Intra-Abdominal Sporadic Desmoid Tumors with Canonical CTNNB1 and Uncommon Wnt/β-Catenin Pathway Somatic Mutations—A Clinicopathologic and Genetic Study of Five Cases

Desmoid tumors (DTs) may be sporadic or associated with familial polyposis syndromes, including familial adenomatous polyposis (FAP) and its variant, Gardner syndrome (GS). DTs are pathogenetically linked to activation of the Wnt/β-catenin signaling pathway. In sporadic DT, CTNNB1 is most frequently implicated, with exon 3 somatic mutations (T41A, S45F and S45P) being the most commonly reported. APC is implicated in FAP/GS-associated DTs and occasionally in sporadic DT, most often through alterations involving the exon 15 mutation cluster region. In this study of five sporadic intra-abdominal DTs, we identified uncommon somatic missense mutations in three cases involving APC (exons 2 and 13), LRP6 (exon 3) and TCF7L2 (exons 3, 6, 8 and 10). One case harbored the canonical activating CTNNB1 exon 3 p.S45P mutation, whereas another one case showed no detectable genomic alterations. Multi-algorithm in silico assessment using AlphaMissense, REVEL, CADD, SIFT and PolyPhen-2 provided supportive computational evidence for potential functional effects of several variants, particularly TCF7L2 p.P113L, p.R243W and p.C337Y, and CTNNB1 p.S45P, while predictions were variable for other variants. All five tumors arose intra-abdominally and presented as abdominal emergencies requiring surgical intervention. During a median follow-up of 24 months (range, 18–68 months), four patients remained recurrence-free, whereas one case developed multifocal intra-abdominal recurrence approximately five years after the initial resection and underwent repeat surgery. These findings broaden the spectrum of Wnt/β-catenin pathway alterations observed in intra-abdominal DTs, although the functional consequences of the uncommon variants require experimental validation.