Background Aberrant crypt foci of the colon are possible precursorsof adenoma and cancer, but these lesions have been studied mainlyin surgical specimens from patients who already had colon cancer.
Methods Using magnifying endoscopy, we studied the prevalence,number, size, and dysplastic features of aberrant crypt fociand their distribution according to age in 171 normal subjects,131 patients with adenoma, and 48 patients with colorectal cancer.We also prospectively examined the prevalence of aberrant cryptfoci in 11 subjects (4 normal subjects, 6 with adenoma, and1 with cancer) before and after the administration of 100 mgof sulindac three times a day for 8 to 12 months and comparedthe results with those in 9 untreated subjects (4 normal subjectsand 5 with adenoma). All 20 subjects had aberrant crypt fociat base line.
Results We identified 3155 aberrant crypt foci, 161 of whichwere dysplastic; the prevalence and number increased with age.There were significant (P<0.001) correlations between thenumber of aberrant crypt foci, the presence of dysplastic foci,the size of the foci, and the number of adenomas. After sulindactherapy, the number of foci decreased, disappearing in 7 of11 subjects. In the untreated control group, the number of fociwas unchanged in eight subjects and slightly increased in one(P<0.001 for the difference between the groups).
Conclusions Aberrant crypt foci, particularly those that arelarge and have dysplastic features, may be precursors of adenomaand cancer.
Aberrant crypt foci were described by Bird as lesions consistingof large, thick crypts in methylene blue–stained specimensof colon from mice treated with a carcinogen (azoxymethane).1Subsequently, they were identified in rat colon, appearing afew weeks after treatment with a carcinogen and becoming largerwith time, with more marked nuclear atypia or dysplasia.2 Inthe rat model, the formation of aberrant crypt foci was enhancedby cancer promoters (such as chenodiol) and suppressed by chemopreventiveagents (docosahexaenoic acid and aspirin).3,4,5 Increased proliferativeactivity and K-RAS mutations of aberrant crypt foci were alsodemonstrated.6,7,8,9,10,11,12,13
Aberrant crypt foci similar to those in rodents have also beenreported in colonic mucosa in humans.14,15,16,17 Patients withcolon cancer had more aberrant crypt foci than patients withnoncancerous lesions16 and 58 to 73 percent had K-RAS mutations.7,9,11These results suggested that aberrant crypt foci are not onlymorphologically but also genetically distinct lesions and areprecursors of adenoma and cancer. However, the studies mainlyanalyzed surgical specimens from patients with colon canceror dissected colonic tissues obtained at autopsy with stereoscopicmicroscopy. Data are lacking on normal subjects or patientswith adenoma, and such data could provide essential informationabout the relation of aberrant crypt foci to colon cancer.
Using magnifying endoscopy, we studied the prevalence, number,size, and dysplastic features of aberrant crypt foci and theirdistribution according to age in normal subjects, patients withadenoma, and patients with cancer and determined the prevalenceof K-RAS mutations in the biopsy specimens. We also evaluatedthe chemopreventive effects of nonsteroidal antiinflammatorydrugs (NSAIDs) on the formation of the foci in patients withheart disease or osteoarthritis and their therapeutic effecton existing foci.
Methods
Subjects and Study Design
The study was approved by the ethics committee of Muroran ShinnittetsuHospital, an affiliate of Sapporo Medical University. We enrolled370 subjects: 49 with colorectal cancer, 142 with adenoma, and179 normal subjects. Normal subjects were defined as subjectswith no apparent lesions of the colon on endoscopy. All subjectsprovided written informed consent before enrollment.
We used endoscopy to assess the prevalence, number, size, anddysplastic features of aberrant crypt foci and their distributionaccording to age in 48 patients with colorectal cancer, 130patients with adenoma, and 147 normal subjects. We determinedthe prevalence of aberrant crypt foci in 25 subjects with eitherheart disease or osteoarthritis who had been treated with NSAIDs,including 100 mg of sulindac (Clinoril, Banyu, Tokyo, Japan)three times daily and 220 mg of aspirin (Takeda, Tokyo, Japan)three times daily, for more than one year. We also prospectivelyexamined the prevalence of aberrant crypt foci in 11 subjects(4 normal subjects, 6 patients with adenoma, and 1 patient withcancer) before and after the administration of 100 mg of sulindacthree times daily for 8 to 12 months and compared the resultswith those in an untreated group (4 normal subjects and 5 patientswith adenoma). All 20 subjects were assessed for aberrant cryptfoci twice in a period of 10 to 12 months. The base-line characteristicsof the subjects are shown in Table 1.
