Milea Timbergen

9 The second type, “sporadic-DTF”, derives from a single progenitor cell 10 and is the focus of this thesis. In contrast to hereditary DTF, sporadic DTF is commonly localized extra-abdominally (trunk or extremities) or in the abdominal wall 6 . As a result, sporadic DTF is rarely fatal but can cause substantial morbidity and thereby sincerely impairing quality of life. The precise aetiology remains tenuous. Several studies report correlations with (spontaneous or iatrogenic) trauma and hormones, although translational studies, investigating the biological rational of these correlations, are lacking 11 . The majority of sporadic DTF tumours, about 85%, have mutations in the CTNNB1 (β-catenin) gene 12-14 . These mutually exclusive mutations are located in exon 3 and most commonly cause the following changes: a replacement of threonine to alanine at codon 41 (T41A), a replacement of serine for phenylalanine (S45F), or a replacement of serine for proline (S45P) at codon 45. These mutations block the phosphorylation and subsequent degradation of β-catenin, which consequently leads to its stabilization and an increased level of β-catenin in the cytoplasm and in the nucleus 15 . This aberrant level of β-catenin is useful for the diagnosis of DTF as immunopositivity for β-catenin can distinguish DTF from other myofibroblastic proliferations 16 . The group without a mutation in the CTNNB1 gene, about 5-15%, has been designated as “wild-type” in the past 13 . However, this group decreases over time as more sensitive sequencing tools, such as Next Generation Sequencing, become more widely available and reveal other rare mutations in CTNNB1 or other genes such as APC 13, 17, 18 . Diagnosis and Treatment During the diagnostic work-up, imaging (i.e., magnetic resonance imaging (MRI), ultrasound, or computed tomography) and a histologic tissue biopsy are obtained. The differential diagnosis of DTF is broad and includes scar tissue, keloid, nodular fasciitis, low-grade fibromyxoid sarcoma, and low-grade myofibroblastic sarcoma amongst other soft tissue tumours 16 . Once the diagnosis of DTF is confirmed, using β-catenin immunopositivity and sequencing of the CTNNB1 gene, treatment in a sarcoma-specialised centre is a necessity 19 . The treatment of DTF has dramatically changed over the past decade. Despite a doctors’ natural urge to start any form of treatment immediately after diagnosis, active surveillance (i.e., “wait and see”) has become the first treatment strategy for asymptomatic DTF tumours 19 . Various retrospective studies show that “active surveillance” is safe 20 , and that a minority of patients need to switch to an “active form” of treatment 21 . Furthermore, 1