Sessile serrated lesions with dysplasia: is it possible to nip them in the bud?

Abstract

The serrated neoplasia pathway constitutes an “alternative route” to colorectal cancer (CRC), and sessile serrated lesions with dysplasia (SSLDs) are an intermediate step between sessile serrated lesions (SSLs) and invasive CRC in this pathway. While SSLs show indolent growth before becoming dysplastic (> 10–15 years), SSLDs are considered to rapidly progress to either immunogenic microsatellite instable-high (MSI-H) CRC (presumably 75% of cases) or mesenchymal microsatellite stable (MSS) CRC. Their flat shapes and the relatively short window of this intermediate state make it difficult to detect and diagnose SSLDs; thus, these lesions are potent precursors of post-colonoscopy/interval cancers. Confusing terminology and the lack of longitudinal observation data of serrated polyps have hampered the accumulation of knowledge about SSLDs; however, a growing body of evidence has started to clarify their characteristics and biology. Together with recent efforts to incorporate terminology, histological studies of SSLDs have identified distinct dysplastic patterns and revealed alterations in the tumor microenvironment (TME). Molecular studies at the single-cell level have identified distinct gene alterations in both the epithelium and the TME. Mouse serrated tumor models have demonstrated the importance of TME in disease progression. Advances in colonoscopy provide clues to distinguish pre-malignant from non-malignant-SSLs. Recent progress in all aspects of the field has enhanced our understanding of the biology of SSLDs. The aim of this review article was to assess the current knowledge of SSLDs and highlight their clinical implications.

The histologic features, molecular features, detection and management of serrated polyps: a review

“…In contrast, the prevalence rates of SSLs exhibit minimal variation across different age groups, while the association between prevalence and sex remains a topic of ongoing debate ( 7 , 8 ). Recent empirical findings indicate that approximately 55% of SSLs are observed in women, and among the 137 instances of SSL-Ds or SSLs with carcinoma, 61% were reported in women ( 9 ). When considering TSAs, they typically occur in older patients (typically over 50 years of age) and do not show a significant preference for either gender ( 10 ).…”

“…This leads to the continuous activation of the MAPK signaling cascade, resulting in the disruption of crypt cell proliferation and differentiation. The CpG island methylator phenotype (CIMP) is recognized as the primary mechanism in the serrated pathway, causing the inactivation of several tumor suppressor genes and propelling the development of CRCs ( 9 , 11 , 12 ).…”

“…It is commonly believed that HPs are non-malignant lesions. Nevertheless, certain HPs (especially those larger than 5 mm and/or located in proximal regions) have the potential to develop into SSLs and SSL-Ds, ultimately leading to CRCs ( 9 , 19 ).…”

“…Conversely, GCHPs display an elevated count of goblet cells and possess a more inconspicuous serrated appearance resembling surface tufting, thereby posing challenges in distinguishing GCHPs from normal mucosa. It is worth noting that the differentiation between MVHPs and GCHPs holds no clinical significance ( 9 , 20 , 23 ).…”

“…SSL-Ds serve as an intermediary stage within the serrated pathway, bridging the gap between SSLs and invasive CRCs. These lesions are relatively uncommon, with an estimated occurrence rate of approximately 0.5% among average-risk patients, accounting for approximately 4-8% of all SSLs ( 9 ). It is hypothesized that these infrequent lesions exhibit a brief period of residence during the transition from dysplasia to carcinoma ( 27 ).…”