Frequent β-Catenin Nuclear Labeling in Sessile Serrated Polyps of … · 2017-06-24 · satellite...

416 Am J Clin Pathol 2008;129:416-423416 DOI: 10.1309/603UQKM7C2KELGJU

© American Society for Clinical Pathology

Anatomic Pathology / β-Catenin and CdX2 in Serrated PolyPS

Frequent β-Catenin Nuclear Labeling in Sessile Serrated Polyps of the Colorectum With Neoplastic Potential

Julie M. Wu, MD,1 Elizabeth A. Montgomery, MD,1 and Christine A. Iacobuzio-Donahue, MD, PhD1,2

Key Words: Serrated adenoma; Hyperplastic polyps; Wnt pathway; Colorectal

DOI: 10.1309/603UQKM7C2KELGJU

A b s t r a c tWe obtained 22 sessile serrated adenomas (SSAs)

and 19 hyperplastic polyps (HPs) and performed immunolabeling for cytokeratins (CKs) 7 and 20, CDX2, β-catenin, and p53 to determine the role of these markers in aiding distinction of lesions with neoplastic potential. Patients with SSAs more frequently had a prior or coexistent tubular adenoma (P = .004) that was right-sided (P = .00001) and larger (P = .03). No difference in CK7, CK20, or p53 labeling was found after correction for colonic location. However, CDX2 labeling was significantly lower in SSAs (P = .02) and was predominantly confined to the crypt bases, whereas it was diffusely positive in HPs (P < .001). Surprisingly, aberrant nuclear labeling for β-catenin was found in 9 (41%) of the SSAs but in none of the HPs (P < .002). We propose that β-catenin and/or CDX2 immunolabeling may have diagnostic usefulness in the evaluation of serrated polyps. These findings also suggest that Wnt signaling has a role in SSA development.

Sessile serrated adenomas (SSAs) are lesions of the colon only recently recognized as distinct from the common hyperplastic polyps (HPs) owing to their neoplastic potential. Previously, it was proposed that HPs and serrated adenomas constituted a morphologic continuum within the same neo-plastic pathway owing to their architectural similarities.1,2 However, some have now suggested that HPs and serrated adenomas may be separate entities that are morphologically similar but genetically distinct.

In the largest morphologic study thus far, Torlakovic et al3 analyzed a large series of serrated colonic polyps and iden-tified 2 groups of polyps based on morphologic and expres-sion profiles of hMLH1 and hMLH2. Left-sided serrated polyps, which were less likely to show loss of MLH1 and MLH2 expression, corresponded to the commonly diagnosed hyperplastic/metaplastic polyp with no malignant potential. HPs were further divided into 3 morphologic categories: vesicular cell type, goblet cell type, and mucin-poor type. By contrast, right-sided serrated polyps, which were more likely to show a defect in the mismatch repair pathway, were characterized by abnormal proliferation, crypt distortion and dilatation, larger size, and decreased numbers of endocrine cells. The authors termed these right-sided polyps “sessile ser-rated adenomas” to reflect their increased neoplastic potential. A similar morphologic profile was delineated by Goldstein et al4 in a study of SSAs preceding microsatellite unstable or site mismatch repair–deficient adenocarcinomas. These charac-teristics included an expanded crypt proliferation zone, crypt basilar dilatation, serrated crypt architecture in the basilar region, decreased maturation, and dysmaturation.

Concurrent analyses of molecular profiles further sup-port the notion that HPs and SSAs may represent distinct

Am J Clin Pathol 2008;129:416-423 417417 DOI: 10.1309/603UQKM7C2KELGJU 417


Anatomic Pathology / original artiCle

pathologic lesions. HPs are more commonly found to have K-ras mutations, whereas SSAs frequently contain BRAF mutations5-7 and show a CpG island methylator phenotype.8,9 Moreover, cancers arising in association with SSAs frequently show a constellation of alterations with resulting loss of hMLH1 and microsatellite instability,10 sometimes seen in the SSAs themselves,10 which make SSAs morphologically and biochemically distinct from the tubular adenoma-adenocarci-noma pathway proposed by Vogelstein et al.11

Although the molecular differences between SSAs and HPs have been relatively well delineated, consistent recogni-tion of SSAs coupled with a relative paucity of a distinctive immunohistochemical profile may pose challenges in every-day practice. SSAs have a known association with cancers with hMLH1 loss; however, hMLH1 labeling is often retained in SSAs until the development of frank epithelial dysplasia, and, thus, hMLH1 immunohistochemical analysis cannot be used to separate SSA and HP.12 Thus, the diagnosis of SSA rests primarily on morphologic criteria, which becomes problematic in cases with overlapping morphologic features, poorly oriented biopsy specimens, and small lesions. Given the implications of cancer risk and surveillance strategies associated with SSAs, the ability to reliably distinguish SSAs from HPs becomes critical.