Table 1. Base-Line Characteristics of the Subjects According to Study-Group Assignment.
Magnifying Endoscopy
A magnifying endoscope (model EC7-CM2, Fujinon, Tokyo, Japan)that magnifies objects by a factor of 40 and was equipped withan autofocusing device was used throughout the examination.All subjects underwent total colonoscopy. In three consecutivesubjects (a normal subject, a patient with adenoma, and a patientwith cancer), the entire colon was washed with 0.5 percent glycerin,sprayed with 0.25 percent methylene blue solution, washed againwith warm water, and examined for aberrant crypt foci. In theother subjects, only the lower rectal region was surveyed withthis staining method. Typically, the entire procedure requiredno more than 30 minutes, including total colonoscopy (10 to15 minutes) and examination for aberrant crypt foci (10 to 15minutes). All procedures were recorded on videotape and evaluatedby two independent observers who were unaware of the subjects'clinical histories.
Criteria Used for Endoscopic Diagnosis
Aberrant crypt foci were defined as lesions in which the cryptswere more darkly stained with methylene blue than normal cryptsand had larger diameters, often with oval or slit-like lumensand thicker epithelial linings.14,15,16,17 Dysplastic aberrantcrypt foci were defined as crypts in which each lumen was compressedor not distinct, with an epithelial lining that was much thickerthan that of normal surrounding crypts. Nondysplastic aberrantcrypt foci were classified as hyperplastic or nonhyperplastic.Hyperplastic aberrant crypt foci were those with lumens shapedlike asteroids or slits, whereas nonhyperplastic foci were thosewith oval or semicircular lumens.14,15
Histologic Examination
A total of 105 biopsy specimens with aberrant crypt foci wereobtained, and the foci were histologically classified into oneof three groups depending on the grade of dysplasia or hyperplasiaaccording to previously described criteria.14,15,18,19 The specimenswere graded by two independent pathologists who were not awareof the subjects' histories. The rate of diagnostic agreementbetween graders was 92.4 percent (97 of 105); the 8 biopsy specimenswhose results were in dispute were not included in the evaluationof the accuracy of endoscopic diagnosis.
Detection of Point Mutations at K-RAS Codon 12
The point mutations at codon 12 of the K-RAS gene were analyzedby the polymerase-chain-reaction–restriction-fragment–lengthpolymorphism method.20
Statistical Analysis
The prevalence and number of aberrant crypt foci in age-stratifiedgroups of normal subjects, patients with adenoma, and patientswith cancer were compared by age-adjusted logistic-regressionanalysis21 and the Wilcoxon rank-sum test,22 respectively. Correlationsbetween the number of adenomas and the number or size of aberrantcrypt foci were evaluated by Spearman's test. Data from theprospective study of the effect of NSAIDs on aberrant cryptfoci were analyzed with use of Fisher's exact test with a dichotomousvariable consisting of a group in which there was a reductionin aberrant crypt foci and a group in which there was not.22All analyses were two-tailed.
The sensitivity and specificity of endoscopic diagnosis werecalculated on the basis of the rates of agreement and disagreementwith the histologic diagnosis.23
Results
Endoscopic and Histologic Features of Aberrant Crypt Foci
Using magnifying endoscopy, we found a total of 3155 aberrantcrypt foci among 147 normal subjects, 130 patients with adenoma,and 48 patients with cancer. We examined the entire colorectalmucosa of one normal subject, one patient with adenoma, andone patient with cancer and found aberrant crypt foci, as definedpreviously with the use of stereoscopic microscopy14,15,16,17,18— that is, crypts that were larger, thicker, and moredarkly stained than normal crypts — in all three subjects.The aberrant crypt foci were mainly confined to the rectosigmoidalregion: one of one focus in the normal subject, two of threefoci in the patient with adenoma, and six of eight foci in thepatient with cancer. On the basis of these findings and to minimizethe examination time, we confined further examinations to thelower rectal region from the middle Houston valve to the dentateline. Figure 1A, Figure 1B, Figure 1C, Figure 1D, Figure 1E,and Figure 1F shows three representative endoscopic and histologicexamples of the possible combinations of small, medium, andlarge foci with dysplasia, without dysplasia or hyperplasia,and without dysplasia but with hyperplasia.
