Polyposis Syndromes

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PEDIATRIC GASTROINTESTINAL ENDOSCOPY

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POLYPOSIS S Y N D R O M E S Pediatric Implications Warren Hyer, MB ChB, MRCPCH, MRCP

Polyposis syndromes have been managed in the past by geneticists and adult gastroenterologists, but now increasingly fall into the remit of the pediatric gastroenterologist. Gastrointestinal polyps in children most commonly present with rectal bleeding, but of more concern may have potential for malignant change. This article reviews the polyposis syndromes, their malignant potential, and their management algorithms. The genetics of these syndromes and future advances are also discussed. HISTOPATHOLOGIC CLASSIFICATION

Gastrointestinal polyps in children fall into two major categories: (1)hamartomas and (2) adenomas: Adenomatous polyposis syndromes Familial adenomatous polyposis Turcot's syndrome Hamartomatous polyps Solitary juvenile polyp Juvenile polyposis syndrome Peutz-Jeghers syndrome Bannayan-Riley-Ruvalcaba syndromes Gorlin's syndrome Cowden disease Lymphoid nodular hyperplasia Inflammatory polyps Mixed polyposis syndrome From the Department of Pediatrics, St. Mark's Hospital, Harrow, Middx, United Kingdom

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Solitary polyps in children are most commonly hamartomas, predominantly of the juvenile type. Of the familial syndromes, familial adenomatous polyposis (FAP) is more common than juvenile polyposis or Peutz-Jeghers polyposis. Table 1 outlines the different histologic features with examples in Figure 1. CLINICAL MANAGEMENT

The most common manifestation of a large bowel polyp is painless rectal bleeding. Other symptoms attributed to polyps include abdominal pain, altered bowel habit, or prolapse of polyp or rectum. Some children are completely asymptomatic; their polyps may be found as part of a screening program for a FAP. Of 730 patients with rectal bleeding referred to a single center, 29 children were found to have colorectal polyps; 24 polyps were juvenile polyps, 2 were Peutz-Jeghers polyps, 2 were inflammatory, and 1 was an adenomatous polyp.42Nine of the polyps were located proximal to the sigmoid-descendingjunction suggestingthat such children should have a full colonoscopy and not a limited flexible sigmoidoscopy.

Table 1. PATHOLOGIC FEATURES OF POLYPS SEEN IN CHILDREN Macroscopic Appearance

Microscopic Appearance

Dysplasia

Juvenile

Pedunculated 1-3 cm in size, rarely larger with smooth red surface, "Swiss cheese" cut surface

PeutzJeghers

Sessile or pedunculated with lobulated surface 0.5-3 cm in size, pink or tan cut surface & ulceration

Tubular adenoma

Pedunculated smooth, red lobulated surface 0.5-5 cm in size Sessile, broad-based papillary surface 1-5 cm in size

Dilated cysts filled with mucin; abundant lamina propria with prominent inflammatory infiltrate; ulcerated surface with underlying granulation tissue; glands branched, haphazardly arranged Elongated branching glands lined by epithelium native to polyp location; arborizing strands of smooth muscle; less stroma and cysts than juvenile polyps Glands and tubules & inflammatory infiltrate

Always present graded mild, moderate, or severe

Villous structures & inflammatory infiltrate

Always present graded mild, moderate, or severe

Polyp TYPe

Villous adenoma

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Figure 1. A, Juvenile polyp showing typical cystic dilatation of glands, abundant lamina propria with surface ulceration, and inflammation. Atypical features are sometimes seen in juvenile polyposis syndrome, such as hyperplastic glands. 6, Low power view of multiple tubular adenomas with oligocryptal adenoma in colonic mucosa in a patient with familial adenomatous polyposis. (Courtesy of I. Talbot, St. Mark's Hospital.) (See also color plate, Fig. 4.)

