Identification of High-Risk Aberrant Crypt Foci and Mucin-Depleted Foci in the Human Colon With Study of Colon Cancer Stem Cell Markers

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Abstract

Background:

During colonoscopic screening, only macroscopic lesions will be identified, and these are usually the result of multiple genetic abnormalities. Magnification endoscopic detection of aberrant crypt foci (ACF), long before they acquire complex genetic abnormalities, is promising. However, the features of high-risk ACF-like lesions need to be identified.

Materials and Methods:

In the present cross-sectional study, grossly visible normal mucosal flaps were shaved from 152 colectomies, including 96 colorectal cancer (CRC) cases and 56 controls (22 control specimens with disease with malignant potential and 34 without malignant potential). Methylene and Alcian blue stains were performed directly on the unfixed mucosal flaps to identify ACF and mucin-depleted foci (MDF). Detailed topographic analyses, with immunohistochemical staining for β-catenin and cancer stem cell (CSC) markers (CD44, CD24, and CD166) were performed.

Results:

ACF, MDF, and β-catenin–accumulated crypts were detected more in specimens with adjacent CRC. The left colon had ACF with a larger diameter and greater crypt multiplicity, density, and gyriform pit pattern and were considered the high-risk ACF group. MDF, more commonly associated with dysplasia, is also a marker of possible carcinogenesis. The CD44 CSC marker was significantly upregulated in ACF specimens compared with normal controls. Our 3-tier ACF-only pit pattern classification system showed better linearity with mucosal dysplasia than did the 6-tier Kudo classification.

Conclusion:

High-risk ACF, when detected during chromoendoscopic screening, should be followed up. CSCs might play an important role in pathogenesis. Larger studies and genotypic risk stratification for definite identification of high-risk ACF are needed.

Microscopic earliest preneoplastic lesions of human colon, as aberrant crypt foci and mucin depleted foci, have enormous potential to be used as targets for cancer screening in high risk individual, especially with the advent of chromoendoscopic and narrow band endoscopic techniques. Though, these lesions have been described in human, the exact pit pattern, distribution across different clinical groups and characteristics to identify the high risk ACF/MDF are not clear. In this study 156 human colectomy specimen were screened for these lesions, after shaving the mucosa, away from the tumor mass, fixed, stained with methylene blue/alcian blue stain and observed under 40x magnification of light microscopy, to mimic the chromoendoscopic procedure. We described a 3-tier ACF only crypt pattern, which shows good predictability for presence of dysplasia. Also the features of high risk ACF were described. Colon cancer stem cell markers were studied in these lesions, in comparison to normal colon and carcinoma, and up-regulation of CSCs were noted in ACF, supporting their preneoplastic nature. CSC might play an important role in carcinogenesis.

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