Figure 1. Endoscopic and Histologic Features of Aberrant Crypt Foci.
Endoscopy with methylene blue staining reveals a small focus consisting of four crypts with semicircular or oval lumens (Panel A). The aberrant crypts stained more darkly, were larger, and had a thicker epithelial lining and a larger pericryptal zone than normal crypts. Histologically, there was slight enlargement, irregularity, and elongation of the ducts, findings consistent with the previously reported features of aberrant crypt foci without dysplasia or hyperplasia (Panel B, hematoxylin and eosin, x180). Panel C shows a medium focus consisting of 13 crypts, each with an asteroid or slit shape. Histologically, there was a serrated luminal pattern, characteristic of aberrant crypt foci with hyperplasia (Panel D, hematoxylin and eosin, x150). Panel E shows a large focus with a deformed and slightly raised shape. The epithelial lining was thicker than those of the foci shown in Panels A and C, and each lumen was compressed or not distinct. Histologic examination revealed a loss of polarity, hyperchromatism of the nuclei, and stratification of the nuclei of crypt epithelium, findings in agreement with the previously reported features of dysplastic aberrant crypt foci (Panel F, hematoxylin and eosin, x120).
Validity of Endoscopic Diagnosis
We assessed the validity of endoscopic diagnosis by examiningthe degree of agreement between this method and histologic diagnosisin 97 samples from 83 patients. The diagnoses were concordantin the case of 53 specimens without dysplasia or hyperplasia,19 specimens without dysplasia but with hyperplasia, and 20specimens with dysplasia. The results were discordant for fivespecimens. One focus that was defined histologically as nondysplasticand hyperplastic was defined endoscopically as nondysplasticand nonhyperplastic; two samples that were defined histologicallyas nondysplastic and nonhyperplastic were defined endoscopicallyas nondysplastic and hyperplastic; and two samples that weredefined histologically as nondysplastic and hyperplastic weredefined endoscopically as dysplastic. Therefore, the sensitivityof the diagnosis of nondysplastic, nonhyperplastic foci was96.4 percent (53÷(53+2)), the sensitivity of the diagnosisof nondysplastic, hyperplastic foci was 86.4 percent (19÷(19+1+2)),and the sensitivity of the diagnosis of dysplastic aberrantcrypt foci was 100 percent (20÷(20+0+0)). The respectivespecificities were 97.6 percent ((19+20+2)÷(19+20+2+1)),97.3 percent ((53+20)÷(53+20+2)), and 97.4 percent ((53+19+2+1)÷(53+19+2+2+1)).
Among the 3155 aberrant crypt foci identified by endoscopy,161 (5.1 percent) were dysplastic, 457 (14.5 percent) were nondysplasticand hyperplastic, and 2537 (80.4 percent) were nondysplasticand nonhyperplastic. These findings are consistent with thoseof previous studies that evaluated surgical specimens.19,24Since most hyperplastic foci also had areas without hyperplasia,they were subsequently combined with the group of foci withoutdysplasia or hyperplasia.
Prevalence and Number of Aberrant Crypt Foci in Age-Stratified Groups
The prevalence and number of aberrant crypt foci according toage are shown in Table 2. The prevalence of aberrant crypt fociin normal subjects under the age of 40 was 10.0 percent, from40 to 49 years of age it was 53.6 percent, and from 60 to 69years of age it was 65.7 percent. Three of the four patientswith adenoma who were under the age of 40 had aberrant cryptfoci, and the prevalence increased gradually with age, reaching90.2 percent by the age of 60. In patients with cancer, theprevalence was 100 percent in all age groups examined. Logistic-regressionanalysis showed that the difference among the three groups ofsubjects was significant (P<0.001). When the age-stratifiedprevalence of dysplastic foci (Table 2) was compared with thatof nondysplastic foci, the differences among the three groupsof subjects were more marked: the estimated relative risks ofdysplastic foci for patients with adenoma and patients withcancer, as compared with normal subjects, were 4.26 and 18.14,respectively, and the estimated relative risks of nondysplasticfoci were 1.14 and 1.29, respectively. Results of the analysisof the numbers of aberrant crypt foci according to age weresimilar to those for prevalence (Table 2).
