APC (Familial adenomatous polyposis) – risk management

Familial adenomatous polyposis (FAP) is an autosomal dominant condition caused by a germline pathogenic variant in the APC gene.

Classical familial adenomatous polyposis (FAP) is defined by the presence of >100 colorectal adenomas (cumulative count), autosomal-dominant inheritance and young age of onset of polyposis (mean age approximately 15 years).  

Atypical/attenuated familial adenomatous polyposis (AFAP) is defined by the presence of <100 colorectal adenomas (cumulative count) and autosomal-dominant inheritance, with later onset of adenomas and cancer compared with classical FAP. 

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow-up. 

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

• Known carrier of APC pathogenic variant

Exclusion criteria

• Person at 50% risk of inheriting a known APC pathogenic variant who have chosen not to have predictive testing
• Person at 50% risk of FAP where predictive testing is not possible because an affected relative has not been tested
• Person with multiple colorectal adenoma meeting clinical criteria for FAP who has uninformative genetic testing (including APC)
• Person with multiple colorectal polyps (mix of adenoma and other histological types) with no APC pathogenic variant identified

 *This data is from classical FAP and does not take the impact of surveillance into account
^** Source: Australian Institute of Health and Welfare (AIHW) 2020 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/>. (2016 data)
^ Abdominal surgery, APC mutation site and positive family history for desmoid-type fibromatosis influence the risk^r

The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.

*** The impact of lifestyle on general cancer risks should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.
^¶ FAP = classical familial adenomatous polyposis; AFAP = atypical/attenuated familial adenomatous polyposis.

Colorectal polyps and cancer

In classic FAP extensive colonic adenomatous polyposis is typically evident early in the second decade of life (but can develop earlier). In atypical FAP polyps typically develop at a later age, although the age at first polyps varies from adolescence to mid-to-late adulthood. Without polypectomy and/or colectomy polyps eventually become malignant. Colorectal cancer occurs most often in adulthood but is occasionally seen in childhood or adolescence.

Multiple studies have demonstrated that surveillance colonoscopy from early childhood with appropriately timed colectomy reduces CRC incidence and mortality.^r The natural history of polyposis supports annual surveillance in classical FAP. It also supports surveillance by either sigmoidoscopy or colonoscopy until polyps are first detected, and then by colonoscopy.^r

Some experts recommend less frequent (2-3 yearly) colonoscopy for individuals at risk of atypical FAP who have not developed polyps. They recommend an increase to 1-2 yearly colonoscopy once polyps have been detected, with the frequency guided by polyp burden.^r Others recommend annual surveillance because of the variability in polyp phenotype that is seen both between and within families. In AFAP polyps have a more proximal colonic preponderance and colonoscopy should be used for surveillance (not sigmoidoscopy).

Gastric, duodenal and small bowel polyps and cancer

Gastric, duodenal and jejunal polyps may be evident by the second decade of life. Progression to malignancy is uncommon.^r The recommended upper GI surveillance protocol is based on published literature and expert opinion.^r

Desmoid-type fibromatosis

Although desmoid-type fibromatosis is a benign fibroblastic neoplasm, intra-abdominal desmoids can cause substantial morbidity in patients with FAP, and contribute to FAP-related mortality. Abdominal surgery, APC pathogenic variant site and positive family history for desmoid-type fibromatosis are consistent risk factors for development of desmoid-type fibromatosis.^r There is conflicting evidence regarding female gender, pregnancy and oestrogen exposure. Some experts recommend annual surveillance using abdominopelvic MRI for patients who have had abdominal surgery and have a family history, but there is no evidence of benefit.

Other cancers

The American College of Gastroenterology recommends hepatoblastoma surveillance from birth to age 7 years. However, there is substantial controversy about surveillance as the absolute risk of hepatoblastoma is small and there is no evidence of benefit of surveillance.^r

The cribriform-morular variant of papillary thyroid cancer is more common in FAP patients, especially females. Some experts recommend annual clinical examination of the neck from mid-teenage years,^r others recommend periodic thyroid ultrasound. There is no evidence of benefit for either approach.

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Bibliography

Bulow, S. 2003. "Results of national registration of familial adenomatous polyposis." Gut. 52(5):742-746.

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BACKGROUND AND AIMS: The Danish Polyposis Register was established in 1971 with the aim of improving the poor prognosis of familial adenomatous polyposis (FAP), and in 1975 the register became national. The aim of the present study was to evaluate the prevalence of colorectal cancer and survival rate in FAP patients before and after the establishment of the Danish Polyposis Register. PATIENTS AND METHODS: The Danish Polyposis Register was established by collecting information on probands and construction of their pedigrees. Family members at risk were offered prophylactic endoscopic and molecular genetic examination, and affected individuals were treated by colectomy. RESULTS: At the end of 2001, the Danish Polyposis Register included 434 patients from 165 families. The incidence rate was 1.90x10(-6) and the prevalence rate 4.65x10(-5). Colorectal cancer on the basis of FAP constituted 0.07% of all colorectal cancers in the 1990s. Colorectal cancer was diagnosed in 170/252 probands (67%) and in 5/182 call-up patients (3%) (p <0.001). The cumulative crude survival was 94% in call-up patients compared with 44% in probands (p <0.0001). A comparison of two periods, 1900-1975 and 1976-2001, demonstrated a decreased prevalence of colorectal cancer from 60% to 27% (p <0.0001), and an increased use of colectomy from 52% to 93% (p <0.00001). The cumulative crude survival in FAP showed substantial improvement with time (p <0.00001). CONCLUSION: Since the establishment of the Danish Polyposis Register, the prevalence of colorectal cancer has decreased considerably and the prognosis has improved substantially. The work of the Danish Polyposis Register is probably the main cause of this improvement

Groves, C. J., B. P. Saunders, A. D. Spigelman, et al. 2002. "Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a 10 year prospective study." Gut 50(5):636-641.

