J Gastroenterol (2016) 51:327–336
DOI 10.1007/s00535-015-1107-7

ORIGINAL ARTICLE—ALIMENTARY TRACT

Endoscopic and clinical evaluation of treatment and prognosisof Cronkhite–Canada syndrome: a Japanese nationwide survey
Chikako Watanabe1 • Shunsuke Komoto1 • Kengo Tomita1 • Ryota Hokari1 •Masanori Tanaka2 • Ichiro Hirata3 • Toshifumi Hibi4 • Jonathan D. Kaunitz5 •Soichiro Miura1

Received: 20 May 2015 / Accepted: 13 July 2015 / Published online: 28 July 2015
Ó The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract
Background First reported in 1955, Cronkhite–Canada
syndrome (CCS), a rare syndrome characterized by ectodermal abnormalities and inflammatory changes of thegastrointestinal tract mucosa, has been associated with apoor prognosis and life-threatening malignant complications. In a large population survey, we endeavored tocharacterize the course and treatment outcome of CCS
through clinical and endoscopic assessment, and to explore
its optimal treatment and surveillance strategy.
Methods A retrospective analysis of 210 patients with
CCS was conducted via a questionnaire-based nationwide
survey of 983 teaching hospitals located throughout Japan.
We assessed clinical features, endoscopic findings, treatments used, and short- and long-term outcomes.

Electronic supplementary material The online version of thisarticle (doi:10.1007/s00535-015-1107-7) contains supplementarymaterial, which is available to authorized users.
& Chikako Watanabechikakow@ndmc.ac.jp

Results The average age at diagnosis was 63.5 years. In
all cases, upper or lower gastrointestinal tract polyposis
was confirmed, accompanied by characteristic ectodermal
abnormalities. Of the treatments used, oral corticosteroids(30–49 mg/day) were the most effective treatment for
active disease, with adjunctive nutritional support considered beneficial. With corticosteroid treatment, abdominal
symptoms were relieved within a few months, whereas
polyp regression often required more than 6 months.
Maintenance of endoscopic remission with or without
steroids for 3 years significantly lowered the developmentof CCS-related cancer, compared with relapsers or nonresponders, underscoring the importance of sustained endoscopic remission for cancer prevention.
Conclusions The prognosis of CCS has greatly improved
through the use of improved medical treatment. Although
CCS continues to be relentlessly progressive, carrying ahigh cancer risk, a sufficient dose and duration of corticosteroid therapy accompanied by nutritional support andperiodic endoscopic surveillance appears to improve its
natural history.
Keywords Acquired gastrointestinal polyposis
syndrome  Malnutrition  Gastric cancer  Colon cancer

1

Department of Internal Medicine, National Defense Medical
College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan2

Department of Pathology and Laboratory Medicine, Hirosaki
City Hospital, Aomori, Japan

Introduction

Department of Gastroenterology, Fujita Health University,
Aichi, Japan

Cronkhite–Canada syndrome (CCS) is an uncommon gastrointestinal polyposis syndrome characterized by dermatologic manifestations associated with chronic diarrhea,
malnutrition, and enteric protein wasting due to chronic
inflammatory changes of the intestinal mucosa [1–5]. The
risk of colon cancer in CCS patients may be elevated owing
to difficulties in detecting premalignant adenomas in the

3

4

Center for Advanced IBD Research and Treatment, Kitasato
Institute Hospital, Tokyo, Japan

5

Greater Los Angeles VA Medical Center and Department ofMedicine and Department of Surgery, David Geffen Schoolof Medicine, University of California, Los Angeles,
Los Angeles, CA, USA

