GASTROINTESTINAL SURGICAL BIOPSY INTERPRETATION

Brian Wilcock, D.V.M., Ph.D.

Introduction:
The introduction of endoscopic techniques suitable for use in almost all sizes of dogs or cats has been nothing short
of a revolution in clinical medicine and in surgical pathology. Previously, the use of gastrointestinal biopsies had
been limited to those instances in which there was radiographic or other physical evidence of an intestinal mass, or
intestinal malfunction of such severity that the danger and expense of exploratory surgery and full thickness
intestinal biopsies could be justified. Noninvasive biopsy procedures were limited to the use of rigid proctoscopes
to obtain mucosal biopsies from the distal portion of descending colon. Now, the widespread availability of suitable
fiber optic flexible endoscopes has reached beyond institutions into many private practices even in smaller
communities, so that pathologists everywhere can anticipate receiving endoscopic mucosal biopsies from stomach,
duodenum, ileum, and colon.
The guidelines for interpreting intestinal biopsies are similar to those used in the “pattern analysis” approach to skin
biopsy. The assumption is that the types of leucocytes, the location of the leucocytes, and the nature of the epithelial
changes will give useful information as to the specific nature of the intestinal disease. In the case of skin biopsy, the
credibility of this approach has been greatly aided by the correlation of the histologic pattern to the subsequent
response to therapy, or to the demonstration of specific etiologic agents such as mites, yeast, or bacteria.
Unfortunately, such a system for improving the reliability of intestinal biopsy interpretation has not been
forthcoming. Part of the reason is that few of the gastrointestinal disorders in dogs or cats have an infectious cause,
which is in sharp contrast to gastrointestinal diseases in farm animals. Also, owners often are unwilling to try the
“response to specific therapy” approach to validating a histologic:clinical correlation because of the serious
consequences of continued diarrhea or vomiting on the household furnishings- let alone on the patient! Thus,
intestinal diseases tend to be treated simultaneously with such things as hypoallergenic diets, intestinal motility
modifiers, bulking agents, various anti-inflammatory drugs, and even antibiotics. With a few exceptions, intestinal
biopsy in its current form is most useful in distinguishing inflammatory disease from neoplasia, and in establishing
that there is indeed a morphologic lesion within the intestine that is capable of causing vomiting or diarrhoea. Only
occasionally do we encounter a lesion of such specificity that it typifies a particular named disease (such as
histiocytic ulcerative colitis of boxers), and even more rarely can we demonstrate a causal infectious agent.
The interpretation of gastrointestinal biopsies is very much dependant on understanding of the general pathology of
the bowel. Understanding regional variation in anatomy, mechanisms of intestinal injury and repair, and the
fundamentals of intestinal immunopathology is essential for adequate biopsy interpretation. Some of the best review
articles and textbooks dealing with these issues are listed below, and in this text we will only touch upon some of the
most important issues that one must master before interpreting gastrointestinal biopsies.
The correlation between the macroscopic observations (usually via endoscopy) and the subsequent histologic lesions
varies with the experience of the observers (in both cases!). For example, endoscopic observation of mucosal
hyperemia or increased granularity is confirmed by histology in less than half of the cases. In contrast, endoscopic
observation of normal mucosa is almost always in agreement with subsequent histologic observations, as is
observation of more severe mucosal lesions such as outright haemorrhage or ulceration.

THE STOMACH
Gastric biopsies are most often submitted from animals with a history persistent vomiting, from animals with a
radiographically evident gastric mass, or from animals with any kind of persistent digestive upset in which the
gastric biopsies are simply part of a general endoscopic sampling of all accessible parts of the gastrointestinal tract.
Even though vomiting may not be part of the recent clinical history, observations made in the stomach are frequently
helpful in adding credibility to the subjective interpretations of altered mucosal structures in small intestine or colon.
Because gastric lesions are very often limited to one region of stomach, it is critical that multiple samples from
fundus, body, and pyloric region be taken. It is also critical that the pathologist understand the dramatic regional

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differences in normal mucosal histology, including differences in the amount of connective tissue, the magnitude
and type of glandular mass, and differences in overall mucosal thickness.
Our ability to interpret gastric biopsies is still quite rudimentary, but in truth the situation in human gastrointestinal
pathology is not much better. In most instances we can only describe the microscopic alterations, if any, in each of
the biopsies. Defined clinical syndromes, or specific etiologic diseases, are rarely diagnosed. The occasional
observation of infectious agents like Helicobacter, Cryptosporidium, Chlamydia, or various nematodes usually is of
unknown significance because there is as yet very little convincing evidence to link the observation of these agents
with clinical disease or even with histologic lesions.

The classification that we use is based entirely on the general pathology of the gastric mucosa. The most
controversial part of that classification is also the most prevalent, namely the entity of chronic mucosal gastritis. It
is defined by an increase in mononuclear leucocytes, with or without increased eosinophils, within the superficial
lamina propria. Mucosal atrophy and fibrosis are frequent, but not invariable, accompaniments. Conversely, we
occasionally see mucosal atrophy and/or fibrosis without accompanying inflammation, although we are sceptical
about whether these events ever occur in isolation from a previous inflammatory disease. Better-defined entities
include diffuse or focal gastric mucosal hypertrophy, and the gastric neoplasms that are dominated by gastric
adenocarcinoma and lymphoma.

GENERAL PATHOLOGY OF THE STOMACH

In most instances, the interpretation you make of a stomach biopsy will simply be a summary of the general
pathology that you observe. This task is not as simple as it may sound, for it requires a sound understanding of the
variation among biopsy specimens that relate to anatomic location and species, and probably to such variables as
age, diet, microbial flora, and immune status. We are often in the position of having to admit our inability to
determine the functional significance of these general pathology changes. Those dealing with human
gastrointestinal biopsies face the same dilemma, in that there is poor correlation between the severity of histologic
change and the severity of clinical signs. We frequently experience “abnormal” gastrointestinal microanatomy from
clinically healthy dogs, and histologically normal biopsies that are derived from dogs with vomiting and diarrhea.

INFECTIOUS AGENTS SEEN IN GASTRIC BIOPSIES

Unlike the situation in food-producing animals, in which there is a strong causal association between various
infectious agents and the development of lesions within various parts of the gastrointestinal tract, it is quite
uncommon for us to make such an association in dogs or cats. Listed below are some of the bacterial, chlamydial,
protozoal and metazoon agents that have been described in the stomach of dogs or cats. Some, particularly the
nematodes, are regularly associated with localized inflammatory lesions but clinical disease (and thus, the use of
biopsies) is very uncommon. Others, notably Helicobacter and related organisms, are being strenuously investigated
as possible causes of gastritis and gastric ulceration in dogs or cats. Much of the stimulus for this interest, of course,
stems from the recent establishment of these organisms as a major cause of peptic ulcer in people. To date, there is
no convincing evidence of a causal role in canine gastritis, and the evidence in cats is only slightly better.

GASTRITIS (CHRONIC SUPERFICIAL MUCOSAL GASTRITIS, IDIOPATHIC)

Histologic appearance
 The hallmark lesion is an increase in lymphocytes and plasma cells within the superficial third of the gastric
mucosa. The lesion may be diffuse, or found in only one or two of the biopsies. When localized, the lesion is
more likely to be found in biopsies from pyloric antrum than from body or cardia.
 The addition of eosinophils to the superficial mucosal infiltrate is quite common, although it is sometimes easier
to see the eosinophil granules than it is to detect intact cells. Eosinophils are inconspicuous is the normal
stomach.
 Depending on the duration of the disease, there frequently is an increase in fibroblasts or in mature collagen
within the superficial half of the mucosa.

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 In some instances, the inflammation is found diffusely throughout the mucosa, in which case some degree of
glandular atrophy or mucus metaplasia is common.
 Alteration in the character of the surface epithelium is distinctly uncommon. In those few cases in which
ulceration is present, neutrophils are likely to be added to the infiltrate within the adjacent lamina propria.

Occurrence
 Idiopathic lymphocytic-plasmacytic or eosinophilic gastritis is a very commonly encountered lesion is both
dogs and cats with a history of persistent, or chronic sporadic, vomiting. Rarely is any etiology or pathogenesis
identified.

