Clinicopathologic and Molecular Analysis of Traditional Serrated Adenoma and Its Possible Precursor Lesions With Special Reference to RSPO Fusion Status

Colorectal serrated lesions are divided into hyperplastic polyps (HP), sessile serrated lesions (SSL), and traditional serrated adenomas (TSA) in the sixth edition of the WHO classification. In 2018, superficially serrated adenoma (SuSA) was proposed as a new subtype of colorectal serrated lesions and a possible precursor of traditional serrated adenoma (TSA). However, tumorigenesis in the serrated pathway remains uncertain. In this study, 271 colorectal serrated lesions (13 SuSAs and 258 TSAs) were collected, and the clinicopathologic features, including the coexistence of possible precursor components (SuSA/SSL/HP), and molecular features (RSPO fusion and KRAS/BRAF mutation status) were investigated. In 13 SuSAs, RSPO fusion was detected in 13 cases, and KRAS mutations were detected in 9 cases. Among the 258 TSAs, RSPO fusion and KRAS and BRAF mutations were detected in 103, 92, and 102 cases, respectively. RSPO fusion-positive TSAs harbored KRAS and BRAF mutations in 62 (60%) and 18 (17%) cases, respectively, and were accompanied by SuSA/SSL/HP in 31/4/4 cases, respectively. KRAS-mutated TSAs exhibited RSPO fusion in 62 cases (67%), accompanied by SuSA/SSL/HP in 29/1/1 cases, respectively. BRAF-mutated TSAs exhibited RSPO fusion in 18 (18%) cases and SuSA/SSL/HP in 2/20/12 cases, respectively. These findings indicate that SuSA could be a possible precursor of TSA with KRAS mutation and RSPO fusion, whereas SSL and HP (microvesicular hyperplastic polyp) are possible precursors of TSA with BRAF mutation. RSPO fusions are more strongly associated with KRAS mutation and SuSA than with BRAF mutation and SSL/HP in serrated pathway tumorigenesis.