For our study, we used a panel of immunohistochemical markers to evaluate the role of ancillary techniques in mak-ing this important distinction. We chose cytokeratin (CK) 7 because it was found to have increased labeling in serrated colorectal polyps13 and CK20 and CDX2 because reduced labeling of both markers has been associated with micro-satellite instability–positive colorectal neoplasia,14,15 and, thus, we postulated similar differential expression in sessile serrated colorectal polyps. We also chose markers of the con-ventional pathway to colorectal carcinomas, namely p53 and β-catenin, to determine the relationship of cytokeratin and CDX2 labeling in SSAs to known markers of conventional tumorigenic pathways. Finally, this panel of markers was also selected because most are commonly available immu-nohistochemical stains that can be used to distinguish these polyps in everyday practice.

Materials and Methods

Sample Collection

We identified 52 polyps with serrated morphologic fea-tures in the Johns Hopkins Pathology archives (Baltimore, MD) using the terms “hyperplastic polyp,” “sessile ser-rated adenoma,” and “sessile serrated polyp” for the period February 2006 to July 2006. All samples were reviewed and classified using the proposed criteria of Torlakovic et al.3

SSAs were identified based on features of prominent basilar crypt dilation, abundant intracellular and extracellular mucin, dystrophic goblet cells, and abnormal proliferation. HPs (microvesicular type) were identified based on the features of thickened surface basal membrane, thickening and extension of the muscularis mucosae, presence of Kulchitsky cells, and decreased overall architectural distortion. Goblet cell HPs were identified based on features of minimal serration, thick-ening of the mucosa and muscularis, and the exclusive pres-ence of mucin in the form of goblet cells. Polyps with mixed features of SSA and HP were included in the SSA category.

For 11 serrated polyps, there was a lack of consensus among the original diagnosis and the reviewers as to the diag-nosis (SSA or HP), and these cases were excluded. Polyps with mixed adenomatous and hyperplastic features were also excluded. A total of 22 SSAs and 19 HPs were retained for further evaluation. Clinicopathologic data for each patient whose polyps were used for the study were obtained. The project was approved by the institutional review board.

Immunohistochemical StainingImmunohistochemical labeling was performed using

standard methods. Unstained 5-µm sections were cut from paraffin blocks, and the slides were deparaffinized by routine techniques followed by incubation in 1× sodium citrate buf-fer (diluted from 10× heat-induced epitope retrieval buffer, Ventana-Bio Tek Solutions, Tucson, AZ) before steaming for 20 minutes at 80°C. Slides were cooled for 5 minutes and incu-bated with CK7 (monoclonal antibody, catalog No. m7018, 1:500 dilution; DAKO, Carpinteria, CA), CK20 (monoclonal antibody, catalog No. M7019, 1:500 dilution; DAKO), CDX2 (monoclonal antibody, catalog No. MU392A-UC, 1:50 dilu-tion; BioGenex, San Ramon, CA), p53 (monoclonal antibody, catalog No. M7001, 1:2,000 dilution; Ventana), and β-catenin (monoclonal antibody, catalog No. 610154, 1:1,000 dilution; Transduction Laboratories, Lexington, KY) using the Bio Tek TechMate 1000 automated stainer (Ventana-Bio Tek Solutions). Immunolabeling was detected per kit instructions (Ventana IVIEW Detection Kits, catalog No. 760091).

