Defining absolute postoperative desmoid risk in familial adenomatous polyposis according to APC genotype and family history: retrospective cohort study.

backgroundDesmoid disease is a major cause of morbidity and mortality in familial adenomatous polyposis (FAP), particularly after prophylactic colorectal surgery. Although APC genotype and family history are recognized risk factors, previous sizeable studies report relative rather than absolute risks. This study aimed to quantify absolute postoperative desmoid risk in FAP patients undergoing risk-reducing colectomy, stratified by APC genotype, and to assess the modifying effect of family history.

methodsThis retrospective observational study used records from a prospectively maintained registry. Patients with an APC pathogenic variant (PV) 3' of codon 1399 were classified as high risk, and those with an APC PV 5' of (or at) codon 1399 were classified as low risk. Patients who had not undergone prophylactic colectomy, with < 5 years of postoperative follow-up, or those with a desmoid diagnosed before or at the time of surgery were excluded. Clinical records were reviewed for details of surgery, desmoid diagnosis, and family history. A positive family history was defined as a first-degree relative with genetically confirmed FAP and a diagnosis of desmoid disease (clinical and/or radiological).

resultsAmong 48 high-risk patients, 30 (63%) developed desmoid, with no significant difference between colectomy and proctocolectomy (54% versus 70%, respectively; χ2 = 1.42; P = 0.233). Family history was present in 35 of the 48 patients (73%) and increased desmoid risk relative to no family history (80% versus 15%, respectively; P < 0.01). Among the 1213 low-risk patients, 154 (12.7%) developed desmoids, with no significant effect of surgical procedure (13.9% versus 12.1% for proctocolectomy and total/partial colectomy, respectively; χ² = 0.77; P = 0.380). Family history increased desmoid risk relative to no family history (30% versus 10%, respectively; P < 0.01).

conclusionA family history of desmoid disease appears to be an important determinant of postoperative desmoid risk in FAP. Although APC PV 3' of codon 1399 does confer a high overall risk, this is largely confined to individuals with first-degree relatives with desmoid. In the absence of a family history, postoperative desmoid risk appeared relatively low regardless of genotype. This supports a more individualized approach to perioperative counselling and surgical decision-making in patients with FAP. In addition, these data highlight that patients with both a 3' APC PV and a positive family history are a particularly high-risk subgroup who may represent an appropriate target population for future chemoprevention trials.