Familial adenomatous polyposis (FAP) is an autosomal dominant condition characterized by the development of large numbers of colorectal adenomatous polyps that inevitably lead to colorectal cancer. It is the most common inherited polyposis syndrome with an estimated prevalence between 1:5000 and 1:17,000 (1) caused by an inactivating germline mutation in the adenomatous polyposis coli (APC) tumor suppressor gene located at chromosome 5q21 (2,3). Certain mutations are associated with a more aggressive disease types and larger polyp burden (4). The majority of pediatric patients with FAP are asymptomatic and undergo evaluation based on their family history (5). Although the average age of colorectal cancer diagnosis in patients with FAP is 42 years, colonic polyps begin to appear at an average age of 16 years. Furthermore, there have been isolated reports of adenomatous polyps and carcinoma during the first decade of life (6,7). Current recommendations suggest initiation of colonic screening with a flexible sigmoidoscopy or colonoscopy at 10 to 12 years of age (1,8). Although colonic surveillance is essential, colectomy is the uniformly recommended therapy to decrease the risk of colorectal cancer in patients with FAP. The age at which colectomy is indicated is controversial too, and is dependent on disease burden and psychosocial factors. Surgical options include subtotal colectomy with ileorectal anastomosis, total proctocolectomy with continent ileostomy, and proctocolectomy with mucosal proctectomy and ileoanal pull-through with pouch formation. Patients with subtotal colectomy require routine endoscopic surveillance of the remaining rectum every 6 months for recurrent adenomas and/or carcinomas. Patients after total colectomy are also at risk of developing adenomas and cancer in the ileal pouch and require surveillance at annual intervals (9,10).
In the remainder of the gastrointestinal tract, the occurrence of duodenal adenomas confers increased risk of 3% to 4% of progression to duodenal and periampullary carcinoma (11), whereas more distal small bowel tumors are rare. Most authorities recommend upper endoscopic surveillance of the stomach, duodenum, and periampullary region during the third decade of life, although the age at which to start surveillance is controversial (12). In addition to intestinal polyps and associated morbidities, there are numerous extraintestinal manifestations of FAP that include an increased risk of brain, thyroid, hepatic, and pancreatic malignancy. In particular, the risk of hepatoblastoma is 850 times greater in patients with FAP than in the general population (13). Nonmalignant associated conditions include desmoid tumors, epidermoid cysts, osteomas, congenital hypertrophy of the retinal pigment epithelium (CHRPE), fibromas, and lipomas. Gardner syndrome is defined as the presence of FAP with colonic polyps and extraintestinal tumors.
Our review of the literature on FAP in the pediatric population suggested that there are continued controversies in the optimal recognition and management of this condition. The aim of the present analysis was to identify pediatric patients diagnosed with FAP in a 16-year period with attention to disease presentation, genetic profile, extraintestinal manifestations, treatment, and surveillance.
PATIENTS AND METHODS
The present study was conducted at The Children's Hospital of Philadelphia (CHOP) and with the approval of the institutional review board.
FAP Cohort Definition
All children 18 years of age and younger at the time of FAP diagnosis between 1990 and 2005 at CHOP were included in the present study. FAP was defined as the presence of polyps on colonoscopic examination and histopathology consistent with adenomatous polyps. Reasons for exclusion from the study included children with juvenile polyps, hamartomatous polyps, a solitary adenomatous polyp, inflammatory polyps, or pseudopolyps.
Our FAP pathology cohort was obtained from CHOP computerized endoscopy records, pathology and operative reports, billing database, and medical records. Data on patient demographics, family history, indications for evaluation, endoscopic findings (macroscopic and histologic), number and location of polyps, genetic testing results, radiographic findings, type and timing of surveillance, extraintestinal manifestations, and surgical procedures were collected.
Genetic and Statistical Analysis
The genetic testing was performed by isolating genomic DNA from peripheral lymphocytes and used as a template for amplification of exon 15 of the human APC gene followed by sequencing. Data were analyzed using STATA version 10.0 (StataCorp, College Station, TX). Data were reported as raw numbers and as proportions. Descriptive statistics for basic subject characteristics and histopathological findings were reported as mean and medians depending on the variable distributions.