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To plan management appropriately, the pediatrician treating a child with a gastrointestinal polyp must know the histopathologic type, the number and site of polyps, and whether or not there is a family history of polyps or colorectal cancer. The clinician must also examine for associated extraintestinal manifestations of polyposis syndromes. JUVENILE POLYP (SOLITARY AT DIAGNOSIS) Children with a solitary juvenile polyp present at a mean age of 4 years with painless rectal bleeding or perianal polyp protrusion. Since the introduction of colonoscopy in pediatric practice it is clear that up to 60% of juvenile polyps may lie proximal to the sigmoid colon.51A review of 73 patients with juvenile polyps (mean age 6 years) demonstrated that up to 40% (29 of 73) of patients had multiple polyps; 16%in the descending colon, 20% in the transverse colon, and 18% in the ascending colon and rectum. This reaffirms the need for full colonoscopy even if a polyp is found in the rectosigmoid. The risk of malignant change for a solitary juvenile polyp is almost negligible; there are only eight cases in the literature of patients developing neoplasia. The age range of these patients was 1.5 to 67 years, with a mean age of 24 years.25In addition, a review of 82 patients with a solitary juvenile polyp (mean age at diagnosis 32 years, range 3 to 71 years) showed no increased risk of colorectal cancer or of dying as a result of the polyp.54 Although the risk of developing malignancy in a solitary juvenile polyp is very small, such polyps should be removed even when discovered incidentally. If a polyp is found to be solitary after full colonoscopy, and there is no relevant family history, endoscopic polypectomy is sufficient treatment. If the patient is discharged, parents must be aware that juvenile polyps may be the first feature of juvenile polyposis. If fresh symptoms arise, the child should be reinvestigated. When, however, there is a positive family history, or when multiple juvenile polyps are found, the possibility of juvenile polyposis syndrome (JPS) is raised and a different management strategy should be used. JUVENILE POLYPOSIS Juvenile polyposis syndrome is a rare autosomal-dominant condition characterized by multiple juvenile polyps in the gastrointestinal tract. In children, the most common presentation is at a mean age of 9 years with rectal bleeding, anemia, or prolapse of either the polyp or rectum. Less commonly, the condition presents in infancy with anemia and hemorrhage, diarrhea, protein-losing enteropathy, and rectal bleeding.63 In this scenario the entire gastrointestinal tract is usually affected and there may be mild dysmorphic features (e.g., macrocephaly, clubbing, and nail dystrophy); the prognosis seems to be related to the severity and extent of gastrointestinal involvement. The course in such infants is fulminant and death occurs before the age of 2 years in severe cases.64

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Compared with patients with solitary juvenile polyps, patients with JPS have more polyps, and are more likely to have right-sided polyps, polyps with adenomatous change, and anemia.36As the condition progresses, the number of polyps rises to 50 to 200. Polyps are found primarily in the colon, but also in the stomach and small intestine.I9The number of polyps needed to make the diagnosis remains controversial. Jass et a139proposed five, whereas Giardiello et alZ5suggested that as few as three juvenile polyps was sufficient. This number was based on a retrospective review of 57 patients with JPS, which reported that 9 of 19 patients with three or more polyps developed colorectal neoplasia compared with only 1 of 28 patients with only one or two polyps. A significant proportion of patients with juvenile polyposis have been reported to have other morphologic abnormalities including digital clubbing, macrocephaly, alopecia, cleft lip or palate, congenital heart disease, genitourinary abnormalities, and mental retardation.l8 There is little doubt that juvenile polyposis is a premalignant condition. There is a 15%incidence of colorectal carcinoma occurring in patients under the age of 35 years, leading to a cumulative risk of colorectal cancer of 68% by age 60 years.39A retrospective study of 57 patients with JPS demonstrated a mean age of onset of colonic neoplasia of 38 years with a range of 6 to 58 years.25Adenomatous changes in JPS, however, have been seen in children as young as 3 years old.25Neoplastic changes have been documented both in the polyps and in flat apparently normal colonic mucosa. Malignancies in the stomach, duodenum, and pancreas have been described in adults. Patients with features suggestive of JPS should have surveillance colonoscopy with random biopsies of polyps and flat mucosa every 2 years (Fig. 2). When the number of polyps is small, endoscopic polypectomy and follow-up may suffice; but it is not clear whether endoscopic surveillance is adequate to prevent malignancy. When there are numerous polyps or symptoms persist, such as bleeding and diarrhea, prophylactic colectomy should be considered after adoles~ence.'~ As yet, there are insufficient data to justify prophylactic colectomy solely for the risk of colorectal carcinoma.25The role of cyclooxygenase inhibitors in pediatric JPS is unclear. In three of eight JPS families, polyps were identified in asymptomatic first-degree relativesz5First-degree relatives of patients with JPS should be screened by colonoscopy starting at age 12 years, even when the subject is asymptomatic. Even if the colonoscopy is negative, some authorities continue to screen at 3-year intervals. There may also be an increased risk of bowel cancer in unaffected relative^.^'

Genetics of Juvenile Polyposis A family history is found in 20% to 50% of patients, the inheritance apparently being autosomal dominant. There is evidence for genetic heterogeneity in JPS. Subsets of families have mutations in the tumor suppressor gene PTEN located at 10q23.3,46 but these patients may

Diagnosis of juvenile polyposis made at colonoscopy and histology

-

Screen first degree relatives.

