Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 2.1.0
• GENE/GENE PANEL: APC
• Condition: Familial Adenomatous Polyposis
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• APC ⇔ 175100: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Colorectal cancer (AFAP only) / Colonoscopy with polypectomy	2	3A	2B	2	9AB
Colorectal cancer / (Procto)colectomy	2	3A	3B	1	9AB
Advanced-stage thyroid cancer / Annual surveillance	2	0C	0D	3	5CD
Upper GI (stomach or duodenum) cancer / Periodic EGD	2	2C	2B	2	8CB
Morbidity from desmoid tumor / Regular physical exam and imaging	2	2A	0B	3	7AB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Estimates of the prevalence of FAP vary from 1:6,850 to 1:37,600 live births. [1, 2, 3, 4, 5, 6]

Clinical Features

Classical FAP is characterized by the presence of ≥100 adenomatous polyps, with cases usually developing hundreds to thousands of adenomatous polyps. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Extracolonic manifestations are variably present and include polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, epidermoid cysts, adrenal gland adenoma, hepatoblastoma, thyroid cancer, and brain tumors. A milder phenotype of the disorder is referred to as attenuated FAP (AFAP), which occurs in approximately 8% of cases and is characterized by a milder course of the disease. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]

Natural History

The average age of classic FAP diagnosis in patients presenting with symptoms is 35.8 years (range, 4–72 years). Colorectal adenomatous polyps begin to appear, on average, by age 16 (range: 7-36 years). By age 35, 95% of FAP patients have polyps. In virtually all cases, the adenomas will develop into CRC if left untreated. The mean age of CRC diagnosis in untreated individuals is has been reported between 34-50 years; with cancer developing nearly universally by age 50. Although unusual, CRC has been reported as early as 9 years of age. Although rare, asymptomatic individuals in their 50s have been reported. Duodenal cancer and desmoid tumors are the most common causes of death in patients with FAP after colorectal cancer. Duodenal adenocarcinoma occurs has been reported to occur between ages 17 and 81 years, with the mean age of diagnosis between 45 and 52 years. The incidence of desmoid tumors in FAP is highest in the second and third decades of life, with 80% occurring by age 40, and generally occurring within 5 years of colectomy. 5-10% of individuals with FAP experience morbidity and/or mortality from desmoid tumors, with the highest mortality rate reported for intra-abdominal tumors. The mean age of diagnosis of thyroid cancer is 28 years, ranging from 12 to 62 years, with a female preponderance observed. The majority of hepatoblastomas occur prior to age five years and exhibit a male preponderance.
While the phenotype of AFAP is not well defined, widely used clinical criteria include the following: a delay in onset of adenomatous polyposis and colorectal cancer of 10–25 years compared with classical FAP; <100 adenomatous polyps at 25 years of age or older; and/or a late onset of disease (≥45 years of age) irrespective of polyp number. [1, 2, 3, 4, 7, 8, 11, 12]

2. How effective are interventions for preventing harm?

Patient Management

The recommendations detailed below are largely applicable to classic and attenuated FAP; however attenuated FAP, with its milder course, may be manageable by colonoscopy and polypectomy and these patients may never require colectomy depending on polyp burden. (Tier 2) [4, 7, 11, 12]

Recommendations and evidence for classical FAP are presented here.

Treatment for FAP should include thorough counseling about the nature of the syndrome and the need for compliance with recommendations for management and surveillance. Patients should be managed ideally by clinicians with expertise in FAP and in the setting of a multidisciplinary team. (Tier 2) [2, 7, 10, 14]

A systematic review of studies comparing CRC incidence and mortality before and after registry commencement, found 8 studies (3101 individuals) examining CRC incidence and 6 studies examining CRC mortality. Odds ratios for CRC incidence following registration range from 0.09-0.44, with all but one study showing a statistically significant effect. Odds ratios for CRC-related mortality range from 0.11-0.22, all significant. (Tier 1) [9]