Twelve children with FAP diagnosis were identified during the study period (Table 1). Among 12 subjects, 25% were girls, 83% were white, and 17% were African American. The age range of patients at diagnosis was between 7 and 18 years. Seven patients (58%) were evaluated due to symptoms and the remaining 5 (42%) due to positive family history alone. Rectal bleeding was the presenting symptom in 86% of symptomatic patients, of which 2 had evidence of anemia on laboratory testing. One patient presented with abdominal pain alone. Of interest, in our cohort, the youngest age at which polyps were detected was 7 years, and the youngest symptomatic patient was 10 years of age. Eight patients (66.6%) had positive family history of FAP (2 in mother and 6 in father). All of the affected parents had undergone a colectomy by the time of initial evaluation of their children. Two families had multiple members with FAP. All of the patients were referred for genetic counseling and testing. Four patients had genetic testing performed, 1 patient had a chromosome 5q15-22 deletion, which spans the APC gene, and 3 patients had an APC gene mutation identified: 3205delTCAA, Q625X, and R1450X.
Patients were studied by 5 different gastroenterologists for 3.4 years on average (range 1–13 years). Four patients were lost to follow-up, 2 moved out of the area, and 4 were transitioned to the care of an adult gastroenterologist. The total number of performed endoscopic procedures was 47, of which 1 was endoscopic retrograde cholangiopancreatography, 19 esophagogastroduodenoscopies (EGDs), 14 colonoscopies (10 full colonoscopies and 4 to the extent of ascending colon), 2 flexible sigmoidoscopies, and 11 pouch examinations. The disproportionate number of EGDs compared with colonoscopies in this series is because of the fact that majority of patients underwent early colectomy. No clear timeline of surveillance endoscopic examination pre- or postsurgery was noted. The number of polyps at the time of full colonoscopy or colectomy was documented in 6 patients: an 8-year-old with 5q15-22 deletion had 3 sessile polyps at initial evaluation and >200 polyps 1 year later, two 11-year-olds had 8 and 25 polyps, respectively, and three 13-year-olds had >50, 100, and 200 polyps, respectively. One patient was diagnosed as having rectal cancer in situ at 18 years of age. Six patients (50%) were found to have gastric polyps visually and fundic gland hyperplasia on histology, whereas 9 patients had duodenal polyps visualized, of which 6 showed histologic adenomatous changes. With regard to surveillance of the remainder of the gastrointestinal tract, 3 patients underwent small bowel x-ray imaging, and no polyps were detected. Three additional patients had small bowel video capsule endoscopy (CE) performed. One patient was found to have several small suspected polyps in the duodenum and the jejunum (Fig. 1) and was referred for consideration of side-viewing endoscopy and/or push enteroscopy. Comparison of small bowel x-ray and video CE could not be made because none of the patients had both studies performed.
Three patients were diagnosed with Gardner syndrome and 1 with CHRPE. In addition to our initial cohort of 12 patients, 1 additional patient was diagnosed as having hepatoblastoma at 6 weeks of age at CHOP and then as having FAP at 18 years of age at an outside adult hospital. Because those records were not available for review, the patient was excluded from the initial cohort analysis. Among subjects identified based on family screening, we were not able to determine whether these subjects were screened for hepatoblastoma in earlier years.
With regard to colectomy practices, 7 patients (58%) underwent ileal pouch-anal anastomosis, all within 1 year from diagnosis except in 1 patient who underwent surgery 5 years later (age range 8–13 years). Five different surgeons performed surgical procedures, in 1 to 3 stages. No major complication of surgery was identified. All of the patients complained of frequent bowel movements after surgery, which improved with time, and 1 patient reported fecal incontinence.
FAP is a rare condition associated with 100% risk of malignancy that requires careful and standardized surveillance. The literature describes that the majority of pediatric patients with FAP are brought to medical attention because of their positive family history (5). In our cohort, however, more than half of the patients presented to medical attention based on their symptoms. In particular, although 8 patients were eventually determined to have a positive family history of FAP, only 5 patients presented for the indication of family history alone. One 18-year-old patient in our cohort series was found to have rectal carcinoma in situ.
In addition to colonoscopy, other screening investigations among family members with FAP include genetic testing and eye examination. Although genetic testing in the setting of counseling was offered to all of the patients in this series, only 33% had the testing done. The data were not available to determine whether this was due to family preference or the expense of testing, which may or may not be covered by particular insurance providers. In the setting of a known mutation in a family, genetic testing can be offered and can discriminate between affected and unaffected individuals with a high degree of certainty, with >900 mutations that can now be detected (14). A child found to be mutation negative in a family with an identified mutant APC allele has the same colorectal cancer risk as the general population (15). The impact of genetic testing has been studied in the pediatric setting of FAP and found not to cause significant distress in the first year following predictive genetic testing provided by clinical genetics service (16). Another study found that depression, anxiety, behavioral problems, and competence scores were within normal range before and 3 months after predictive genetic testing (17). Genetic counseling needs to be offered with genetic testing and the guidelines are available (18). Finally, among FAP family members with known CHRPE, a retinal examination can be undertaken to establish the diagnosis of FAP. The presence of >4 pigmented ocular fundus lesions carries a 100% positive predictive value for FAP (15). The prevalence of CHRPE in the general population is 1.2%. Only 1 patient had this examination done.