Correct anaemia and malnutrition if relevant

,

1

Colonoscopy, and polypectomy at least every two years*

v Adequate control of polyp number and size - continue screening

If unable to control symptoms e.g. bleeding or diarrhoea, or polyps are too numerous and difficult to control via endoscope

v Consider surgery - ileorectal anastomosis or proctocolectomy Figure 2. Management of juvenile polyposis in childhood. *Considerupper GI surveillance.

have features suggestive of other polyposis syndromes (e.g., Cowden disease).80A proportion of JPS patients do not have germline mutations in PTEN; instead, they have mutations in SMAD4/DPC4 located at 18q21.37,48 This seems to be the more relevant mutation in JPS patients without stigmata of other polyposis syndrome^.^^ Other members of the SMAD family (i.e., SMAD1,2,3, or 5) do not seem to be involved in the pathogenesis of JPS.' It seems that germline SMAD4 mutations predispose to hamartomas and cancer through disruption of the transforming growth factor-j3 signaling pathway. Further studies are needed to identify the genetic basis for JPS, including work on the components of the transforming growth factor-j3 signaling pathway, to explore the route leading to neoplastic transformation in these patients. Multiple genetic alterations (including APC mutations and K-ras mutations) seem to play a role in the neoplastic transformation of juvenile polyps of JPS patients.83

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PEUTZ-JEGHERS SYNDROME

Peutz-Jeghers syndrome (PJS) is a rare autosomal-dominant condition in which gastrointestinal polyps occur in association with macular melanin pigmentation. Polyps arise primarily in the small bowel, and to a lesser extent in the stomach and colon. Pigmentation occurs in most, although not all, patients and is seen most frequently on the lips and buccal mucosa (Fig. 3) and occasionally on the hands, feet, and eyelids. The primary concern to the pediatrician is the risk of small bowel intussusception causing intestinal obstruction, vomiting, and pain. In addition, intestinal bleeding leading to anemia can occur. The risk of neoplasia is well documented in young adults and includes development of unusual tumors, such as Sertoli cell tumor of the ovary and testicular tumors in prepubescent 84 Most patients with PJS present before adulthood with symptoms, such as abdominal pain (and intussusception) or anemia. Of 70 cases of PJS in childhood summarized after a literature search, 50 had episodes of abdominal pain, 13 of gastrointestinal bleeding, and 11 of anemia.72Such data must be interpreted carefully, because reported cases are more likely to reflect complicated patients. Controversy exists over the management of the young child with midgut polyps. There is a high reoperation rate after initial laparotomy for small bowel obstruction; this rate might be reduced in skilled hands by intraoperative enteroscopy (possiblythrough a surgical enterotomy) to remove other polyps. Over half the patients with PJS followed by St. Mark's Hospital (London) from 1943 to 1987 had two or more laparotomies; the average age at initial laparotomy was 15 years (range 2 to 39 years, N = 23). Polyp-induced complications were responsible for 75% (23 of

Figure 3. Macular pigmentation of the lips in a child with Peutz-Jeghers syndrome.

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31) of the relaparot~mies.~~ Intraoperative small bowel endoscopy picked up 38%more polyps at laparotomy (17 additional polyps) compared with external palpation and small bowel transillumination. At present it is not possible to be prescriptive about management of polyps of different sizes. The advantages and disadvantages of prophylactic polypectomy for asymptomatic patients should be discussed with the family. At diagnosis, patients follow the PJS algorithm (Fig. 4) and management is influenced by the size of the polyps and their location (Fig. 5). This protocol is adapted from adult practice, and the size of polyps requiring resection may be smaller in young children. Symptomatic children with sizable midgut polyps (larger than 1.5 cm in size) should be referred for laparotomy and intraoperative enteroscopy (Fig. 6). For children who are asymptomatic with small polyps (less than 1 cm in size), the parents should be counseled about the risk of intussusception; if the child later develops symptoms, he or she should also be referred for consideration for enteroscopy. The management of children with polyps between 5 and 10 mm depends on the number. Children with multiple midgut polyps may benefit from prophylactic polypectomy. Although this method of clearing small bowel polyps has not been subjected to controlled Diagnosis made by phenotype or family history of PJS plus symptoms

