Familial Adenomatous Polyposis affects 1 in 10,000 to 30,000 Americans who experience 100% risk of colon cancer, and FAP doesn't end with a total colectomy for removal of their hundreds of polyps. Follow this journey of two real FAP patients through pancreatitis from symptomatic ampulla polyps, surgical resection of giant small bowel polyps, bowel obstruction from abdominal desmoid tumors, and Wilm's tumor of the kidney. How do we diagnose, monitor and support our FAP patients? Can pharmacotherapy reduce risk of polyp growth in FAP? What are the extracolonic manifestations of the APC gene mutation? Our responsibility doesn't end when the colon does.

1. FAP Mishap:
A Tale of Two Patients
Patricia Raymond MD FACG
Rx For Sanity
Norfolk VA

2. Disclosure: Relationships with commercial interest organizations whose
products are related to the program content include: NONE
The Society of Gastroenterology Nurses and Associates, Inc. is accredited as a
provider of continuing nursing education by the American Nurses Credentialing
Center’s (ANCC) Commission on Accreditation.

3. Objectives
•Discuss the natural history of Familial Adenomatous Polyposis and
construct proper endoscopic diagnosis and management
•Review the additional extra colonic medical complications
attributable to the FAP gene and current management and
surveillance for these conditions
•Illustrate an understanding of FAP related disease with assessment
of two patients histories

4. Familial adenomatous polyposis (FAP):
411
• Autosomal dominant disease caused by mutations in the Adenomatous
Polyposis Coli (APC) gene on chromosome 5q21-q22
• Classic FAP >100 adenomatous colorectal polyps (may be thousands)
• 100 percent risk of colorectal cancer (CRC)
• Attenuated FAP (aFAP) with 10-20 cumulative polyps, later age of onset
• 80 percent lifetime risk of CRC
• 3 per 100,000 individuals
• Less than 1 percent of all colorectal cancers in the United States
• Affects both sexes equally
• Seen worldwide
Bisgaard ML, Fenger K, Bülow S, et al. Familial adenomatous polyposis (FAP): frequency,
penetrance, and mutation rate. Hum Mutat 1994; 3:121.

5. Familial adenomatous polyposis (FAP):
411
• Autosomal dominant pattern of inheritance
• Nearly complete penetrance of colonic polyposis
• Variable penetrance of the extracolonic manifestations of the
disease.
• Up to 25 percent of FAP cases are due to new or de novo APC
mutations
• More than 1000 different mutations of the APC gene associated with
FAP
• Most lead to frame shifts and premature stop codons
• Large deletions in up to 15 percent of cases.
Bisgaard ML, Fenger K, Bülow S, et al. Familial adenomatous polyposis (FAP): frequency,
penetrance, and mutation rate. Hum Mutat 1994; 3:121.

6. Treatment: Colectomy for FAP
FAP: high polyp number makes endoscopic control unrealistic
aFAP: may be able to endoscopically manage with frequent colonoscopy
When to do FAP colectomy:
• Documented or suspected colorectal cancer
• Severe symptoms related to colonic neoplasia (eg, severe
gastrointestinal bleeding)
• Adenomas with high-grade dysplasia or multiple adenomas larger than
6 mm
• Marked increases in polyp number on consecutive exams
• Inability to adequately survey the colon because of multiple diminutive
polyps

7. Surgical Options for FAP Patients
• Total proctocolectomy with end-ileostomy
• Total proctocolectomy with ileal pouch anal anastomosis (IPAA)
• Subtotal colectomy with ileo-rectal anastomosis (IRA)
Must weigh the preventive effect against the impact on post-
operative quality of life
The patient MUST know what procedure they had performed

8. from https://www.jhmicall.org
Total proctocolectomy with end-ileostomy

9. from https://www.jhmicall.org
Subtotal colectomy with ileo-rectal anastomosis (IRA)

10. from https://www.jhmicall.org
Total proctocolectomy with ileal pouch anal anastomosis (IPAA)

