Genetic Alterations in Sclerosing Angiomatoid Nodular Transformation of the Spleen

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a rare benign lesion with distinctive morphologic features, but its pathogenesis remains controversial. To clarify its biological nature, we analyzed 24 SANT cases using targeted next-generation sequencing with histologic and immunohistochemical evaluation. Three adjacent normal spleen samples served as controls. Most (95.8%) lesions were solitary and detected incidentally (87.5%), with a mean size of 4.5 cm (range: 2.2 to 8.2 cm). All cases showed characteristic multinodular architecture composed of sclerotic stroma, vascular channels, and inflammatory infiltrates; no cases had clinical evidence of IgG4-related disease. Genetic alterations were identified in 12 of 24 (50%) cases, including mutations and copy number gains involving 14 genes. Recurrent alterations affected JAK1, RPS6KB1, MLH1, FGFR3, EPHA5, and CCND1. The most frequent alteration was a JAK1 p.V658F mutation (n=4), followed by MLH1 (n=2) and EPHA5 (n=2) mutations. Two cases each carried copy number gains of RPS6KB1, FGFR3, and CCND1. All SANT cases exhibited low tumor mutational burden (TMB) (mean: 2.26 mutations per megabase) and low microsatellite instability (mean, 2.51%; range: 0% to 7.4%). No genetic alterations were detected in 3 normal spleen samples. Pathway analysis highlighted cell cycle progression as the predominant altered signaling pathway. Compared with negative cases, SANT cases with genetic alterations had fewer IgG4-positive plasma cells (0% vs. 60%, P=0.012) and a trend toward increased CD31-positive endothelial cells (63% vs. 20%, P=0.135). These findings demonstrate that approximately half of SANT cases harbor somatic genetic alterations, supporting a clonal, neoplastic basis for at least a subset of these lesions.