Gastrointestinal Pathology: Controversies in Non-neoplastic Biopsy Interpretation
Moderators: Robert D. Odze, Marie E. Robert, Donald A. Antonioli
Section 3 -
Diagnostic Problems in Biopsy Interpretation of Colorectal Inflammatory
Donald A. Antonioli
Beth Israel Deaconess Medical Center and Harvard Medical School,
The category of "idiopathic inflammatory bowel disease" (IBD) is classically defined
as being composed of two disease entities, ulcerative colitis (UC) and Crohn's disease (CD). Since the
etiology of neither condition is known, there is no gold standard for their diagnosis. As a result,
diagnosis is achieved by eliminating known causes of enteritis and colitis (such as ischemia, infections
and allergies) and by recognizing clinical, imaging, endoscopic and histologic features characteristic of
these two conditions. Although the classic forms of UC and CD are well described in the pathology
literature, recent advances in imaging techniques, the increasing use of upper gastrointestinal endoscopy
and colonoscopy to evaluate these conditions, and the use of diagnostic procedures early in the course of
disease have led to the recognition of deviations from typical aspects that may confound the diagnosis of
UC and CD and even raise the possibility of other types of inflammatory bowel disease. The findings of
classic UC and CD in the colon will be reviewed, but the emphasis will be on atypical and newly-described
aspects that may cause diagnostic difficulties in pediatric and adult patients.
Histology of the Normal Colonic Mucosa
Since most colonic inflammatory conditions are diagnosed in mucosal biopsy specimens,
the normal histology of this layer of the colonic wall will be briefly reviewed, with an emphasis on
findings that should not be overinterpreted as representing disease.
Crypt architecture and cells
The colonic crypts are arranged in parallel array within the lamina propria from the cecum
to the rectum. Throughout most of the colon, the crypts extend to the top of the muscularis mucosae;
however, in the rectum, the bases of crypts end a few millimeters above this landmark. In addition,
crypts in the distal rectum and upper anal canal may be dilated or slightly irregular in contour and be
accompanied by fibres of smooth muscle extending into the lamina propria from the muscularis mucosae.
These findings, perhaps due to mucosal prolapse or prior minor injury, are non-specific and should not be
overinterpreted as evidence of chronic inactive colitis, particularly in young patients without a
previous history of IBD. A final normal feature is the presence of crypts having an inverted-"V"
appearance, with the apex of the "V" at the luminal surface of the mucosa. This configuration is a
manifestation of dividing crypts and contrasts with the irregular branching typical of chronic colitis
The crypts are lined predominantly by enterocytes and goblet mucous cells. Endocrine
cells and Paneth cells are located at the base of the crypts, and a small number of intraepithelial
lymphocytes may be identified along the length of the crypt
Paneth cells normally are present
only from the cecum to the proximal transverse colon; their identification distal to this point is
considered a manifestation of metaplasia secondary to prior injury such as involvement by IBD .
However, a small number of Paneth cells is sometimes identified in otherwise completely normal mucosa of
the rectosigmoid colon in children. As in the case of the mild architectural abnormalities in the rectum
described earlier, these distal Paneth cells are most likely the result of minor prior injury and, in
isolation, should not be used as evidence of IBD unless there are supportive clinical data and/or
abnormalities in specimens from more proximal parts of the colon.
Cells of the lamina propria
The lamina propria contains lymphocytes and plasma cells throughout the colon;
however, there is typically a decrease in their number from the cecum to the rectum. In addition, these
mononuclear cells, as well as macrophages, are concentrated in the upper half of the lamina propria
except in the cecum and proximal right colon, where they occupy the full thickness of this layer
Recognition of the full-thickness extent and greater density of inflammatory cells in the lamina propria
of the normal cecum/proximal right colon will prevent overinterpretation of a biopsy specimen from this
area as "chronic colitis", particularly Crohn's disease, when more distal specimens are unremarkable .
In the resolving phase of an acute self-limited colitis (such as bacterial-induced
injury), mononuclear inflammatory cells are increased in the lamina propria, but hallmarks of chronic
colitis, such as crypt architectural distortion and basal plasmacytosis proximal to the cecum, are absent
As a rule, apparently increased lamina propria mononuclear inflammation in isolation should be
interpreted with caution .