11. Which operation?
•Severity and distribution of colorectal adenomas
•Risk of desmoid tumors
•Patient’s age and comorbidities
•Specific APC genotype may predict the severity of colorectal polyposis and the risk of
desmoid tumor
•IPAA is more extensive surgery as compared with IRA
•Increased risk of bleeding and reduction in fertility in women
•Patients with IRA who subsequently develop severe rectal polyposis will require a
secondary proctectomy
•Polyp number >1000 is an indicator for a more extensive resection (proctocolectomy
with IPAA versus subtotal total colectomy with IRA).
•If rectal polyposis at diagnosis, choose wisely
Genotype-phenotype correlations as a guide in the management of familial adenomatous polyposis. Nieuwenhuis MH,
Mathus-Vliegen LM, Slors FJ, et at. Clin Gastroenterol Hepatol. 2007;5(3):374.

12. Still at Risk
• Polyps and cancer may arise from the anal transition zone (“rectal cuff”) or
within the ileal pouch
• Endoscopy annually (or every other year for end-ileostomies)
• 212 FAP patients who underwent IPAA at a mean follow-up of 7.9 years
25 (12 percent) developed an adenoma with advanced pathology in pouch
4 (2 percent) developed a cancer in pouch
• Median interval from prior endoscopy and the detection of cancer was
25 months.
• Pouchitis may develop in a subset of patients but is usually less severe than
that found in patients with inflammatory bowel disease
Risk of developing adenomas and carcinomas in the ileal pouch in patients with familial adenomatous polyposis. Friederich P, de Jong AE,
Mathus-Vliegen LM, et al. Clin Gastroenterol Hepatol. 2008;6(11):1237.

13. OF WHAT ELSE
DO WE NEED TO BE AWARE?
No more colon with FAP

14. Meet Patient A
Sonya

16. Sonya: Index appointment 05/06/2010
• Age 34 African American
• Initial referral to GI because optometrist saw bilateral CHRPE
• Colonoscopy 2005 with Dr H, “100s of polyps”
• Offered and refused surgery at age 29 (IPAA)
• Repeat colonoscopy 2010 (PR), only 12 polyps in descending
colon and rectum
• Most with low to moderate grade dysplasia
• Genetic testing for FAP positive for APC gene mutation

17. Sonya 2010
• Epigastric burning pain, persistent x months
• 6/10 in severity, nausea without vomiting
• No melena or hematochezia
• Labs:
• Lipase 87 (normal to 60)
• Normal CMP
• Hgb 7.9, microcytosis

18. Sonya 2010
• EGD 2010 unremarkable
• SBFT normal
• Family history: Father with Gardner syndrome
• Colon cancer at age 38
• Duodenal cancer as cause of death
• Agreed to have colectomy
• Done?

19. NOPE

20. Sonya Intervening years
• Ileoanal pull through (Proctocolectomy with ileoanal J
pouch)
• Polyp at ampulla with biliary colic; consideration Whipple
• Desmoid tumor in retroperitoneum
• TVA at anal margin

21. Sonya Ampulla Presentation
• Annual EGD with front and side view scope 2012, 2013,
2014
• Polyp in esophagus, polyps duodenum, polyp ampulla
• Polyp at ampulla simple adenoma without dysplasia
• Prominent appearing ampulla without polypoid features

22. Sonya Ampulla Adenoma 2014
• Biliary pain with intermittent modest elevation liver tests, lipase
• US and qHIDA unremarkable
• Possibly ampullary adenoma tissue with intermittent obstruction?
• Surgical consultation, consideration of whipples
• Consideration of endoscopic ampullectomy
• Trial ursodeoxycholic acid (Urso) with improvement symptoms
• Continued surveillance with ampullectomy for dysplasia

23. Sonya Desmoid Tumor Presentation
• To ED for severe abdominal and back pain,
vomiting
• CT with right ureteral obstruction and 13 cm mass
with urinary obstruction
• Ureteral stent placed
• Surgical debulking and ureteral reconstruction
• Pathology Desmoid Tumor