Table 2. Prevalence and Number of Aberrant Crypt Foci According to Age.
Correlation between the Number of Adenomas and the Number, Size, and Dysplastic Features of Aberrant Crypt Foci
There was a significant correlation (r=0.62, P< 0.001) betweenthe number of aberrant crypt foci and the number of adenomas(Figure 2A). When the patients who had dysplastic foci wereanalyzed separately, an even stronger correlation was observed(r=0.85, P<0.001). Similarly, when aberrant crypt foci wereclassified according to the number of crypts per focus (small,1 to 9 crypts per focus; medium, 10 to 19 crypts per focus;and large, 20 crypts or more per focus), there was a clear correlationbetween the number of adenomas and the size of the foci (r=0.49,P<0.001) (Figure 2B).
Figure 2. Correlation between the Number of Adenomas and the Number, Size, and Dysplastic Features of Aberrant Crypt Foci in Patients with Adenoma.
Panel A shows the relation between the number of adenomas and the number of aberrant crypt foci. A significant correlation was observed (r=0.62, P<0.001 by Spearman's test). When the patients who had dysplastic foci were analyzed separately, the correlation was stronger (r=0.85, P<0.001). Panel B shows the relation between the number of adenomas and the size of aberrant crypt foci. There was also a significant correlation (r=0.49, P<0.001 by Spearman's test).
Location of Adenomas in Relation to Aberrant Crypt Foci
In 16 of 130 patients with adenoma (12 percent), no aberrantcrypt foci were found in the lower rectal region. In 109 ofthe 114 patients with adenoma and aberrant crypt foci (96 percent),adenomas were found in the left colon. Thirteen of the 16 patientswith adenoma who did not have aberrant crypt foci had adenomasin the right colon (9 in the ascending colon and 4 in the righthalf of the transverse colon).
Point Mutations of K-RAS at Codon 12 in Aberrant Crypt Foci and Adenoma
In nondysplastic aberrant crypt foci, the prevalence of K-RASmutations in biopsy specimens was high in all three groups ofsubjects: normal subjects, 80 percent (16 of 20); patients withadenoma, 85 percent (23 of 27); and patients with cancer, 92percent (22 of 24). The prevalence of K-RAS mutations in dysplasticaberrant crypt foci was lower both overall (57 percent, 8 of14 subjects) and in each group (normal subjects, 50 percent,1 of 2; patients with adenoma, 60 percent, 3 of 5; and patientswith cancer, 57 percent, 4 of 7).
Effect of NSAIDs on the Formation of Aberrant Crypt Foci
Only 1 of 25 patients (4 percent) who received NSAIDs for morethan one year had an aberrant crypt focus (a small nondysplasticaberrant crypt focus and an adenoma were detected concomitantly).We prospectively administered sulindac to 11 subjects (4 normalsubjects, 6 patients with adenoma, and 1 patient with cancer)with aberrant crypt foci (Figure 3). After 8 to 12 months offollow-up, the number of foci significantly decreased in thegroup as a whole and completely disappeared in seven subjects.In contrast, in the untreated control group (four normal subjectsand five patients with adenoma), the number of foci was eitherunchanged (eight subjects) or slightly increased (one subject,P<0.001 for the difference between groups) (Figure 3).
Figure 3. Effect of Sulindac on Aberrant Crypt Foci.
Eleven subjects with aberrant crypt foci were given 300 mg of sulindac per day, and nine subjects did not receive sulindac. After 8 to 12 months, the number of aberrant crypt foci was reassessed by endoscopy. The number of foci was markedly reduced in the subjects who received sulindac, and the foci completely disappeared in seven subjects. In contrast, in the nine control subjects, the number was either unchanged (eight) or slightly increased (one). There was a significant difference between the two groups (P<0.001 by Fisher's exact test).