It may be a normal finding (cecum), represent a resolving acute injury,
may be the result of geographic variation in the "normal" number of such cells, or may be an artifact due
to abnormally thick sections. Overinterpretation of this minor change as "chronic colitis" or
"non-specific chronic inflammation" may result in unnecessary procedures (e.g., imaging studies),
heightened anxiety about IBD, or even empiric therapy for UC or CD
Although neutrophils are completely absent or identified only in small numbers in normal
colonic mucosa, eosinophils are consistently present . Interpretation of the range of normal numbers
and the significance of the eosinophils, however, remain major problems in evaluating colonic mucosal
biopsies. Limited published data suggest that the "normal" number of eosinophils in children varies in
different parts of the colon: The largest number is in the cecum, with a gradient of decreasing numbers
to the rectum. In addition, the numbers is various segments of the colon may vary in different parts of
the United States
Finally, eosinophils are increased as part of the overall inflammatory
cellular response to injury, especially in chronic forms of colitis.
Given these difficulties, when should eosinophils be interpreted as "abnormally present"?
Criteria for suggesting an abnormality (allergic condition; drug reaction) include (1) a large number of
eosinophils in mucosal biopsy specimens from throughout the colon unaccompanied by an increase in other
inflammatory cell types and (2) eosinophils as the sole or predominant inflammatory cell in foci of
cryptitis and crypt abscesses. In infants younger than six months of age ultimately shown to have
allergic proctitis, eosinophilic cryptitis/crypt abscesses and greater than 60 eosinophils per 10
high-power fields in the lamina propria are criteria that distinguish this condition from other acute
colitides such as infections . These criteria for distal allergic colitis, however, have not been
validated in older infants and children. Occasional eosinophils infiltrating the surface epithelium are
a common finding, the significance of which in isolation is unclear .
Lymphoid nodules, with or without follicular centers, are another frequent and normal
finding in the colonic mucosa. The nodules and adjacent crypts form so-called "lymphoglandular
complexes". The crypts at the periphery of the complexes are typically splayed apart. These complexes
are sites of antigen presentation and processing; as a result, the surface epithelium overlying the
complex is mucin-depleted and contains increased intraepithelial lymphocytes. The splayed crypts also
exhibit goblet cell mucin depletion, epithelial cell damage and increased intraepithelial inflammation
(lymphocytes; neutrophils). These changes in lymphoglandular complexes should not be overinterpreted in
isolation as "focal active colitis". In problematic cases, examining multiple levels through the biopsy
specimen can be helpful. In lymphoglandular complexes, the crypts, although splayed, do not exhibit
irregular branching or crypt destruction by active inflammation. Detection of the latter features
supports the diagnosis of a true inflammatory condition
Senescent colonic epithelial cells are eliminated at the mucosal surface either by
extrusion into the lumen or by apoptosis and removal within the subjacent lamina propria. Therefore,
some apoptotic cellular debris may be normally found in the superficial lamina propria . In contrast,
apoptosis of more than a rare epithelial cell at the base of the crypt could be an iatrogenic effect of
certain bowel cleansing agents (see next section), but it could also represent a pathologic finding
secondary to immunodeficiency, certain infections, or graft-versus-host disease.
Artifacts in Colonic Mucosal Biopsies that should not be Confused with Disease
Effects caused by the endoscopic procedure
The colonoscope itself may cause minor injury to the mucosa. At colonoscopy, the
entire colon (and, often, the terminal ileum) are first examined, then biopsy specimens obtained as the
last part of the procedure. As a result, there has been sufficient time for the endoscope to irritate
the mucosa. Therefore, vascular congestion and edema/fresh hemorrhage in the lamina propria when
unaccompanied by epithelial damage or an inflammatory infiltrate are best interpreted as iatrogenic in
origin. These changes are most often identified in the distal colon
During colonoscopy, air is introduced to dilate the colon. If the colonoscope causes
defects in the mucosal surface, or if mucosal erosions or ulcers are already present, air can enter the
lamina propria and produce irregular clear spaces and secondary crypt architectural irregularity. This
phenomenon has been termed "pseudolipomatosis" because of its superficial resemblance to adipocytes in
the lamina propria. Distinction from the latter cell type is easily made by recognizing that the spaces
are irregular and lack cell membranes or peripherally located nuclei .
Effects of colonic cleansing procedures
A variety of preparations have been used to cleanse the colon for endoscopy. Oral
non-absorbable lavage agents and isotonic saline enemas are relatively gentle, and do not damage the
colonic mucosa . The process may be prolonged, however, resulting in poor compliance and inadequate
cleansing. Therefore, a more vigorous and shorter cleansing protocol using sodium phosphate (taken
orally or in the form of enemas), oral magnesium citrate and/or bisacodyl enemas and suppositories may be
favored. These agents may produce mucosal lesions.