Etiology
 Despite ample speculation, virtually nothing is known about the etiology of this most common of all gastric
lesions. While various infectious agents are commonly seen associated with gastric mucosa in both dogs and
cats, attempts to prove any consistent pathologic effects have been, in general, unsuccessful.
 Virtually all normal dogs have gastric colonization by tightly coiled spiral bacteria (“gastrospirilla”)
morphologically similar to Helicobacter felis or Gastrospirillum hominus. There is no apparent correlation
between the magnitude of colonization and the magnitude of the mucosal lymphoid population. In this study,
Helicobacter was isolated from only six of 39 stomachs despite the fact that organisms of appropriate
morphology were seen in all. Helicobacter pylori, an important organism in the pathogenesis of human gastric
ulcers, was not isolated.
 Infection of gnotobiotic dogs with a pure culture of Helicobacter felis resulted in mild hyperplasia of deep
mucosal lymphoid aggregates, and an even milder increase in mononuclear leucocytes and eosinophils in the
subglandular portion of the lamina propria. We do not consider either change to be “pathologic” in
conventional dogs.
 While most of the recent interest has focused on Helicobacter spp. because of its importance in the pathogenesis
of human peptic ulcers, a variety of other infectious agents have been described in the canine or feline gastric
mucosa. Most of these have not been associated with any clinical or histologic change, with the exception of
gastric nematodes.
 Undue sensitivity to one or more elements of the diet is frequently suspected in the pathogenesis of gastritis (as
well as enterocolitis) in both dogs and cats. To our knowledge, a causal role for food allergy or sensitivity in
the pathogenesis of gastritis has never been proven.

Differential diagnosis
 The main problem is in deciding when the number of leucocytes, or the degree or either atrophy or fibrosis,
qualifies as a lesion at all! Fortunately, the normal dog or cat stomach contains relatively few leucocytes of any
type, particularly within the superficial third of the lamina propria. It is absolutely imperative that one becomes
familiar with variation in the amount of connective tissue, and glandular mass, within various regions of the
stomach in order to avoid embarassing overinterpretation of biopsy specimens.
 In the only published study of its type, 11 of 19 clinically healthy dogs had histologically-diagnosed gastritis or
gastric mucosal atrophy/fibrosis. These observations, plus our own painful experiences over the years, have
caused us to be very conservative when interpreting the significance of subtle changes in proprial cellularity or
glandular mass anywhere in the intestinal tract!

Helpful Hint: Eosinophilic vs. Lymphocytic/plasmacytic

Does it matter whether one chooses to name a gastric lesion “eosinophilic” rather than
“lymphocytic/plasmacytic”? Probably not, at least in terms of therapy or even pathogenesis. We tend to take the
“kinetic” view and assume that even a few of the short-lived eosinophils in a mucosal lesion indicates a daily influx
of eosinophils that exceeds the influx or in situ proliferation of the long-lived mononuclear leucocytes. The
eosinophils may thus be the most actively recruited leucocyte in the living lesion, and is thus the most logical target
for therapeutic intervention.

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GASTRIC ULCERATION

Histologic appearance
 The mildest lesion is focal or multifocal shallow erosion, without encroachment upon underlying lamina
propria. Cells at the margin of the defect may be basophilic and flattened, typical of early regeneration, or may
be pyknotic and beginning to detach from the basement membrane, suggesting that the ulcer was captured as it
was about to enlarge. Observation of either of these changes is helpful in distinguishing genuine erosion or
ulceration from tissue handling artefact.
 Neutrophils are commonly found in the immediately adjacent lamina propria (neutrophils are very uncommon
in gastric biopsies, except in association with ulceration).
 Deep ulcers will be accompanied by varying degrees of glandular necrosis, neutrophil infiltration, and
granulation tissue typical of early repair in any mucus membrane.

Occurrence
 Despite the fact that gastric ulcers are commonly seen in stressed dogs and cats coming to post mortem, and
may be quite frequently encountered in endoscopic examination, they are relatively infrequent in biopsy
specimens. This may be because endoscopists will avoid taking biopsies directly from sites of ulceration,
knowing that the resultant histologic changes are unlikely to do anything but confirm the obvious!
 Gastric ulceration is commonly associated with some specific drug therapies (see below), but these are seldom
biopsied.

Etiology
 The majority of gastric ulcers are of unknown cause, but are commonly seen in dogs and cats in veterinary
hospitals under stressful circumstances.
 Probably the most common exogenous cause for gastric ulcers is the use of nonsteroidal anti-inflammatory
drugs, including aspirin, flunixin meglumine, naproxen and indomethacin. The mechanism by which
nonsteroidal anti-inflammatory drugs induce gastric ulceration probably involves more than one pathway,
including reduction in mucosal blood flow, initiation (or failure to prevent) neutrophilic microvascular
thrombosis and neutrophil-mediated endothelial injury, and inhibition of a variety of epithelial functions
including the synthesis of mucus glycoproteins and bicarbonate. The injury to the mucosa is dose-dependent
and rapid, occurring in as little as four hours after aspirin administration.
 Systemic states such as Zollinger-Ellison (hypergastrinemia) syndrome, malignant mast cell tumors, and uremia
are all capable of causing gastric ulceration but seldom is the diagnosis made on the basis of biopsy.

Differential diagnosis
 The observation of shallow or deep gastric ulcers carries with it no particular etiologic implication, and the
cause for the ulceration is usually determined by considering the circumstantial evidence, including history of
hypotension, stress, intercurrent systemic disease such as uremia, and a history of drug usage that includes
corticosteroids or nonsteroidal anti-inflammatory agents.
 A solitary deep ulcer is a typical presentation for gastric carcinoma, but endoscopic biopsy of the ulcer itself
usually reveals only granulation tissue and suppuration.

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GASTRIC MUCOSAL HYPERTROPHY

Histologic appearance
 The fundamental lesion is focal, regional, or diffuse hypertrophy of the gastric mucosa because of proliferation
of mature foveolar epithelium. The focal lesion, which is by far the most common, resembles a gastric polyp
when viewed grossly or endoscopically.
 If the biopsy has been obtained via endoscopy, it is likely that the only lesion will be papillary, branching
hypertrophy of the foveolar mucosa. The lamina propria is thrown into folds, covered by a single layer of
mature, normal or elongated foveolar-type surface epithelium. In many cases, there is an associated mild
lymphocytic-plasmacytic superficial gastritis.
 If the biopsy is a full thickness resection, you may see glandular hyperplasia and cystic distension in addition to
the above-described foveolar hyperplasia. Hypertrophy of the circular muscle layer is more easily appreciated
by the surgeon than it is by the pathologist, but hypertrophy of the circular muscle layer (with or without
associated mucosal hypertrophy) is reported as one of the variants contributing to the clinical syndrome of
pyloric obstruction.
 There is one report of intraepithelial Campylobacter-like organisms in a young dog with pyloric mucosal
hypertrophy. The casual role for these organisms was not proven, and as yet there have been no large follow-up
studies looking for these organisms, specifically, in the epithelium of cases of idiopathic mucosal hypertrophy.

Occurrence
 This is a relatively common lesion in dogs but is very rare in cats. Most cases are focal or regional and affect
the pyloric antrum much more frequently than the body of the stomach.
 The literature is not uniform in the nomenclature of this syndrome, and indeed it is not clear whether all papers
are reporting the same disease. For example, the syndrome of “hypertrophic pyloric gastropathy” includes
some dogs with just mucosal hypertrophy, some with combined mucosal and muscular hypertrophy, and some
with muscular hypertrophy alone. In contrast, multiple polyps of the gastric mucosa have been described
which, in retrospect, are histologically identical to focal antral hypertrophic gastropathy.
 A more diffuse form of hypertrophic gastropathy, similar to human Menetrier’s disease, affects the fundus and
body of the stomach. The thickened gastric rugae create a cerebriform appearance to the gastric mucosa. The
histologic lesion resembles the changes described above for the focal form, except that muscular hypertrophy
has not been described as part of the syndrome. Cystic glandular dilatation, loss of parietal cells accompanied
by hyperplasia of mucus cells, and a mononuclear infiltrate in the lamina propria have all been described as
routine accompaniments.