Discussion
Most of the aberrant crypt foci in our subjects were in therectum and left colon. Therefore, for convenience, we confinedour study to the lower rectal region from the middle Houstonvalve to the dentate line. We found lesions that were similarto the aberrant crypt foci previously observed by stereoscopicmicroscopy in surgical specimens from patients with cancer14,15,16,17,18not only in patients with cancer, but also in normal subjectsand patients with adenoma. Moreover, we were able to distinguishthe subtypes of aberrant crypt foci: dysplastic, nondysplasticand hyperplastic, and nondysplastic and nonhyperplastic.14,15,19
When differences in the prevalence and number of aberrant cryptfoci among age-stratified groups of normal subjects, patientswith adenoma, and patients with cancer were assessed by logistic-regressionanalysis, significant stepwise increments in the prevalencefrom normal subjects to patients with adenoma and to patientswith cancer were apparent, particularly in those with dysplasticaberrant crypt foci. In normal subjects, both the prevalenceand the number of aberrant crypt foci in subjects under 40 yearsof age were very low and increased abruptly between the agesof 40 and 50, although there were not more than five aberrantcrypt foci in any normal subject regardless of age. Conversely,patients with cancer had a consistently high prevalence andlarge numbers of aberrant crypt foci regardless of age. In patientswith adenoma, the age-associated increment in the prevalenceand number of aberrant crypt foci was intermediate. We alsofound that the number, size, and dysplastic features of aberrantcrypt foci correlated with the number of polyps in patientswith adenoma. Moreover, in some patients, polyps overlappedaberrant crypt foci (data not shown). These results provideevidence to support the view that aberrant crypt foci, particularlythose that are large and have dysplastic features, may be precursorsof adenoma and cancer.
Since the prevalence and number of aberrant crypt foci increasedwith age, particularly after the age of 40, periodic endoscopicsurveillance of patients is recommended. Furthermore, our observationsthat the increase in the number of foci occurred slowly andthat many foci were no longer apparent after treatment withsulindac suggest that the feasibility of endoscopic monitoringevery few years after treatment should be considered. Evaluationof additional patients is important.
Nondysplastic aberrant crypt foci had a relatively high prevalenceof K-RAS mutations (80 to 92 percent). The prevalence of suchmutations in dysplastic aberrant crypt foci was lower (57 percent).This difference suggests that genetic alterations other thanthose affecting K-RAS may be involved in the formation of dysplasticaberrant crypt foci.
The progression of adenoma to carcinoma is one of the routesto colon cancer, and this sequence is commonly found in theleft colon. Since aberrant crypt foci were present in almostall patients with adenoma or cancer and frequently appearedin the left colon, where polyps are often found,25,26 we hypothesizethat aberrant crypt foci may eventually evolve into polyps and,subsequently, cancer. It should be noted, however, that theywere not found in 12 percent of patients with adenoma (16 patients),most of whom had adenomas of the right colon. This finding isin accord with the suggestions of others that there is an alternativeroute of colon carcinogenesis27,28 that does not proceed fromadenoma to carcinoma.
It has been reported that NSAIDs such as aspirin and sulindacreduce the risk of colon cancer by 40 to 50 percent.29,30,31Sulindac was shown to reduce the number and size of adenomasin patients with familial adenomatous polyposis.32,33 However,another study of patients with sporadic polyps found no chemopreventiveeffect of sulindac.34 Although we did not examine many patients,we found that the prevalence of aberrant crypt foci was significantlylower in patients who received NSAIDs than in normal subjectsand that the number of aberrant crypt foci was significantlyreduced by the administration of sulindac. These findings shouldbe evaluated in larger studies.
Supported by grants from the Ministry of Education in Japanand the Molecular Gastrointestinal Association of Japan.
Source Information
From the Fourth Department of Internal Medicine (T.T., S.K., Y.T., M.O., S.S., J.K., K.K., Y.N.) and the Department of Public Health (H.M.), Sapporo Medical University, Sapporo; and Muroran Shinnittetsu Hospital, Muroran (S.N.) — both in Japan.
Address reprint requests to Dr. Niitsu at the Fourth Department of Internal Medicine, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo, Japan.
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