24. Sonya Desmoid Tumor
• Debulk procedure usual management
• Chemotherapy from VOA for residual/recurrent
• Recurrence “independent of margin status”
• <1/2 with positive margins recur
• Aggressive resection with widely negative margins recur 16 to
39%
• “Excessive mortality” with aggressive resection
• CT q 6 months x 3 years, q 12 months until year 6, then q 24
months

25. Desmoid Tumor
• Patients with FAP are 852 x more likely to develop desmoid tumors than
general population
• Abdominal surgery in FAP patients may provoke desmoid tumors; mean
interval from surgery to desmoid tumor is 2.3 years
• In FAP patients, “recurrences can become more frequent or aggressive
with each surgical intervention”
• Encases mesenteric vasculature, requiring resection of segments of
intestine

26. DONE?

27. NOPE

28. Sonya TVA
• IPAA with retained cuff mucosa
• “Flex sig” of pouch and cuff each year done with
EGD to examine duodenum
• In 1 year interval, grew a 2.5 cm TVA without
dysplasia just above anal verge
• Removed carefully with cautery, APC touch up

29. Sonya: Most recent visit late 2017
• FFS- no recurrent TVA on white light and NBI
• Abdominal pain with bulky foods, likely adhesions. Trial abdominal
massage
• EGD- few 3 mm polyps in duodenum , no ampulla dysplasia
• SBFT not remarkable
• CT: Scarring of peritoneal surface with calcifications and surgical
clips, mildly enlarged lymph nodes, no recurrent masses
• Hgb 13.7 with MCV 84
• Normal CMP
• Lipase 51

30. Sonya 2017
• 18 yo daughter colonoscopy: No polyps
• What’s next for her?

31. TO BE CONTINUED…

32. Surveillance for
Associated Conditions

34. Upper GI tract polyps with FAP
• 30 to 100% of patients have polyps in proximal GI tract
• Gastric fundic gland polyps, small, perhaps 100s
• Dysplasia occurs in nearly 50% of fundic gland polyps
• Rarely progress to cancer*
• Gastric adenomatous polyps
• Isolated and located in the antrum
• Low but real risk of progression to cancer.

35. Upper GI tract polyps with FAP
• Duodenal polyps occur in 45 to 90%
• Usually adenomatous, duodenal adenomas can progress to cancer
• 4 to 12% lifetime risk of duodenal cancer
• >50% adenomatous change of the periampullary region
• 5 to 10% develop periampullary cancer.
• Adenomas of gallbladder, bile duct, and the small bowel (distal ileum)

36. Management gastric polyps
• Small proximal gastric polyps should be biopsied in patients with FAP to
confirm their histology
• Large or irregular appearing polyps should be biopsied or resected
completely to assess for dysplasia
• Low-grade dysplasia is common in fundic gland polyps, recommend
surgery only for high-grade dysplasia or cancer
• Antral polyps are usually adenomas
• Completely endoscopic resection
ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW, American College of Gastroenterology
Am J Gastroenterol. 2015;110(2):223. Epub 2015 Feb 3.

37. Management duodenal polyps
• Complete polypectomy or sampling of duodenal polyps should be performed at the time of
initial discovery and on each subsequent examination
• Abnormal-appearing papilla should be biopsied.
• Adenomas identified at the ampulla of Vater should be removed endoscopically if
possible
• Management of high-grade dysplasia in the periampullary region (surgery/ablative therapy
versus more frequent surveillance) is controversial and should be individualized based on the
patient’s age and the number of duodenal adenomas
• Ampullectomy rather than Whipple
• N= 26 FAP patients
• Procedure can be performed safely
• Ongoing surveillance as recurrences common
Prevention and management of duodenal polyps in familial adenomatous polyposis.
Brosens LA, Keller JJ, Offerhaus GJ, Goggins M, Giardiello FM Gut. 2005;54(7):1034.

