterized by architectural
gland distortion, mucosal atrophy with a reduction in crypt numbers and an
5 Diagnosis of Ulcerative Colitis: Morphology and Histopathological Characteristics
Fig 5.3 Colonic biopsies from (a) right colon,
(b) transverse colon and (c) rectum: typical
histological pictures of ulcerative colitis,
with a diffuse and continuous inammatory
inltrate of the lamina propria with the
highest grade of severity in the rectum (c).
Hematoxylin-eosin stain; magnication 4× (a),
10× (b,c)
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Fig. 5.4 Granulomas in colonic biopsies. (a) A granuloma related to mucin extravasation in an
active ulcerative colitis with cryptitis and gland rupture. (b) A typical granuloma of Crohn’s
disease, with a giant cell and not associated with gland disruption. Hematoxylin-eosin stain;
magnication 40× (a,b)
increase in the chronic inammatory inltrate of the mucosa, even though an
island of “normal-appearing” mucosa can be observed, mainly as a result of the
therapy (MH), giving a patchy appearance to the colon [18, 37, 53], particularly
in the rectum (rectal sparing). The extension of the disease can also change
in long-standing UC, turning from diffuse and continuous to non-diffuse and
discontinuous [37, 53].
66
Fig. 5.5 Active ulcerative colitis: mucosal architecture distortion with gland distortion and diffuse
transmucosal inammation with basal crypt plasmacytosis. There is an evident presence of an
active inammatory component causing cryptitis and crypt abscesses with mucin depletion and
gland regeneration. Of note the presence of a substantial eosinophilic component. Hematoxylineosin stain; magnication 4× (a); 20× (b)
A. D’Errico and D. Malvi
Fig. 5.6 Examples of crypt abscesses: on the left, a crypt abscess causing glandular destruction;
on the right, a non-destroying crypt abscess. Hematoxylin-eosin stain; magnication 40× (a,b)
Therapy can also produce alterations which modify the typical histological
picture until there is complete MH, which is the primary endpoint of the new
guidelines [57, 58]. The pattern distribution of colitis is also modied, with a
discontinuous and patchy appearance of the disease giving rise to other possible
differential diagnoses, above all of Crohn’s colitis (particularly in the absence
of sufcient clinical data).
Histology can be used, to dene a situation of chronic active or chronic
inactive colitis (where signs of chronicity are found) or simply active colitis (in
the absence of any signs of chronic mucosal damage).
The signs of activity (Fig. 5.5) are represented by:
• neutrophilic inltrate in the lamina propria with the presence of cryptitis,
crypt abscesses with glandular destruction (Fig. 5.6);
5 Diagnosis of Ulcerative Colitis: Morphology and Histopathological Characteristics
Fig. 5.7 Chronic inactive ulcerative colitis: the images show architectural distortion with glandular
branching, dilatation and shortening of the crypts and glandular atrophy. Fibrosis of the lamina
propria and thickening of muscularis mucosae are also visible. A mild increase in the chronic
inammatory inltrate (with the typical basal plasmacytosis together with focal Paneth cell
metaplasia) is also evident. Hematoxylin-eosin stain; magnication 2× (a), 4× (b)
67
• erosion/ulceration of the epithelium;
regenerative features of the glandular cells with a reduction in mucinous
•
cells and mucin production.
The signs of chronicity (Fig. 5.7) are:
•
architectural distortion which includes branching and loss of glandular
parallelism, dilatation/shortening of the crypts and/or glandular atrophy with
a reduction in gland density;
brosis of the lamina propria;
•
•
reduplication and/or thickening of muscularis mucosae;
increased chronic inammatory cells, including basal plasmacytosis (increase
•
in the plasmacell inltrate along the basal region of the crypts) and/or the
presence of basal lymphoid aggregates (follicular lymphoid aggregates also
with a germinal center, located between the basal portion of the crypt and the
muscularis mucosae;
•
Paneth cell metaplasia, particularly in the left colon.
Several histological scoring systems have been created in order to analyze
and compare UC histology, not only regarding the clinical management of the
patients, but also regarding the purpose of clinical trials [49]. Among the most
widely known and used histological classication systems (Table 5.1) are the
Truelove and Richards index (which is based on a three-grade scale system)
[59], Riley index (which takes into account six histological parameters, each
rated on a four-point scale) [45], and the Geboes scale (which analyzes six
histological features, each rated on a 0–3 or 0–4 scale) [60].
Currently, few studies exist which have correlated the histological
modication and the effect of therapy in UC patients and only a few of them
include alterations after biological drugs, possibly due to the late identication
of this type of therapeutic agent [5].