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face of multiple inflammatory pseudopolyps. Since it was
first reported by Cronkhite and Canada [6], more than 400
cases of CCS have been reported worldwide, with 75 %reported from Japan [1, 3, 7–10]. Given the rarity of CCS,
current understanding is based on anecdotal reports andsmall case series, [10, 11], with no published systematicinvestigations based on endoscopic features. CCS issometimes difficult to diagnose for clinicians and pathologists alike, owing to the considerable overlap of histologic
and clinical features shared among CCS-related, juvenile,and inflammatory polyps [3, 12–14]. Its clinical course ischaracterized by progressive disease with occasional
spontaneous remissions and frequent relapses [15–18], withrare progression to malignancy [1, 19, 20]. Concomitantcancers occurring in the gastrointestinal tract have beenreported, although no systemic investigation of the cancer
risk and prognosis has been published since the 1980s [11,19–23]. The mortality of CCS can be up to 50 % if it isuntreated or if treatment is delayed or inadequate [11].
Nevertheless, no treatment in use to date is based on systematically acquired data based on the study of a large
population of CCS patients.
Current CCS treatments used individually or in combination include steroids [1, 11, 17, 18, 24], nutritional
therapy [25], 5-aminosalicylate acid [26], histamine H2
receptor antagonists [27], anti-tumor necrosis factor a(TNF-a) agents [28], immunomodulators [28], and eradication of Helicobacter pylori [29]. Steroids are considered
the mainstay of medical treatment, although the recommended dose and duration of their use have varied widelyin the literature, with no current ‘‘gold standard’’ [11, 17,
18, 30]. Since symptom relapse is common during a steroid
taper, a steroid-sparing strategy is needed.
The risk of gastrointestinal cancer may warrant
aggressive screening of CCS patients. Since it is nearly
impossible to endoscopically detect malignant polyps orconcurrent adenocarcinoma given the myriad of inflammatory-type polyps in CCS patients, an evidence-based
surveillance program is needed. Therefore the aims of thisstudy were (1) to elucidate the endoscopic characteristics,
long-term prognosis, and cancer risk of CCS, and (2) to
identify whether corticosteroid therapy can improve primary and long-term outcomes, and if so, what dose andduration are optimal, and (3) to suggest the ideal endoscopic surveillance schedule for CCS, by the use of datafrom a nationwide survey in Japan.

Materials and methods
A questionnaire-based nationwide survey of CCS was conducted in 983 Japanese teaching hospitals specializing in
gastroenterology. To obtain the most accurate endoscopic

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information, clinical and endoscopic data were collectedfrom hospitals registered with the Japanese Society of Gastroenterology. The preliminary survey asked: ‘‘Has yourinstitute treated patients with Cronkhite–Canada syndrome?
If yes, how many?’’ Responses were received from 591 of
983 facilities (60.1 %), revealing 213 patients with CCS
were treated in 140 facilities between 2000 and 2013. A
detailed survey was sent to these facilities, with information
obtained from 139 facilities describing 210 patients. The
detailed survey consisted of 133 question items organized
into 11 sections requesting detailed clinical features,
including endoscopic findings, polyp pathology, response totreatment, and prognosis, with an emphasis on the risk ofdeveloping gastrointestinal cancer.
Demographic and explicit clinical, laboratory, andendoscopic data were collected at the time of diagnosis.
Clinical symptoms such as diarrhea and ectodermal
abnormalities, and laboratory tests including testing forprotein-losing enteropathy, autoimmunity, or H. pylori
infection were documented. Endoscopic features included
the distribution pattern and size of polyps, and the mucosal
appearance of polyps, noting if they appear to be friable,
edematous, or engorged [31]. Histological features such as
gland dilation or crypt distortion such as branching orwithering and the degree of inflammatory cell infiltration
were noted.
Treatment outcome was evaluated in two stages. Early
outcome was evaluated 6–12 months after the start oftreatment or initial diagnosis. Treatment outcome wasassessed primarily on the basis of endoscopic improvementof mucosal findings. Early outcomes were classified into‘‘good response’’ and ‘‘no-response’’ groups. ‘‘Good early
response’’ was defined as partial regression of polyposis
with mild friability or decreased erythema. ‘‘Endoscopic
remission’’ was defined as the absence of polyposis withnormal appearance of mucosa, accompanied by a clinicalresponse. ‘‘No early response’’ was defined as no significant endoscopic improvement irrespective of clinicalresponse. ‘‘Clinical response’’ was defined as regression ofclinical symptoms accompanied by normalization of theserum albumin concentrations (clinical remission).
The subsequent outcome was evaluated over a 3-year
period after initial induction treatment with corticosteroids
had started, and patients were classified into ‘‘long-term
response‘‘ and ‘‘no long-term response’’ groups. ‘‘Longterm response’’ includes the maintenance of complete
remission and partial remission. ‘‘Complete remission’’
was defined as endoscopic and clinical remission without
ongoing medical treatment. ‘‘Partial remission’’ wasdefined as near endoscopic remission accompanied byclinical remission while the patient was receiving stablecorticosteroid therapy at less than 10 mg/day for more than
1 year. ‘‘No long-term response’’ includes episodically

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active disease and clinically chronic active disease withouta long-lasting endoscopic remission or improvement. In
episodic active clinical disease, frequent use of corticosteroids was necessary to prevent endoscopic relapse. In
chronic active disease, sustained endoscopic improvement
was not achieved, even with long-term, high-dose corticosteroid therapy. The v2 test was used to compare two
discrete variables, whereas the nonparametric test was used
to compare discrete and a continuous variable. Significancewas taken as 5 %. The study was approved by the Ethics
Committee of the National Defense Medical College.

