Disparate cell proliferation and p53 overexpression in colonic crypts with normal epithelial lining found below the neoplastic canopy of conventional adenomas

Abstract

We previously found colonic crypts with normal epithelial lining but with corrupted shapes (NECS) beneath the adenomatous tissue of conventional adenomas (CoAs). Here we assessed the distribution of proliferating cells (PCs) and explored the possible occurrence of p53‐upregulated cells in the NECS in a cohort of CoAs. Sections from 70 CoAs and from 12 normal colon segments were immunostained with the proliferation marker Ki67. In 60 of the 70 CoAs, additional sections were immunostained for the tumor suppressor p53 protein. NECS with asymmetric, haphazardly distributed single PC or PC clusters were recorded in 80% of the CoAs, with a continuous PC domain in one or both slopes of the crypts in 17%, and with haphazardly distributed single PCs in the remaining 3% of the CoAs. In the 12 normal segments (controls), the colon crypts demonstrated normal shapes with symmetric PC domains limited to the lower third portion of the crypts. In 30% of the 60 CoAs immunostained with p53 the NECS revealed haphazardly distributed p53‐upregulated cells, singly or in clusters. In sum, the apparently normal epithelium of the NECS beneath the adenomatous tissue of CoAs revealed an unprecedented relocation of the normal PC domains. This unexpected event and the occurrence of p53‐upregulated cells strongly suggest that the crypts beneath the neoplastic tissue of CoAs harbor somatic mutations. The accretion of putative mutated NECS beneath the neoplastic canopy of CoA emerges as a previously unaddressed major event, an event that might play an important role in the histogenesis of CoA in the human colon.

Two intertwined compartments coexisting in sporadic conventional colon adenomas

“…51 Thus, the apparently normal epithelium of the CCS beneath the adenomatous tissue of sporadic polypoid conventional adenomas concurred with an unprecedented relocation of the natural PC domains, and with p53-upregulated cells, suggesting thereby, possible mounting somatic mutations in the CCS of those neoplastic lesions. 50 In another investigation, this time with 48 non-polypoid adenomas, we found that 88% of the CCS exhibited haphazardly asymmetrically-distributed PC-domains, 8% continuous PCdomains in one or both slopes of the CCS, and 4%, asymmetrically-haphazardly distributed single PC. 46 The CCS in 29% of the 48 non-polypoid adenomas also showed p53-upregulated often as single cells.…”

“…Those unexpected findings suggested that the CCS in the stalk were possibly undergoing somatic mutation. 50…”

“…3 ). None of the more than 200,000 crypts investigated in 22 colon segments, proximal or distal to surgically removed colon cancer revealed crypts with p53-upregulated cells [ 50 ]. It should be mentioned that in previous studies of colon adenomas we found p53 upregulation in the adenomatous tissue in 28% out of 501 adenomas [ 51 ].…”

“…It should be mentioned that in previous studies of colon adenomas we found p53 upregulation in the adenomatous tissue in 28% out of 501 adenomas [ 51 ]. Thus, the apparently normal epithelium of the CCS beneath the adenomatous tissue of sporadic polypoid conventional adenomas concurred with an unprecedented relocation of the natural PC domains, and with p53-upregulated cells, suggesting thereby, possible mounting somatic mutations in the CCS of those neoplastic lesions [ 50 ].…”

“…While studying sporadic polypoid conventional adenomas we detected in the mucosa of the stalk, CCS without neoplastic tissue on top, strongly suggesting that CCS developed independently of the control of the neoplastic tissue [ 50 ]. Sections immuno-stained with the proliferation marker Ki-67 and with p53 showed that the CCS in the stalk of sporadic polypoid conventional adenomas displayed haphazardly asymmetricallydistributed PC-domains and p53 upregulated cells.…”