Investigate relevant symptoms (eg. pain or anaemia) by upper and lower endoscopy, and barium FT

Only small ('smm) polyps Present

Polyps 5-1 Omm, evaluate according to number

Presents with mid gut intussusception

Large polyp > 1.5cm counsel and resect by polypectomy -b with intra operative small bowel endoscopy

Refer for exploratory laparotomy with intra operative endoscopy and polypectomy

v

Counsel parents, regular follow up Re image according to symptoms

Depending on symptoms (eg anaemia or pain), carry out upper and lower endoscopy and barium FT at intervals (e.g. every 2 years)

Figure 4. Management of Peutz-Jegherssyndrome (PJS) in childhood.

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Figure 5. Small bowel barium study showing large intussusception caused by a 2-cm PeutzJegher polyp.

Figure 6. Two-cm (PJS) pedunculated polyp obstructing the lumen of ileum of an 8-yearold girl with intestinal obstruction taken at intraoperative enteroscopy. (See also color plate, Fig. 5.)

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one could speculate that it would lead to less repeated bowel resections and later malignancy. The risk of developing malignancy, both in the gastrointestinal tract and in extraintestinal sites, is greater in adults with PJS than in the general p o p u l a t i ~ nOut . ~ ~ of 70 PJS patients identified by literature search under 16 years, 5 had tumors, 2 of which were adenocarcinomas, one gastric, the other jejunal." A survey of 72 patients at St. Mark's Hospital up to 1989 found 16 malignancies, 10 gastrointestinal and pan~reatic.~~ The youngest affected from this cohort was age 26 years. Subsequently, the Mayo clinic published their experience: 26 cases of cancer developed in 18 of 34 patients with PJS, 10 gastrointestinal and 16 extraintestinaL3The youngest affected patient in the Mayo clinic cohort who developed cancer was 23 years. Clinicians caring for adolescents with PJS should be aware of unusual symptoms (e.g., caused by a feminizing testicular tumor) and have a low threshold for investigating potential malignancies. A recommended screening program for PJS patients after adolescence follows, but it is not clear that such a program reduces morbidity or mortality. Annual investigation Hemoglobin Pelvis ultrasound, gynecologic and breast examination (girls) Testicular ultrasound (boys) Two-yearly investigations Upper and lower endoscopy Small bowel contrast radiograph Other investigations Cervical smear every 3 years Breast mammography every 5 years from age 25 years

Genetics of Peutz-Jeghers Syndrome The gene for this condition has recently been identified. The mutated gene LBKlISTK11 encodes a serine-threonine kinase and is located on chromosome 19p 13.3.35,40,77 The LKBl mutations lead to loss in kinase activity. Other cancer-susceptible syndromes have been associated with activation of kinase activity. It seems that S T K l l is a tumor suppressor gene that might act as a gatekeeper regulating the development of hamartomas and adenocarcinomas in PJS.32Allelic imbalance (allele loss and loss of heterozygosity) has previously been reported in a number of PJS polyps and has been found in a colonic adenoma from a PJS patient, strongly suggesting the existence of a hamartoma-carcinoma sequence in tum~rigenesis.~~ There is marked interfamily and intrafamily phenotypic variability in PJS. The availability of predictive genetic testing may have some value, but cannot determine the likely severity of phenotype.50In addition, not all PJS patients have the demonstrated LKB1-STK11 gene, including 1 of 12 patients reported by Hemminki et al,35 and 3 of 20 families reported

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by Olschwang et a157;there remain potential loci for alternative mutated genes predisposing to PJS.If the gene mutation is known for previous affected cases in the family it might have a role in presymptomatic testing in those patients with no pigmentation (or even potential prenatal diagnosis). Genetic testing in PJSis especially problematic, however, because the onset of the disease is often in childhood, and the matter has to be approached carefully.