Etiology
 A significant proportion of hypertrophic gastropathies may be sequels to chronic gastritis, with mucosal
hyperplasia stimulated by release of mucosal cytokines as a misguided outcome of mucosal repair. Excess
gastrin production, stimulated by inflammatory prostaglandin, may also be a part of the pathogenesis.
 Diffuse gastric mucosal hypertrophy occurs as a familial disease in basenji dogs as part of a more generalized
protein-losing lymphocytic-plasmacytic gastroenterocolitis. While the gastric hypertrophy occurs in many
basenjis with diffuse lymphocytic-plasmacytic enterocolitis, it is also true that some basenjis with a chronic
enterocolitis have no gastric lesions. It is speculated, but by no means proven, that the proliferative gastric
disease is an outcome of malfunctioning T-lymphocytes, resulting in a chronic excess of prostaglandin
inflammatory mediators that stimulate epithelial hyperplasia. In basenjis, the mode of inheritance is unknown,
and there appear to be environmental contributions such as stressful environments, dietary intolerance, and
bacterial overgrowth.

Differential diagnosis
 When the biopsy depth is adequate, the changes of foveolar and glandular proliferation, with or without cystic
distension, are characteristic.

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 It is not known whether the presence or absence of inflammatory infiltrate indicates different fundamental
disease processes that should be given separate names. Similarly, lesions that are distinctly polypoid have been
termed gastric polyps but the lesion is identical to focal mucosal hypertrophy and probably does not deserve a
separate name.

GASTRIC CARCINOMA

Histologic appearance
 There are two basic histologic patterns, although these are by no means mutually exclusive. About two-thirds
of all canine gastric carcinomas are diffusely infiltrative scirrhous anaplastic carcinomas with little if any acinar
or glandular formation. Most of the remaining one-third, in contrast, are characterized by relatively well
differentiated acini and tubules, formed by tall columnar epithelium with obvious intracytoplasmic mucin. This
latter variant tends to be much less scirrhous than the more common diffuse type.
 In the diffuse type, the usual histologic picture is a scirrhous transmural infiltrate with pleomorphic epithelioid
cells that sometimes are mistaken for macrophages or even reactive fibroblasts. The presence of lakes of
extracellular mucin, or the ability to see abundant mucin within the cytoplasm of some of the tumor cells, is a
very reliable histologic clue. For this reason, routine use of PAS stains in suspected gastric carcinoma is
recommended.
 Most diffuse carcinomas have at least some classical “signet ring” cells, so named because of an eccentric,
crescentic nucleus at the periphery of a cell distended by a clear mucin accumulation.
 Routinely, packets of tumor cells and accompanying mucin are found on the serosal surface, and may be seen
implanting along the serosa at sites distant from the main perforating lesion.
 Since most of the tumor mass is found in submucosa and tunica muscularis rather than within the mucosa itself,
this is one diagnosis that, if suspected, is much more easily confirmed with full-thickness biopsies than with
endoscopic biopsies. Very frequently, the mucosal portion of the tumor is almost obliterated by the ulceration
and granulation tissue which is the hallmark of this tumor when viewed endoscopically.

Occurrence
 One form or the other of gastric carcinoma is by far the most prevalent gastric neoplasm, accounting for
between one-half and two-thirds of all gastric neoplasms.
 Gastric carcinomas in cats resemble those in dogs, but are much less prevalent. In a twelve-year period, we
have diagnosed 45 gastric carcinomas in dogs but only 6 in cats.
 In both species, the most common clinical presentation is one of chronic vomiting, weight loss, and melena.
Radiographically, one may see regional thickening of the gastric wall; endoscopically, one is able to visualize a
deep craterous ulcer, typical of a mucosal presentation of gastric carcinoma, in anywhere from 50-75% of cases.
The pyloric mucosa is the preferred site, accounting for at least 50% of all of the canine tumors.

Differential diagnosis
 Gastric carcinoma, when present in its well differentiated acinar/tubular form, is very distinctive. The
transmural spread of the tumor is not easily mimicked by anything else. - The more common diffuse
scirrhous form can be a real challenge, particularly if your own view is in an endoscopic biopsy that is
dominated by the granulation tissue and inflammation associated with the typical mucosal ulceration. Even in a
transmural biopsy, the tumor may resemble granulomatous transmural gastritis more than neoplasia. The
strongest clue is the observation of mucin lakes within the tunica muscularis, with hyperchromatic epithelioid
cells and a few signet ring cells identified as the actual malignancy.

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Behaviour
 In both species, gastric carcinomas have a very poor prognosis because the tumors are usually identified only in
the later stages of their progression. The initial signs of vomiting and weight loss are relatively nonspecific, and
gastric neoplasms are not sufficiently prevalent in either species so as to arouse immediate suspicion.
 Proliferation of the tumor through to the serosal surface has occurred in almost all cases at the time of initial
diagnosis. Metastasis to local lymph nodes is seen in anywhere from 80-100% of cases at the time of initial
diagnosis. Distant metastasis, at the time of initial diagnosis, is present in anywhere from 25-80% (presumably,
depending on how early in the clinical course one makes the diagnosis).
 There are a few reports of survival of up to one year following radical resection of the tumor. As is so often the
case, much of the behavioral data is biased by the relatively advanced stage of the neoplasm at the time of
diagnosis. There are no published papers that discuss prognosis following excision of tumors diagnosed by
endoscopy, which should allow for diagnosis earlier in the course of the disease. One would expect to see
longer survival times, although probably not any real improvement in the overall case fatality rate.

The diagnosis of gastric carcinoma by endoscopy is very challenging because the mucosal
lesion is usually a deep granulating ulcer with raised “volcanic” margins. Since biopsy
forceps cannot ordinarily reach submucosa, the endoscopic biopsy you receive will
almost certainly be dominated by the granulation tissue and neutrophilic inflammation
of the ulcer, and it is very difficult to identify neoplastic cells even if they are present
amid the granulation tissue. PAS stain to accentuate the mucin production is a very
useful technique. Surprisingly, mucin production is retained even in the most anaplastic
examples.

OTHER GASTRIC NEOPLASMS

In dogs, other reported gastric neoplasms include (in order of prevalence) leiomyoma, lymphoma, and
leiomyosarcoma. Because malignant lymphoma is accessible to endoscopic sampling whereas the smooth muscle
tumors ordinarily are not, lymphoma greatly outnumbers smooth muscle tumors in most surgical pathology
collections. As all of these tumors are more commonly encountered in intestine, they are discussed more fully under
that heading.
 Malignant lymphoma is the most common gastric neoplasm in cats. Based upon ultrasonography or surgical
exploration, between 10 and 20 percent of feline alimentary lymphoma cases are localized to stomach, while the
majority involve stomach, intestine, and mesenteric lymph nodes. Generalized lymphadenopathy is not usually
a feature, but commonly there is hepatic involvement. Response to excision and chemotherapy has traditionally
been poor, but use of endoscopy will probably result in earlier diagnosis and improved prognosis via
chemotherapy.
 There is a single case report of a gastric squamous cell carcinoma in the pyloric antrum of an old dog. After
reviewing the photographs, we would have called it gastric carcinoma with abundant squamous metaplasia. Its
growth habit and clinical behavior were as described for diffuse gastric carcinomas.
 Plasmacytomas can occur in stomach, although their most common location within gastrointestinal tract is in
rectal submucosa. In the single gastric tumor described, there was regionally extensive infiltration of lamina
propria and submucosa by pleomorphic plasma cells typical of these tumors anywhere else. The dog was cured
by a combination of surgical excision and chemotherapy with cyclophosphamide and prednisone.
 Mast cell tumors may affect the gastric mucosa as well as other portions of intestinal tract and liver. They are
probably relatively more frequent in cats than in dogs. A high percentage of cases have bone marrow
involvement, and thus the intestinal lesions probably qualify as localizations of mast cell leukemia rather than
primary intestinal disease.

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 We have seen two cases of primary gastric eosinophilic sarcoma in which there was an infiltrative of blastic and
maturing eosinophils in a crater-like fashion within the gastric mucosa and submucosa. One dog was cured by
surgical excision, and the other survived symptom-free for two years after excision, before a return of vomiting
and a radiographically- detected gastric mass triggered elective euthanasia. Neither dog had bone marrow
involvement.

