The Normal Epithelium of Crypts Accruing Below Nonpolypoid Adenomas Thrives With Relocated Proliferating Cell-domains and p53-Up-regulated Cells

Abstract

Background/Aim: Colonic crypts with normal epithelium albeit with corrupted shapes (CCS) were previously found beneath nonpolypoid adenomas (NPA). This study aimed to analyze the distribution of proliferating cells (PC) and p53-up-regulated cells in CCS. Materials and Methods: Sections from 48 NPA were immunostained with the proliferating-marker Ki67 and against the tumor-suppressor protein p53. Results: Asymmetric-haphazardly distributed PC were found in 87.5% of the NPA, continuous PC-domains in 8.3%, asymmetric-haphazardly distributed single PC in 4.2% and p53-up-regulated cells in 29.2%. In 12 controls, the normal-shaped crypts revealed symmetrically-distributed PCdomains in their lower thirds, and no p53-up-regulated cells. Conclusion: The normal epithelium that lines the CCS below NPA, thrives with relocated PC-domains, and with occasional p53-up-regulated cells. These findings strongly suggest that the normal epithelium of CCS beneath NPA might harbor somatic mutations. The accretion of putative mutated CCS might play an important role in the evolution of nonpolypoid adenomas in the human colon.In 1985 Muto et al., detected at colonoscopy, small nonpolypoid mucosal lesions measuring up to one cm in diameter (1). At histologic examination, those lesions were found to be adenomas. Flat adenomas (FA), as they were called, were subsequently found associated with a more aggressive clinical behavior than their polypoid counterpart (2).The further improvement of optical devices together with the use of mucosal dyes, permitted endoscopists to more easily visualize previously undetected FA. In 1994, Jaramillo et al.(3) identified by the aid of high-resolution video colonoscopy and chromoscopy, a colon carcinoma arising in a FA. In 1995, the same group reported a collection of 109 flat neoplastic lesions: 97% were FA and the remaining 3%, FA with submucosal invasion (4). In 1999, one of us (CAR), trained in Western and Japanese pathology (5), reviewed 781 FA collected at the four main Hospitals in Tokyo, Japan and at the Karolinska Hospital, Stockholm, Sweden (6). The results showed that high-grade dysplasia was present in 42% out of 420 FA in Japanese patients, but only in 14% of the 361 FA in Swedish patients. Intramucosal or submucosal carcinomas were found in 15% of the FA in Japan, but only in 3% of the FA excised in Sweden (6). Thus, Japanese patients had more advanced FA (in terms of high-grade dysplasia) and more aggressive FA (in terms of intramucosal and submucosal invasion) than Swedish patients (6, 7). Those findings confirmed the claims of histological differences between flat colonic neoplasias in Japan and in Western countries (8, 9). According to Gotoda, the differences in the histological classification of gastrointestinal epithelial neoplasias between Western and Japanese pathologists, have been largely resolved by adopting the Vienna classification (10,11).In 1997, Kudo et al. reported non-polypoid (flat) colon neoplasms with a lateral diameter greater than 10 mm; they were called laterally-spread...

Two intertwined compartments coexisting in sporadic conventional colon adenomas

“…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. 46 Thus, the CCS accruing beneath the neoplastic tissue of non-polypoid adenomas also thrived with relocated PC-domains and p53 upregulated cells (the latter in nearly one-third of the polypoid adenomas), suggesting cellkinetic alterations and possibly mounting somatic mutations.…”

“…46 The CCS in 29% of the 48 non-polypoid adenomas also showed p53-upregulated often as single cells. 46 Thus, the CCS accruing beneath the neoplastic tissue of non-polypoid adenomas also thrived with relocated PC-domains and p53 upregulated cells (the latter in nearly one-third of the polypoid adenomas), suggesting cellkinetic alterations and possibly mounting somatic mutations. On the other hand, neither asymmetrically-haphazardly dis-tributed PC-domains, nor p53 upregulated cells were found in any of the more than 200,000 normal colon crypts, including occasional, single CCS in controls.…”

“…2). 46 In contrast, the crypts of 12 normal colon segments (controls) exhibited crypts with normal shapes having symmetrically distributed PC-domains predominantly limited to the lower third portion of the crypts. It should be mentioned that in early observations, Maskens and Deschner 47 found upward shift of the proliferative zone in the normal crypts in patients with colon carcinoma.…”

“…Redistributed Proliferating Cells and p53-Upregulated Cells When sections from 60 sporadic polypoid conventional adenomas were immune-stained with the proliferation marker Ki-67, different abnormal cell-proliferation phenotypes were found in the CCS below the neoplastic tissue: 45,46 (1) haphazardly asymmetrically-distributed single proliferating cell (PC) or PC clusters in 80%; (2) continuous PC domains in one or both slopes of the crypts in 17%; and (3) single, haphazardly distributed PCs in the remaining 3% (Fig. 2).…”

Two histologic compartments in nonpolypoid conventional colon adenomas

“…p53-Upregulated cells were regarded only those having the same intense immunoreactivity for the p53 tumor-suppressor protein as those in the neoplastic tissue on top. 57 The tumor-suppressor protein p53 was overexpressed in the dysplastic compartment in 39.6% (19/48) of the SNPCoAs. 57 This percentage was somewhat higher than that found in a previous survey at this department, where 25% out of the 433 polypoid conventional adenomas showed p53overexpression in the neoplastic tissue.…”