The patient was then diagnosed as CCS according to her symptoms, endoscopic findings, and pathology report. We prescribed Chinese herbal medicines and Arsanyl 100 mg tid in addition to esomeprazole 20 mg p.o. Bid for her. The treatment principle of Chinese herbal medicines was nourishing the liver and kidney according to the theory of traditional Chinese medicine, the chief medicinal was prepared rehmannia root, Radix Rehmanniae Praeparata.
Cronkhite-Canada syndrome (CCS) is characterized by polyposis, which can occur anywhere in the gastrointestinal tract except the esophagus. Initially CCS was considered to be a hamartomatous polyposis syndrome, but it is now thought that the polyps can additionally be inflammatory, adenomatous, and hyperplastic in type. Other clinical manifestations of CCS include ectodermal changes, such as onychomadesis, alopecia, and cutaneous hyperpigmentation. Symptoms include diarrhea, weight loss, abdominal pain, taste abnormalities, and features of malnutrition. Anemia, serum electrolyte disturbances, and hypoproteinemia are common in CCS patients as a result of chronic diarrhea and malnutrition. Osteoporotic fractures may result from malabsorption of calcium or prolonged glucocorticoid therapy or both 3 and death can occur for a variety of reasons including severe infection and malignant change. Goto divided the disease into 5 types according to the principal symptom:2 Diarrhea (type 1), dysgeusia (type 2), sensory abnormalities in the mouth accompanied by thirst (type 3), abdominal symptoms other than diarrhea (type 4), and alopecia as a predominant symptom (type 5). All patients must have gastrointestinal polyposis and hyperpigmentation although there is a report of a possible case of CCS without polypsis but severe atrophy and diffuse marked edema of the gastric and duodenal mucosa.4 As ectodemal change and vitiligo are prominent, scalp biopsy has shown noninflammatory loss of follicular units, miniaturization of the hair shafts, markedly dilated follicles, and heavy deposition of glycosaminoglycans in the reticular dermis.5
The initial symptoms of our case were abdominal pain, purulent diarrhea with rectal bleeding. Consequently, she would have been classified as type I, as the other features including the partial loss of taste and the ectodermal changes, such as onychomadesis, alopecia, and hyperpigmentation, appeared later. It was interesting to note that in our case, following treatment with mesalamine and dexamethasone, the abdominal pain and diarrhea were the first features to be relieved. The improvement in onychomadesis and regrowth of hair followed later raising the possibility that the first features to appear maybe the first to improve with treatment.
The cause of CCS is completely unknown and there is no evidence that it is a hereditary disease other than 1 case report of the condition occurring in a 50-year-old man and his son.6 There have been reports of increased levels of IgG4 or IgG4 containing plasma cells in the polyps of CCS 7,8 although this could not be confirmed in another study where out of 7 cases only 1 showed an increased IgG4-positive plasma cells. Consequently, the current evidence for some form of immune abnormality is not sufficient to draw any firm conclusions.
Some cases have been reported to be associated with hypothyroidism.9 In our case the TSH was minimally elevated 4.31 μIU/mL (0.27–4.2) although the T3, T4, Free T3, and Free T4 were all normal. Interestingly thyroid nodules were found on ultrasound examination.
There is also some preliminary work from Asia suggesting there may be some relationship with H. pylori infection.10–12 However, in view of the ubiquitous distribution of this organism in Asia it would be of interest to assess the prevalence of CCS in geographical areas with a low prevalence of H. pylori.
There is no specific treatment for CCS although a variety of approaches have been tried on an empirical basis.
Symptomatic and supportive treatment is important and may lead to improvement.13 This includes nutritional support with high-protein supplements or enteral feeding, correction of anemia and electrolyte imbalance, replacement of any mineral or vitamin deficiencies, as well as treatment of any associated infection.14–16 Proton pump inhibitors may also be worth prescribing.11
Progressive remission, including regression of the polyps, after H. pylori eradication has been reported 10–12 although in some of the reports it is not clear what the H. pylori status of the patients was before the start of treatment. CCS does appear to be common in Asia where the prevalence of H. pylori is high and it is noteworthy that there is a report incriminating this organism as a risk factor for the development colorectal adenomas.17 However, our patient had a negative carbon-13 breath hydrogen test and therefore was not given H. pylori eradication therapy.