SMALL AND LARGE INTESTINE

While diseases of small intestine and of colon are usually listed separately in clinical textbooks, there is no good
reason to do so in terms of the interpretation of intestinal biopsies. The histologic differences between various parts
of the digestive tube are relatively minor and are quantitative rather than qualitative, and all share virtually identical
general pathologic reactions to injury. In addition, some of the most important intestinal diseases (such as the
clinical catch-all of “inflammatory bowel disease” and intestinal lymphoma) frequently affect multiple portions of
the intestinal tract to one degree or another. It would be redundant to have to consider what is essentially the same
lesion in each of its multiple locations. The interpretation of intestinal and colonic biopsies is best with the same
difficulties as outlined above for the stomach, namely our inability to define the broad range of normal, and our
inability to correlate the presence of histologic lesions with any functional abnormality. Because the lamina propria
of intestine and colon normally is rich in various leucocytes, the problem of determining when the population is
greater than “normal” is a very real one. In addition, because this population plays a normal physiologic role in
modulating the immune response to the wide variety of intralumenal antigens, it is not at all clear under what
circumstances an expansion of this population should be considered “pathologic”, and when the expansion is the
appropriate, even necessary response to changes in this antigenic challenge. When viewed in this light, the myth of
“inflammatory bowel disease” in dogs and cats is an excellent example of the truism that an opinion, when repeated
often enough, becomes accepted as fact! Even when we are quite convinced that a mucosal biopsy from an animal
with diarrhea has more lymphocytes, plasma cells or eosinophils than usual, we should not blindly assume that this
increase in leucocytes is the cause for the clinical syndrome. It is at least as likely that these cells are there in
response to some kind of alteration in intestinal barrier, or alteration in lumenal flora. They may have nothing
whatsoever to do with the pathogenesis of the diarrhea, yet they may still play a useful role as a microscopic marker
for the disease syndrome. It is recognition of this last point that we present the various types of inflammatory
intestinal lesions, perhaps unwisely running the risk of further sanctifying some very tenuous histologic-clinical
associations.

GENERAL PATHOLOGY OF SMALL AND LARGE INTESTINE

The aspects of normal intestinal form and function that are most important for biopsy interpretation include an
understanding of normal mucosal kinetics, intestinal blood supply, and at least some of the most important aspects
of mucosal immune function. Many other features of intestinal anatomy and physiology are important for a
thorough understanding of gastrointestinal diseases, but most of these are not directly relevant to biopsy
interpretation. An understanding of intestinal epithelial kinetics is critical to an understanding of mucosal repair,
and for the differential susceptibility of various compartments within the mucosa to injury by infectious agents,
drugs, or ischemic insults. The same basic pattern pertains to all parts of the bowel: continuous mitotic replication
within the basilar portion of the crypts, and orderly migration and maturation of daughter cells from the crypts to the
mucosal surface where they exfoliate. The mucosal turnover time varies within the intestine, and also varies
somewhat with age, diet, and the antigenic mass within the intestinal lumen. In general, intestinal turnover time
ranges from 3-5 days. Put in perspective, this very rapid turnover time allows for very rapid wound healing, so that
a shallow surface ulcer can be healed in a matter of hours by cell sliding, and normalizes within less than a day
because of the large maturing population that is already in place to deal with the normal surface exfoliation. The
replicative population is restricted to the crypts, explaining why agents that act only on replicative cells (such as
parvoviruses and radiomimetic cancer drugs) cause only cryptal necrosis. In contrast, agents that injure only mature
cells will cause only surface necrosis, even though theoretically they may injure the small population of mature cells
that remain within the crypts. We rarely see histologic evidence of this mature-cell cryptal necrosis, presumably
because their numbers are small in comparison to the replicative population. Increased surface cell loss of any
pathogenesis initiates a compensatory expansion in the replicative cryptal compartment, seen microscopically as
increased basophilia and an increase in both the number and the distribution of mitotic figures. In some cases,
presumably with chronic or very profound stimulation, the cryptal proliferation becomes quite dysplastic.

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Villus atrophy is a very prevalent lesion in food-producing animals suffering from various viral infections that target
the mature surface epithelium. It is an infrequent lesion to encounter in dogs or cats, although it certainly can be
seen with coronavirus infection in dogs, and as an idiopathic observation in either species. Villus atrophy is the
nonspecific result of an imbalance between surface loss and cryptal proliferation, and ordinarily is caused by
increased surface cell loss. What determines the crypt-villus ratio in each individual is not precisely known,
although it is clear that assault upon the aging surface enterocytes by members of the lumenal flora, and perhaps by
other chemical or antigenic ingredients of the ingesta, play a major role. Conventionalization of germ-free animals,
for example, or even weaning of conventional animals, results in a dramatic increase in lumenal flora and a
concomitant dramatic reduction in villus length coupled with an expansion of the proliferative compartment and an
increase in the overall intestinal turnover time. It is reasonable, therefore, to assume that changes in flora or in other
constituents of the ingesta can continue to influence crypt:villus ratios in animals of any age, and might be expected
in conditions such as bacterial overgrowth and food sensitivities. This being said, it is difficult to appreciate subtle
villus atrophy in biopsy specimens because rarely do we capture longitudinal sections through enough villi to make
this assessment. Furthermore, the size of endoscopic biopsy instruments does not permit a full thickness mucosal
biopsy in dogs or cats, and thus we can never evaluate crypt:villus ratios. Indirect evidence for villus atrophy comes
from observation of abnormal broad villi, or villi covered by basophilic flattened epithelium that lacks a distinct
brush border. The functional significance of villus atrophy is most obviously a decrease in absorptive efficiency,
both because of loss of the microvillus border which increases absorptive surface by 15-40 times, and also because
of the presumed immaturity of the absorptive machinery resident within these surface enterocytes. The
compensatory cryptal hyperplasia may, on its own, contribute to fluid loss because the undifferentiated epithelial
cells have net secretion of fluid.
The prognosis for lesions characterized by mucosal necrosis often rests upon our understanding of mucosal kinetics.
Surface cell loss is rapidly replaced, usually with no residual lesion providing that the lamina propria and its blood
supply have remained intact (as is the case, for example, with coronaviral and rotaviral infections). Conversely,
diseases such as parvovirus or radiomimetic drug toxicity damage the progenitor cells within the crypts and cause a
subsequent villus atrophy because of lack of replacement of normal senescent cells. The prognosis, in this instance,
is almost totally dependent upon the magnitude of the original damage. Following a severe lesion of parvoviral
enteritis, it may take weeks or even months to return that affected segment of intestine to normal structure and
function. Intestinal blood supply is a very important issue in all domestic species because of the frequency with
which ischemic injury to the mucosa occurs, and because of the importance of a good blood supply in predicting the
outcome of mucosal regeneration. The peculiar patterns of injury following ischemic damage are determined, in
part, by the distribution of blood vessels within the bowel wall, and in part by the differing susceptibilities of the
various portions of the wall to ischemic damage. Briefly, branches from the mesenteric circulation penetrate
through the tunica muscularis to form an anastomosing network within the submucosa. Each villus is supplied by a
single unbranched endartery from this submucosal plexus. When the villus arteriole nears the villus tip, it breaks
into an arborizing capillary network just below the epithelial basal lamina, and this network drains into veins within
the villus that then enter a venous plexus within the submucosa. Depending on the portion of intestine, the crypts
may be supplied by extensions from the villus capillary network, or be supplied by a separate arteriole arising from
the submucosal vascular plexus. Similarly, the tunica muscularis is supplied from the submucosal plexus, with the
outer longitudinal muscle layer being supplied last. Because the longitudinal muscle and the villus tip are most
distant from the vascular supply, it is these two areas that are most susceptible to ischemic damage under
circumstances of reduced intestinal perfusion. The villus tip, in particular, is susceptible because of the high
metabolic rate of the enterocytes in comparison to the smooth muscle cells, and because of the deleterious effect of
digestive enzymes and products of the lumenal flora upon enterocytes that are not optimally supplied by blood.

