Lower Rate of CTNNB1 Mutations and Higher Rate of APC Mutations in Desmoid Fibromatosis of the Breast A Series of 134 Tumors

Desmoid fibromatosis (DF) is a rare, locally aggressive, nonmetastasizing fibroblastic/myofibroblastic tumor with a tendency to recur and an unpredictable clinical course. A ``wait-and-see'' policy is the new standard of care. DF are characterized by activating alterations of the wnt/beta-catenin pathway:CTNNB1or adenomatous polyposis coli gene (APC) mutations (these mutations being mutually exclusive). Desmoid-type fibromatosis of the breast (DFB) is rare with an incidence of 0.2% of breast tumors. The diagnosis of DFB is difficult, as it must be distinguished from metaplastic carcinoma and other spindle cell lesions. Sequencing of 128 DFB identified a lower rate ofCTNNB1mutations using Sanger (65.6%) or Sanger+next-generation sequencing (77.7%) and a higher rate ofAPCmutations (11.8%) than in all-site DF. By excluding patients with familial adenomatous polyposis (n=2), the rate ofAPCmutations in DFB was high (10.7%). The distribution ofCTNNB1mutations in DFB was different from all-site DF, with a higher rate of T41A (68.9%), a lower rate of S45F (5.7%), and a similar rate of S45T (12.6%). By combining the 2 molecular techniques in a 2-step manner (Sanger, then next-generation sequencing), we increased the detection rate ofCTNNB1mutations and lowered the rate of wild-type tumors from 34.4% to 9.8%, therefore improving the diagnosis of DFB. The identification of the exon 3CTNNB1mutation in breast spindle cell lesions is a highly specific tool for the diagnosis of DFB, in addition to extensive immunohistochemical analysis. Our study also underlines the importance ofAPCin DFB tumorigenesis. These findings have significant implications for patient care and management.