For the CK7, CK20, and CDX2, polyps were evaluated for the absolute presence or absence of labeling (cytoplasmic for CK7 and CK20 and nuclear for CDX2), the percentage of positive labeling in each polyp, and the distribution of positive labeling within the polyp epithelium. The percent-age of positively labeled cells was scored on a 10-tiered scale ranging from 10% to 100%. The distribution of labeling was scored as confined to the bottom half of crypts, the upper half of crypts including surface epithelium, or the entire crypt and surface epithelium. For β-catenin and p53, labeling was evaluated with respect to membranous and/or nuclear loca-tion. An abnormal labeling pattern for β-catenin was consid-ered present when nuclear labeling accompanied by a loss of



Wu et al / β-Catenin and CdX2 in Serrated PolyPS

membranous labeling was seen outside the crypt bases where the β-catenin positive progenitor cell population normally resides.16 For p53, a normal labeling pattern was defined as 10% or less nuclear labeling confined to the bottom third of colonic crypts, and an abnormal labeling pattern was defined as more than 10% nuclear labeling and/or the extension of nuclear labeling to the surface epithelium. Scoring was per-formed by two of us (J.M.W. and C.A.I.-D.) at a 2-headed microscope.

StatisticsFor comparing parametric distributions, the Student t test

was used, and for frequency distributions, a χ2 test was used. The Fisher exact test was used for samples fewer than 5. P values of .05 or less were considered statistically significant.

Results

Clinicopathologic Features

A total of 22 SSAs and 19 HPs from 39 patients were studied. Among the SSAs, 9 contained foci of classic HP adjacent to the SSA (mixed SSA-HP) and 13 were pure SSA. There were no significant differences in patient age, race, or sex between the 2 groups of patients zTable 1z. However, SSAs and HPs differed in colonic location and context of occurrence. SSAs were more likely to occur in the right side of the colon than were HPs (P < .00001) and were larger (P < .03). Furthermore, patients with SSAs were more likely to have a history of tubular adenoma (P < .004). All mixed SSA-HPs were right-sided.

Immunolabeling for CK7, CK20, and CDX2

No differences among SSAs and HPs were identified by labeling with CK20. In all cases, the crypt epithelium within the polyp and the adjacent normal mucosa were uniformly positive for CK20 zImage 1z. By contrast, SSAs showed a significantly lower frequency of positive CK7 labeling than did HPs (P < .0003) zTable 2z. However, among the positive SSAs and HPs, the percentage of cellular label-ing within the polyps was similar, as was the distribution of positively labeled cells (Image 1). The adjacent normal mucosa showed an absence of labeling with CK7, although in 4 samples of normal mucosa adjacent to a left-sided HP, rare scattered positive cells (~1%-2% of cells) were present at the crypt bases.

To address the possibility that the difference in CK7 labeling is a reflection of colonic location,17 we compared the CK7 labeling of all polyps specifically in relation to the right and left sides of the colon. This comparison revealed a statistically significant relationship among positive CK7 labeling and left-sided location (P < .001) zTable 3z. Moreover, when we compared CK7 labeling among right- and left-sided SSAs specifically, we again found a signifi-cant relationship among positive CK7 labeling and colonic location (P < .02). Thus, we conclude that the apparent dif-ferential expression of CK7 may actually be a reflection of the most common sites of origin of SSAs and HPs, similar to that found among CK7 labeling and location of colorectal carcinomas.17

All polyps were also labeled for CDX2. Although no difference in the absolute presence or absence of nuclear CDX2 labeling between SSAs and HPs was found, there was a significant difference in the percentage of positively labeled nuclei within these 2 groups (P < .02) (Table 2). The distribution of labeling within positive cases was also compared. CDX2 labeling was predominant within the crypt bases in 10 of 12 positive SSAs, whereas in all 10 positive HPs, CDX2 labeling extended to the crypt surface (P = .0001) zImage 2z. Considering our findings with CK7, however, we again determined if differences in the percent-age of CDX2 labeling were a reflection of colonic location. A trend toward increased CDX2 labeling among left-sided polyps was found but did not reach statistical significance (P = .08). The adjacent normal mucosa was uniformly and diffusely strongly positive for CDX2 in all cases of SSA and HP and always was more strongly positive than the polyp epithelium (Image 2).

