Desmoid Tumors: Probing the Wnt Pathway
VY Jo, RD LeGallo. University of Virginia, Charlottesville, VA
Background: Aggressive fibromatosis (desmoid tumor) occurs sporadically or in the setting of Gardner syndrome, which is characterized by mutations in the adenomatous polyposis coli (APC) gene. The majority of desmoid tumors demonstrate nuclear accumulation of β-catenin, which is normally degraded by APC in the Wnt-signaling pathway. Recently there has been speculation that the extracolonic manifestations of Gardner syndrome may reflect a disorder of primary cilia, as ciliary function involves the Wnt pathway. End-binding protein 1 (EB1) is an APC-binding protein involved in intraflagellar transport, and normally binds APC in the region that is frequently lost in APC mutations. In vivo studies show that EB1 is normally present in fibroblasts and when absent, primary cilia assembly and ciliogenesis is attenuated. We compare immunohistochemical staining of β-catenin and EB1 in desmoid tumors, and examine immunostaining for cyclin D1 and WT1, which are also part of the Wnt pathway.
Design: A tissue microarray was constructed from 47 archival formalin-fixed, paraffin-embedded desmoid tumors resected from 35 patients, as well as other spindled cell tumors: malignant peripheral nerve sheath tumor (1), synovial sarcoma (4), gastrointestinal stromal tumor (5), solitary fibrous tumor (5), inflammatory myofibroblastic tumor (3), low-grade fibromyxoid sarcoma (2), and fibrosarcoma (2). Immunohistochemistry was performed for β-catenin, EB1, cyclin D1, and WT1. Results were recorded as nuclear versus cytoplasmic staining, or negative.
Results: There were 12 men and 23 women. Eight patients had Gardner syndrome, 21 tumors were intra-abdominal and 26 were extra-abdominal, and 11 patients had local recurrence. Nuclear β-catenin was present in 25 tumors (53%) and prominent cytoplasmic accumulation was seen in 16 tumors (34%), neither of which were seen in the 22 non-desmoids. Nuclear staining for EB1 was observed in 38 tumors (84%) and in two non-desmoid tumors (1 MPNST, 1 LGFMS). 24 (51%) desmoid tumors showed nuclear staining for cyclin D1. WT1 was negative in all desmoid tumors. There was no correlation between immunohistochemical staining and the evaluated clinical parameters, including Gardner syndrome.
Conclusions: The immunohistochemical expression of EB1 and cyclin D1 in desmoid tumors may reflect accumulation secondary to loss of APC and dysregulation of the Wnt pathway. EB1 accumulation may indicate an etiologic role for or at least shared signaling pathways with ciliary dysfunction. Nuclear β-catenin staining is known to be focal in practice, and EB1 immunohistochemistry may offer diagnostic utility.
Category: Bone & Soft Tissue
Monday, March 22, 2010 1:00 PM
Poster Session II # 9, Monday Afternoon