Case 2 -
Cronkhite-Canada Syndrome, Involving the Stomach, Small Bowel, and Colon
The Cleveland Clinic
Click on each slide thumbnail image for an enlarged view
The patient is a 71 year old woman with six month history
of a severe gastrointestinal illness which presented clinically with diarrhea and a protein-losing
enteropathy. The symptoms began after travel to the east coast of the United States. The patient was
also recently found to have positive IgM titers for Lyme disease, for which she received treatment.
Endoscopy showed marked polypoid abnormalities throughout the stomach, small bowel, and colon, but no
biopsies were obtained. The esophagus appeared normal. The patient received oral steroids for her
gastrointestinal illness with some resolution in symptoms. A repeat endoscopy demonstrated persistent
polypoid abnormalities with minimal interval improvement. Biopsies were taken from polyps and
intervening mucosa. Serologic markers for gluten sensitive enteropathy were pending at the time of
Case 2 - Figure 1
Colon Flat Mucosa - Histologic abnormalities are seen in polypoid and nonpolypoid colonic mucosa. Sections from "flat" colonic mucosa demonstrate separation of the crypts by an edematous lamina propria.
Case 2 - Figure 2
Sigmoid polyp 2 - Focal nuclear enlargement and hyperchromasia is seen at the surface of a polyp.
Case 2 - Figure 3
Sigmoid polyp 3 - Some of the colonic crypts are cystically dilated.
Case 2 - Figure 4
Sigmoid polyp 4 - This sigmoid polyp demonstrate marked crypt architectural distortion. The crypts are widely separated by an edematous and inflamed lamina propria.
Case 2 - Figure 5
Small bowel - Occasional crypts are cystically dilated.
Case 2 - Figure 6
Small bowel 2 - Crypts are unevenly spaced in an edematous and inflamed lamina propria.
Case 2 - Figure 7
Small bowel 3 - Small bowel biopsies exhibit lamina propria edema and inflammation.
Case 2 - Figure 8
Stomach Flat Mucosa - The intervening nonpolypoid mucosa exhibits lamina propria edema and inflammation similar to that seen in the stomach polyps.
Case 2 - Figure 9
Stomach polyp 1 - The lamina propria exhibits marked edema and inflammation including lymphocytes and eosinophils. There is also foveolar hyperplasia.
Case 2 - Figure 10
Stomach polyp 2 - A stomach polyp exhibits foveolar hyperplasia with lamina propria edema and inflammation.
Case 2 - Figure 11
Stomach polyp 3 - Inflammation and marked lamina propria edema in a gastric polyp.
Cronkhite-Canada Syndrome, Involving the Stomach, Small Bowel, and Colon
Cronkhite-Canada Syndrome (CCS) was described in 1955 by Drs. Cronkhite and Canada in their series of
patients with multiple gastrointestinal polyps, onycholysis, alopecia, and skin hyperpigmentation .
CCS is now recognized as a nonhereditary gastrointestinal polyposis associated with ectodermal changes,
diarrhea, and weight loss. In the series by Daniel et al., initial symptoms of diarrhea, abdominal
discomfort and anorexia were followed by weight loss and edema, with ensuing ectodermal manifestations
over weeks to months, although in a few patients, nail changes and/or hair loss were the initial symptoms
. Other clinical features of CCS include protein-losing enteropathy, weight loss, weakness,
hematochezia, vomiting, and xerostomia. Paresthesias, seizures, and tetany may occur, presumably related
to the severe fluid and electrolyte losses. A wide variety of extraintestinal manifestations have also
been reported in patients with CCS, including patchy vitiligo, marked peripheral edema, glossitis,
thrombosis, schizophrenia, eosinophilic gastroenteritis, hypothyroidism, arthritis, and cataracts. Five
clinical types have been outlined based on initial clinical features 
As in our case, the diagnosis of CCS is made based on the combination of clinical, endoscopic, and
histologic features. The distinctive clinical picture is crucial because when taken out of their
clinical context, the histologic features are largely nonspecific. CC polyps are histologically similar
to juvenile polyps and characterized by a broad, sessile base, edematous stroma, and cystically dilated
glands . The polyps are partly translucent in resection specimens, probably due to their edematous
nature . Biopsy specimens obtained from the polyps and the intervening, nonpolypoid mucosa both
demonstrate lamina propria edema and inflammation, associated with cystic gland dilatation. A key
feature of CCS lies in the fact that, unlike other polyposis syndromes, in CCS the histologic
abnormalities are seen both in the polyps and in the intervening, flat mucosa. Inflammation is variable
but generally mild, and smooth muscle fibers may be seen. The esophagus is characteristically spared.
The etiology and pathogenesis are unknown. CCS treatment is largely supportive (rehydration, electrolyte
correction), although steroid, antibiotic, and surgical therapies have been administered with varying
success. Controlled clinical trials are unfeasible due to the rarity of the disease, but combination
therapies including steroids, antibiotics, histamine receptor antagonists, and cromolyn sodium have been
used with success
Complications of malnutrition, bleeding, infection, and fluid/electrolyte
imbalances may be fatal in a high proportion of patients (50-60%).
Although the polyps are generally accepted as non-neoplastic in nature, there are numerous reports of
CC occurring in association with gastric and colonic carcinomas and adenomas
and the association
of CCS with gastrointestinal carcinomas is not well understood. In most patients, the polyps are not
dysplastic, but in a large series 15% of patients (8 of 55) had a gastrointestinal malignancy at the time
of diagnosis . However, whether CCS contributes to malignant transformation or CCS becomes
superimposed on neoplastic epithelium has not been delineated.
1. Gastric hyperplastic polyps: While isolated gastric polyps may be impossible to distinguish based
on histologic grounds alone, intestinal and colonic involvement are not seen in association with gastric
2. Juvenile polyps/Juvenile polyposis syndromes: A comparison between CC polyps and juvenile
polyposis has been outlined . Three gastrointestinal syndromes are characterized by juvenile polyps –
juvenile polyposis syndrome, Cowden syndrome, and Bannayan Riley Ruvalcaba syndrome . The
hamartomatous polyps of Cowden syndrome are similar in histology and distribution to those of CCS. These
processes are distinguished by their extraintestinal manifestations and the normal intervening mucosa
found in juvenile polyposis.
3. Inflammatory pseudopolyps/Inflammatory polyposis: Strictly speaking, an inflammatory pseudopolyp
is an area of regenerating mucosa surrounded by ulcer, but the term is sometimes referred to many
inflamed, nonneoplastic polypoid lesions. Since CC polyps are not surrounded by ulcers, they are not
strictly "pseudopolyps." Whether the inflammation is a primary or secondary phenomenon is unknown.
4. Ménétrier's disease: Also characterized by a protein-losing enteropathy, diarrhea, and sometimes
edema, the thickened gastric folds of Ménétrier's disease may mimic the diffuse mucosal abnormality seen
in CCS. Polypoid lesions can also be seen in Ménétrier's disease. Ménétrier's disease involves the
gastric body and fundus, and is not characterized by the marked lamina propria edema seen in CCS. Of
note, similar histologic features can also be seen in association with cytomegalovirus infection. In
CCS, the clinical context and involvement of the small and large intestine are distinctive.
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