Sodium phosphate preparations (and, to a lesser extent, magnesium citrate) may produce
aphthous ulcers. At endoscopy, these are recognized as discrete, sharply defined lesions, 1 to 3 mm in
diameter, surrounded by an erythematous halo. Most often detected in the rectosigmoid, they are
identified in a background of otherwise unremarkable mucosa with a prevalence of 6% to 24% in recent
At histologic examination, the correlate of the aphthous ulcer is either an erosion
overlying a lymphoid aggregate or a focal, often superficial, ischemic-type lesion with mucin-depleted
crypts, modest active inflammation and fibrinous exudates . In a patient being evaluated for the
cause of diarrhea, these findings raise the differential diagnosis of infectious colitis, drug-related
(e.g., NSAID) injury and low-grade IBD, especially Crohn's disease. Integration of all clinical data
plus recognition of the possible iatrogenic origin of aphthous ulcers should permit correct
categorization of the findings.
Oral sodium phosphate preparations may also induce increased epithelial cell proliferation
and mild abnormalities at the base of crypts
The latter takes the form of apoptosis and a
modest infiltrate of neutrophils (mild cryptitis) unaccompanied by crypt destruction (i.e., crypt abscess
formation), increased mononuclear inflammation in the surrounding lamina propria, or crypt architectural
In clinical practice, this finding raises a dilemma: is it iatrogenic or a
manifestation of disease? Such minimal deviations from normal should be interpreted with caution and
categorized as "non-specific" in nature rather than an unequivocally disease-related "focal active
colitis" with all the implications inherent in the latter diagnosis . As discussed by Xin and
colleagues, focal active colitis that is likely caused by disease is characterized by more florid
cryptitis (with or without crypt abscesses) surrounded by an increased concentration of lymphocytes and
macrophages (or even mucin granulomas] in the lamina propria . The significance of this type of
focal active colitis in isolation will be discussed in greater detail later.
Effects due to endoscope cleaning and the biopsy procedure
A variety of substances have been used to disinfect colonoscopes. If these cleansing
agents are incompletely removed prior to the next use of the endoscope, the residual disinfectant may
injure the mucosa. For example, glutaraldehyde will produce an acute ischemic colitis, and hydrogen
peroxide may induce pseudolipomatosis
Fortunately, recognition of these possible
complications has resulted in a marked reduction in their incidence due to more thorough cleaning of
Finally, obtaining and processing the biopsy specimens may cause problems that may have an
impact on accurate interpretation of the tissue
If the muscularis mucosae is not included in the
specimen, the crypts may be artifactually separated from one another and distorted, thus giving a false
impression of architectural features of chronic colitis. Tissue at the edge of biopsy specimens that has
been compressed by forceps may give the false impression of atrophy and fibrosis because crypts have been
crushed or extruded from the lamina propria. Findings limited to distorted edges of specimens,
therefore, should be interpreted with caution. Detection of active inflammation and/or granulation
tissue in these locations is helpful in determining that the changes are due to intrinsic disease rather
Histologic Features of Mucosal Colitis
A major consideration in evaluating colonic mucosal biopsy specimens is the
distinction of an acute self-limited process from idiopathic inflammatory bowel disease, given the
psychological and medical impacts of the latter group of diagnoses. The problem is compounded by the
fact that the usual cases of self-limited colitis (due, for example, to infections and allergies) are
diagnosed by a combination of clinical, epidemiological and microbiological findings. As a result, it is
only the unusual cases with a prolonged clinical course, atypical laboratory findings and/or negative
infectious workups that eventuate in colonoscopy. Biopsy specimens from these patients may contain
indeterminate findings that are difficult to categorize with certainty. The histologic features of
active and chronic colitis in mucosal specimens will be reviewed, followed by a brief discussion of the
distinction between IBD and an acute self-limited disease.