68
Table 5.1 Three of the most widely used histological activity index scores
Index Grading System Parameters evaluated
Truelove and Richards
Activity Index [59]
Riley Activity
Index [45]
Geboes Activity
Index [60]
Three-grade scale system Inammatory inltrate of the lamina
propria graded from none to severe
Six parameters, each rated
in a four-grade scale
system (none, mild,
moderate, severe)
Six parameters (grades),
each rated in a 0–3 or 0–4
scale system (subgrades)
- Neutrophilic inltrate in the lamina
propria
- Crypt abscesses
- Mucin depletion
- Surface erosion
- Chronic inammatory cell inltrate
in the lamina propria
- Crypt architectural distortion
Grade 0: architectural alteration
Grade 1: chronic inammatory inltrate
Grade 2: neutrophils (2A) and eosinophils
(2B) in the lamina propria
Grade 3: neutrophils in epithelium
Grade 4: crypt destruction
Grade 5: erosion or ulceration
5.3 Differential Diagnosis
A. D’Errico and D. Malvi
5.3.1 Crohn’s Disease and Indeterminate Colitis
The most common types of IBD which can affect the colon are UC and Crohn’s
Disease (CD); the distinction can be made easily if their clinical and endoscopic
presentations are typical and each IBD type exhibits its classical histological
features. The former is characterized by the presence of diffuse and continuous
ulceration of the mucosa from the rectum to the proximal colon (the rectum is
nearly always involved in non-treated UC) [61] and the latter is characterized
by the presence of segmental inammation of the intestine, with the presence
of deep transmural ssuring ulcers and stulas, aphthous mucosal erosion and
granulomatous reaction [62].
Some patients, however, show features which overlap between UC and CD,
and differentiating them can be difcult, especially on biopsy samples, leading the
pathologist to a provisional diagnosis of “indeterminate colitis”. This denition
was initially coined to describe cases of fulminant colitis with colonic dilatation
(i.e., toxic megacolon), proximal colon involvement and extensive ulceration
of the mucosa sometimes with a ssuring appearance and marked inammatory
component extending throughout the gut wall [63]. This histological picture
can be confounding since right-sided pathological disease, ssuring ulcers and
transmural colonic wall inammation are typically considered to be diagnostic
of CD, but they can also be found in acute and severe UC [62, 64–67].
5 Diagnosis of Ulcerative Colitis: Morphology and Histopathological Characteristics
69
The pathologist should avoid the category of “indeterminate colitis”
especially regarding preoperative biopsies. The European Consensus Guidelines
of 2013 proposed the denition of “IBD unclassied” when the patients “clearly
have inammatory bowel disease based on the clinical history but macroscopy
and/or endoscopic biopsies show no denitive features of ulcerative colitis or
Crohn’s disease” and underlines that this is a “temporary” denition of the
disease [6]. Every attempt should be made to achieve the correct diagnosis
since the treatments and surgical procedures used for UC and CD patients are
different. For the most part, UC patients undergo total colectomy associated with
pouch ileo-anal anastomosis (IPAA), a surgical procedure which is generally
contraindicated in patients with CD due to the high risk of complications [68].
Nevertheless, some studies have demonstrated that the majority of cases of
indeterminate colitis are actually cases of atypical/acute UC while 10–40%
have been retrospectively proven to be Crohn’s colitis [69–71]. Regardless of
the diagnosis, in this acute situation, an IPAA procedure has an overall 20% risk
of complications; this is intermediate between that of typical UC patients (10%)
and that of CD patients (30–40%) [72, 73].
Recently, however, studies have shown the presence of UC displaying CD-
like features, such as segmental disease, ssuring ulcers and appendiceal/right-
sided involvement in patients with left-sided UC [61]. On the other hand, some
studies have described the presence of CD limited only to the colon at the initial
presentation with particular attention to a sub-group of patients in which the
histological and clinical features mimic those of UC (ulcerative-like CD). In
these patients, the clinical manifestations consist of total/sub-total colitis (more
commonly left-sided disease in patients with ulcerative-like colitis), showing a
lower percentage of strictures and stenosis, and a younger age at presentation.
Histology shows supercial inammation limited to the mucosa and submucosa,
but other features more typical of CD can be found (i.e., perianal disease, skip
lesions, granulomas) [61, 74].
Another confusing situation is represented by the presence of so-called
“backwash ileitis” in acute and severe UC; the ileo-cecal valve allows the
retrograde ow of colonic content into the distal ileum inducing a condition of
inammation which may be erroneously regarded as distal ileitis in CD [75, 76].
The presence of patchy and mild inammation in the lamina propria (supercial
inammatory inltrate), together with some cryptitis and regenerative aspects,
are the histological features found, for the most part, without the presence of
other features characteristic of CD, i.e., moderate-severe inammatory inltrate
extending to the submucosa, granulomas, deep ulceration of the mucosa and
pyloric gland metaplasia.
In conclusion, there are several situations of atypical presentation of UC:
• discontinuity in UC due to long-standing colitis in response to topical
therapy or rectal sparing, in cases of good response to topical therapy or as
an initial presentation, mainly in children [74];
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