INTESTINAL IMMUNOLOGY
The natural defence mechanisms of the gastrointestinal tract are numerous, including the cleansing action of
peristalsis, the antibacterial properties of gastric acid and various other intestinal secretions, an intact epithelial
surface with a mucus coat, and a rich, varied normal flora which competitively inhibit pathogens from establishing a
niche. The aspect of intestinal defences that receive the most attention, however, is the intestinal immune system
which is usually considered the largest accumulation of immunocytes in the body. The immunocyte population is
structurally and functionally varied, and includes a mixture of lymphocytes, plasma cells, and macrophages that
inhabit specific niches within the epithelium, diffusely within the lamina propria, and in gut-associated lymphoid

9
aggregates and follicles. The latter, sometimes known as GALT (gut-associated lymphoid tissue) consists of
lymphoid follicles that surround the muscularis mucosae, as well as the mesenteric lymph nodes themselves. The
Peyer’s patches are the best-known members of the GALT, but small lymphoid nodules that are not macroscopically
visible are readily apparent microscopically throughout all portions of the gastrointestinal tract, from stomach to
rectum. Anything approaching a thorough review of intestinal immunology is clearly beyond the scope of this text,
but there are certain features that are important to the day-today interpretation of intestinal biopsies, and those
features will be reviewed here.
In most studies, the diagnosis of various types of inflammatory bowel disease in dogs and cats has rested primarily
on the subjective belief that there is an increase in the number of lymphocytes and other leucocytes within the
lamina propria. Since we are unaware of any study that tabulates the normal number of such leucocytes in various
parts of the canine or feline intestine, or charts the kinds of variations one might expect with changes in age, diet, or
other environmental variables, to base a diagnosis on such an ill-defined and subjective parameter seems to us to be
treading on thin ice indeed. In one study used immunoperoxidase techniques to examine the relative numbers and
distribution of immunoglobulin-containing cells within the lamina propria of normal juvenile and adult. In this very
preliminary study, there was three-to-fourfold variation in the number of these cells (most were presumed to
represent plasma cells) at the same level of the gut among the five adult dogs studied, and adults had approximately
four times as many positive cells as did puppies between three and five weeks of age. There was also substantial
variation among different levels of the bowel, with duodenum consistently having the highest number, dropping by
half in the jejunum and by a further half in the ileum. This study, of course, measured only immunoglobulin-
producing cells, and would not have identified the larger population of T-lymphocytes or other resident leucocytes.
Similarly, the number of intraepithelial lymphocytes per hundred epithelial cells is approximately twice as high in
adult dogs as it is in puppies under two weeks of age. This increase is interpreted as being a response to weaning,
when puppies are suddenly exposed to a much greater concentration and range of food antigens, as well as to a rapid
shift in intralumenal bacterial flora. Limited though these studies are, they give us at least some indication of how
variable the mucosal leucocyte population is likely to be. To my knowledge, there is no study that has quantitatively
assessed the populations of T-lymphocytes or eosinophils, which are the other constituents of lamina propria that are
most often cited in descriptions of inflammatory bowel disease in dogs or cats.
The diffusely distributed lymphocytes within intestinal lamina propria are both B and T cells, with the majority
(perhaps as much as 80%) being T cells. Of these, T helper cells predominate, and many appear to be in a state of
partial activity, presumably in response to the continuous antigenic dribble from the intestinal lumen. Almost all of
the intraepithelial lymphocytes are T cells, generally considered to function as suppressor cells. Juvenile, mature,
and effete mast cells (the latter commonly known as globular leucocytes) are also common within the epithelium,
although their precise function in that location is unknown.
Under normal circumstances, the intestinal immune system acts in a highly integrated fashion to protect the intestine
against foreign agents, to dampen unnecessary immune responses to intralumenal antigens, and probably to regulate
intestinal epithelial kinetics. Most of the antigen uptake probably occurs through the Peyer’s patches and other
lymphoid aggregates, where specialized flattened epithelial cells (M cells) overlying the lymphoid aggregates
capture and transmit antigens to macrophages and dendritic cells, which in turn present the antigens to the B cells
and/or T cells which dominate in the germinal centers and interfollicular areas of the Peyer’s patches, respectively.
Much of the antigen processing is probably done by the B cells, which ultimately present the processed antigen to
the T cells. Regardless of whether the antigen is presented by B cells, macrophages, or dendritic cells, the T cells
become activated and, in turn, stimulate the adjacent B cells to switch from IGM-producing cells into IGA-
producing cells. Very little, if any, IGG is produced within the intestinal lamina propria. Lymphocytes that have
been “switched” from IGM to IGA production must first leave the intestinal mucosa through high endothelial
venules adjacent to the germinal centers, migrate through mesenteric lymph nodes in spleen, and eventually return to
the intestinal lamina propria where they will begin to produce antigen-specific IGA. The mechanism by which these
cells “home” back to the intestine is unknown. Part of the answer probably lies in specific interactions involving
adhesion molecules of the post-capillary high endothelial venules. In addition to preventing colonization by various
microorganisms resident within the intestinal lumen, secretory IGA may also prevent the absorption of various food
antigens, therefore blunting the potential for food-induced hypersensitivity reactions. We are only beginning to
understand the complex interaction of various interleukins within the intestinal mucosa, which are important not
only in modulating immune responses but also apparently in intestinal proliferation and in absorption-secretion
functions.

10
LYMPHANGIECTASIA

Histologic appearance
 The most characteristic lesion is dramatic dilatation of villus lacteals, usually with no other histologic change in
epithelium or lamina propria. Not every villus is affected equally, and there are some disturbing instances in
which the macroscopic appearance of club-shaped edematous villi distended by entrapped, white chyle is not
supported by convincing microscopic dilatation of the lacteals.
 In full thickness biopsies, distension of lymphatics as they penetrate the muscularis mucosae, and similar
distension of lymphatics within submucosa, tunica muscularis, and on the serosa, provides more convincing
evidence than the distension of lacteals.
 There may be perilymphatic accumulation of foamy, lipid-laden macrophages within the lamina propria, but
ordinarily such accumulations are more striking on the serosal surface and within the mesentery. These
accumulations may form grossly visible white masses up to 1 centimeter in diameter, running along the
mesenteric border of the intestinal serosa and radiating parallel to the lymphatics within the mesentery itself.
There may also be saponification of mesenteric fat. It is not known with certainty whether this granulomatous
reaction is the result of lymphatic distension and leakage, or whether in some instances it might actually be the
cause of the lymphangiectasia. In the majority of cases, we believe it is a predictable sequel to the
lymphangiectasia.
 Ordinarily, lesions are not found in colon, and even the small intestinal lesion may be very patchy. Because of
the profound hypoproteinemia, there may be diffuse edema within submucosa and lamina propria, from
stomach to anus.
 In the vast majority of cases, no cause for the lymphangiectasia can be identified within intestine, lymph nodes,
or elsewhere.

Occurrence
 Lymphangiectasia is a relatively common, sporadic disease of the small intestine of dogs. A breed-associated
increase in prevalence is seen in wheaten terriers and in the Lundehund, an uncommon Norwegian Spitz-like
dog. It appears to be extremely rare in cats.
 The clinical syndrome is one of chronic diarrhea with protein-losing enteropathy, lymphopoenia, and
hypocalcemia.

Etiology
 The cause of lymphangiectasia is unknown, and the pathophysiology appears to be quite complex. Obstruction
of lymphatics within the mesentery, or ligation of thoracic duct, produces slow-onset lymphangiectasia with
resultant hyperprotenemia, but not the profound diarrhea and weight loss characteristics of the naturally
occurring clinical syndrome.
 The mesenteric granulomatous lymphangitis and perilymphatic lipogranulomas appear to be consequences of
the lymphangiectasia rather than the cause.
 Its occurrence in wheaten terriers, at least, is frequently accompanied by lymphocytic-plasmacytic enteritis. A
similar coincidence of lymphangiectasia and inflammatory bowel disease is seen in many other sporadic cases,
leading me to speculate that the lymphangiectasia, per se, is responsible for only a portion of the clinical signs,
and the inflammatory bowel disease accounts for others.