FAMILIAL ADENOMATOUS POLYPOSIS

In children, gastrointestinal adenomas are almost always associated with hereditary adenomatous polyposis syndromes. Whenever one colorectal adenoma is found in a child, total colonoscopy with dye spray is mandatory. FAP is the most common of the adenomatous polyposis syndromes. Patients with FAP typically develop multiple adenomas throughout the large bowel, usually more than 100 and sometimes more than 1000 (Fig. 7). Polyps begin to appear in childhood or adolescence and

Figure 7. Colectomy specimen demonstrating carpeting with dense polyposis in an adolescent with FAP. (See also color plate, Fig. 6.)

increase in number with age. By the fifth decade colorectal cancer is almost inevitable if colectomy is not performed. Adult patients with FAP are also at increased risk of malignancies of the duodenum, ampulla of Vater, thyroid, and pancreas. Papillary carcinoma of the thyChildren under 5 years of age roid has been reported in adole~cence.~ may develop hepatoblastoma.' It may be advisable to measure serum alpha-fetoprotein levels or carry out abdominal ultrasound in at-risk children. Patients with FAP are at risk of neoplasia at different sites (Table 2). There are three ways in which a patient with FAP may present to the pediatrician. 1. Most are called for screeningbecause of a positive family history. 2. Some present with colorectal symptoms, such as bleeding or diarrhea 3. A minority present with extracolonic manifestations. General pediatricians treating a child with an unusual lesion, such as maxillary osteoma, or a rare tumor, such as hepatoblastoma, should consider the possibility of FAP, particularly if there are multiple tumors or another sibling is affected.13

Genetics of Familial Adenomatous Polyposis

The prevalence of FAP is estimated at 1 : 10,000. It is inherited as an autosomal-dominant trait with high penetrance but with a variable age of

Table 2. EXTRACOLONIC MANIFESTATIONSOF FAP IN CHILDREN AND YOUNG ADULTS Site

Bone Dental abnormalities Connective tissue

Eyes CNS Adenomas

Carcinomas Liver

Examples

Osteomas, mandibular and maxillary Exostosis Sclerosis Impacted or supernumerary teeth Unerupted teeth Desmoid tumors Excessive intra-abdominal adhesions Fibroma Subcutaneous cysts Congenital hypertrophy of the retinal pigment epithelium Glioblastomas (e.g., Turcot's syndrome) Stomach Duodenum Small intestine Adrenal cortex Thyroid gland Thyroid gland Adrenal gland Hepatoblastoma

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onset. The rate of spontaneous mutations is relatively high, reported as 10%to 30%.62 The gene responsible for FAP, adenomatous polyposis coli (APC), was localized to chromosome 5q21 in the late 1980s.4,31,41,43 The APC gene seems to be a tumor suppressor gene. Most mutations are small deletions or insertions, which result in the production of a truncated APC protein. In FAP a germline mutation inactivates one of the two APC alleles, which underlies the predisposition to adenoma formation. Mutations are widely distributed throughout the 5' half of the gene, although two hot spots are found at codons 1061 and 1309 (Fig. 8). These account for around one third of all mutations detected and are associated with a more severe phenotype. Other phenotype-genotype correlations have been observed.56A variant of FAP has been described that is characterized by fewer colonic polyps and a generally milder phenotype, so-called attenuated FAP. APC mutations have been described for this condition at the 5' and 3' extremes of the gene.5,46 These correlations are not absolute and there may be considerable intrafamilial variation suggesting that there are other factors involved in the pathogenesis of the disease. Some of the phenotypic variability seen in patients cannot be explained by the location of their APC mutation. Environmental factors and other genes, often termed modifier genes, may have critical effects on APC function and disease expression. The gold standard for genetic testing is seeking the mutation directly from DNA from blood. The initial step may often be an RNA protein truncation test or DNA single-strand conformation polymorphism analysis. Direct sequencing-mutation analysis is the optimal genetic test and directly detects the presence of the APC gene mutation.59More than 300 different germline mutations have been described and finding the mutation may be a formidable task. Families need to be aware that the mutation may only be detected in 60% to 80% of cases. It is only in these cases that a predictive test can be offered to at-risk individuals.

Classicall Severe PAP

~rtenuaren

Attenuated APC

168

1578

Common mutations: 1061 1068

1309

0

400

800

1200

1600

CODON NUMBER

Figure 8. Structure of the APCgene.

