—  SPECIALTY CONFERENCE  —

Gastrointestinal Pathology

Case 2 - Cronkhite-Canada Syndrome, Involving the Stomach, Small Bowel, and Colon

Lisa Yerian
The Cleveland Clinic


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Clinical History:
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 biopsy review.


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.

Final Diagnosis:
Cronkhite-Canada Syndrome, Involving the Stomach, Small Bowel, and Colon

Discussion:
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 [1]. 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 [2]. 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 [3]

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 [4]. The polyps are partly translucent in resection specimens, probably due to their edematous nature [5]. 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 [6, 7]. 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 [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18], 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 [2]. However, whether CCS contributes to malignant transformation or CCS becomes superimposed on neoplastic epithelium has not been delineated.

Differential Diagnosis
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 hyperplastic polyps.

2. Juvenile polyps/Juvenile polyposis syndromes: A comparison between CC polyps and juvenile polyposis has been outlined [4]. Three gastrointestinal syndromes are characterized by juvenile polyps – juvenile polyposis syndrome, Cowden syndrome, and Bannayan Riley Ruvalcaba syndrome [19]. 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.

References:
  1. Cronkhite LW, Canada WJ. Generalized gastrointestinal polyposis; an unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. N Engl J Med 1955;252(24):1011-5.

  2. Daniel ES, Ludwig SL, Lewin KJ, Ruprecht RM, Rajacich GM, Schwabe AD. The Cronkhite-Canada Syndrome: An analysis of clinical and pathologic features and therapy in 55 patients. Medicine (Baltimore) 1982;61(5):293-309

  3. Blonski WC, Furth EE, Kinosian BP, Compher C, Metz DC. A case of Cronkhite-Canada syndrome with taste disturbance as a leading complaint. Digestion 2005;71(4):201-5.

  4. Burke AP, Sobin LH. The pathology of Cronkhite-Canada polyps: A comparison to juvenile polyposis. Amer J Surg Pathol 1989;13(11):940-946.

  5. Kindblom LG, Angervall L, Santesson B, Selander S. Cronkhite-Canada syndrome: Case report. Cancer 1977;39:2667-2673.

  6. Ward EM, Wolfsen HC. Pharmacological management of Cronkhite-Canada syndrome. Expert Opin Pharmacother 2003;4(3):385-9.

  7. Ward E, Wolfsen HC, Ng C. Medical management of Cronkhite-Canada syndrome. South Med J 2002;95(2):272-4.

  8. Watanabe T, Kudo M, Shirane H, Kashida H, Tomita S, Orino A, Todo A, Chiba T. Cronkhite-Canada syndrome associated with triple gastric cancers: a case report. Gastrointest Endosc. 1999 Nov;50(5):688-91.

  9. Egawa T, Kubota T, Otani Y, Kurihara N, Abe S, Kimata M, Tokuyama J, Wada N, Suganuma K, Kuwano Y, Kumai K, Sugino Y, Mukai M, Kitajima M. Surgically treated Cronkhite-Canada syndrome associated with gastric cancer. Gastric Cancer. 2000 Dec 27;3(3):156-160.

  10. Malhotra R, Sheffield A. Cronkhite-Canada syndrome associated with colon carcinoma and adenomatous changes in C-C polyps. Am J Gastroenterol 1988 Jul;83(7):772-6.

  11. Kaneko Y, Kato H, Tachimori Y, Watanabe H, Ushio K, Yamaguchi H, Itabashi M, Noguchi M. Triple carcinomas in Cronkhite-Canada syndrome. Jpn J Clin Oncol 1991;21(3):194-202.

  12. Murai N, Fukuzaki T, Nakamura T, Hayashida H, Okazaki M, Fujimoto K, Hirai T. Cronkhite-Canada syndrome associated with colon cancer: report of a case. Surg Today 1993;23(9):825-9.

  13. Nakatsubo N, Wakasa R, Kiyosaki K, Matsui K, Konishi F. Cronkhite-Canada syndrome associated with carcinoma of the sigmoid colon: report of a case. Surg Today 1997;27(4):345-8.

  14. Yamaguchi K, Ogata Y, Akagi Y, Sasatomi T, Ozaki K, Ohkita A, Ikeda H, Shirouzu K. Cronkhite-Canada syndrome associated with advanced rectal cancer treated by a subtotal colectomy: report of a case. Surg Today 2001;31(6):521-6.

  15. Jain A, Nanda S, Chakraborty P, Kundra A, Anuradha S, Reddy BS, Kar P. Cronkhite-Canada syndrome with adenomatous and carcinomatous transformation of colonic polyp. Indian J Gastroenterol 2003;22(5):189-90.

  16. Nagata J, Kijima H, Hasumi K, Suzuki T, Shirai T, Mine T. Adenocarcinoma and multiple adenomas of the large intestine, associated with Cronkhite-Canada syndrome. Dig Liver Dis 2003;35(6):434-8.

  17. Takeuchi Y, Yoshikawa M, Tsukamoto N, Shiroi A, Hoshida Y, Enomoto Y, Kimura T, Yamamoto K, Shiiki H, Kikuchi E, Fukui H. Cronkhite-Canada syndrome with colon cancer, portal thrombosis, high titer of antinuclear antibodies, and membranous glomerulonephritis. J Gastroenterol 2003;38(8):791-5.

  18. Yashiro M, Kobayashi H, Kubo N, Nishiguchi Y, Wakasa K, Hirakawa K. Cronkhite-Canada syndrome containing colon cancer and serrated adenoma lesions. Digestion 2004;69(1):57-62.

  19. Chow E, Macrae F. Review of juvenile polyposis syndromes. J Gastroenterology and Hepatology 2005;20:1634-40.