Differential diagnosis
 The characteristic dilatation of villus lacteals, and transmural and/or mesenteric lymphatic ectasia, is
characteristic.
 We are not sure whether lymphangiectasia can be induced as an endoscopic biopsy artefact, for we quite
frequently encounter dilated lacteals in a substantial proportion of the villus tips captured in the usual duodenal
endoscopic biopsy, yet the clinical syndrome is certainly not compatible with a diagnosis of lymphangiectasia.
It is for this reason that we recommend full thickness intestinal biopsies in suspected cases of lymphangiectasia,
believing that the dilatation of lymphatics in submucosa and tunica muscularis is more specific than dilatation
of lacteals.

11
CANINE INFLAMMATORY BOWEL DISEASE

Histologic appearance
 Histological diagnosis rests on the subjective evaluation of three different parameters: increases in various types
of leucocytes within the lamina propria, changes in the character of the enterocytes themselves, and changes in
the architectural configuration of the mucosa, particularly in terms of proprial edema or fibrosis that results in
undue separation of crypts from one another and from the muscularis mucosae.
 An increase in leucocyte numbers within lamina propria is the most prevalent, and most controversial, criterion
used to diagnose inflammatory bowel disease. The great difficulty stems from knowing what is “normal” for
that individual patient. Most studies cite a subjective increase in lymphocytes and plasma cells within villus
and intercryptal lamina propria. In the most severe cases, there is distension of villi by these mononuclear
leucocytes (filled villus syndrome) and accompanying dilatation of the lacteals. Eosinophils, and less
frequently, neutrophils, are also described as being increased, but absolute counts are never given and there is
no description of the normal eosinophil or neutrophil population of the lamina propria in various portions of
intestine. In our own experience, we find increases in eosinophil numbers easier to determine than changes in
the lymphocytic-plasmacytic population, and I suggest a diagnosis of eosinophilic enterocolitis much more than
lymphocytic-plasmacytic enterocolitis.
 Only in the most severe cases does one see changes in the enterocytes. Subtle basophilia and jumbling of the
surface epithelium suggest recent erosion, and occasionally one is able to see outright erosion or ulceration.
Only the most severe cases have similar changes within crypts, and in such there usually substantial fibrosis
within the lamina propria which attests to the severity of the original lesion. In small intestine, villus atrophy
and fusion may be present in such severe cases.
 During active disease, there usually is edema within lamina propria, causing distension of villi and separation of
crypts, both from each other and from the underlying muscularis mucosae (“lifting” of the crypts).

Occurrence
 Lymphocytic-plasmacytic or eosinophilic inflammatory bowel disease is very common in dogs. The majority
of cases involve all portions of the gastrointestinal tract, although the histologic lesions may vary in intensity
among these different segments, and the clinical signs may be predominantly related to gastric, small intestinal
or colonic involvement. Nonetheless, the fact that all portions of gut have histologic changes is a strong
argument for biopsying all accessible portions of gastrointestinal tract when investigating vomiting,
malabsorption and/or diarrhoea in dogs. There is no age or sex predilection, but various studies have suggested
various (and different) breed predilections. The most persistent claims relate to German shepherds and basenjis.

Etiology
 In the great majority of cases, no etiology is determined, and even the pathogenesis remains obscure.
 The widely held assumption is that the disease represents a dysregulation in the normal mucosal tolerance for
intralumenal food antigens. The nature of this dysregulation is, at the moment, almost completely unknown.
Dogs with naturally occurring eosinophilic or lymphocytic-plasmacytic enteritis tentatively diagnosed as food
allergy, or dogs sensitized to various food antigens by parenteral hyperimmunization, react with mucosal edema
and hyperaemia within minutes of intragastric infusion of the food extracts to which they are sensitive. The
rapidity of the response implies a type I hypersensitivity, but no histologic studies were done on these patients.
What percentage of naturally occurring inflammatory bowel disease in dogs is truly dietary hypersensitivity
remains unknown, although feeding of a so-called “hypoallergenic” diet is frequently the first therapeutic
approach attempted by clinicians.
 Infectious agents have almost always met with failure. The original papers equating eosinophilic enteritis with
visceral larval migrans, while accurate for the specific population being reported in those studies, have been
greatly misinterpreted and overinterpreted as meaning that parasitic migration is significant in a substantial

12
 proportion of cases of eosinophilic inflammatory bowel disease. There is no support whatsoever for that
conclusion, and in the great majority of cases, affected animals do not have any detected endoparasitism. In
addition, the lesions of this larval migrans within intestine and other tissues are distinctive and quite different
from the “garden variety” eosinophilic gastroenterocolitis that we see as a day-to-day disease.

Differential diagnosis
 The main differential diagnosis is “normal intestine”. Since the range of normal leucocyte numbers within the
lamina propria have not been defined for dogs, and since preliminary evidence suggests a very wide range in
such numbers, this imprecision remains a major barrier to clinical-histologic correlation.
 When the lymphocytic-plasmacytic increase within lamina propria is dramatic, intestinal lymphoma is a major
rule-out. In lymphoma, there is dramatic effacement of intestinal architecture and transmural involvement.
Unfortunately, with endoscopic biopsies, this involvement of submucosa and tunica muscularis may not be
visible, and distinguishing between relatively early cases of lymphoma and inflammatory bowel disease can be
extremely difficult. There are numerous reports of chronic lymphocytic-plasmacytic enterocolitis progressing
to outright lymphoma, but it is not absolutely certain whether this is indeed a progression, or whether the
disease was lymphoma from the onset. (This dilemma is not limited to interpretation of intestinal lymphoma in
dogs, in that it occurs in intestinal lymphoma in other species and in cutaneous lymphomas of various types.)
 Neither histiocytes nor neutrophils are regularly a part of “garden variety” inflammatory bowel disease in dogs.
When histiocytes are prominent, consider such diagnoses as regional (transmural) granulomatous enteritis or
histiocytic ulcerative colitis or even histoplasmosis. When neutrophils are conspicuous, consider a diagnosis of
genuine bacterial enteritis as occurs, albeit rarely, with yersiniosis,salmonellosis and perhaps with clostridial
enteritis.. A few neutrophils, however, may be anticipated below epithelium that has been ulcerated in the
course of any inflammatory bowel disease.
 Dilatation of lacteals is commonly seen in idiopathic inflammatory bowel disease. If it is particularly
prominent, and especially if it includes transmural distension of lymphatics, you may wish to consider the
disease as a primary lymphangiectasia. Since dilatation of lacteals is commonly seen in lymphocytic-
plasmacytic enterocolitis, and since some subjective increase in leucocytes is commonly seen in apparently
primary lymphangiectasias, the relationship between these two idiopathic syndromes remains obscure.

INFLAMMATORY BOWEL DISEASE IN CATS (INCLUDING LYMPHOCYTIC-PLASMACYTIC AND

EOSINOPHILIC ENTEROCOLITIS)

Histologic lesions
 The histologic lesions in cats are virtually identical to those seen in dogs, with a subjective increase in the
number of lymphocytes, plasma cells, and/or eosinophils within the lamina propria. Neutrophils are not
prominent, although a few may be found in the superficial lamina propria immediately adjacent to foci of
injured epithelium.
 In the most severe cases, there is evidence of enterocyte injury, usually most obvious at the lumenal surface, but
occasionally also affecting crypts.
 The increase in leucocytes, combined with edema, results in separation of crypts one from the other and from
the muscularis mucosae.
 A feature that we think is unique to cats is the presence of a horizontal band of fibrosis at the crypt-villus
junction, which we believe to be a sequel to previous inflammatory bowel disease. This fibrosis may occur in
intestines that otherwise have no active inflammation, or may be seen concurrently with more active
inflammatory lesions in cases that we assume have had recurrent bouts of mucosal inflammation.
 As with dogs, involvement of submucosa or tunica muscularis is not a feature of the “garden variety”
inflammatory bowel disease.

13
Occurrence
 Although clinical syndromes of chronic malabsorption or diarrhoea appear to be relatively less frequent in cats
than in dogs, biopsies meeting the criteria for inflammatory bowel disease are by no means infrequent in cats.
Despite this, published reports are relatively few.
 As with dogs, there is no age or sex predilection. Unlike dogs, no breed predilection has been suggested in cats.
 Vomiting is said to be a more frequent and prominent clinical sign in cats with inflammatory bowel disease than
is the case in dogs.

