Clinical characteristics: APC-associated polyposis conditions include (classic or attenuated) familial adenomatous polyposis (FAP) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).
FAP is a colorectal cancer (CRC) predisposition syndrome that can manifest in either classic or attenuated form. Classic FAP is characterized by hundreds to thousands of adenomatous colonic polyps, beginning on average at age 16 years (range 7-36 years).
For those with the classic form of FAP, 95% of individuals have polyps by age 35 years; CRC is inevitable without colectomy. The mean age of CRC diagnosis in untreated individuals is 39 years (range 34-43 years). The attenuated form is characterized by multiple colonic polyps (average of 30), more proximally located polyps, and a diagnosis of CRC at a later age than in classic FAP.
For those with an attenuated form, there is a 70% lifetime risk of CRC and the mean age of diagnosis is 50-55 years. Extracolonic manifestations are variably present and include polyps of the stomach and duodenum, osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE), benign cutaneous lesions, desmoid tumors, adrenal masses, and other associated cancers.
GAPPS is characterized by proximal gastric polyposis, increased risk of gastric adenocarcinoma, and no duodenal or colonic involvement in most individuals reported.
Diagnosis/testing: The diagnosis of an APC-associated polyposis condition is established by identification of a heterozygous germline pathogenic variant in APC.
Management: Treatment of manifestations: Resection of all colonic polyps larger than 5 mm found on colonic surveillance. There is an absolute indication for colectomy when CRC is diagnosed or suspected, or when there are significant symptoms (e.g., bleeding, obstruction). Relative indications for colectomy include presence of multiple adenomas larger than 10 mm that cannot be reasonably removed endoscopically, a significant increase in adenoma number between surveillance exams, presence of adenomas with high-grade dysplasia, or inability to adequately survey the colon (e.g., due to innumerable diminutive adenomas or limited access to or compliance with colonoscopy). Endoscopic or surgical removal of duodenal adenomas is considered if polyps exhibit villous change or severe dysplasia, exceed 1 cm in diameter, or exhibit advanced stage using Spigelman scoring system. Gastrectomy is considered if advanced gastric neoplasia is found on upper endoscopy. Osteomas may be removed for cosmetic reasons. Desmoid tumors may be surgically excised or treated with nonsteroidal anti-inflammatory drugs (NSAIDs), anti-estrogens, cytotoxic chemotherapy, and/or radiation if at advanced stage. Standard treatment when needed for adrenal masses and thyroid carcinoma. Several studies have shown that NSAIDs and erlotinib have caused regression of adenomas and decreased the polyp burden in individuals with FAP, though there are currently no FDA-approved chemopreventive agents for FAP, given an unclear impact on subsequent cancer risk.
Prevention of primary manifestations: Colectomy to reduce the risk for CRC in individuals with classic FAP. For individuals with attenuated FAP, colectomy may be necessary, but in approximately one third of individuals, the colonic polyps are limited enough in number that surveillance with periodic colonoscopic polypectomy is sufficient to prevent CRC. It is currently unknown if prophylactic gastrectomy should be considered in individuals with GAPPS.
Surveillance: Colorectal screening by colonoscopy every one to two years beginning at age ten to 15 years for classic FAP and in late adolescence for attenuated FAP; esophagogastroduodenoscopy with visualization of the ampulla of Vater by age 20 to 25 years or prior to colon surgery, with consideration of complete small bowel visualization in the setting of advanced Spigelman stage. Annual thyroid palpation, thyroid ultrasound, neurologic examination, and abdominal examination (for desmoids). Liver palpation, liver ultrasound, and measurement of serum alpha-fetoprotein every three to six months until age five years for hepatoblastoma. The efficacy of screening for gastric cancer in individuals with GAPPS is currently unknown.
Agents/circumstances to avoid: Multistage surgeries in those at high risk for desmoids; total colectomy with ileal pouch anal anastomosis in women prior to childbearing.
Evaluation of relatives at risk: Molecular genetic testing for early identification of at-risk family members improves diagnostic certainty and reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant.
Genetic counseling: APC-associated polyposis conditions are inherited in an autosomal dominant manner. Approximately 75%-80% of individuals with an APC-associated polyposis condition have an affected parent. Offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant in APC. Prenatal testing and preimplantation genetic testing are possible if a pathogenic variant has been identified in an affected family member.
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