Current colorectal endoscopic screening recommendations among FAP family members give an age range of 10 to 12 years as the time to start flexible sigmoidoscopic or colonoscopic examination. Several case reports of early cancer in patients with FAP have been published including a series of 11 patients younger than 16 years of age (19), a 9-year-old (20), a 10-year-old (21), and 11- and 12-year-old siblings (22). The risk of developing malignancy younger than 21 years of age in pediatric patients with FAP ranges from estimates as low as 0.21% to as high as 7% of this population (14,23,24). Clearly, there is a balance between the benefit of surveillance for early but rare malignancy against risks of unnecessary procedures and establishment of a diagnosis that carries significant psychological effect for not only the patient but also their families. We recommend screening annual colonoscopic examination in asymptomatic patients beginning at 10 years of age.
The recommendations for surveillance of the remainder of the gastrointestinal tract are also controversial (Table 2). In our cohort, half of the patients had evidence of stomach polyps and fundic gland polyposis, and two thirds had evidence of duodenal adenomatous changes. No high-grade dysplasia or cancer was identified. Given the risk of duodenal adenocarcinoma and large proportion of patients with duodenal lesions, we agree with the conclusions of a pediatric study recommending EGD surveillance from the time of initial colonoscopy (12). If any lesions are identified on initial EGD, then additional screening should be carried out with a side-viewing upper endoscope.
Besides duodenal lesions, small bowel carcinoma is rarely reported in patients with FAP. Contrast studies are routinely used to investigate the small bowel; however, since the introduction of small bowel video CE there have been several reports on its utility in FAP. In our cohort, none of the 4 patients who underwent radiologic examination of the small bowel had any polyps detected, but 1 of 3 patients who underwent CE had several jejunal and ileal polyps identified. In a prospective adult study of 29 patients with FAP who underwent capsule examination and push enteroscopy, 21 (72%) were found to have duodenal adenomas (25). In 16 (76%) of these patients, jejunal polyps were appreciated on both studies, whereas 5 (24%) additional patients had jejunal and ileal polyps observed on CE beyond the reach of push enteroscopy. In a similar study CE was found to underestimate the number of small bowel polyps, but was suggested as an adjunctive tool to upper endoscopy (26). This approach has been questioned because cancer beyond the duodenum in patients with FAP is exceedingly rare (27). No patient in this series had both studies done, so no comparison could be made. At the present time, we use both small bowel contrast imaging and CE at diagnosis. Because of concerns about radiation exposure in pediatric patients, magnetic resonance imaging (MRI) may become an attractive option to evaluate for small intestinal polyps. A recent study compared MRI and CE for the detection of polyps of the small bowel in patients with polyposis syndromes (28). Polyps >15 mm were detected similarly with the 2 modalities, and MRI was more reliable for determining the location of polyps and their exact size. Moreover, MRI revealed 2 previously unidentified desmoid tumors in 1 patient with FAP. However, MRI was less sensitive for detecting smaller polyps, with polyps <5 mm being exclusively seen with CE. The significance of finding a small polyp in the asymptomatic child is questionable, and additional studies are required to determine the natural history of small bowel polyps in patients with FAP.
With regard to extraintestinal manifestations, 1 patient who had hepatoblastoma diagnosed in infancy was found to have been diagnosed with FAP 18 years later. Although the incidence of hepatoblastoma in the general population is approximately 1 per million, the risk is approximately 850 times greater in patients with FAP than in the general population. In families with FAP, some experts recommend yearly screening with α-fetoprotein levels and hepatic ultrasounds from birth to 5 years of age (29). If the family APC genetic mutation is known, then testing children for the APC gene in infancy or prenatally may better assess patients' risk of hepatoblastoma. In children with hepatoblastoma, it is also recommended that these patients and their families be tested for FAP. Guidelines for hepatoblastoma screening in family members with FAP and FAP screening in patients with hepatoblastoma and family members are not well established and are a matter of debate. For family members of known FAP probands, we recommend annual α-fetoprotein levels and hepatic ultrasounds from birth to 5 years of age. For patients with hepatoblastoma, we recommend a careful family history to investigate for the presence of FAP, consideration for FAP genetic testing if FAP is identified in family members, and consideration for a screening colonoscopy at 10 years of age.