Etiology
 Speculations about the etiology and pathogenesis of feline inflammatory bowel disease are virtually identical to
the speculation described previously for dogs. In neither species is there any convincing evidence that such
speculations, in fact, are valid.
 As is true in dogs, some cases apparently progress to malignant lymphoma. Whether this is genuine
progression or a failure to make an accurate diagnosis of lymphoma in the initial biopsies is not entirely clear.

Differential diagnosis
 The main differential diagnosis in cats, as in dogs, is intestinal lymphoma. In inflammatory bowel disease there
usually is a mixture of lymphocytes, plasma cells and, variably, eosinophils with edema and hyperaemia. In
lymphoma, vascular phenomena associated with inflammation are not present, and there is an infiltration of
lamina propria, submucosa, and tunica muscularis by a uniform population of lymphocytes which obliterates
normal architectural features. Unfortunately, it may be extremely difficult to distinguish early cases of
lymphoma, because the neoplastic cells are intermingled with normal resident leucocytes, and there is not yet
the obliteration of normal architectural elements nor the transmural growth habit that typifies the fully-
developed disease. In the cases in which we have been proven wrong by subsequent biopsies or necropsy, in
most cases we were able to review the previous biopsy and see the neoplastic cells that we had missed the first
time around. We do not know whether the claims that lymphoma can emerge from chronic inflammatory bowel
disease are valid, or represent a failure to come to grips with one’s own diagnostic shortcomings!

GRANULOMATOUS AND/OR EOSINOPHILIC TRANSMURAL (REGIONAL) ENTEROCOLITIS

Histological lesions
 This is a morphologic diagnosis, not a specific etiologic entity.
 The archetypal lesion is a segmental (usually ileal, occasionally colonic) necrotizing, ulcerative, granulomatous
lesion which, when chronic, results in segmental thickening and stenosis of the bowel.
 The precise histologic lesion varies widely from case to case, and we do not know how many different diseases
may masquerade under this general classification. Perhaps the most frequent lesion is one of coalescing
transmural necrotizing granulomas, most easily seen in submucosa but existing to one degree or another right
through the tunica muscularis to the serosa. The overlying epithelium usually is ulcerated. Other variations
include granulomas that are rich in eosinophils, diffusely granulomatous lesions that do not involve discrete
granuloma formation, or transmural eosinophilic and necrotizing disease in which histiocytes are relatively
inconspicuous. Virtually all examples, however, have some degree of ulceration, participation of macrophages,
and eosinophils.

Occurrence

14
 This is, fortunately, an uncommon-to-rare disease that is seen in both dogs and cats. Reports have been too few
to comment on age, breed, or sex predilections, although those cases associated, for example, with visceral larva
migrans are expected to be in dogs under 2 or 3 years of age.

Etiology
 Since this is a morphologic diagnosis rather than an etiologic one, we presume that quite a number of different
diseases may share this histologic range. The best known example is undoubtedly visceral larva migrans related
to Toxacara canis, but other diseases such as blastomycosis or cryptococcosis, feline infectious peritonitis, or
even mycobacterial infections. In the vast majority of cases, no etiologic agent is seen in section or identified in
any subsequent clinical or laboratory investigation.

Differential diagnosis
 The immediate task is to discriminate between idiopathic regional granulomatous/eosinophilic enteritis and
disease caused by one of the above-mentioned etiologic agents. Special stains such as PAS, methenamine
silver, and acid fast stains will help eliminate these infectious possibilities.
 FIP usually presents with a greater concentration of lesions in the subserosa and outer muscle layer, but some
cases will have genuine transmural disease. The lesion tends to be centered on blood vessels, and has the
almost diagnostic combination of lymphocytic-plasmacytic perivasculitis with neutrophils and fibrin. Truly
granulomatous lesions are uncommon, and eosinophilic necrotizing granulomas do not occur.
 Lymphoma and mast cell tumours, and occasionally scirrhous intestinal adenocarcinomas, may resemble
transmural granulomatous enterocolitis. While the debate is perhaps more relevant to similar lesions in people
and in horses, where the debate about distinguishing granulomatous transmural enteritis from pleomorphic
(“Mediterranean”) lymphoma rages on without any absolute consensus, we do have some difficulty
distinguishing pleomorphic lymphoma from this syndrome. Again, there is no problem if the disease is
characterized by discrete granulomas, but in those cases which are diffusely granulomatous, making a definitive
diagnosis may be impossible. A similar problem, of course, confronts us with lymphocytic-plasmacytic
enterocolitis that in some cases seems to undergo progressive transformation into outright lymphoma.
 For scirrhous intestinal colonic carcinomas, the use of PAS stains will accentuate the mucus production which
almost always is retained by these tumours, even when they are so anaplastic and scirrhous that the
identification of tubular or acinar profiles is impossible.

HISTIOCYTIC ULCERATIVE COLITIS (“BOXER COLITIS”)

Histological features
 The earliest lesion is multifocal aggregation of eosinophilic, foamy macrophages in the deep half of the lamina
propria and superficial submucosa of the colon.
 Coalescence of these histiocytic aggregates results in a thick diffuse band of macrophages that straddle the
muscularis mucosae, causing lifting and separation of the crypts. Overlying mucosa is ulcerated, and there
frequently is dysplastic regeneration of crypts.
 There frequently is involvement of submucosa, but usually much less dramatic than in the deep portion of the
lamina propria. While other leucocytes may accompany the histiocytes, the dramatic influx of large pale foamy
macrophages is absolutely characteristic.
 Special stains looking for intracellular bacteria are not rewarding. Despite reported observations of chlamydia-
like intracellular inclusions in these macrophages, and the occasional isolation of mycoplasma or Escherichia
coli from affected dogs, there has been no report of successful reproduction of the disease with any of these
agents.

Occurrence

15
 Because the disease appears to be restricted to boxers and breeds sharing genetic similarities (Boston terriers,
pugs, French bulldogs), the geographic prevalence of the disease parallels the geographic popularity of these
various breeds.
 Most affected dogs are young, usually less than 2 years old (and most often much younger when clinical signs
first appear).
 The persistent large bowel diarrhoea, with blood and mucus, responds poorly to therapy and euthanasia is the
eventual outcome. The dogs become very emaciated.

Differential diagnosis
 The histologic lesion, coupled with the characteristic age and breed predilection, is usually considered
diagnostic.
 Histoplasmosis may produce a very similar lesion, although the disease usually is not ulcerative, and the
macrophages contain large numbers of characteristic yeast bodies. Also, the lesions are not restricted to colon
and, as far as we know, the disease has no predilection for young boxers or French bulldogs.

INTESTINAL NEOPLASIA
There are remarkably few published reports dealing with the prevalence and behaviour of primary intestinal
neoplasia in either dogs or cats. Most of the studies are descriptive papers based on tumours discovered at post
mortem, and these studies are biased not only by those tumours large enough to be detected at necropsy or that have
caused clinical signs, but also by the likelihood that early intestinal lymphomas or papillary canine colonic
carcinomas are under-represented because they are not easily detected during routine post mortems. Despite the fact
that a wide range of neoplasm has been reported within the small intestine or colon, in reality the vast majority fit
into four diagnostic categories: intestinal lymphoma, transmural invasive adenocarcinoma, papillary colonic
carcinoma-in-situ, and smooth muscle tumours arising from the tunica muscularis. There is little point in presenting
the scant available data on the relative prevalence of the various types, for the data are greatly biased by the nature
of the detection methods used. Some studies, for example, are based on observation at necropsy, while others are
based on a cohort of animals presenting with clinical signs of gastrointestinal disease. A very different set of
figures, for example, would emerge if one were to examine endoscopic biopsy data (in which instance colonic
papillary carcinomas and lymphoma would undoubtedly dominate) as opposed to information gathered from
exploratory surgery or necropsy, in which smooth muscle tumours and transmural small intestinal carcinomas would
predominate. Neither of these latter two tumours would be detectable with endoscopic examination.
We are again haunted by inconsistencies in nomenclature, and by changing diagnostic criteria. In some studies in
the 1970s and early 1980s, diagnoses of intestinal carcinoids were fashionable even though unsupported by electron
microscopy or immunohistochemistry. We rarely make that diagnosis today, and there are suggestions that many of
the tumours once thought to be carcinoids would probably be reclassified as mast cell tumours or even lymphomas.
In another area of controversy, the nomenclature applied to the papillary colonic carcinomas-in-situ, which are
undoubtedly the most common intestinal neoplasm in dogs, varies from nondescript colonic “polyp” to adenomatous
hyperplasia to, as we prefer, carcinoma-in-situ. Even the diagnosis of intestinal lymphoma is fraught with
interpretive difficulties, although in this case the difficulty is at least an honest one in that everyone has great
difficulty deciding at what point a chronic lymphocytic-plasmacytic enteritis might be undergoing transition to
lymphoma, an event which apparently occurs in both dogs and cats.
Rapid changes in diagnostic sophistication (particularly, in various imaging techniques) and advances in both
surgical management and chemotherapy, make reference to any prognostic data published in the past 20 years
invalid. We are once again best by the misleading survival data based upon discovery of the tumours very late in
their natural progression, so that a short survival time prior to the onset of clinical signs related to metastatic disease
is predictable. As client education and sophistication of diagnostic techniques improves, we are almost certainly
discovering these tumours at an earlier stage in their evolution, and that fact alone should result in a much longer
post-diagnosis survival interval.