Results
Of 210 patients with CCS, 136 were men and 74 were
women, yielding a male-to-female ratio of 1.84:1. The
mean age of onset of symptomatic disease was 63.5
(31–86) years. The observation period was 5.93 ± 4.85
(0.5–28) years. All patients were Japanese, except for two
non-Japanese Asian women. There was no evidence ofpolyposis in any blood relatives. Of the 210 patients, 33(15.7 %) had died at the time of the survey. Of the 33
deaths, ten were disease-related (three patients died ofgastric cancer, three patients died of colon cancer, and four
patients died of sepsis caused by colitis and pancreatitis),whereas the other 23 patients died of illness presumed to beunrelated to the primary disease (e.g., lung cancer, cerebral
stroke, and cardiac disease).
Two hundred three patients underwent esophagogastroduodenal endoscopy and/or ileocolonoscopy. The jejunal
and ileal mucosae were visualized by contrast radiography,
enteroscopy, and capsule endoscopy in 59, 29, and 37
patients, respectively. Table S1 gives the location and
Fig. 1 shows the endoscopic appearance of gastrointestinal
polyps. In this survey, in contrast to prior reports [10, 11],the esophagus was involved in 26 cases (12.3 %). Most of
the esophageal biopsies revealed nonspecific inflammation,and some showed squamous papilloma of the esophagus.
Compared with the stomach and colon, the jejunum andileum were not as severely involved, mostly populated withsparsely distributed smaller polyps (less than 10 mm),which are likely difficult to detect among the markedly
inflamed mucosa. Gastric and colonic polyps were mostly
sessile (2–40 mm) with engorged mucosa and rare punctate
hemorrhages. Gastric polyps were smaller and more confluent than their colonic counterparts (Fig. S1). The useful
distinguishing feature of juvenile polyps is abnormal-appearing edematous and reddish mucosa between polyps[12, 18], which was observed in the stomach and colon in
74 and 57.6 % of cases, respectively.
Analysis of the histological results of 189 stomach
biopsies and 197 colon biopsies revealed that nearly half of329

the gastric polyps (52.4 %; 99 of 189) and 57.9 % ofcolonic polyps (114 of 197) displayed common features
typical of CCS polyps such as focal dilated cystic glands,
some filled with proteinaceous fluid or inspissated mucus,
whereas the others displayed hyperplastic, inflammatory, or
adenomatous features. Prominent infiltration of eosinophils, lymphocytes, and neutrophils was present in one
third. Typically, the polyp and interpolyp area was edematous, with congestion and chronic inflammation of thelamina propria and submucosa, even though endoscopically the mucosa appeared normal (data not shown).
As shown in Table 1, 60 separate gastrointestinal tract
carcinomas (19 gastric cancers and 41 colon cancers) werediagnosed either at initial presentation or during theobservation period, with adenomas diagnose in 72 patients.
Cancer or adenoma was limited to the stomach or colon,with no dysplastic lesions located in the esophagus or in thesmall intestine. In the colon, 36 CCS patients (17.1 %)adenomatous changes were diagnosed at the first endoscopy. No preferential localization of colon cancer waspresent in CCS patients, with advanced colon cancers
evenly distributed throughout the large intestine (sixascending colon, one transverse colon, five sigmoid colon,
five rectum, two multiple sites).
The common symptoms or prevalent physical findings,
and laboratory data are shown in Table 2. Chronic diarrhea
was reported in 78.3 % of patients. Ectodermal changes
were present in more than 70 % of patients, with 91.3 %having the single finding of alopecia, onychodystrophy, or
skin hyperpigmentation (Fig. S1). Hyperpigmentation was
described as lentigo-like to light to dark brownish macules,
distributed on the palms and soles, upper extremities, face,and chest. Although rare, one of the important CCS complications is intestinal bleeding. Of 20 patients with gastrointestinal bleeding, two bled massively; one from aneroded gastric polyp, and the other from an advanced
gastric cancer. Another major complication is intussusception: ten patients developed colo-colic intussusception
due to a polyp serving as the intussuscipiens, with threerequiring surgical therapy.
As shown in Table 2, a significant decrease in total protein
and albumin was initially present, which improved after
initial treatment. Fecal a1-antitrypsin clearance or 99mTcalbumin scintigraphy revealed a high prevalence of gastrointestinal tract protein loss. Of 113 patients screened forH. pylori, 61 (54.0 %) were positive, with successful eradication in 15, with endoscopic remission or response attainedin 8 (53.3 %), although one patient developed gastric cancer
after successful eradication. Of the 19 CCS patients withgastric cancer (not included in the H. pylori screened subjects), two were negative for H. pylori, and six were positive.
Figure 2 depicts a flow diagram for the treatment andclinical course of the 210 patients. Nine patients did not