Activity is characteristic of both the acute self-limited colitides and IBD. The
features of activity are well known: neutrophils in the lamina propria, cryptitis, crypt abscesses,
erosions and ulcers. Neutrophils confined to the endothelial layer of small vessels (marginated
neutrophils) may be the result of the bowel preparation or the colonoscopic procedure itself; therefore,
they are not included as a manifestation of active colitis. These findings may be focal or diffuse and,
in my opinion, their number and distribution cannot reliably be used to distinguish infectious colitis
from IBD. However, inflammatory pseudomembranes, heightened eosinophilia of the lamina propria, and
mucin-depleted crypts associated with a relative paucity of neutrophils are findings most suggestive of
an ischemic injury or infection with toxin-producing bacteria such as Clostridium difficile or
enterohemorrhagic E. coli
The histologic features of chronic colitis are summarized in Table 1. As discussed
earlier, determination of increased mononuclear inflammation in the lamina propria is the most subjective
and probably the least reliable criterion of chronic injury
Precision in diagnosis is important
because the pathologist's diagnosis of "increased mononuclear inflammation" or "nonspecific chronic
inflammation" in colonic mucosa may be translated by the clinicians to mean IBD . In most cases of
IBD, other features to support chronicity will be present, particularly if multiple specimens are
submitted. Crypt atrophy refers to a decrease in the length and/or number of crypts and crypt distortion
to abnormalities in shape; villiform surface change presumably develops secondary to crypt distortion and
prominent surface regeneration. Lymphoid aggregates confined to the base of the lamina propria, basal
plasma cells in the lamina propria distal to the cecum, and Paneth cells distal to the hepatic flexure
are all useful hallmarks of chronic injury
Basal plasmacytosis distal to the cecum is an
excellent marker of chronicity, but may be absent in the early phase of IBD and may diminish over time in
inactive disease .
These changes, however, are not synonymous with IBD; they may develop with the healing of
any severe mucosal injury such as that due to ischemia or chronic infections (e.g., schistosomiasis). As
a result, the diagnosis of IBD must be supported by appropriate clinical, imaging and endoscopic
findings. If the pathologist has no information about the patient, it is probably best to diagnose such
biopsy specimens descriptively as "findings compatible with healed injury" rather than "chronic inactive
colitis", since the latter phase will typically be interpreted as IBD by the clinicians. As with active
colitis, the changes of chronic injury may be focal or diffuse within a specimen or among specimens.
Also, finding only a single feature listed in Table 1 is sufficient to support a diagnosis of chronic
injury. Multiple abnormalities may be infrequent in IBD, particularly in the earlier phases of disease
and/or with limited sampling of the mucosa .
In mucosal biopsy specimens of both acute self-limited colitis and IBD, active and chronic
inflammation and crypt damage may be focal or diffuse within the specimen. In IBD, active inflammation
is distributed throughout the lamina propria whereas it tends to be limited to the upper half of the
lamina propria in the self-limited conditions ; however, this feature may not be evident if only a
single specimen is available for review. The major discriminator between acute non-relapsing colitis and
IBD is the presence of features of chronicity in initial or follow-up biopsy specimens
established chronicity, clinicians will correlate this finding with the remainder of the patient's
profile to exclude known causes of chronic injury (such as Yersinia infections) before establishing a
diagnosis of IBD.
Inflammatory Bowel Disease
The classic features of UC and colonic CD will be reviewed, followed by a discussion
of newer and, in some cases, controversial findings that may obscure or delay the correct diagnosis.
Accurate distinction of these two conditions has become increasingly important for several reasons.
Surgery is classically considered curative for UC but not for CD. Patients with UC but not CD are
candidates for creation of ileoanal pouches. Finally, specific therapies are now becoming available for
these diseases; for example, use of imfliximab ( a chimeric monoclonal antibody to tumor necrosis factor
alpha) is a
successful management modality in patients with CD
Both UC and CD develop more commonly in Caucasians than in other races, but they have an
equal sex distribution and are common causes of colitis in young patients. Approximately 30% of cases
are diagnosed before the age of 25 years; about 10% of all cases develop before 15 years of age .
The clinical findings of pediatric UC and CD are, in general, similar to those in adults (e.g., varying
combinations of diarrhea, rectal bleeding, abdominal pain, weight loss, fever and anemia] . However,
features of IBD unique to pediatric patients are growth retardation and delayed puberty. Growth
retardation is twice as prevalent in CD as compared to UC, is related more to disease activity than to
corticosteroid therapy and is particularly associated with ileal disease
IBD is characterized by exacerbations and remissions, but the natural histories of UC
and CD are somewhat different . At first presentation, UC is characterized by more extensive
endoscopic and histologic disease in children than adults. In recent series, pancolitis has been
documented in up to 50% of children compared to 8% to 20% of adults; conversely, proctitis or localized
left-sided disease is present in approximately 25% of children but in up to half of adults at initial
Over time, progression to more extensive disease, including pancolitis, occurs in
50% to 70% of children with initially limited disease (compared to 10% to 30% of adults), especially
those with an early age of onset and/or severe disease
At least one relapse will have been
documented in about 90% of pediatric UC patients after 10 years of follow-up, and approximately one-third
will have had a colectomy, chiefly because of unresponsiveness to medical therapy, prepubertal growth
failure or fulminant colitis ("toxic megacolon")
. Since by current definition UC is a disease
confined to the colon, proctocolectomy is curative, and the patients are excellent candidates for
creation of an ileoanal pouch.