In view of reports of a possible immunological basis for CCS, immunosuppression by corticosteroids or long-term azathioprine has been reported to lead to improvement.7,8,18 Corticosteroids are more frequently used to maintain remission although they carry the risk of osteoporotic fracture.3 Not surprisingly, there have been no controlled trials assessing the optimal dosage or duration of treatment with corticosteroids or azathioprine for the treatment of CCS. Furthermore, following any remission, it is still uncertain whether medication should be continued and if so, at what dose. The possibility of using mesalazine has also been explored with the suggestion that some patients might improve with this drug or sulphasalazine .15,19 In cases where there is a failure to respond to steroids, cyclosporine may be worth considering.20 In addition, a recent study has shown that TNF may play an important role in the development of CCS. Consequently, infliximab may be worth considering and Watanabe and colleagues have tried this drug in a patient suffering from frequent relapses with high levels of tumor necrosis factor alpha (TNF-α) in tissue affected by CCS. They showed that after 20 months of treatment the patient experienced a complete remission with disappearance of the polyposis.21 The role of surgery in the treatment of CCS is unclear, but it may have to be considered if complications develop.16 Adenomas found at endoscopy should be removed and followed up by surveillance endoscopy to facilitate early detection of any malignancies which can then be treated appropriately.
The literature suggests that CCS has a poor prognosis with Poulson and colleagues suggesting a 5-year mortality of 55%.22 Furthermore there also seems to be a relatively high risk of malignancy at a variety of sites both inside and outside the gastrointestinal system. However, because the condition is so rare, estimates of survival rates and the prevalence of cancer in CCS are unlikely to be very accurate. However, as there seems to be some evidence that better treatment regimes are being developed for CCS these figures might be expected to improve.
There seems little doubt that the majority of cancers in CCS are in the gastrointestinal with the suggestion that ∼14 % of patients develop this complication.23 Gastric cancer seems to be the most common malignancy with a Japanese study reporting a prevalence of 10.2%. Some cases had multiple gastric cancers of the stomach which tended to be well differentiated and often limited to the submucosa. 24,25 Carcinomas also occur in colon 26 and rectum.27,28 Serrated adenomas appear to account for 40% of the polypoid lesions in CCS which is much higher than their prevalence in polyps in the general population and patients with colorectal cancer associated with CCS frequently have polyps containing serrated adenomas.29
Interestingly, patients with CCS seem to have a tendency to develop extra-intestinal cancer, such as cholangiocellular carcinoma,30 giant cell bone tumor, 31 and lung cancer.32 In addition, some cases of CCS have been associated with cancer in >1 organ with one report describing cancer in the esophagus, stomach, and lung 32 and another concomitant esophageal and gastric cancers.33
Steroids and anti-TNF treatment seems to show promise in the treatment of CCS and there is a report of raised CEA levels falling after treatment with steroids. In addition, if the disappearance of polyps previously reported following the use of an anti-TNF 21 can be confirmed, this suggests that these drugs should perhaps be introduced at an earlier stage. Obviously, there is a strong need for long-term follow-up studies in order to determine whether some of the more encouraging treatment results reported recently are maintained over time. In 1 case of CCS, the CEA level increased remarkably and then decreased following prednisolone treatment. Whether steroid or anti-TNF therapy can lower the risk of carcinomas in the long term will need longer follow-up of patients taking this type of medication.
In view of the fact that malignant change in the gastrointestinal system is a significant risk in CCS, appropriate screening needs to be put in place, although there are currently no guidelines on how this should be done and at what frequency.