38. EGD screening
• Forward-viewing endoscope for gastric polyps AND a side-viewing
duodenoscope for duodenal polyps
• Start in patients with FAP (classic or attenuated) at the onset of
colonic polyposis or around age 25 to 30 years (whichever earlier)
• If no duodenal adenomas, we perform a repeat upper endoscopy with
duodenoscopy every three years to five years
Prevention and management of duodenal polyps in familial adenomatous polyposis.
Brosens LA, Keller JJ, Offerhaus GJ, Goggins M, Giardiello FM
Gut. 2005;54(7):1034.

39. Other associations with FAP
•Desmoid tumors, sebaceous or epidermoid cysts, lipomas,
osteomas, fibromas, supernumerary teeth, juvenile nasopharyngeal
angiofibromas
•Multiple and bilateral patches of congenital hypertrophy of the
retinal pigment epithelium (CHRPE)
•Slit lamp examination: discrete, darkly pigmented, round, oval, or
kidney shaped lesions.
•Bilateral or multiple (more than four) lesions is specific (94 to
100 percent) but only moderately sensitive (58 to 84 percent)
for FAP

40. Thyroid cancer
• Annual thyroid ultrasound in FAP patients starting in the late teens
• Physical examination alone is insufficient to detect malignancy.
• 192 FAP patients screened for thyroid cancer
• 0 of 5 diagnosed with thyroid cancer were dx by history and
neck exam
• Prospective screening program that included 205 patients with
FAP
• one half of patients had at least one thyroid nodule
• one third required fine-needle aspiration biopsyScreening for thyroid cancer in patients with familial adenomatous polyposis.
Jarrar AM, Milas M, Mitchell J, et al. Ann Surg. 2011;253(3):515.
Characteristics of benign and malignant thyroid disease in familial adenomatous polyposis patients and recommendations for disease surveillance.
Feng X, Milas M, O'Malley M, et al.

41. Hepatoblastoma in Infancy
• For family history of hepatoblastoma
• Genetic testing for familial adenomatous polyposis during infancy
• Screening affected children with serum alpha-fetoprotein and
ultrasounds every six months from infancy until 5 to 10 years of
age
• AFP is elevated in approximately two-thirds of patients with a
hepatoblastoma
• No elevated AFP at diagnosis indicates poor prognosis
• 80 to 100% survival with liver transplant if not metastatic at dx
Risk of hepatoblastoma in familial adenomatous polyposis.
Hughes LJ, Michels VV Am J Med Genet. 1992;43(6):1023.

42. Desmoid Tumors
CT scan for desmoid in the following patients:
• Prior to colectomy in patients at increased risk for desmoids
• Personal or family history of desmoid
• Adenomatous Polyposis Coli mutation beyond codon 1444
• Palpable abdominal mass on physical examination
• Symptoms suggestive of abdominal organ obstruction

43. Adrenal Tumors- we don’t care
• Adrenal tumor prevalence is 7 to 13 %
• Rarely malignant
• Routine surveillance is not recommended
• Other associated conditions?
Extra-intestinal manifestations of familial adenomatous polyposis.
Groen EJ, Roos A, Muntinghe FL,et al. Ann Surg Oncol. 2008;15(9):2439. Epub 2008 Jul 9.

44. YEP.

45. Meet Patient B
Debbie

46. Debbie 2010
• Seen initially by partner Dr P
• Ileorectal anastomosis in 2009 for >20 polyps, some
advanced
• Genetic testing negative for APC gene mutation
• No FH polyposis syndrome

47. Debbie: My index appointment 11/2012
• Age 48, Caucasian
• Now with 6-10 watery BMs daily, control with Imodium
• Fecal incontinence issues
• Recent variant APC gene mutation on testing by Oncology
• Wilms tumor at age 4, blastocytoma of jaw, cysts on neck age 2
• Was found to have SB polyps with occasional symptoms of PSBO