In contrast, CD first presents as small bowel disease in 40% of patients, as ileocolitis
in 30% and colitis in 30%. Early surgery is much more common than in UC: up to 50% of young patients
with CD will have surgery for complications of the disease within 5 years of diagnosis and up to 90% will
have an operation within 15 years . Surgery is performed for reasons like those for UC and for
additional CD-related indications including treatment of intestinal fistulas and abscesses, gut
obstruction and intractable perianal disease . Since CD is a condition that may involve the entire
gastrointestinal tract, surgery is limited to removal of clinically significant lesions and is usually
not curative. Asymptomatic recurrences have been documented in up to 70% of patients within one year of
surgery, and symptomatic recurrent disease is common within five years. Recurrences typically occur
proximal to sites of previous anastomoses or ostomies. Patients with CD are usually not considered good
candidates for ileoanal pouches because of the risk of recurrent disease in the pouch
The pathologic features of UC and CD are identical in children and adults and have
been codified in many recent reviews
The distinguishing features of classic UC and colonic
CD are summarized in Table 2.
Classic UC begins in the rectum and, if it progresses, does so in a continuous retrograde
fashion. Although by definition UC is confined to the colon, it may be accompanied by superficial mild
non-specific mucosal inflammation in the terminal ileum ("backwash ileitis") (see later discussion). At
microscopy, the inflammatory process in UC is superficial (confined to the mucosa and submucosa) and is
diffuse within the mucosa of the involved segment
In contrast, colonic CD typically begins as localized right-sided or multifocal disease
and progresses in a patchy fashion, with "skip areas" of uninvolved mucosa. Characteristic histologic
findings include granulomas, deep or transmural inflammation (often characterized by the presence of
lymphoid aggregates in the muscularis propria and/or at the muscularis/serosal interface), deep mural
fissures or fistulas, and, in a minority of patients, a necrotizing or giant cell vasculitis. In the
mucosa, the inflammatory lesions are often focal rather than diffuse
Although diagnostically important, granulomas are not invariably present in otherwise
typical cases of Crohn's colitis. Even with serial sectioning, granulomas are detected in only
approximately one-third of mucosal biopsy specimens from patients with Crohn's colitis. However,
granulomas have been found in 56% to 82% of CD colonic resections. This higher yield is related to the
greater amount of tissue available for examination and to the fact that the submucosa is the most common
site for granuloma formation
In children with Crohn's colitis, granulomas tend to be more
common in the rectosigmoid than elsewhere in the colon. Also, prospective data suggest that the
prevalence of granulomas decreases with increasing duration of disease, perhaps due to the effects of
medical therapy; thus, granulomas may be more often detected in children than in adults .
The sarcoid-like granulomas characteristic of CD must be distinguished from foreign
body-type granulomas and from the non-specific mucin granulomas that may be present in both UC and CD.
Mucin granulomas are typically adjacent to or in direct contact with inflamed or ruptured crypts, tend to
be poorly formed and often contain giant cells
Their true nature can be determined by detection
of intracytoplasmic mucin using stains such as the alcian blue-PAS with diastase pretreatment. Also
characteristic of CD are so-called "microgranulomas": small collections of macrophages in the lamina
propria away from damaged glands or crypts. They can be highlighted by positive immunohistochemical
staining with CD68 .
In mucosal biopsy specimens from untreated patients, the presence of non-mucin granulomas
or microgranulomas and focality of colitis are the best discriminators for CD
colitis in the rectosigmoid in children, however, should be interpreted with caution since it may be
present at the onset of UC in this population (see later discussion). In adults, villiform surface
change, crypt architectural distortion and crypt epithelial mucin depletion are said to be more common in
UC than CD
but I have not found these to be particularly helpful distinguishing characteristics
in pediatric IBD. The pathologist can offer the largest amount of useful information if, at the onset of
pediatric IBD, colonoscopy (rather than flexible sigmoidoscopy) with protocol sampling of even
endoscopically unremarkable mucosa is performed. Of 42 pediatric patients ultimately proven to have IBD
in one recent study, 10 had normal rectosigmoid biopsy specimens. Additional, more proximal, sampling
confirmed a diagnosis of CD in 60%; the remaining four patients were later classified as either UC or
indeterminate colitis .