2000

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Interpretation of the Genetic Test and Clinical Screening in Familial Adenomatous Polyposis To define which screening protocol is appropriate for a given family, the first step is to determine, where possible, which mutation is present in the FAP-affected index case. At this stage, if a mutation cannot be found, the genetic testing is noninformative and it is not possible to offer predictive testing to asymptomaticat-risk relatives. For the 60% to 80% in which a mutation is detected, at-risk relatives can be tested. A negative test is considered accurate in excluding FAP and the subject should be considered to hold an average population risk for the subsequent development of adenomas and cancer. Such genotypenegative individuals can be discharged from follow-up, although some authorities believe that such individuals should still undergo endoscopic screening (less frequently than those individuals with an identified mutation). In addition, those patients where the deletion has not been sequenced, but has been excluded by linkage analysis with intragenic markers alone (a less reliable method for determining the risk of carrying the APC gene mutation) should not be discharged and they should undergo endoscopic surveillance. A positive test confirms the diagnosis of FAP and patients should undergo endoscopic assessment. The diagnosis is confirmed by finding polyps at flexible sigmoidoscopy, histologically confirmed as adenomas (Fig. 9). At St. Mark's Hospital, affected individuals undergo annual flexible sigmoidoscopy from the age of 11 to 14 years until adenomas are found. Annual flexible sigmoidoscopies should be adequate because there is rectal involvement early in the condition in virtually all patients.

Figure 9. Endoscopic appearance of colon showing occasional adenomas in 12-year-old patient with FAP. Dye spray emphasizes small polyps down to less than 0.5 mrn.

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In families in which the genotype is not known, protocols vary. The St. Mark's approach is to perform annual sigmoidoscopy on all firstdegree relatives until adenomas are found. In addition, from the age of 20 years, colonoscopy with dye spray is performed every 5 years. A summary of the St. Mark's screening protocol is provided in Figure 10. Most gene-positive children have had a full colonoscopy by the age of 16 years to determine polyp density and location, and degree of dysplasia. With this information, and understanding the family situation, and the psychosocial and schooling needs of the child, a decision can

I

Positive family history genetic counselling and

Fasnily genotype

Family genotype

positive gene

Start annual sigmoidoscopy fiom age 10-14, until confirm rectal adenomas

I 1

Family genotype laown, negative gene ter

1

Discharge

I

regarding timing for colectomy; consider colonoscopy +I- dye spray.

continue annual sigmoidoscopy, add in 5 yearly colonoscopy

Annual pouch examination sigmoidoscopy and remove polyps >5mm Figure 10. Management protocol for screening children and adolescents at risk for FAP.

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be made regarding the timing and type of surgery. Clinicians, patients, and parents should be aware that colonoscopic surveillance alone is not a safe enough method of preventing colorectal malignancy, and has its own complication rate.52,60 The presence on indirect ophthalmoscopy of more than four pigmented ocular fundus lesions (congenital hypertrophy of the retinal pigment epithelium) carries a 100%positive predictive value for FAP in at-risk families, particularly if the lesions are large. The absence of pigmentation, however, is of no predictive value. No patient should undergo screening for FAP without detailed counseling. Expert genetic counseling of newly diagnosed patients and their relatives and the involvement of a clinical geneticist or genetic counselor is recommended. It is essential that the individual being screened understands the nature of the test and its possible outcomes.23Issues, such as emotional, family, insurance, and employment implications of a positive result, should be discussed before testing and there should be a clear protocol for post-test management. Recent evidence demonstrates that many individuals who underwent genetic tests for FAP received inadequate counseling and some had been given poorly interpreted results.24 Controversy surrounds the issue of screening in childhood for a condition that causes few problems before late adolescence. Those children found not to carry the mutation are relieved to find they do not have FAP and are spared an infrequent but anxiety provoking annual sigmoidoscopy. For those found to have the mutation, there is the removal of uncertainty and doubt, and improved compliance with screening tests, allowing greater flexibility in surgical treatment options. Early knowledge of the child's disease status, however, may have detrimental effects; lead to denial, anger, or anxiety; result in harm to the child's self-conception; or even affect relationships within the family.33~76 Even if test results are negative, parental anxiety may remain. Many authorities believe that the child should be involved in the decision-making process and the diagnosis be delayed until the child is old enough to contribute to the screening program (e.g., from the age of 11 years onward). Some children understand the genetic screening and its consequences at a younger age (e.g., 8 years); each family situation should be considered individually. Severe dysplasia and even malignancy have been documented in children with FAP under the age of 12 years. Consequently, those children from families in which severe dysplasia or carcinomas have been found at a young age should undergo screening at an earlier age.20This is particularly so if the family has one of the mutations associated with a severe phenotype (e.g., 1309 in exon 15)." Duodenal and ampullary cancers are currently the most common cause of cancer deaths in patients treated for FAP. Upper endoscopic surveillance of the stomach, duodenum, and periampullary region with a side-viewing endoscope is recommended after age 20, unless the patient