Immunolabeling Patterns of β-Catenin and p53 ProteinsFinally, we evaluated labeling patterns of β-catenin and

p53, 2 molecular markers of the conventional pathway to co-lorectal neoplasia. All 19 HPs showed strong positive membra-nous labeling with β-catenin that was predominantly located in

zTable 1zCase Distribution

Hyperplastic Sessile Serrated Polyp Adenoma P

No. of patients 18 21 No. of polyps 19 22 Mean ± SD age (y) 58.9 ± 10.6 63.7 ± 13.12 NSSex (M/F) 8:10 13:8 NSRace* White 10 15

NS Black 5 2 Location Right side 3 19 <.00001 Left side 16 3 Mean ± SD size (cm) 0.38 ± 0.15 0.71 ± 0.32 <.03History of tubular adenoma Yes 3 13 <.004 No 15 8

NS, not significant.* Information unavailable for 7 patients.




the bottom half of the crypts. At higher power, scattered cells with strong positive nuclear labeling were also seen at the crypt bases zImage 3z. This pattern is consistent with increased Wnt signaling common at the crypt bases of intestinal epithelium.16

To our surprise, predominant nuclear labeling of β-catenin was found in 9 of 22 SSAs (41%; P < .002). In 1 of these SSAs, intense nuclear labeling was present through-out a single serrated crypt, and in the remaining 8 SSAs, nuclear labeling was present throughout the polyp epithe-lium representing 10% to 25% of all nuclei (Image 3). In all polyps with nuclear labeling, membranous labeling was significantly decreased in intensity compared with adjoining normal mucosa or was absent. Of the 9 polyps with nuclear

labeling, 6 were pure SSAs and 3 were mixed SSA-HPs. Moreover, regions of classic-appearing HP adjacent to SSAs with nuclear labeling also showed nuclear labeling. There was no difference in the location of SSAs with or without nuclear labeling, nor was there a difference in the mean ± SD polyp size (SSAs, 0.62 ± 0.33 cm, vs HPs, 0.86 ± 0.28 cm). Among the 13 SSAs that were positive for β-catenin but did not show nuclear accumulation, the labeling pattern was similar to that found for conventional HPs.

None of the HPs or SSAs showed an abnormal nuclear labeling pattern for p53. In all cases, p53 labeling, when pres-ent, was focal and located within scattered cells at the lower third of crypts.

A B

C D

zImage 1z Cytokeratin 20 labeling in a hyperplastic polyp (A) and a sessile serrated adenoma (B). Both indicate strong positive labeling throughout the epithelium that is most prominent in the upper half of crypts. Cytokeratin 7 labeling, when positive, also showed a similar pattern of labeling as seen in this hyperplastic polyp (C) and sessile serrated adenoma (D) (A-D, ×200).




Discussion

Improved recognition of serrated polyps with neoplastic potential is paramount to the stratification of patients toward appropriate clinical management. Although not the purpose of this study, we found that even in a large tertiary care center

with a high-volume gastrointestinal pathology service, there was diagnostic variability in 21% of the serrated lesions. Thus, we used a panel of immunohistochemical stains com-monly available at most institutions on a series of serrated polyps to determine the role of ancillary studies in the diagno-sis of serrated lesions with neoplastic potential and to better understand the molecular features of these lesions.

Consistent with findings of previous studies, we found no sex predilection among SSAs and HPs, and SSAs were more likely to arise in the right side of the colon compared with HPs, which were more likely found in the left side of the colon.3,18,19 Moreover, patients with SSAs were almost 4

zTable 2zImmunohistochemical Profile of Serrated Polyps

Hyperplastic Sessile Serrated Polyp Adenoma (n = 19) (n = 22) P

Cytokeratin 20 Positive 19 22 NS Negative 0 0 Cytokeratin 7 Positive 16 6 <.00002 Negative 3 16 Mean No. ± SD of 33.8 ± 29.4 33.6 ± 26.1 NS positive cells/polyp* CDX2 Positive 10 12 NS Negative 9 10 Mean No. ± SD of 52.5 ± 29.7 30.0 ± 16.5 <.02 positive cells/polyp* Distribution of labeling* Crypt base 0 10 <.0001 Entire crypt 10 2 β-Catenin Nuclear 0 9 <.002 Membranous 19 13 p53† Positive 0 0 NS Negative 19 22

* Values refer only to the subset of polyps with positive labeling.† The designations positive and negative refer to the presence of an abnormal labeling

pattern defined as >10% nuclear labeling and/or nuclear labeling that extends to the surface epithelium.

zTable 3zRelationship of Cytokeratin 7, CDX2, and β-Catenin Immunolabeling Patterns to Colonic Location

Colonic Location

Right Side Left Side P

Cytokeratin 7 Positive (all polyps) 5 13 <.001 Negative (all polyps) 12 2 Positive (SSA only) 3 3 <.02 Negative (SSA only) 16 0 CDX2 Mean No. ± SD of 30.9 ± 17.0 46.7 ± 31.9 NS positive cells/polyp* β-Catenin nuclear labeling in SSAs Positive 8 1 NS Negative 11 2

SSA, sessile serrated adenoma.* Values refer only to the subset of polyps with positive labeling (see Table 2).