Once FAP is identified, surgery is the only recognized treatment for reduction of colon cancer risk in patients with FAP. The timing of surgery is best decided on a patient-by-patient basis. One approach is to delay colectomy until after adolescence, when patients can more actively participate in the decision-making process. Our approach is to offer early surgical intervention to minimize the risk of cancer. Once colectomy is performed, patients continue to be at risk of developing adenomas and cancer in the small bowel pouch. An adult study found the average risk of pouch adenoma to be 23% 5 years after resection (30). In our cohort, patients underwent approximately 1 endoscopic pouch examination per year of follow-up and no adenomas were identified. We recommend yearly endoscopic surveillance of the pouch after colectomy.
The role of chemoprevention in the treatment of colorectal and duodenal adenomas in children with FAP is not clearly defined. Sulindac has been shown to cause a reduction in the number of established colorectal adenomas in adults by about 50% (31,32); however, it did not prevent the primary development of adenomas in FAP (33). Celecoxib, a selective cyclooxygenase-2 inhibitor, has shown some promise in reducing the number of colorectal adenomas as well as duodenal adenomas (34,35). A randomized, double-blind phase III study is being conducted to test whether celecoxib can be used to prevent colorectal polyp formation in children with FAP (www.clinicaltrials.gov identifier: NCT00585312). Although chemoprevention should not replace surgical treatment for colonic FAP, it may play a role in delaying colectomy in patients with mild colonic polyposis (36).
There were several limitations of our study, which include a small number of patients, short follow-up time, incomplete data, and the retrospective study design. In addition, there was significant heterogeneity in our approach to patients with FAP in terms of initial screening, genetic testing, surveillance, and timing of colectomy. This raises the question of the need for a multidisciplinary team approach to provide optimal patient care of the patient with FAP and his or her family members. This team should be composed of a pediatric gastroenterologist, an adult gastroenterologist, a geneticist, a surgeon, and a pediatric general practitioner. A referral to a polyposis center has been previously shown to improve outcomes and should be considered to help guide management (37).
In conclusion, FAP is a systemic disorder with significant implications for affected patients and family members. We identified 1 patient with rectal cancer in situ and a high proportion of patients with duodenal adenomatous lesions. Early physician recognition of the systemic manifestations of familial adenomatous polyposis and adherence to established guidelines in patients and family members may help prevent significant morbidity and mortality in this population.
Special thanks to Jill Stopfer, MS, Certified Genetic Counselor, Abramson Cancer Center, University of Pennsylvania, for help in the preparation of this manuscript.
1. Corredor J, Wambach J, Barnard J. Gastrointestinal polyps in children: advances in molecular genetics, diagnosis, and management. J Pediatr 2001; 138:621–628.
2. Groden J, Thliveris A, Samowitz W, et al
. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991; 66:589–600.
3. Kinzler KW, Nilbert MC, Su LK, et al
. Identification of FAP locus genes from chromosome 5q21. Science 1991; 253:661–665.
4. Lynch HT, Smyrk T, McGinn T, et al
. Attenuated familial adenomatous polyposis (AFAP). A phenotypically and genotypically distinctive variant of FAP. Cancer 1995; 76:2427–2433.
5. Durno CA. Colonic polyps in children and adolescents. Can J Gastroenterol 2007; 21:233–239.
6. Rustgi AK. Hereditary gastrointestinal polyposis and nonpolyposis syndromes. N Engl J Med 1994; 331:1694–1702.
8. Levin B, Lieberman DA, McFarland B, et al
. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008; 134:1570–1595.
9. Hyer W, Beveridge I, Domizio P, et al
. Clinical management and genetics of gastrointestinal polyps in children. J Pediatr Gastroenterol Nutr 2000; 31:469–479.
10. Hurlstone DP, Saunders BP, Church JM. Endoscopic surveillance of the ileoanal pouch following restorative proctocolectomy for familial adenomatous polyposis. Endoscopy 2008; 40:437–442.
11. Bjork J, Akerbrant H, Iselius L, et al
. Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: cumulative risks and APC gene mutations. Gastroenterology 2001; 121:1127–1135.