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Fig. 1 Endoscopic findings of gastrointestinal polyps in patients with
Cronkhite–Canada syndrome. A distribution and size of polyps. The
outer circle shows the distribution pattern, and the inner circle shows
the predominant size of the polyps. Data are expressed as thepercentage of the total number of patients. The dominant types in thesmall intestine were sparsely distributed smaller polyps. The polyps inthe stomach were more confluent than those in the colon (81.9 % vs54.5 %, p \ 0.01), and smaller (in the stomach 18.1 % were larger
than 15 mm, 51.4 % were 5–10 mm, and 30.5 % were smaller than

5 mm, and in the colon 30.4 % were larger than 15 mm, 44.6 % were
5–10 mm, and 25 % were smaller than 5 mm; p \ 0.05). B endoscopic appearance of polyps. Appearance was classified into four
categories (edematous, engorged, with erosion, or with hemorrhage)according to the most dominant appearance. C the endoscopic
appearance in the mucosa between the polyps was classified as
normal or abnormal. Abnormal usually indicates edematous or
reddish coarser mucosa than normal (74 % in the stomach and57.6 % in the colon, p \ 0.01)

Table 1 Number of Cronkhite–Canada syndrome patients associated with gastric and colorectal cancer or adenoma
CancerAdenoma

Gastric
Early

Colon
Advanced

Total

Early

Gastroduodenal
Advanced

Colon

Total

Associated patients
At initial presentation

7 (3.3 %)

6 (2.9 %)

13 (6.2 %)

11 (5.3 %)

15 (7.1 %)

26 (12.4 %)

4 (1.9 %)

36 (17.1 %)During observation

2 (1.0 %)

4 (1.9 %)

6 (2.9 %)

10 (4.8 %)

5 (2.4 %)

15 (7.1 %)

3 (1.4 %)

29 (13.8 %)Observation period (years)

10 ± 7.1

11.7 ± 7.0

11.0 ± 6.2

8.8 ± 4.6

10.2 ± 8.2

9.2 ± 5.9

7.7 ± 7.4

6.4 ± 4.8

Total

9 (4.3 %)

10 (4.8 %)

19 (9.1 %)

21 (10.1 %)

20 (9.5 %)

41 (19.5 %)

7 (3.3 %)65 (31.0 %)Therapeutic outcome
Endoscopic resection

6

16

3

35

Surgery

9

19

3

2

Death

3

3

3

1

Total of 210 patients. Adenomas bearing carcinomatous foci (n = 7), and adenomas that evolved into carcinoma (n = 28) were regarded ascancer. Three patients had both gastric and colon cancers, which were counted individually. All early colon cancers were found close to the
adenoma.

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331

Table 2 Clinical variables: symptoms and laboratory findings in Cronkhite–Canada syndrome
Symptoms

At initial diagnosis (%)

Overall frequency (%)

Diarrhea

70.0

78.3

Dysgeusia

64.8

81.3

Alopecia

49.0

80.0

Onychodystrophy

64.4

89.0

Hyperpigmentation

48.8

70.1

Bleeding

1.44

9.6

Intussusception

0.96

4.8

Laboratory findings

At initial diagnosis

After initial treatmentpb

Hemoglobin (g/dl)

13.0 ± 2.49

13.9 ± 2.02

0.68

Total protein (g/dl)

5.35 ± 0.94

6.37 ± 0.88

\0.01Albumin (g/dl)

2.96 ± 0.74

3.83 ± 0.63

\0.01

Total cholesterol (mg/dl)

147.2 ± 34.9

196.9 ± 42.0

\0.01

C-reactive protein (mg/dl)

0.94 ± 2.53

0.16 ± 0.38

\0.01

Laboratory findings

At initial diagnosis

Normal range

IgG (n = 91)
Positive ANA test result (n = 72)

812.6 ± 296.2 mg/dl
27.7 %

680–1620 mg/dl

Zinc (n = 65)

73.6 ± 21.7 lg/dl

80–160 lg/dl

Elevated a1-antitrypsin clearance (n = 30)

93.3 %\20 ml/day

Positive 99mTc-albumin scintigraphy finding (n = 56)

75 %Helicobacter pylori positivity (n = 113)a

54.0 %

Total of 210 patients.
ANA antinuclear antibodiesaDiagnostic testing for H. pylori was performed with one of or a combination of rapid urease testing, culture, histology, IgG antibodies to H.
pylori, or fecal antigen.