Cronkhite-Canada syndrome is a rare nonhereditary polyposis condition, which needs to be differentiated from other polyposis syndromes such as Peutz–Jeghers syndrome, familial adenomatous polyposis, juvenile polyposis syndrome, and Cowden syndrome. This should not be difficult when all the other features are present but when they appear later, as in our case, the diagnosis can be more difficult to establish.
The observation that remission can sometimes be induced by the eradication of H. pylori suggests that some form of infection might be important in the pathogenesis of CCS. However, not all cases are associated with H. pylori infection, raising the possibility that the antibiotic combination used for the eradication of H. pylori might be clearing another, not yet identified, organism. Perhaps a lesson needs to be learned from Whipples disease and the subsequent identification Tropheryma whipplei.
Another possible mechanism that has been implicated in the pathogenesis of CCS is autoimmunity. Some support for this hypothesis comes from reports that the condition seems to improve with immunosuppressive therapy such as corticosteroids, azathioprine, cyclosporine, and more recently anti-TNF treatment. However, it remains to be determined whether anti-infectives or immunosuppressives should be used alone and, if so, which is best. Furthermore, some form of a combination of these 2 approaches might achieve even better results than the 2 treatments alone.
It has been traditional to consider that CCS is associated with a poor prognosis and a 5-year mortality of 55% after diagnosis has been reported.22 However, in the cases reported from China, the mortality has not been so high and, so far, our patient's illness has been relatively mild. In addition, with the advent of treatment modalities that seem to have a significant impact on the course of the disease, it is likely that the outlook will improve further.
Rather than relying on a series of case reports with variable follow-up, a strong case could be made for the introduction an international CCS patient registry to enable the prognosis and treatment of CCS to be far more accurately established.
The patient has given written informed consent for her case to be reported. Because it was not a clinical trial and no off-label drugs was used, the ethical approval is not necessary for this case report.
1. Cronkhite LW Jr, Canada WJ. Generalized gastrointestinal polyposis; an unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. N Engl J Med
2. Goto A. Cronkhite-Canada syndrome: epidemiological study of 110 cases reported in Japan. Nihon geka hokan. Archiv Japanische Chirurgie
3. Yuan B, Jin X, Zhu R, et al. Cronkhite-Canada syndrome associated with rib fractures: a case report. BMC Gastroenterol
4. De Petris G, Chen L, Pasha SF, et al. Cronkhite-Canada syndrome diagnosis in the absence of gastrointestinal polyps: a case report. Int J Surg Pathol
5. Allbritton J, Simmons-O’Brien E, Hutcheons D, et al. Cronkhite-Canada syndrome: report of two cases, biopsy findings in the associated alopecia, and a new treatment option. Cutis
6. Patil V, Patil LS, Jakareddy R, et al. Cronkhite-Canada syndrome: a report of two familial cases. Indian J Gastroenterol
7. Sweetser S, Ahlquist DA, Osborn NK, et al. Clinicopathologic features and treatment outcomes in Cronkhite-Canada syndrome: support for autoimmunity. Dig Dis Sci
8. Riegert-Johnson DL, Osborn N, Smyrk T, et al. Cronkhite-Canada syndrome hamartomatous polyps are infiltrated with IgG4 plasma cells. Digestion
9. Bettington M, Brown IS, Kumarasinghe MP, et al. The challenging diagnosis of Cronkhite-Canada syndrome in the upper gastrointestinal tract: a series of 7 cases with clinical follow-up. Am J Surg Pathol