*

A B

zImage 2z A, In this hyperplastic polyp, nuclear CDX2 extends from the crypt bases to within the upper half of the crypt epithelium (indicated by arrows). A normal colonic crypt is also present (asterisk) that has diffuse, positive nuclear labeling of a stronger intensity than that seen in the polyp epithelium. B, In this sessile serrated adenoma, the nuclear CDX2 labeling is confined to the lower half of crypts, predominantly at the crypt base (arrow and inset) (A, B, and inset, ×200).




times more likely than patients with HPs to have a history of tubular adenoma, despite the similarity in average age of the 2 groups,20 indicating a possible proneoplasia phenotype of the colonic mucosa in patients with SSAs for which these lesions may be a marker.

Perhaps most surprising in this study was that a subset of SSAs (41%) displayed prominent nuclear labeling of β-catenin, implicating the role of aberrant Wnt signaling in the development of a subset of SSAs.16 By contrast, normal membranous labeling for β-catenin was found in HPs, includ-ing regions of classic HP within mixed polyps.

A review of the literature revealed at least 2 additional studies in which nuclear labeling for β-catenin was reported

in serrated adenomas, although in the study reports, the absolute distinction among sessile serrated and polypoid ser-rated adenomas was not made.6,21 In adenomatous polyps and colorectal carcinomas, nuclear accumulation of β-catenin is a reliable marker of inactivating mutations in APC or activating mutations of β-catenin itself,22 although β-catenin mutations have also been described in association with colorectal cancers with microsatellite instability.23,24 It is important to note that nuclear labeling for β-catenin may also occur in the absence of mutations in the APC/β-catenin pathway,6 where it may reflect a generalized hyperactivity of Wnt signaling described in a variety of human tumors.25 Because Wnt pathway activity is known to maintain stem cell populations and limit epithelial

A B

C D

zImage 3z A, In hyperplastic polyps, β-catenin labeling is confined to the crypt bases. Intense labeling is present in a membranous pattern with scattered positive nuclei (arrow) (×400). B and C, Diffuse nuclear labeling of β-catenin in 2 sessile serrated adenomas (×200). D, β-Catenin labeling in a sessile serrated adenoma without nuclear labeling. In this polyp, the labeling pattern is similar to that seen in the hyperplastic polyp shown in A (×400).




including its relationship to known molecular features of these lesions, such as BRAF.5,8

From the Departments of 1Pathology and 2Oncology, Johns Hopkins Medical Institutions, Baltimore, MD.

Supported by grant CA106610 from the National Institutes of Health, Bethesda, MD (Dr Iacobuzio-Donahue), and Doris Duke grant 2005023, Doris Duke Charitable Foundation, New York, NY.

Address reprint requests to Dr Iacobuzio-Donahue: Dept of Pathology, Division of Gastrointestinal and Liver Pathology, the Johns Hopkins Hospital, 1550 Orleans St, CRBII 343, Baltimore, MD 21231.

References

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differentiation,25-27 we propose the intriguing hypothesis that the β-catenin nuclear labeling seen in SSAs may be a marker of an expanded population of abnormal colonic progenitor cells. At the very least, additional studies to clarify the role of Wnt signaling in SSAs are warranted.