Colonscopic clearance of adenomas in patients with classical FAP cannot guarantee that cancer will be prevented; therefore, removal of the at-risk epithelium ((procto)colectomy) is considered the standard of care, Decisions regarding the timing and type of operation to be performed (including rectal sparing or pouch construction) should be made by the patients after being fully informed about the natural history of the disease in relation to the individual’s polyp burden and the pros and cons of the surgical options. Removal of the colon should be undertaken at a premalignant stage, typically before age 25-30. Nonrandomized studies have demonstrated individual merits of each surgical approach. (Tier 2) [1, 2, 4, 7, 10, 11, 12, 15]

There remains a risk of adenoma and CRC after colectomy, and the extent of risk is influenced by the type of procedure chosen and type of tissue-sparing. The risk of adenoma has been estimated at 10% - 51% and the risk of cancer less than 1% to about 2% in studies after the modern surgical techniques became available. However, some registries have estimated the risk of mortality from rectal cancer in rectal-sparing procedures (ileorectal anastomosis) to be up to 12.5% for patients with a high rectal polyp burden. (Tier 2) [1, 2, 4, 7, 10, 11, 12, 15, 16]

Surveillance

Endoscopic surveillance (i.e., flexible sigmoidoscopy or colonoscopy) is recommended until the polyp burden necessitates that colectomy is performed. Surveillance is generally recommended annually; however, some guidelines recommend screening every 6 months or every two years. During surveillance, polyp burden should be recorded and several polyps biopsied. (Tier 2) [1, 2, 4, 7, 10, 11, 12, 15, 16, 17]

A systematic review of patients with FAP found that 26 of 27 studies showed a statistically significant reduction in CRC incidence with surveillance (odds ratios ranged from 0.01 to 0.37) in screened patients compared to those who presented symptomatically with polyposis/CRC outside of a screening program. Eight studies examined CRC mortality, all of which showed a significant reduction in CRC mortality (odds ratios ranged from <0.01 to 0.16) in screened (N= 1028) versus symptomatic groups (N= 947). Two studies provided evidence for complete prevention of CRC-related deaths during surveillance, although the duration of follow-up was short (2-4 years). (Tier 1) [9]

Surveillance for gastric and proximal small bowel tumors with esophagogastroduodenoscopy using forward and side-viewing endoscopes should begin at age 20 to 30. Most guidelines base the surveillance interval on endoscopic findings (Spigelman score for duodenal adenomatosis staging) at baseline. (Tier 2) [1, 2, 4, 7, 10, 11, 12, 15, 18]

While surveillance with selective polypectomy/ampullectomy has been shown to decrease the Spigelman score, and higher Spigelman scores are associated with higher risk of cancer, guidelines note it is unclear if endoscopic prevention of all duodenal cancers is possible. (Tier 2) [1, 10]

There is some evidence that screen-detection of duodenal cancer may improve survival; FAP patients have been shown to have a median survival after a screen-detected cancer of 8 years (95% CI, 5.9 - not estimated), versus 0.8 years (95% CI, 0.03-1.7) after symptomatic cancer (p < 0.0001). (Tier 5) [19]

Malignant progression of fundic gland polyps of the stomach is uncommon and surveillance is considered adequate for monitoring for gastric cancers. (Tier 2) [7]

A regular physical exam with evaluation for palpable masses suggestive of desmoids is recommended with consideration for the use of computed tomography or magnetic resonance imaging based on family history. (Tier 2) [4, 7, 11, 12]

The first line of treatment in patients with large or growing intra-abdominal or abdominal wall tumors is sulindac, usually in combination with tamoxifen, toremifene, or raloxifene. Surgery is reserved for small, well-defined tumors when a clear margin can be obtained; however, even in selected patients recurrence rates are high and the overall benefit of resection is not clear. Chemotherapy or radio therapy may be beneficial. (Tier 2) [1, 10, 11, 12]