Atypical Features and Controversial Issues in the Diagnosis of IBD
Unusual features in rectosigmoid mucosal biopsies at the onset of pediatric UC
At first presentation and before therapy, the majority of adult patients with UC
(>90%) will have diffuse active colitis, usually with features of chronicity, in rectosigmoid mucosal
Initial rectosigmoid specimens in children ultimately shown to have UC, however,
demonstrate focal colitis and/or the absence of chronic changes in approximately one-third of patients
and are completely normal in 4% to 8%
These atypical findings are not specifically related to the patients' ages at the onset of
colitis (although they are predominantly found in patients younger than 10 years), the duration of
symptoms before endoscopy, the symptoms themselves, or the ultimate evolution of UC (i.e., development of
diffuse distal disease, proximal progression over time)
The reasons for these findings are
unknown. One suggestion is that children may be evaluated earlier in the course of UC than adults
however, it is also clear that changes of chronicity may develop within a few weeks or months
of symptom onset
This presentation of UC with focal disease and a paucity or lack of features of chronicity
in pediatric patients raises several diagnostic possibilities and stresses the need for a complete
evaluation of the patient. First, it should be recognized that ulcerative colitis is not excluded
by these findings
Second, they may represent a non-relapsing, infectious-type colitis,
which often is patchy and may have rectal sparing 44). Crohn's disease also enters the differential
diagnosis; detection of focal proximal colitis, granulomas, ileal disease or perianal disease would
support that diagnosis. Finally, allergic conditions in children typically exhibit focal colitis but can
be excluded by the clinical workup and the absence of numerous eosinophils in tissue specimens ;
also, in the follow-up of allergic colitis (as of most colonic bacterial infections), mucosal healing is
characterized by reversion to a normal architecture with minimal or no features of chronic injury
The predictive value of focal active colitis for development or recognition of CD once the
confounding conditions discussed in the preceding paragraph have been eliminated has recently been
examined. In a cohort of 29 pediatric patients with focal active colitis, 8 (28%) developed CD; most of
the remainder had either infectious colitis or remained idiopathic . In contrast, focal active
colitis in adults evolved into a diagnosis of CD over time in fewer than 15% of patients
possible reason for the difference in outcome between the two populations is that unlike the case in
adults, colonoscopy in children is typically performed for evaluation of abdominal pain, diarrhea or
hematochezia rather than cancer surveillance, thus creating a bias towards detection of inflammatory
diseases. As in children, many cases of focal active colitis (particularly those with minor
abnormalities) in adults are likely secondary to effects of bowel cleansing agents such as sodium
Effects of medical therapy on the histology of UC in colonic mucosal biopsy specimens
The classic teaching has been that quiescent UC heals with fixed morphologic changes that
permit continued recognition of the colonic mucosa as injured. In 1993, however, Odze and colleagues
demonstrated that medical therapy of left-sided UC with topical 5-aminosalycylic acid caused reversion of
colonic mucosa to a normal appearance in 64% of patients . Since that time, several authors have
confirmed and extended this observation. The results of these studies document that in patients with
established extensive or pancolitis receiving contemporary medical therapy, histologic diffuse disease
has become focal within the colon in up to 54% of patients and the rectum has become unremarkable in up
to 34% on one or more occasions during follow-up
These results were not related to the
duration of disease or the type of therapy employed (systemic, topical, et cetera)
Rectal sparing and focal colitis are typical of CD. Thus, to avoid diagnostic confusion,
it is important to know the medication history of patients with presumed UC in whom such findings are
documented. In both children and adults with chronic IBD, unfortunately, such information is often not
available at the time of biopsy specimen interpretation. In this situation and in the absence of
granulomas, focality and rectal sparing should be described but not interpreted, with the comment that
prior medical therapy may have affected the histologic findings.
Appendiceal involvement as a "skip lesion" in UC
In several retrospective studies of colectomy specimens, the authors have attempted to
determine the prevalence of appendiceal inflammation in patients with UC of various extents. Appendiceal
involvement by UC must be distinguished from incidental acute appendicitis and has been defined as a
lesion confined to the mucosa with architectural and cellular features of chronicity that may or may not
be accompanied by activity . Not unexpectedly, the prevalence of chronic appendicitis in patients
with pancolitis (whether due to UC or CD) is high, being in the range of approximately 60% of cases
Of greater interest is the prevalence of this finding in UC patients with less than
pancolitis (i.e., with at least cecal/right-sided sparing in the colectomy specimen). In this group,
appendicitis has been reported in 15% to almost 100% of pediatric and adult patients, giving rise to the
notion of appendicitis as a "skip lesion" in otherwise classic UC
In a follow-up study of
ileoanal anastomoses performed on patients with appendicitis as a presumed "skip lesion" of UC, there
were no cases with outcomes suggesting that a diagnosis of CD had been missed .