48. Debbie SB Polyps
• Push enteroscopy and M2A several large duodenal and jejunal polyps
• Evaluation of unreachable jejunal polyps
• MR enterography- motion artifact , suspicion of large lesions
• Balloon enteroscopy Wake Forrest 08/2016, JH 12/2016
• Flat possibly circumferential lesions in proximal and distal jejuneum,
ileum
• Large (one >6 cm)
• Not amenable to endoscopic resection

49. "A NOVEL TREATMENT FOR SMALL BOWEL
DYSMOTILITY: THERAPEUTIC ACOUSTIC EFFECT
OF 'SONIC BOMBARDMENT' BY LYNYRD SKYNYRD"
Sonic

50. Debbie SB Polyps
• Due to size and symptoms, decision to laparoscopically resect 2017
• 40 cm (total) segmental laparoscopic resection at JH with three
enteroenterostomies
• > 300 cm small bowel remaining
• Path adenoma x 3 = 6.6 cm, 1.5 cm, 1.2 cm; hamartoma 1.9 cm

51. Debbie PSBO
• Follow up M2A early 2018
• Additional polyps
• Got stuck x 4 hours at an anastomosis, symptoms PSBO
• KUB with passage capsule (Whew!)
• SBFT after “localized” SB dilation mid abdomen with narrowing at an
anastomosis
• Anastomoses identified with staples
• Follow up JH with surgeon, meanwhile on soft diet

52. IS THAT ALL DEBBIE IS
DEALING WITH?

53. NOPE

54. Debbie Issues with Final Kidney
• CT while evaluating jejunal polyps at Hopkins
• Exophytic lesion lower pole right kidney
• 7 mm lesion suspicious for small renal cell carcinoma
• Followed closely by JH Urology
• Elevated K on Sulindac, suspicious lesion right kidney— so
unable to do chemoprophylaxis for additional SB polyps
• Limited by solitary kidney
• Low dose sulindac, cruciferous vegetables, curcumin

55. NOPE

56. CPI
• Better on creon
• MR and EUS pancreas OK
• Pancreas involvement in FAP not rare
• Pancreatic adenocarcinoma RR 4.46
• IPMT
• Acinar cell tumor
The Pancreas in FAP J Pancreas Online 2008;9(1):9-18.

57. NOPE

58. Thyroid
• 2016 US
• Multiple hypoechoic nodules, mostly cystic
• Low suspicion for malignancy (Whew!)
SIBO
• 2017 Breath testing
• Related to CPI and PSBO
• Occasional antibiotics

59. CAN WE DO ANYTHING (OTHER
THAN SURVEILLANCE) TO
PREVENT THE OTHER POLYP
ISSUES IN FAP

60. YEP.

61. Chemoprevention and FAP
• Celecoxib (Cox-2 inhibitor)
• modest reduction in the number of colonic and duodenal
adenomas in patients with FAP
• increased risk of cardiovascular disease
The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.
Steinbach G, Lynch PM, Phillips RK, et al. N Engl J Med. 2000;342(26):1946.
A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in fa
The safety and efficacy of celecoxib in children with familial adenomatous polyposis.Lynch PM, Ayers GD, Hawk E, et al. Am J Gastr

62. Chemoprevention and FAP
• Aspirin
• 206 patients with FAP were assigned to aspirin (600 mg) and/or resistant
starch
• neither intervention significantly reduce polyp number or size
• Sulindac
• reduce the rectal polyp burden following surgery and as an adjunct to
endoscopic surveillance
• can cause regression of colorectal adenomas in FAP, regression is incomplete
and the degree of protection from the development of colorectal cancer is
unknown
• ineffective in delaying the time of initial development of adenomas
A randomized placebo-controlled prevention trial of aspirin and/or resistant starch in young people with familial adenoma
Cancer Prev Res (Phila). 2011;4(5):655.