16
TRANSMURAL INTESTINAL ADENOCARCINOMA

Histological features
 This tumour is virtually identical in microscopic appearance and in behaviour to gastric carcinomas, in that
most specimens are very invasive scirrhous carcinomas.
 Several different architectural variations occur, but many tumours have a mixture of types. Solid scirrhous
carcinomas are perhaps the most frequent, but some are well-differentiated tubular and acinar adenocarcinomas.
All exhibit very aggressive transmural invasion, so there seems not much prognostic significance to
distinguishing among the architectural subtypes.
 Mucin production, as in gastric tumours, is highly conserved and even the most anaplastic tumours will usually
have small lakes of mucin to mark the transmural footprints of the tumour.
 Signet ring cells often are present, but are not necessary to establish the diagnosis. Only very anaplastic small
cell carcinomas present a diagnostic challenge, sometimes difficult to distinguish from granulomatous
transmural enteritis or even atypical “histiocytic” lymphomas.

Occurrence
 Small intestinal adenocarcinomas are relatively more frequent in cats than in dogs, and almost invariably
present as segmental scirrhous annular tumours affecting the ileum. Because of the fibrous tissue, the tumour
will often present under clinical circumstances mimicking intestinal obstruction, and over half are palpable
upon routine physical examination.
 In cats, colonic carcinoma is virtually indistinguishable from the typical small intestinal variety described
above.
 Invasive adenocarcinomas of the canine colon are rare, and the vast majority of canine colonic neoplasms are
exophytic papillary carcinoma-in-situ, which have almost no potential for transmural invasion.
 In dogs, there is no breed predilection, but the age range for affected animals is unusually broad, with the
prevalence in 5 year old dogs as high as in dogs in the traditional “cancer age” of 9, 10, or 11.
 It is claimed that Siamese cats are at greatly increased risk for small intestinal carcinomas, when compared to
other breeds.

Differential diagnosis
 These tumours are distinctive, and ordinarily present no difficulty in diagnosis.
 The most frequent difficulty is seen with very anaplastic and scirrhous carcinomas which do not have good
tubular or acinar formation, and which may be confused with granulomatous transmural enteritis. PAS stain to
accentuate goblet cells or extracellular lakes of mucin within tunica muscularis is a very powerful diagnostic
tool. For unexplained reasons, mucin production by these tumours appears to be highly conserved.

Behaviour
 Published papers paint a uniformly dismal picture, with survival times following intestinal resection being no
more than a few weeks in cats, and 2 or 3 months in dogs. The transmural migration of tumour gives rise to
widespread involvement of mesenteric lymph nodes, transperitoneal implantation, and metastasis to liver and
other abdominal organs.
 It seems reasonable to assume that better imaging techniques, and a general increase in the frequency and
quality of veterinary care (especially for cats) should result in earlier diagnoses and, inevitably, a longer post-
surgical survival time. Theoretically, early detection of these segmental transmural carcinomas could result in
some cures by early and complete excision. To our knowledge, there is no information on chemotherapy or
radiation.

17
LEIOMYOMA/LEIOMYOSARCOMA

Histological features
 These are classical smooth muscle tumours, similar in all respects to tumours of the same name developing in
other tubular viscera.
 There is no clear distinction between the benign and malignant variants, with the name leiomyosarcoma being
applied to those with more cellular pleomorphism, more mitotic figures, and a less well circumscribed growth
habit than the benign tumours.
 Broad interlacing bundles of plump spindle cells, with classical blunt-ended “cigar-shaped” nuclei characterize
all variations of this tumour.
 Ordinarily, they arise within the tunica muscularis and grow as exophytic firm white nodules (although the
occasional example remains intramural or even bulges into the intestinal lumen).

Occurrence
 Smooth muscle tumours are relatively common (second to intestinal carcinomas) in dogs, but are apparently
quite rare in cats.
 Most are behaviourally benign, small, flat or pedunculated masses visible only from the serosal surface and thus
not detectable by endoscopic examination.

Differential diagnosis
 When occurring in their typical configuration, there is no real differential consideration. One report claims
intestinal fibrosarcomas to be almost as prevalent as leiomyomas, but the criteria for making the distinction
were not given and no photographs were published.
 Particularly within colon, disgorgement of mucin from goblet cells results in apparent “goblet cell atrophy” that
is a very sensitive and rapid indicator of any type of mucosal irritation.
 In the vast majority of cases, there is no involvement of submucosa or tunica muscularis. If such involvement is
prominent, then you should consider alternative diagnoses such as lymphoma, mast cell tumour, transmural
granulomatous (regional) enteritis, or (for eosinophilic disease) visceral larval migrans.

RECTAL/COLONIC ADENOMATOUS HYPERPLASIA (RECTAL POLYP, CARCINOMA-IN-

SITU)

Histological lesions
 There is abrupt, focal exophytic (intralumenal) papillary hyperplasia of the colonic/rectal epithelium.
 Within the polypoid lesion, the epithelium is hyperchromatic, more than one cell layer thick, and somewhat
jumbled. However, the cells usually retain a high degree of columnar maturation.
 The transition from normal mucosa to the polypoid lesion is usually very abrupt, and the lesion often seems to
be "grafted" on to the surface of the underlying normal mucosa.
 There is almost never invasion by the atypical cells through the muscularis mucosae. Such invasion is seen in
about one percent of cases, and justifies the diagnosis of rare, genuine colonic carcinoma.

Occurrence
 This is a lesion seen exclusively in dogs, where it is quite common. It is by far the most frequent "neoplastic"
lesion anywhere within the canine intestine.

Etiology
 Unknown

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Differential Diagnosis
 The only consideration would be whether this tumor is going to be limited to a superficial growth habit, or will
be one of the rare examples that seems to undergo transition into truly invasive colonic carcinoma.
 The key to the distinction is the presence or absence of invasion across the muscularis mucosae. In many
surgical samples, you may not have sufficient depth to make that judgment.

Behavior
 With rare exceptions, these are solitary tumors that are easily cured by routine excision. It is hard to judge
whether the occasional recurrence is due to an unusually infiltrative behavior, or just to improper initial
excision.
 About one percent have submucosal invasion, and potential for invasion into regional lymph nodes. Systemic
metastasis is extremely rare. I do not know whether this represents malignant transformation within the
originally benign tumor, or whether the tumor was malignant from the start.

RECTAL PLASMACYTOMA

Histologic appearance
 a relatively well-circumscribed nodule of pleomorphic hyperchromatic round cells within the rectal mucosa and,
especially, the submucosa.
 the histologic features are similar to plasmacytomas elsewhere, with features like delicate fibrovascular stromal
packaging, all occasional mononuclear gigantism with extensive nuclear convolution, and at least some hint of
plasmacytoma aid maturation.
 at least some examples have evidence of peripheral invasion, and it greater degree of nuclear pleomorphism
than is usual

Occurrence
 This tumor is uncommon, but not rare, in older dogs.

Behavior
 Rectal plasmacytoma is frequently locally infiltrative, presenting a challenge in terms of surgical cure. Invasion
into the tunica muscularis, pelvic cavity, and even into regional lymph nodes occurs in unknown percentage of
cases.

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