b

Statistical comparison laboratory data between ‘‘at initial diagnosis‘‘ and ‘‘after initial treatment’’receive any intervention. Among them, three experienced
spontaneous complete symptomatic remission without
medication or nutritional therapy, sustained for more than
5 years. Among 201 treated patients, 178 received corticosteroid treatment, with the others were treated either withnutritional therapy or with surgical or endoscopic treatment
alone. Treatment outcomes at 1 year were available for 173
patients: in the 23 patients who did not receive steroids, 21
were classified as having no early response, whereas a goodearly response was reported by 80.0 % (120/150) of thegroup in whom corticosteroid therapy was initiated andcontinued for 1 year. Among 30 no early response cases,
seven patients failed to respond who had progressive disease requiring intensive therapy, with 86 % receiving
intensive therapy, such as calcineurin inhibitors, octreotide,and anti-TNF-a agents, attaining a good early response.
Among those who were treated with corticosteroids for
1 year, the subsequent outcome was evaluated in 108
patients over the following 3 years.
Nutritional therapy, including total parenteral nutrition
and a defined-formula diet, frequently accompanied steroid

therapy. Among 150 patients receiving corticosteroid
treatment for 1 year, concurrent nutritional therapy wasused in 68 (45.3 %), with 94 patients receiving nutritional
therapy, including total parenteral nutrition and a definedformula diet. Yet, no significant difference in the goodearly response group was noted between groups receiving(90 %; 60 of 68) or not receiving (81 %; 61 of 75) nutritional therapy, suggesting no apparent additional beneficial
effect of the nutritional therapy used.
Figure 3 shows the time course of clinical features by
cumulative clinical remission rate after the induction of
medical treatment. Remission of diarrhea occurred over
51 days, followed by reversal of dysgeusia (84 days) andectodermal changes (97 ± 11.2 days). Decrease in the size
and number of polyps was slower, averaging 248 days for
gastric polyps and 238 days for colonic polyps.
Steroid therapy regimens differed among centers.
Although dose escalation improved therapeutic outcomes,
it was accompanied by severe side effects such as sepsis
and thrombosis for dosages exceeding 60 mg/day.
Table S2 depicts the 1-year endoscopic response (good

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early response) stratified by initial dose. Since a greaterthan 85 % response was observed with dosages exceeding
30 mg/day, dosing at 30–49 mg/day appears optimal.
The subsequent course of patients treated with corticosteroids is shown in Fig. 4. Among 108 CCS patients
who were initially treated with steroids and who wereregularly evaluated for more than 3 years, 61.1 % (66 of
108) had a long-term response, whereas 38.9 % (42 of 108)
had no long-term response. Of 66 patients who went into
endoscopic remission (long-term response) after completion of an initial trial of steroid therapy, 36 patients(54.5 %) remained in endoscopic remission without further
steroid therapy during the observation period (complete
remission), and 30 patients (45.4 %) had sustained endoscopic remission with stable low-dose corticosteroid therapy (less than 10 mg; partial remission). Of the 42 patients
who could not achieve sustained endoscopic remission (nolong-term response), 16 (38.0 %) experienced frequent
relapses after corticosteroid withdrawal (episodic active)
and 26 (61.9 %) relapsed during tapering or for themsteroid treatment could not be withdrawn (chronic active
disease).
The ultimate aim of treatment is to prevent thedevelopment of CCS-related cancer. As shown in Fig. 4,
sustained endoscopic improvement correlated with asignificantly diminished risk of developing gastrointestinal cancer and CCS-related death due to complications.
Among 66 patients with sustained endoscopic response(long-term response), only one case of cancer emerged,
with no CSS-related death during the 3 years, whereas inFig. 2 Flow diagram oftreatment choice and clinicalcourse of patients with
Cronkhite–Canada syndrome(CCS) *1 of 23 patients without
steroid treatment, eight patientswere treated with nutritional
therapy and 15 patients
underwent surgical/endoscopic
treatment alone. *2 among 30
patients who failed to respond tocorticosteroid treatment, sevenpatients showing progressive
disease required intensive
therapy with calcineurin
inhibitors (n = 4), octreotide(n = 1), anti-TNF-a agents(n = 1), and colectomy (n = 1).
With the exception of one
patient treated with acalcineurin inhibitor who failed
to respond, the others attainedendoscopic response

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the no long-term response group, a significantly higher
incidence of cancer (17/42) and CSS-related death (7/42)
was observed (p \ 0.01).
After initial steroid treatment, immunomodulators or
anti-TNF-a agents may possibly reduce or eliminate steroid use, preventing the recurrence of CCS-related polyps[5]. Of the five patients receiving azathioprine, two did not
relapse during 2–11 years of monitoring, although threedeveloped cancer with relapse of polyposis. Two patients
who received a calcineurin inhibitor and one patient who
received an anti-TNF-a agent remained in remission for
3 years. Nevertheless, in this survey, therapy with histamine H2 receptor antagonists or 5-aminosalicylate acid,
which were taken by 28 or 46 patients, respectively, did notaffect clinical or endoscopic outcomes or the risk of cancer
when it was combined with other medications (data notshown).
Of 37 surgical operations performed in 36 patients,
seven were for gastric cancer, 19 were for colon cancer,
three were for gastroduodenal adenoma, one was forsevere enteric protein loss, four were for intussusception,
two were for gastric bleeding, and one was for gastricgastrointestinal stromal tumor. No operative complications were reported. The mean duration of posttreatment
follow-up of the surviving patients was 5.1 (0–14) years.
Although symptomatic remission was attained in allcases, remission could not be attributed to the resection,
since medical therapy, in particular steroid treatment,
more likely contributed to the improvement.