10. Okamoto K, Isomoto H, Shikuwa S, et al. A case of Cronkhite-Canada syndrome: remission after treatment with anti-Helicobacter pylori
11. Kim MS, Jung HK, Jung HS, et al. A case of Cronkhite-Canada syndrome showing resolution with Helicobacter pylori
eradication and omeprazole. Korean J Gastroenterol
12. Kato K, Ishii Y, Mazaki T, et al. Spontaneous regression of polyposis following abdominal colectomy and Helicobacter pylori
Eradication for Cronkhite-Canada Syndrome. Case Rep Gastroenterol
13. Lipin SP, Paul B, Nazimudeen E, et al. Case of Cronkhite Canada syndrome shows improvement with enteral supplements. J Assoc Physicians India
14. She Q, Jiang JX, Si XM, et al. A severe course of Cronkhite-Canada syndrome and the review of clinical features and therapy in 49 Chinese patients. Turk J Gastroenterol
15. Takakura HA M, Tsuchihashi N, et al. A case of Cronkhite-Canada syndrome markedly improved with mesalazine therapy. Dig Endosc
16. Ward EM, Wolfsen HC. Pharmacological management of Cronkhite-Canada syndrome. Exp Opin Pharmacother
17. Inoue I, Mukoubayashi C, Yoshimura N, et al. Elevated risk of colorectal adenoma with Helicobacter pylori
-related chronic gastritis: a population-based case-control study. International journal of cancer. J Int Cancer
18. Chadalavada R, Brown DK, Walker AN, et al. Cronkhite-Canada syndrome: sustained remission after corticosteroid treatment. Am J Gastroenterol
19. Ueyama H, Fu KI, Ogura K, et al. Successful treatment for Cronkhite-Canada syndrome with endoscopic mucosal resection and salazosulfapyridine. Tech Coloproctol
20. Ohmiya N, Nakamura M, Yamamura T, et al. Steroid-resistant Cronkhite-Canada syndrome successfully treated by cyclosporine and azathioprine. J Clin Gastroenterol
21. Watanabe D, Ooi M, Hoshi N, et al. Successful treatment of Cronkhite-Canada syndrome using anti-tumor necrosis factor antibody therapy. Endoscopy
2014; 46 (Suppl 1 UCTN):E476–477.
22. Poulsen A, Nielsen MF. Cronkhite-Canada syndrome is a rare polyposis syndrome. Ugeskrift Laeger
23. Fischer R, Breidert M, Paul S, et al. A patient with chronic diarrhoe, head pigmentation and alopecia. Cronkhite-Canada syndrome. Deutsche Medizinische Wochenschrift
24. Isobe T, Kobayashi T, Hashimoto K, et al. Cronkhite-Canada syndrome complicated with multiple gastric cancers and multiple colon adenomas. Am J Case Rep
25. Karasawa H, Miura K, Ishida K, et al. Cronkhite-Canada syndrome complicated with huge intramucosal gastric cancer. Gastric Cancer
26. Nakatsubo N, Wakasa R, Kiyosaki K, et al. Cronkhite-Canada syndrome associated with carcinoma of the sigmoid colon: report of a case. Surg Today
27. Cho N, Tomita F, Tamamoto F, et al. Cronkhite-Canada syndrome associated with rectal cancer. Rinsho hoshasen. Clin Radiography
28. Nagata J, Kijima H, Hasumi K, et al. Adenocarcinoma and multiple adenomas of the large intestine, associated with Cronkhite-Canada syndrome. Dig Liver Dis
29. Yun SH, Cho JW, Kim JW, et al. Cronkhite-Canada syndrome associated with serrated adenoma and malignant polyp: a case report and a literature review of 13 Cronkhite-Canada syndrome cases in Korea. Clin Endosc
30. Hirasaki S, Tanimizu M, Moriwaki T, et al. A case of Cronkhite-Canada syndrome associated with cholangiocellular carcinoma. Jpn J Gastroenterol
31. Triantafillidis JK, Kougioumtzian A, Leivaditou A, et al. Cronkhite-Canada syndrome associated with a giant cell bone tumor. J Gastrointest Liver Dis
32. Kaneko Y, Kato H, Tachimori Y, et al. Triple carcinomas in Cronkhite-Canada syndrome. Jpn J Clin Oncol
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
33. Ito M, Matsumoto S, Takayama T, et al. Cronkhite-Canada syndrome associated with esophageal and gastric cancers: report of a case. Surg Today