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has symptoms, such as upper abdominal pain, which warrant earlier in~estigation.~' Treatment for Familial Adenomatous Polyposis

Colectomy is the only effective therapy that eliminates the inevitable risk of colorectal cancer. In the absence of severe dysplasia, colectomy is usually performed in mid to late teenage years or early 20s to accommodate work and school schedules. Some clinicians advocate colectomy before puberty so the patient can adapt to life without a colon before adolescence; each case should be considered on its own merits. Almost all screen-detected adolescents are asymptomatic and may not contemplate interruptions in their schooling or effects on relationships. The surgical option must not only be timed carefully but also have low morbidity and excellent functional result. The timing of primary preventative surgery may be influenced by knowledge of the mutation site and the likely severity of the polyposis. For example, patients with a deletion at exon 15 at codon 1309 may be offered earlier surgery because this phenotype is characterized by large numbers of polyps and a higher risk of cancer.'' Even though a low polyp density suggests a lower risk of developing malignan~y,'~ it is unsafe to delay surgery on the grounds of polyp density alone. Surgical options include subtotal colectomy with ileorectal anastomosis (IRA) or restorative proctocolectomy with ileoanal anastomosis (pouch procedure). The IRA is a low-risk operation with good functional results but the rectum remains at risk of cancer. Six-monthly surveillance of the rectum is needed postoperatively and despite this, inexperience can result in early cancers being missed. A pouch procedure removes the colorectal cancer risk almost completely, but is more complicated than an IRA, carrying a higher m~rbidity'~,~' and often requires a temporary ileostomy. A nonrandomized study comparing 37 FAP patients with ileoanal pouches with 62 FAP patients (mostly adults) treated by colectomy and IRA showed significantly more complications (60%versus 21%), and reoperations (29%versus 3%) in pouch patients, and a longer hospital stay (24 versus 11 days).47Night evacuation was commoner after a pouch (45% versus lo%), and sexual activity was more often affected (33% versus 0%). Other authors have differing experience and claim acceptable morbidity following pouch construction for FAP, or total colectomy with rectal mucosectomy and straight endorectal pullPouch creation is associated with an as yet unknown risk of pouch neoplasia and the pouch should be examined r e g ~ l a r l y . ~ ~ , ~ ' The author's current practice is to recommend IRA in adolescents because the operative morbidity is very low and the postoperative cancer risk is minimal. Conversion to an ileoanal pouch can be carried out when the patient is much older.66Patients with a large number of rectal polyps, or those with high-risk genotypes may be better with a pouch procedure in the first instance because of the greater risk of m a l i g n a n ~ y . ' ~ ~ ~ ~ ~ ~ ~

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DESMOID DISEASE

Desmoids are locally aggressive but nonmetastasizing myofibroblastic lesions that occur with disproportionately high frequency in patients with FAP. Associated etiologic factors include the germline mutation, estrogens, and surgical trauma. In a St. Mark's series, 74% of 34 intra-abdominal desmoids were preceded by a surgical procedure after a median delay of 24 month^.^' Desmoids occur most commonly in the peritoneal cavity and may infiltrate locally leading to small bowel, ureteric, or vascular obstruction (Fig. 11). These lesions may progress rapidly or may resolve spontaneously, their unpredictable nature making them difficult to treat.15 Patients found to have desmoid disease at laparotomy should be staged by CT scanning. Attempted surgical resection carries a high morbidity and mortality (10% to 60%) and usually stimulates further growth.14 Medical treatments including nonsteroidal anti-inflammatory drugs (NSAIDs) and antiestrogens have limited success. Cytotoxic chemotherapy is used as a last resort. Pediatricians treating children with extraintestinal desmoid tumors should consider the possibility of FAP in the family.13 OTHER POLYPOSIS SYNDROMES

Infrequently, juvenile polyposis may occur as part of the BannayanRiley-Ruvalcaba (also known as Ruvalcaba-Myrhe-Smith syndrome). This is characterized by macrocephaly, intestinal juvenile polyposis, pigmentation of the genitalia, psychomotor delay in childhood, and occasionally lipid storage my~pathy.'~Cowden disease is the association of

Figure 11. Massive abdominal desmoid tumor in a 14-year-oldpatient with FAP.