63. Long-term treatment with sulindac in familial adenomatous polyposis: a prospective cohort study.Cru
Gastroenterology. 2002;122(3):641.
Sulindac causes regression of rectal polyps in familial adenomatous polyposis.
Labayle D, Fischer D, Vielh P, Drouhin F, Pariente A, Bories C, Duhamel O, Trousset M, Attali P Ga
Effect of the non-steroidal anti-inflammatory drug sulindac on colorectal adenomas of uncolectomize
Matsumoto T, Nakamura S, Esaki M, Yao T, Iida M J Gastroenterol Hepatol. 2006;21(1 Pt 2):251.
Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis.
Giardiello FM, Hamilton SR, Krush AJ, Piantadosi S, Hylind LM, Celano P, Booker SV, Robinson CR
N Engl J Med. 1993;328(18):1313.

64. Sulindac & Erlotinib for Duodenal Polyps in FAP
• 2010-2014 Salt Lake City
• Sulindac 150 mg BID and Erlotinib 65 mg daily (N=46) vs placebo (N=46)
• Polyp burden= sums of diameters of duodenal polyps
• Stopped early for superiority
• 87% acne rash (cw 20% placebo)
• Lower duodenal polyp burden in 6 months
• Retesting with intermittent dosing/lower dose
Erlotinib hydrochloride is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other
types of cancer. It is a receptor tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor.
SOJAMA 2016 March;315(12):1266-75

65. IS OUR JOB DONE
AFTER COLECTOMY?

66. NOPE

67. FAP Surveillance AFTER Colectomy
• EGD (front and side view) with ampulla biopsies
• Repeat q year if polyps
• Repeat q3-5 years if none
• Flex sig for pouch or retained rectal tissue q year
• Annual thyroid US
• No surveillance for desmoid
• View pancreas symptoms with high suspicion

68. Family Evaluation for FAP
• At risk for classic FAP
• CRC screening starts around age 10 to 12 years
• Flexible sigmoidoscopy or colonoscopy
• If adenomas are detected, need a full colonoscopy
• Document number, size, and distribution of polyps
• Sample several polyps to confirm histology
• Annual CRC surveillance with colonoscopy pending colectomy
• No polyps, CRC screening should be repeated annually
• APC mutation carriers, lifelong screening
• First-degree relatives of FAP in families without identified APC mutation
• Annual screening can be discontinued at age 40 years if no adenomas on prior
examinations
Guidelines for the clinical management of familial adenomatous polyposis (FAP).
Vasen HF, Möslein G, Alonso A, et al. Gut. 2008;57(5):704. Epub 2008 Jan 14.

69. NOW DO YOU
UNDERSTAND THE
CLINICAL COURSE AND
COMORBIDITIES OF FAP?

71. The FAP Song
(“My Favorite Things”, from
The Sound of Music)

72. Polyps on colons, with colorectal cancer;
Total colectomy's not the whole answer.
Polyps on stomach, ampulla, and things;
These are some miseries FAP brings!
Desmoid and thyroid, hepatoblastoma.
Don't worry 'bout adrenal adenoma.
Pancreas, kidney, and CHRPE and such
There's little that APC gene doesn't touch!
Daughters and sons yearly scoping by age 10
Stopping at 40 if no polyps before then
Autosomal dominant APC gene
All children will need their FAP screen!
FAP bites!
Screening sucks rocks!
Makes me feel so mad--
I take my sulindac and etinonab,
Maybe polyps won't grow so bad!
Polyps on colons, with colorectal cancer;
Total colectomy's not the whole answer.
Polyps on stomach, ampulla, and things;
These are some miseries FAP brings!
Desmoid and thyroid, hepatoblastoma.
Don't worry 'bout adrenal adenoma.
Pancreas, kidney, and CHRPE and such
There's little that APC gene doesn't touch!
Daughters and sons yearly scoping by age 10
Stopping at 40 if no polyps before then
Autosomal dominant APC gene
All children will need their FAP screen!
FAP bites!
Screening sucks rocks!
Makes me feel so mad--
I take my sulindac and etinonab,
Maybe polyps won't grow so bad!

73. Questions?
PLRaymond@RxForSanity.com
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