Progression of dysplasia in sessile serrated lesions with proliferative zone redistribution: 'Top-down growth' as a marker of malignant potential

Abstract

This study aimed to elucidate the morphological and proliferative progression of dysplasia in sessile serrated lesions (SSLs) to submucosal invasive carcinoma (SIC). Seventy-six SSLs with dysplasia, including 20 with SIC, were analysed. Each lesion was systematically partitioned into morphological units (MUs) based on cytological atypia (low/high) and gland pattern (serrated/tubular), resulting in 200 MUs: serrated-low (n = 76), serrated-high (n = 34), tubular-low (n = 26), and tubular-high (n = 64). These MUs were further categorised as SIC-related (n = 21) or -unrelated (n = 179). Ki67 immunostaining defined proliferative zones within each MU: lower (Ki67-L, n = 70), upper (Ki67-U, n = 40), diffuse (Ki67-D, n = 58), and other (n = 32, excluded from statistical analyses). Fisher's exact test was used in the following specific analyses. Significant associations between serrated-low MUs and SIC-unrelated MUs, and between tubular-high MUs and SIC-related MUs (p < 0.001, respectively) were observed. Moreover, Ki67-L patterns were absent in SIC-related MUs (0/70, 0%, p < 0.001), predominantly in serrated-low MUs (45/70, 64%, p < 0.001). Conversely, Ki67-D patterns were enriched in SIC-related (20/58, 34%, p < 0.001) and tubular-high MUs (39/58, 67%, p < 0.001). Furthermore, Ki67-U patterns exhibited intermediate frequencies between Ki67-L and Ki67-D patterns, with one (2.5%) in SIC-related MUs, six (15%) in serrated-low MUs, and 16 (40%) in tubular-high MUs. This study revealed a significant correlation between Ki67 expression patterns and morphological progression of dysplasia in SSLs. Additionally, the observed Ki67 redistribution, from lower to upper mucosa, followed by diffuse downward spread, mirrors the top-down growth pattern observed in conventional adenomas. Further molecular studies focusing on these proliferative zones are crucial for elucidating the underlying mechanisms of dysplasia progression in SSLs.

Keywords: Dysplasia; Ki67 immunohistochemistry; Proliferative zone; Serrated neoplasia pathway; Sessile serrated lesions; Top-down growth.