Annual surveillance for thyroid cancer should be conducted; however, whether this screening should occur via ultrasound or physical exam is inconsistent across guidelines. There are no prospective studies comparing these screening strategies. A study comparing patients with screen-detected cancer to those with incident cancers showed that screening led to detection of smaller tumors with fewer positive lymph nodes. (Tier 2) [4, 7, 10, 11, 12]

Annual physical and neurologic examination starting at age 25 to 30 years may be considered for central nervous system (CNS) cancers, but data to support this practice are lacking. (Tier 2) [7]

Circumstances to Avoid

No circumstances-to-avoid recommendations have been provided for the Adult context.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Estimates of the prevalence of FAP vary from 1:6,850 to 1:37,600 live births. [1, 2, 3, 4, 5, 6]

Pathogenic variants in APC can be identified in 80-95% of FAP cases, meaning that the prevalence of APC mutations should be lower, although similar, to the prevalence of FAP. (Tier 3) [2, 3, 7]

Penetrance

The penetrance information presented here applies to classic FAP unless noted otherwise.

The penetrance of colon cancer is estimated at 90-100% in untreated individuals, within AFAP the risk of cancer approaches 70% by age 80. (Tier 3) [1, 2, 3, 4, 7, 12]

The lifetime risk of duodenal cancers has been estimated at 3-12%. (Tier 3) [1, 2, 3, 4, 7, 10]

Jejunal and ileal polyps can be found in 40-70% of FAP patients. (Tier 3) [4, 18]

A high degree of variability in the frequency of thyroid cancer from 0.4-2% in retrospective reports, to 2.6-11.8% in prospective studies, with a female to male ratio of 80:1. Benign thyroid disease has been reported in 9-80% of patients. (Tier 3) [3, 4, 7, 10]

The lifetime pancreatic cancer risk to age 80 in individuals with FAP was estimated at 1-2%. (Tier 3) [3, 4]

The absolute risk for CNS tumors is 1-2%. (Tier 3) [4]

In a meta-analysis of 10 studies of 4625 patients, 559 (12%) developed desmoid tumor. (Tier 1) [8]

While gastric polyps occur in 23-100% of patients, the lifetime risk for gastric cancer in FAP in Western countries is estimated between 0.5 and 1%. (Tier 3) [4, 7, 8, 13]

Adrenal masses occur in 7-13% of patients; however, most are asymptomatic incidental findings. (Tier 3) [3]

Relative Risk

The relative risk information presented here applies to classic FAP.

Although limited data exist, one study of 197 families with FAP revealed a relative risk for pancreatic cancer of 4.5-5 in individuals with FAP and their at-risk relatives compared to the general population risk. (Tier 3) [3, 4]

The risk for desmoid tumors in individuals with FAP is more than 800-1000 times the risk in the general population. (Tier 3) [3, 8]

The risk of duodenal cancer is 100-300 times higher than in the general population. (Tier 3) [10]

The risk for adrenal masses are 2-4 times greater than the general population. (Tier 3) [3]

Expressivity

Development of colorectal adenomas is variable, including variability in the number of adenomas within families with the same APC mutation. Both inter- and intrafamilial phenotypic variability are common. (Tier 3) [3]

4. What is the Nature of the Intervention?

Nature of Intervention

Endoscopic surveillance is burdensome for individuals. [6]

There is a small but appreciable risk of complications from colonoscopy including perforation, bleeding, and death. [2]

The morbidity and functional outcomes of colectomy can include incontinence, sexual dysfunction, infertility, and pelvic dissection and are partially dependent on the type of procedure chosen and whether the rectum is retained. In addition, an increased risk of desmoid tumors have been noted among individuals with FAP who have undergone abdominal surgery. [2, 4, 6, 7, 10, 11, 12]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. (Tier 4) [5]