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BACKGROUND: Duodenal cancer is one of the leading causes of death in familial adenomatous polyposis (FAP) patients. An endoscopic surveillance programme was therefore initiated in 1988, the outcome of which is described in this paper. METHODS: We report the 10 year follow up of 114 patients with FAP who were prospectively screened for the presence and severity of duodenal adenomas. RESULTS: Six of 114 patients (median age 67 years) developed duodenal adenocarcinoma. Four of these were from 11 patients who originally had Spigelman stage IV disease (advanced duodenal polyposis), which gives a 36% risk within this group of developing cancer. One case of duodenal cancer arose from 41 patients who originally had stage III disease (2%) and one cancer arose from 44 patients with original stage II disease (2%). All six patients have died: five were inoperable and one had recurrence three years after a pancreaticoduodenectomy. There was no association between duodenal cancer and site of germline mutation of the APC gene. CONCLUSIONS: Surveillance for duodenal adenocarcinoma and subsequent early referral for curative surgery has not been effective. Selection of patients with advanced but benign (Spigelman stage IV) duodenal polyposis for prophylactic pancreaticoduodenectomy should therefore be considered and can now be justified on the basis of these results. More comprehensive endoscopic surveillance of high risk (stage III and IV) patients is needed in an attempt to avoid underestimating the severity of duodenal polyposis, and to evaluate the role of endoscopic therapy in preventing advanced disease.

Koornstra, J. J. 2012. "Small bowel endoscopy in familial adenomatous polyposis and Lynch syndrome." Best Pract Res Clin Gastroenterol 26(3):359-368

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Patients with familial adenomatous polyposis (FAP) and patients with Lynch syndrome have an increased risk of developing small intestinal neoplasia. In both conditions, the lifetime risk to develop small bowel cancer is estimated to be around 5%. In FAP, this risk is associated with the degree of duodenal polyposis, classically assessed by the Spigelman classification. For this reason, gastroduodenal surveillance with forward-viewing and side-viewing endoscopy is generally recommended. Studies using video capsule endoscopy and balloon-assisted enteroscopy in FAP patients have revealed that jejunal and ileal polyps occur frequently in FAP, especially in those with extensive duodenal polyposis. Nevertheless, the clinical relevance of small bowel polyps beyond the duodenum appears to be limited. Compared to FAP, little is known about the prevalence and natural history of small bowel neoplasia in Lynch syndrome. Surveillance of the small bowel is not recommended in Lynch syndrome, although recent data using capsule endoscopy provided promising results.

Septer, S., C.E. Lawson, S. Anant, et al. 2016. "Familial adenomatous polyposis in pediatrics: natural history, emerging surveillance and management protocols, chemopreventive strategies, and areas of ongoing debate." Fam Cancer 15(3):477-485.

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Familial adenomatous polyposis (FAP) is a hereditary condition with a near 100 % lifetime risk of colorectal cancer without prophylactic colectomy. Most patients with FAP have a mutation in the adenomatous polyposis coli gene on chromosome 5q22. This condition frequently presents in children with polyps developing most frequently in the second decade of life and surveillance colonoscopy is required starting at age ten. Polyps are found not only in the colon, but in the stomach and duodenum. Knowledge of the natural history of FAP is important as there are several extra-colonic sequelae which also require surveillance. In infants and toddlers, there is an increased risk of hepatoblastoma, while in teenagers and adults duodenal carcinomas, desmoid tumors, thyroid cancer and medulloblastoma are more common in FAP than in the general population. Current chemopreventive strategies include several medications and natural products, although to this point there is no consensus on the most efficacious and safe agent. Genetic counseling is an important part of the diagnostic process for FAP. Appropriate use and interpretation of genetic testing is best accomplished with genetic counselor involvement as many families also have concerns regarding future insurability or discrimination when faced with genetic testing.

Stoffel, E. M., P. B. Mangu, P. J. Limburg, et al. 2015. "Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines." J Oncol Pract 11(3):e437-441.

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Syngal, S., R. E. Brand, J. M. Church, et al. 2015. "ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes." Am J Gastroenterol 110(2):223-262; quiz 263

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This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

Trobaugh-Lotrario, A.D., D. Lopez-Terrada, P. Li, et al. 2018. "Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening." Pediatric blood & cancer 65(8):e27103.

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Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma. All cases of hepatoblastoma in patients with FAP reported in the literature were reviewed. One hundred and nine patients were identified. Thirty-five patients (of 49 with data) were diagnosed with hepatoblastoma prior to a later diagnosis of FAP (often in association with advanced colorectal carcinoma), emphasizing a need to identify patients earlier with germline APC mutations for early colorectal carcinoma screening. Hepatoblastoma may present at birth, and screening for hepatoblastoma in infancy in families with FAP prior to APC mutation testing results may be warranted.

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