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333

Fig. 3 The cumulative clinicalremission rate over time andmean time to remission.
Asterisk the mean time toremission is significantly longer
compared with the mean time
for diarrhea (p \ 0.05 vsdiarrhea), dagger p \ 0.05
versus onychodystrophy, S.E.
standard error

Fig. 4 Three-year outcome ofsteroid treatment in 108 patients
who attained a good response.
Of the 108 patients, 66 achieved
a long-term response (36‘‘complete remission’’ and 30‘‘partial remission’’), and 42 had
no long-term response (16‘‘episodic active’’ and 26‘‘chronic active’’). Among thosepatients, the occurrence ofcancer (4 gastric cancer and 14
colon cancer) and Cronkhite–
Canada syndrome (CCS)-related
death (one death due to sepsis
caused by colitis, two deaths
due to gastric cancer, and four
deaths due to colon cancer) are
shown

Discussion
We investigated the clinical characteristics, response to
medical treatment, and prognosis of 210 patients with CCS.
Contrary to earlier reports [10, 11], the prognosis of CCS has
greatly improved through advances in medical treatment,
although the course of CCS is relentlessly progressive,accompanied by an elevated cancer risk. Corticosteroid
therapy, timely endoscopic evaluation, and the progress of
medical management appear to improve the natural historyof CCS. From our study, the diagnosis of CCS is confirmed
by combination of clinical signs such as ectodermal abnormalities with characteristic foregut and hindgut endoscopic
findings. Small bowel involvement, characterized as sparsely distributed small polyps, was difficult to detect radiologically. Histological diagnosis depends on the sample

location, with the highest yield obtained from biopsies of thepolyp and the adjacent mucosa. Since adenoma or earlycancer commonly exists in the background of severe
inflammation, it is difficult to endoscopically discriminate
malignant polyps or concurrent adenocarcinoma among thenumerous inflammatory CCS polyps.
Clinical manifestations followed a similar course inmost patients, initially diarrhea, followed by ectodermalchanges, which were at times attributed to malnutrition,
since ectodermal changes improved with nutritional
repletion. Lastly, inflammatory polyposis slowly regressed,
taking as long as 240 days, indicating that long-termmonitoring is required to assess treatment outcomes, even,in most cases, after remission of clinical symptoms. We
thus strongly advocate continued endoscopic surveillanceeven after clinical remission has been achieved.

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Traditionally, steroid therapy and nutritional support are
the mainstays of medical treatment [1, 11, 17, 24]. We
confirmed that a 30–49-mg daily dose of orally administered prednisolone was optimal for active CCS. A too-rapid
steroid dose reduction can be associated with early relapse,
suggesting that the prednisolone dose should be slowly
tapered only after endoscopic confirmation of regression ofpolyposis. Poorer nutritional status at diagnosis may haveincreased the time to attain endoscopic remission withsteroid therapy; therefore, those at higher risk from steroid
therapy such as the elderly and those with a history oftuberculosis may benefit from nutritional support andconsequent shortening of the length of steroid regimens.
Steroid-sparing therapies such as cyclosporine A, octreotide, and an anti-TNF-a agent, which showed promise in a
few cases, can be used in steroid-resistant cases in order toinduce or maintain clinical remission. Although azathioprine used with or without steroid maintenance therapy wasreported to be associated with sustained clinical remission[1, 5, 32], we could not confirm this finding. Since
immunological dysregulation is one of the important factors hypothesized to be present in CCS [5, 14, 33–36], thelong-term use of immunoregulatory drugs or biologics may
be useful for active or refractory disease.
One of our major findings was that achievement ofsustained endoscopic remission was unambiguously associated with decreased cancer risk. Formerly, it was reported
that total regression of polyps could not be attained evenafter long-term sustained clinical remission, with ‘‘atrophic’’ polyps observed [37]. Although histological confirmation is difficult, endoscopic documentation ofregression of polyposis is likely to be an important primary
therapeutic end point.
The increased incidence of gastric and colorectal carcinoma suggests the need for regular surveillance [17]. As
previously mentioned, detection of malignancy at initialendoscopy is extremely difficult. Surveillance may be practical only after the diffuse inflammatory polyps have regressedwith steroid therapy, which then reveals the otherwise ‘‘buried’’ adenomas or cancer, even in patients with sustained
clinical remission. In four cases, advanced endoscopic imaging techniques, such as narrow-band imaging, magnifying
endoscopy, and dye-based contrast-enhancement techniques,
were helpful in identifying concurrent premalignant or
malignant lesions that could be successfully resected, as previously reported (data not shown) [38, 39]. The surveillanceinterval thereafter is empiric, but as a minimum annual
surveillance is recommended [1, 17], because in this survey
we observed endoscopic recurrence in several cases before
clinical recurrence approximately 1 year after discontinuation of corticosteroid therapy.
Another key question is the cause of the reversible
ectodermal and gastrointestinal mucosal abnormalities