Because of the high proportion of de novo FAP cases (up to 1/3 of FAP patients), there is a 25% incidence of CRC in newly diagnosed FAP cases. Because of this presentation and the early onset of CRC in FAP patients (prior to population screening age), there is a high chance for FAP patients to escape clinical detection. (Tier 3) [1, 2, 4, 7]

Date of Search: 05.13.2014 (updated 04.09.2018)

Reference List

1. Vasen HF, Moslein G, Alonso A, Aretz S, Bernstein I, Bertario L, Blanco I, Bulow S, Burn J, Capella G, Colas C, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Jarvinen H, Mecklin JP, Moller P, Myrhoi T, Nagengast FM, Parc Y, Phillips R, Clark SK, de Leon MP, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen J. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut. (2008) 57(5):704-13.

2. Cairns SR, Scholefield JH, Steele RJ, Dunlop MG, Thomas HJ, Evans GD, Eaden JA, Rutter MD, Atkin WP, Saunders BP, Lucassen A, Jenkins P, Fairclough PD, Woodhouse CR. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. (2010) 59(5):666-89.

3. KW Jasperson, RW Burt. APC-Associated Polyposis Conditions. 1998 Dec 18 [Updated 2014 Mar 27]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1345

4. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. (2015) 110(2):223-62; quiz 263.

5. Familial adenomatous polyposis. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=733

6. Aretz S, Vasen HF, Olschwang S. Clinical Utility Gene Card for: Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP)--update 2014. Eur J Hum Genet. (2015) 23(6).

7. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal Version 2.2019. (2019) Accessed: 2019-10-01. Website: https://nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

8. Sinha A, Tekkis PP, Gibbons DC, Phillips RK, Clark SK. Risk factors predicting desmoid occurrence in patients with familial adenomatous polyposis: a meta-analysis. Colorectal Dis. (2011) 13(11):1222-9.

9. Barrow P, Khan M, Lalloo F, Evans DG, Hill J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg. (2013) 100(13):1719-31.

10. Herzig D, Hardiman K, Weiser M, You N, Paquette I, Feingold DL, Steele SR. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Inherited Polyposis Syndromes. Dis Colon Rectum. (2017) 60(9):881-894.

11. Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MW, Lu KH, Roach N, Limburg PJ. 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 Clin Oncol. (2015) 33(2):209-17.

12. Balmana J, Balaguer F, Cervantes A, Arnold D. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol. (2013) 24 Suppl 6:vi73-80.

13. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. FAMILIAL ADENOMATOUS POLYPOSIS 1; FAP1. MIM: 175100: 2016 Aug 31. World Wide Web URL: http://omim.org.

14. British Columbia Medical Association. Colorectal Screening for Cancer Prevention in Asymptomatic Patients. (2013) Accessed: 2018-05-03. Website: http://www.bcguidelines.ca/guideline_colorectal_det.html

15. Scottish Intercollegiate Guidelines Network. Diagnosis and management of colorectal cancer. (2015) Accessed: 2018-05-03. Website: http://www.sign.ac.uk/assets/sign126.pdf

16. Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM. American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol. (2009) 104(3):739-50.

17. Royal Australian College of General Practitioners. Guidelines for preventive activities in general practice: 9th edition. (2016) Accessed: 2018-05-07. Website: https://www.racgp.org.au/your-practice/guidelines/redbook/

18. Pennazio M, Spada C, Eliakim R, Keuchel M, May A, Mulder CJ, Rondonotti E, Adler SN, Albert J, Baltes P, Barbaro F, Cellier C, Charton JP, Delvaux M, Despott EJ, Domagk D, Klein A, McAlindon M, Rosa B, Rowse G, Sanders DS, Saurin JC, Sidhu R, Dumonceau JM, Hassan C, Gralnek IM. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy. (2015) 47(4):352-76.

19. Bulow S, Christensen IJ, Hojen H, Bjork J, Elmberg M, Jarvinen H, Lepisto A, Nieuwenhuis M, Vasen H. Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis. Colorectal Dis. (2012) 14(8):947-52.