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multiple hamartomas of stomach, small intestine, or colon with macrocephaly, fibrocystic disease, cancer of the breast, nontoxic goiter, and thyroid cancer. Germline mutations in the tumor suppressor gene PTEN have been found in Cowden and Bannayan-Riley-Ruvalcaba pedigree~;~,~~ but not in some sporadic cases.1° Gorlin's syndrome is an autosomaldominant condition comprising upper gastrointestinal hamartomas and pink or brown macules in exposed areas, such as the face and hands. In addition, patients may have frontal and parietal bossing, hypertelorism, variable skeletal abnormalities, and intracranial calcificati~n.~~ Affected infants should be screened by ultrasound for medulloblastoma. Turcot's syndrome is characterized by concurrence of a primary brain tumor and multiple colorectal adenomas. Patients with a polyposis syndrome and neurologic symptoms should undergo thorough neurologic examination and investigation for possible brain tumor.6 The management of the colonic polyps in Turcot's syndrome is the same as for FAP. In most patients with polyposis, a clear-cut diagnosis can be made (e.g., FAP or PJS). There are some rare cases, however, where distinctions cannot be made on histology (the mixed polyposis syndrome^).^^ The youngest symptomatic patient in St. Mark's mixed polyposis family was 23 years old, and the youngest patient with cancer was age 32; there are as of yet no pediatric implications for this syndrome. ROLE OF THE POLYPOSIS REGISTRIES Polyposis registries have existed since the 1920s. For example, the St. Mark's polyposis registry contains information on more than 600 families with polyposis syndromes. Such registries enable staff to trace and link distant family members, an obvious advantage when genetic testing is required. In addition, the registry team can advise patients, explore their family history, co-ordinate their surveillance and clinical care, and oversee genetic testing. Children from affected families are encouraged by the registry to attend clinics with their parents, and so become familiar with the hospital environment. In addition to maintaining an active research role the registries also provide information for hospital clinicians, general practitioners, and pediatricians. FUTURE CHEMOPREVENTION Studies have suggested that NSAIDs may be protective against colon cancer. NSAIDs inhibit prostaglandin synthesis by their effects on cyclooxygenase. Several trials have shown regression of adenomas using the NSAID s u l i n d a ~ , 2 ~ but , ~widespread ~,~~ use of sulindac has been limited by concerns regarding gastrointestinal side effects with prolonged administration and case reports of rectal cancer despite treatment.53The Concerted Action for Polyposis Prevention study is currently assessing the effectiveness of intervention strategies, such as the administration of aspirin

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and dietary manipulations with resistant starch. Clinical trials using selective cyclooxygenaseinhibitors have reported a reduction in the number of colorectal polyps.69It remains to be seen what role this agent, and also the noncyclooxygenase metabolite of sulindac, sulfone-sulindac," may have in the future management of colorectal and duodenal adenomas. They may have a role before surgery in adolescents and as such are the subject of small-scale trials in a pediatric setting.

SUMMARY The diagnosis of a polyposis syndrome requires knowledge of the site, number, and histologic type of the polyps and an appreciation of any relevant family history. Children and adolescents with a polyposis syndrome are faced with the immediate complications of the polyps, such as intussusception or bleeding, plus the extraintestinal manifestations and the long-term risk of malignancy. Because the conditions are rare, an individual clinician may only see a child with polyposis every few years. Polyposis families need careful and well-informed genetic counseling that is optimally timed. The approach to care of these families should be multidisciplinary, involving a polyposis registry, a pediatric gastroenterologist, colorectal surgeon, pathologist, geneticist, and specialist nurses, all of whom should be familiar with the varied presentations and problems faced by these patients. ACKNOWLEDGMENTS The author thanks Kay Neale and Professor R.K. Phillips (Polyposis registry, St. Mark's Hospital), who manage the polyposis registry and have been involved in much of the original research quoted.

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Address reprint requests to Warren Hyer, MB, ChB, MRCPCH, MRCP Consultant Pediatrician, St. Mark's Hospital Watford Road Harrow Middx HA1 3UJ United Kingdom e-mail: warrenhyerQaol.com