A criticism of these studies relates to their retrospective nature
of the cecum and right colon has not been performed in a standardized fashion, so that the extent of
sampling has been either limited or unknown. Also, information about prior medical therapy and its
possible effects on damaged mucosa has not been provided. Thus, whether or not this portion of the colon
has been truly "normal" at all times is debatable. However, appendiceal involvement has been documented
in some cases that clearly represent otherwise localized left-sided UC . At present, an apparent
appendiceal "skip lesion" should not be construed as evidence of CD without additional supportive
clinical, imaging and/or histologic data.
Cecal periappendiceal orifice inflammation as a "skip lesion" in UC
Another proposed "skip lesion" of UC is endoscopic and histologic colitis confined to the
periappendiceal cecal mucosa in patients with left-sided UC. Strict criteria to exclude CD are needed to
support this interpretation: no granulomas, perianal disease, ileal disease or other documented colonic
skip lesions should be present . The gross periappendiceal mucosal endoscopic findings vary from
erythema and tissue granularity and friability to erosions and ulcers .
In several recent prospective endoscopic and biopsy surveys of patients with left-sided
UC, the prevalence of periappendiceal localized colitis has varied from 54% to 75%
examined from the colon between the left side and the periappendiceal area were normal in most instances
but on occasion demonstrated microscopic foci of colitis in endoscopically normal mucosa .
In the study by Yang and colleagues, the prevalence of focal periappendiceal disease was the same in
patients with and without prior medical therapy , and in an 8-year follow-up of their patients,
d'Haens et al detected no features of CD . Although there are some issues with the interpretation of
the histology in some of these series, the weight of evidence from these prospective studies supports the
idea that the endoscopic periappendiceal cecal patch in children and adults does represent a skip lesion
of UC and in isolation, therefore, should not be interpreted as evidence of CD.
The conundrum of backwash ileitis in UC
A perennial problem in IBD at the imaging, endoscopic and pathologic levels is the
separation of ileitis due to CD from non-specific terminal ileal inflammation in patients with UC
("backwash ileitis"). Part of the problem relates to the lack of a modern consensus-derived gross and
microscopic definition of backwash ileitis . Also, the pathogenesis of the changes is unclear:
originally though to represent a result of reflux of colonic contents into the terminal ileum, backwash
ileitis is now felt to be a primary ileal process . A contemporary provisional diagnosis of backwash
ileitis in UC has been provided by Heuschen et al: a 5.0 cm or longer segment of terminal ileal mucosal
inflammation with no granulomas. In resection specimens, no mural inflammation should be identified
Using this definition, backwash ileitis was identified in colectomy specimens in 22% of
predominantly adult patients with pancolitis and in none of those with localized left-sided disease; in
this cohort, it predicted an increased risk of colorectal carcinoma . In a recent pediatric series,
backwash ileitis (not precisely defined) was identified in 22% of colectomy specimens with pancolitis.
Its presence did not predict any excess of problems with ileoanal pouches (such as refractory pouchitis
and pouch failure)
(29). A combined imaging, endoscopic and histologic study of backwash ileitis (not
published in 2003 gave a prevalence of 39% in 18 pediatric patients with UC . In
the absence of a standardized definition, such studies do not contribute to our understanding of this
condition and its precise relation to IBD.
Upper gastrointestinal tract involvement in inflammatory bowel disease
Upper gastrointestinal inflammatory lesions of the esophagus, stomach, and/or duodenum in
patients with CD have been well described in the literature. Among the possible findings, granulomas,
focal duodenitis and focal gastritis in mucosal biopsy specimens are most closely associated with or are
the best predictors of colonic CD
Focal (or "focally enhanced") gastritis is defined as a
localized and sharply defined area of gastritis, with active and chronic inflammation and gland injury,
that is surrounded by normal mucosa and is easily identified at low-power inspection
In contemporary medical practice, upper gastrointestinal endoscopy with biopsy in often
performed before the institution of therapy in pediatric patients with newly diagnosed colonic IBD (both
UC and CD). This procedure has lead to some interesting findings. The protocols and the extent of
histologic sampling have not been uniform in these studies, but most are prospective in nature.
Although the gross and microscopic abnormalities are not always described in detail, an
intriguing finding in these studies is that the overall prevalence of endoscopic and histologic
inflammatory lesions in the esophagus, stomach and duodenum is roughly equal in patients with newly
diagnosed and typical colonic UC and CD. When known causes of such inflammation (such as reflux
esophagitis and Helicobacter pylori-associated gastritis) are excluded, there still remains a high
prevalence of non-specific lesions, particularly H. pylori-negative diffuse gastritis, in both conditions
Whether this gastritis is incidental or related to IBD is unknown, but the important point is
that the mere presence of upper gastrointestinal inflammatory lesions can no longer be used to
automatically categorize a patient as having CD.