12. Attard TM, Cuffari C, Tajouri T, et al
. Multicenter experience with upper gastrointestinal polyps in pediatric patients with familial adenomatous polyposis. Am J Gastroenterol 2004; 99:681–686.
13. Giardiello FM, Petersen GM, Brensinger JD, et al
. Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 1996; 39:867–869.
14. Erdman SH. Pediatric adenomatous polyposis syndromes: an update. Curr Gastroenterol Rep 2007; 9:237–244.
15. Hyer W. Polyposis syndromes: pediatric implications. Gastrointest Endosc Clin N Am 2001; 11:659–682.
16. Michie S, Bobrow M, Marteau TM. Predictive genetic testing in children and adults: a study of emotional impact. J Med Genet 2001; 38:519–526.
17. Codori AM, Petersen GM, Boyd PA, et al
. Genetic testing for cancer in children. Short-term psychological effect. Arch Pediatr Adolesc Med 1996; 150:1131–1138.
18. Durno CA, Gallinger S. Genetic predisposition to colorectal cancer: new pieces in the pediatric puzzle. J Pediatr Gastroenterol Nutr 2006; 43:5–15.
19. Peck DA, Watanabe KS, Trueblood HW. Familial polyposis in children. Dis Colon Rectum 1972; 15:23–29.
20. Eccles DM, Lunt PW, Wallis Y, et al
. An unusually severe phenotype for familial adenomatous polyposis. Arch Dis Child 1997; 77:431–435.
21. Auricchio R, De Rosa M, Quaglietta L, et al
. A dramatic case of early-onset familial adenomatous polyposis. Clin Genet 2005; 67:104–106.
22. Jerkic S, Rosewich H, Scharf JG, et al
. Colorectal cancer in two pre-teenage siblings with familial adenomatous polyposis. Eur J Pediatr 2005; 164:306–310.
23. Bussey H, ed. Familial Polyposis Coli: Family Studies, Histopathology, Differential Diagnosis, and Results of Treatment
. Baltimore, MD: Johns Hopkins University Press; 1975.
24. Church JM, McGannon E, Burke C, et al
. Teenagers with familial adenomatous polyposis: what is their risk for colorectal cancer? Dis Colon Rectum 2002; 45:887–889.
25. Schulmann K, Hollerbach S, Kraus K, et al
. Feasibility and diagnostic utility of video capsule endoscopy for the detection of small bowel polyps in patients with hereditary polyposis syndromes. Am J Gastroenterol 2005; 100:27–37.
26. Wong RF, Tuteja AK, Haslem DS, et al
. Video capsule endoscopy compared with standard endoscopy for the evaluation of small-bowel polyps in persons with familial adenomatous polyposis (with video). Gastrointest Endosc 2006; 64:530–537.
27. Dray X, Vahedi K, Valleur P, et al
. Is there any need for video capsule endoscopy evaluation in postduodenal small-bowel polyps detection in familial adenomatous polyposis? Gastrointest Endosc 2007; 66:634–635.
28. Caspari R, von Falkenhausen M, Krautmacher C, et al
. Comparison of capsule endoscopy and magnetic resonance imaging for the detection of polyps of the small intestine in patients with familial adenomatous polyposis or with Peutz-Jeghers syndrome. Endoscopy 2004; 36:1054–1059.
29. Hirschman BA, Pollock BH, Tomlinson GE. The spectrum of APC mutations in children with hepatoblastoma from familial adenomatous polyposis kindreds. J Pediatr 2005; 147:263–266.
30. Schulz AC, Bojarski C, Buhr HJ, et al
. Occurrence of adenomas in the pouch and small intestine of FAP patients after proctocolectomy with ileoanal pouch construction. Int J Colorectal Dis 2008; 23:437–441.
31. Cruz-Correa M, Hylind LM, Romans KE, et al
. Long-term treatment with sulindac in familial adenomatous polyposis: a prospective cohort study. Gastroenterology 2002; 122:641–645.
32. Giardiello FM, Hamilton SR, Krush AJ, et al
. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993; 328:1313–1316.
33. Giardiello FM, Yang VW, Hylind LM, et al
. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med 2002; 346:1054–1059.
34. Phillips RK, Wallace MH, Lynch PM, et al
. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 2002; 50:857–860.
35. Steinbach G, Lynch PM, Phillips RK, et al
. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342:1946–1952.
36. Vasen HF, Moslein G, Alonso A, et al
. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 2008; 57:704–713.
37. Bulow S. Results of national registration of familial adenomatous polyposis. Gut 2003; 52:742–746.