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characteristic of CCS. Although numerous factors havebeen suggested, such as genetic abnormalities [40], stress[41], immune dysregulation [5, 34, 35, 42, 43], and lowturnover cell differentiation [37, 44], no consensus has
emerged, likely owing to the rarity of CCS. In our analysis,
no familial occurrence was verified, one patient improved
only after removal of stress, and another achieved prolonged clinical remission with nutrition therapy alone.
Nevertheless, remission in the absence of specific therapies
is difficult to distinguish from spontaneous improvement.
As for immune disorders, only six cases were comorbidwith immunological thyroid disease, one with rheumatoid
arthritis, and 22 were low-titer antinuclear antibodies
positive, inconsistent with an autoimmune cause [42].
There are several reports suggesting the strong associationof CCS with IgG4-related disorders [5, 34], but in thisstudy no examined serum sample was positive for IgG4,
although the number of samples studied was low (n = 10).
Moreover, no IgG4-positive plasma cells were reported inbiopsy specimens (data not shown). Other proposed theories such as dysregulation of crypt cell differentiation andaltered intestinal mucin production await experimental
confirmation [14, 37, 44].
The risk of neoplasia remains controversial, withongoing questions regarding the carcinogenic potential ofthe disease. Among 383 reported cases of CCS in Japan
from 1980 to 2011, 40 patients (54 lesions; 10.2 %) withcoincident gastric cancer and 51 patients (69 lesions) withcoincident colon cancer were identified [7, 9, 22, 45]. In
this study, the prevalence of gastric or colon cancer among
CCS patients was approximately 10–20 %, similar to previous reports, both significantly higher than the prevalenceof these cancers in the general Japanese population [46]. In
our survey, more than 75 % of gastric cancers were welldifferentiated adenocarcinoma, with 34.6 % of polypoid
lesions diagnosed as tubular adenoma. Furthermore, in thecolon, seven cases of adenoma-bearing carcinomatous fociwere detected, with all early colon cancers detected close
to the adenoma. Although these histopathological findings
are consistent with the adenoma–carcinoma sequence
driving CCS-related malignancy, aberrant crypt maturationor chronic inflammation in the lamina propria may increase
malignant potential via inflammation-induced mutation [4,47].
This retrospective study not only describes the largest
number of cases over the longest observation period of all
analogous published studies, it is also the first study
incorporating extensive clinical and endoscopic evaluations, underscoring how endoscopic remission influences
the course of CCS. Nevertheless, these cases were collected exclusively from teaching hospitals in an effort toobtain the most accurate endoscopic information, possibly
inducing selection bias. Another limitation was that the