In addition to the biologic implications of nuclear accumulation of β-catenin in SSAs, the finding of β-catenin nuclear labeling specific to SSAs suggests a role for this pro-tein as a diagnostic tool. We also noted a relationship among CDX2 labeling in that SSAs contained a lower percentage of positively labeled cells. This finding is even more compelling considering that CDX2 is a known target of the Wnt signaling pathway and a marker of differentiated epithelium.28,29 Thus, β-catenin and CDX2 labeling may be of value, particularly in problematic polyps with mixed features or poor orienta-tion. By contrast, we observed no significant difference in CK20 labeling between SSAs and HPs, despite the previously reported decrease or loss of CK20 expression in microsatellite instability–high cancers.14 This suggests that CK20 expres-sion may be retained in adenomas but subsequently lost in carcinomas, consistent with the findings of Sheridan et al,12 who reported loss of hMLH protein expression in serrated polyps at the transition to invasive carcinoma. We also did not find a role for CK7 labeling of serrated polyps. Although HPs exhibited a significantly higher prevalence of CK7 labeling than did SSAs (84% vs 27%), further review indicated this relationship was related to colonic location.

Although defects in the mismatch repair pathway have been implicated in SSAs, immunohistochemical analyses for mismatch repair proteins have yielded equivocal results in the diagnosis of SSAs. Hawkins and Ward10 showed a focal loss of MLH1 protein in hyperplastic and serrated polyps from patients with cancers showing microsatellite instability. In contrast, Sheridan et al12 showed a loss of MLH1 protein expression in dysplastic polyps, with typical SSA areas retain-ing MLH1 expression. Compounded by the limited acces-sibility for performing these stains in the routine pathology laboratory, the usefulness of MLH1 immunohistochemical analysis is called into question. The only other study demon-strating immunohistochemical differences showed increased MUC5AC expression in SSAs vs HPs (11/24 vs 16/61, respectively) and an increased proliferation rate in SSAs vs HPs (29% vs 23%, respectively).18,30 However, this study again failed to specifically address the patterns of labeling in relation to colonic location.

We have shown that β-catenin and CDX2 immu-nostains may aid the discrimination of SSAs from HPs, thus aiding recommendations for the appropriate manage-ment of patients with these lesions. Further studies of a larger and independent sampling of serrated lesions will be required to confirm our findings and to better clarify the role of Wnt signaling in general in the development of SSAs,




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25. Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324-331.

26. Mariadason JM, Bordonaro M, Aslam F, et al. Down-regulation of beta-catenin TCF signaling is linked to colonic epithelial cell differentiation. Cancer Res. 2001;61:3465-3471.

27. Korinek V, Barker N, Moerer P, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 1998;19:379-383.

28. Escaffit F, Paré F, Gauthier R, et al. Cdx2 modulates proliferation in normal human intestinal epithelial crypt cells. Biochem Biophys Res Commun. 2006;342:66-72.

29. Blache P, van de Wetering M, Duluc I, et al. SOX9 is an intestine crypt transcription factor, is regulated by the Wnt pathway, and represses the CDX2 and MUC2 genes. J Cell Biol. 2004;166:37-47.

30. Biemer-Huttmann AE, Walsh MD, McGuckin MA, et al. Mucin core protein expression in colorectal cancers with high levels of microsatellite instability indicates a novel pathway of morphogenesis. Clin Cancer Res. 2000;6:1909-1916.

14. McGregor DK, Wu TT, Rashid A, et al. Reduced expression of cytokeratin 20 in colorectal carcinomas with high levels of microsatellite instability. Am J Surg Pathol. 2004;28:712-718.

15. Hinoi T, Tani M, Lucas PC, et al. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol. 2001;159:2239-2248.

16. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469-480.

17. Zhang PJ, Shah M, Spiegel GW, et al. Cytokeratin 7 immunoreactivity in rectal adenocarcinomas. Appl Immunohistochem Mol Morphol. 2003;11:306-310.

18. Higuchi T, Sugihara K, Jass JR. Demographic and pathological characteristics of serrated polyps of colorectum. Histopathology. 2005;47:32-40.

19. Chlumska A, Boudova L, Zamecnik M. Sessile serrated adenomas of the large bowel: clinicopathologic and immunohistochemical study including comparison with common hyperplastic polyps and adenomas. Cesk Patol. 2006;42:133-138.

20. Rex DK, Smith JJ, Ulbright TM, et al. Distal colonic hyperplastic polyps do not predict proximal adenomas in asymptomatic average-risk subjects. Gastroenterology. 1992;102:317-319.

21. Yamamoto T, Konishi K, Yamochi T, et al. No major tumorigenic role for beta-catenin in serrated as opposed to conventional colorectal adenomas. Br J Cancer. 2003;89:152-157.

22. Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787-1790.

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