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

ArticleinAmerican Journal of Clinical Pathology 129(3):416-23 · April 2008with6 Reads
DOI: 10.1309/603UQKM7C2KELGJU · Source: PubMed
Abstract
We obtained 22 sessile serrated adenomas (SSAs) and 19 hyperplastic polyps (HPs) and performed immunolabeling for cytokeratins (CKs) 7 and 20, CDX2, beta-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 beta-catenin was found in 9 (41%) of the SSAs but in none of the HPs (P < .002). We propose that beta-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.
    • "In this context, REG Iα expression together with aberrant β-catenin expression was associated with high Ki67 immunoreactivity in salivary gland tumors [16]. Recent studies have detected aberrant nuclear accumulation of β-catenin in SSA/Ps [17,18]. Wnt stimulation has been shown to lead to the inactivation of APC and the activation of βcatenin , resulting in nuclear accumulation of β-catenin, which subsequently complexes with the T-cell factor/ lymphoid enhancer factor to activate target gene transcription resulting in cell proliferation [19]. "
    [Show abstract] [Hide abstract] ABSTRACT: Colorectal sessile serrated adenoma/polyps (SSA/Ps) are characterized by asymmetrical distribution of Ki67-positive cells, which varies among crypts and involves the crypt length to a variable extent; the pattern has been designated as aberration of crypt cell compartmentalization. The regenerating gene (REG) Ialpha is a cell growth and/or anti-apoptotic factor and its overexpression might be associated with aberration of crypt cell compartmentalization in SSA/Ps. We investigated REG Ialpha expression in SSA/Ps in comparison to hyperplastic polyps (HPs). A total of 64 cases of serrated polyps (>=10 mm in size), including 53 SSA/Ps and 11 HPs, were included in the present study. Immunostaining was performed using a labeled streptavidin-biotin method. REG Ialpha expression was classified as follows: (i) expression of endocrine cells: grade 0 (a few positive cells) to 3 (marked increase in positive cells); (ii) expression of goblet cells: grade 0 (negative) to 2 (positive for crypts and surface epithelial cells); (iii) staining intensity of goblet cells: grade 0 (negative) to 2 (strong); (iv) staining intensity of crypt (absorptive) cell membranes: grade 0 (negative) to 2 (strong). The presence of aberration of crypt cell compartmentalization was assessed using Ki67 immunostaining. With regard to the REG Ialpha expression of endocrine cells, 8 out of 11 HPs (73%) were grade 0, whereas 51 of 53 SSA/Ps (96%) were grade 1 or higher (p < 0.001). With regard to the distribution of REG Ialpha-immunoreactive goblet cells, 10 of 11 HPs (91%) were grade 1, whereas 50 of 53 SSA/Ps (94%) were grade 2 (p < 0.001). A similar trend was found in the staining intensity of goblet cells or crypt cell membranes (p = 0.011). Aberration of crypt cell compartmentalization was more frequently identified in SSA/Ps (72%) than in HPs (18%; p = 0.002). A significant association was observed between REG Ialpha overexpression and the aberration of crypt cell compartmentalization in serrated polyps (p = 0.037). REG Ialpha overexpression is a characteristic of SSA/Ps, which appears to reflect aberration of crypt cell compartmentalization.
    Full-text · Article · Nov 2013
    • "The normal staining pattern in colonocytes is membranous, compared to nuclear when b-catenin is abnormally stabilized. Altered immunostaining is seen with increasing frequency with serrated polyp progression, although wide variability has been reported [40, 41,484950515253545556. Interpretation of staining pattern including the proportion of cells involved and robust experimental methodology are critical to understanding the role of Wnt signaling in serrated polyps. "
    [Show abstract] [Hide abstract] ABSTRACT: Approximately 30 % of colorectal carcinomas develop via the serrated neoplasia pathway characterized by widespread DNA methylation and frequent BRAF mutation. Serrated polyps represent a heterogeneous group of polyps which are the precursor lesions to serrated pathway colorectal carcinomas. The histological classification of serrated polyps has evolved over the last two decades to distinguish three separate entities: hyperplastic polyp, sessile serrated adenoma (SSA), and traditional serrated adenoma (TSA). The malignant potential of SSAs and TSAs has been clearly demonstrated. SSAs are more challenging to detect by colonoscopy and are likely to account for some interval carcinomas of the proximal colon. Serrated polyposis syndrome is now widely recognized as conferring a high risk of colorectal carcinoma although its cause remains elusive. The current understanding of the actual malignant potential of each serrated polyp subtype is still limited due to the lack of large-scale prospective studies. Patient management guidelines have been recently updated although high-level evidence to support them is still required.
    Full-text · Article · Dec 2012
    • "These findings suggest that Wnt signaling pathway is unlikely to have a major role in the serrated pathway, as opposed to its role in the traditional adenoma-adenocarcinoma sequence. However, previous studies observed nuclear β-catenin accumulation in 9/22 (41%), 35/54 (67%), and 6/16 (38%) of SSAs (Sandmeier et al. 2009; Wu et al. 2008; Yachida et al. 2009). These results are different from those of our present study, and suggest a role for Wnt pathway in the serrated neoplastic pathway. "
    [Show abstract] [Hide abstract] ABSTRACT: The molecular features of serrated polyps of colorectum remain to be elucidated. The expression pattern of adhesive molecules (E-cadherin, α-catenin, and β-catenin) has not been examined in serrated neoplastic pathway. The expression of E-cadherin, α-catenin, and β-catenin were analyzed by immunohistochemistry in 32 hyperplastic polyps (HPs), 28 sessile serrated adenomas (SSAs), 37 traditional serrated adenomas (TSAs), 51 traditional adenomas (TAs), and 10 normal colonic tissues (NCs). Retained membranous expression for E-cadherin, α-catenin, and β-catenin was more frequent in HPs, SSAs, and TSAs than that in TAs (p < 0.001). Nuclear labeling of β-catenin was detected in 19.6% of TAs, but in none of HPs, SSAs, and TSAs (p < 0.001). Cytoplasmic accumulation of β-catenin was found in 3.1% of HPs, 3.6% of SSAs, and 21.6% of TSAs, significantly lower than that in TAs (60.8%, p < 0.001). The membranous co-expression of E-cadherin, α-catenin, and β-catenin was more frequent in HPs (68.8%), SSAs (60.7%), and TSAs (37.8%) than that in TAs (7.8%, p < 0.001). Cell adhesion function is retained in serrated neoplastic pathway. Wnt signaling pathway plays a less active role in the development of colorectal serrated polys than in TAs.
    Article · Sep 2010
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