J Gastroenterol (2016) 51:327–336

bulky questionnaire, intended to accumulate useful objective data, seemed sometimes difficult to answer thoroughly,
resulting in the ‘‘inadequate cases.’’ Because of the rarityof CCS, controlled trials for treatment are extremely difficult in CCS populations. Further prospective studies areneed to gather further data regarding the effectiveness ofsteroid-sparing treatment, such as immunomodulators or
biologics, for the induction of remission for severe disease[48], and for long-term maintenance.
In conclusion, appropriate medical therapy can alter thenatural history of CCS. Oral corticosteroid therapy(30–49 mg/day) appeared to be effective for active CCS.
Its benefits, including clinical improvement and polyp
regression, are usually apparent within 12 months. Durable
polyp regression (endoscopic remission) is associated witha markedly improved prognosis, with decreased cancer
risk. Annual surveillance colonoscopy is recommended toassess mucosal disease activity and to remove adenomas
and other premalignant mucosal lesions.
Acknowledgments This study was supported by a Grant-in-Aid forthe Intractable Disease Project of the Ministry of Health, Labour andWelfare of Japan, and by Grants-in-Aid for Scientific Research fromthe Japanese Ministry of Education, Culture, Sports, Science andTechnology. The authors thank the following institutions for replying
to the questionnaires in the first and second surveys: Asahikawa
Medical University, Sapporo Medical University Hospital, Hokkaido
University Hospital, Kushiro Rosai Hospital, KKR Sapporo Medical
Center, National Hospital Organization Hokkaido Medical Center,
Sapporo Higashi Tokushukai Hospital, Sunagawa City Medical
Center, Iwate Medical University, Tohoku University Hospital, Akita
University Hospital, Nakadori General Hospital, Tokyo Medical
University Ibaraki Medical Center, Jichi Medical University Hospital,
Isesaki Municipal Hospital, Saitama Medical University Hospital,
Dokkyo Medical University Koshigaya Hospital, Saiseikai Kawaguchi General Hospital, Saitama Medical Center Jichi Medical
University, Sekishindo Hospital, Chiba University Hospital, Funabashi Municipal Medical Center, The University of Tokyo Hospital,
Kyorin University Hospital, Keio University Hospital, Tokyo Medical
University Hachioji Medical Center, Tokyo Women’s Medical
University Hospital, Nihon University Itabashi Hospital, NTT Medical Center Tokyo, The Cancer Institute Hospital of JFCR, Hiratsuka
GI Hospital, Kitasato University Kitasato Institute Hospital, Sanno
Hospital, Shiseikai Daini Hospital, Toho University Ohashi Medical
Center, Mishuku Hospital, Kitasato University Hospital, Showa
University Fujigaoka Hospital, St. Marianna University School of
Medicine, Yokohama City Seibu Hospital, Yokosuka Kyosai Hospital, Saiseikai Yokohamashi Nanbu Hospital, Nihon Koukan Hospital,
Yokohama Sakae Kyosai Hospital, Federation of National PublicService Personnel Mutual Associations, National Hospital Organization Shinshu Ueda Medical Center, Niigata City General Hospital,
Kanazawa University Hospital, Public Central Hospital of Matto
Ishikawa, Toyama Rosai Hospital, Gifu Municipal Hospital, Nagano
Chuo Hospital, Toki General Hospital, Juntendo Hospital Shizuoka
Hospital, Hamamatsu Medical Center, Hamamatsu South Hospital,
Nagoya City University Hospital, Fujita Health University Hospital,
Aichi Cancer Center Hospital, Japanese Red Cross Nagoya Daiichi
Hospital, Kainan Hospital, Daiyukai General Hospital, Saiseikai
Matsusaka General Hospital, Japanese Red Cross Society Nagahama
Hospital, Mitsubishi Kyoto Hospital, Osaka City University Hospital,
Osaka Medical College Hospital, Kinki University Hospital, Osaka

335
General Medical Center, Osaka Red Cross Hospital, Kitano Hospital,
Osaka Saiseikai Nakatsu Hospital, Ishikiriseikikai Hospital, Sakai
City Hospital, Yodogawa Christian Hospital, Maki Hospital, Kobe
University Hospital, Hyogo College of Medicine, Takarazuka City
Hospital, St.Mary’s Hospital, Miki-Sanyo Hospital, Yamato Takada
Municipal Hospital, Wakayama Medical University Hospital, Shimane University Hospital, Masuda Red Cross Hospital, Okayama
University Hospital, Kawasaki Medical School Hospital, Hiroshima
City Hiroshima Citizens Hospital, Hiroshima General Hospital ofWest Japan Railway Company, Hiroshima City Asa Hospital, Yamaguchi University Hospital, Tokuyama Central Hospital, Yamaguchi
Red Cross Hospital, Tokushima Prefecture Naruto Hospital,
Tokushima Red Cross Hospital, Uwajima City Hospital, Matsuyama
Red Cross Hospital, National Hospital Organization Kochi National
Hospital, Takamatsu Municipal Hospital, Kurume University Hospital, Kitakyushu Municipal Medical Center, Tagawa Hospital, Kyushu
Central Hospital, Fukuoka Higashi Medical Center, Nagata Hospital,
Wakamatsu Hospital, University of Occupational and Environmental
Health, Japan, Saga University Hospital, Kumamoto University
Hospital, Beppu Medical Center, Nakatsu Municipal Hospital, Nakagami Hospital, Kyushu University Graduate School of Medical
Sciences, Yame General Hospital, Fukuoka Sanno Hospital, University of Miyazaki Hospital, Iizuka Hospital, Kyoto University, Sapporo-Kosei General Hospital, Sannno Hospital, Nanbu Medical
Center/Nanbu Child Medical Center, Jikei University, Jikei University Kashiwa Hospital, Jikei University Katsushika Medical Center,
Nagoya Handa City Hospital, Tsuchiura Kyodo General Hospital,
Yokohama Municipal Citizen’s Hospital, Sano General Hospital, andNational Defense Medical College.
Conflict of interestof interest.

The authors declare that they have no conflictOpen Access This article is distributed under the terms of theCreative Commons Attribution-NonCommercial 4.0 International
License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any
medium, provided you give appropriate credit to the original author(s)and the source, provide a link to the Creative Commons license, andindicate if changes were made.

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