The presence of granulomas in upper intestinal mucosal biopsies is highly specific for a
diagnosis of CD. Their prevalence has varied from 25% to 60% in recent pediatric series, and they are
most often found in gastric mucosa
In contrast, they are much less common in the stomach of
adults with CD (a prevalence of only 5% in the study of Parente and colleagues)
. In children, they
are often detected in gastric and duodenal specimens even when synchronous colonic mucosal biopsies are
negative for this finding
Although focal gastritis can be seen in a minority of UC patients (8% to 12%) and non-IBD
controls (19%), it is more common in patients with CD (43% to 52%) with a calculated positive predictive
value for colonic CD of 70% to 80%
All examples of gastritis, whether focal or diffuse, should
be carefully evaluated to exclude Helicobacter infections as well as allergic and chemical-type
injuries. As in the colon, "IBD-associated gastritis" is a diagnosis of exclusion.
In summary, upper endoscopy can be helpful in classifying colonic IBD. Biopsy specimens
should be obtained from grossly normal as well as abnormal mucosa to detect treatable localized
conditions, such as H. pylori-associated gastritis, and to detect granulomas and focal gastritis
In one recent pediatric study of the stomach in IBD, 87% of patients had various
inflammatory changes in antral biopsies despite the fact that only 38% had endoscopically detectable
mucosal changes (chiefly erythema and small ulcers)
. The recent recognition that diffuse,
non-Helicobacter chronic gastritis is common in patients with classic UC raises an interesting question:
Is it a manifestation of UC? Perhaps adding credence to this possibility is a small number of pediatric
and adult cases of "ulcerative enteritis" developing in patients with classic UC, typically after
colectomy for treatment of the colitis. In these patients, as recently reviewed by Rubenstein and
colleagues, the enteritis is diffuse, confined to the mucosa, lacks granulomas, and responds to the usual
medical therapies for UC .
Clarification of the exact nature of this enteritis (as well as the
non-specific gastritis) will require additional prospective studies.
Approximately 5% to 10% of cases of IBD at some point in their course cannot be accurately
classified as UC on CD based on evaluation of mucosal biopsy specimens or even after examination of
colectomies. Such cases have been categorized as "indeterminate colitis", with the implication that many
( but not all)
of these cases will declare their true identity over time
diagnosis may relate to a lack of or insufficient clinical, imaging or endoscopic data, or, in biopsy
specimens, to issues previously discussed. Among patients with indeterminate colitis, approximately 60%
are ultimately reclassified as UC or CD; however, the others remain diagnostically obscure even after
prolonged follow-up . Reclassified cases turn out to be UC more often than
In resection specimens, the major causes of diagnostic uncertainty are those cases
clinically felt to be UC that have atypical gross features, such as deep-fissuring ulcers, suggestive of
CD. This scenario develops in patients with fulminant colitis in whom bowel dilatation and subsequent
ischemic injury are superimposed on the underlying IBD. Microscopically, deep mural inflammation is
present, often with ulcers and fissures extending into the muscularis propria. Acute ischemic damage
features marked vascular congestion, myocytolysis, and active inflammation accompanying the deep ulcers,
all findings reminiscent of CD. In fulminant colitis, the best features to support a diagnosis of CD
specifically are granulomas and/or transmural lymphoid nodules away from the areas of deep ulceration
In the absence of these features and mural ileal disease, such cases can be provisionally
classified as indeterminate colitis. As noted earlier, subsequent evaluation will clarify the true
nature of the disease in most cases
Serologic testing (p-ANCA; ASCA} has not yet proven to be
especially helpful in sorting out cases of indeterminate colitis
Histologic Features of Chronic Colitis
- Increased mononuclear inflammation in the lamina propria
- Crypt distortion and atrophy
- Surface villiform change
- Basal plasmacytosis and lymphoid aggregates
- Paneth cell metaplasia (distal colon)
Atypical Features and Controversial Issues in Pediatric
and Adult Inflammatory Bowel Disease
- Atypical findings in rectosigmoid mucosal biopsies at the onset of ulcerative colitis
- Effects of medical therapy on the histology of ulcerative colitis
- Appendiceal involvement as a "skip lesion" in ulcerative colitis
- Periappendiceal cecal inflammation as a "skip lesion" in ulcerative colitis
- Backwash ileitis
- Upper gastrointestinal involvement in Crohn's disease and ulcerative colitis
- Indeterminate colitis
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