Children and adolescents with gastrointestinal polyps may present symptoms including rectal bleeding, abdominal pain, or intussusception. Alternatively, they may be asymptomatic, having been referred, because either an adult family member has been affected with early onset colorectal cancers (CRCs), or there is a known family history of a polyposis syndrome. Many children fall under the latter category. They are asymptomatic and polyps are detected only as part of a screening program for an inheritable polyposis syndrome. Managing these children and families requires knowledge of the different polyposis syndromes, their inheritance and genetics, potential for malignant change, and pediatric complications.
Polyp Types
Gastrointestinal polyps in children fall into two major categories: hamartomas and adenomas ( Box 41-1 ). Solitary polyps in children are most commonly hamartomas, predominantly of the juvenile type, and such polyps are benign. Of the familial syndromes, familial adenomatous polyposis is more common than juvenile polyposis or Peutz-Jeghers polyposis. Table 41-1 outlines the different histologic features of the polyps.
Adenomatous polyposis syndromes
Familial adenomatous polyposis (FAP)
MYH -associated polyposis (MAP)
Turcot syndrome
Lynch syndrome
Hamartomatous polyps
Solitary juvenile polyp
Juvenile polyposis syndrome
PTEN —hamartoma tumor syndrome, e.g.
Bannayan-Riley-Ruvalcaba
Gorlin syndrome
Cowden syndrome
Peutz-Jeghers syndrome
Inflammatory polyps
Mixed polyposis syndrome
| Polyp Type | Macroscopic and Microscopic Appearance |
|---|---|
| Juvenile polyp | Pedunculated, multilobulated, very vascular, 1 to 3 cm, and may have ulcerated surface from autoinfarction. At microscopy, dilated cysts filled with mucin, abundant lamina propria with prominent inflammatory infiltrate, haphazardly arranged. |
| Peutz-Jeghers | Sessile or pedunculated with lobulated surface. At microscopy, frond-like structure, elongated, branching strands of smooth muscle. |
| Tubular and villous adenoma | Pedunculated smooth, red lobulated surface, 0.5 to 5 cm. At microscopy, glands and tubules are with or without inflammatory infiltrate. Villous adenomas are sessile and broad based. Dysplasia is always present. |
Clinical Presentation of Gastrointestinal Polyps
The most common clinical manifestation of a large bowel polyp is painless rectal bleeding. Other symptoms attributed to polyps include abdominal pain, altered bowel habit, and prolapse of polyp or rectum. Diagnosis will be made on full colonoscopy and polypectomy. The clinical presentation, endoscopic appearance, pathologic findings, and histologic description of the polyp are all necessary to establish the correct diagnosis of a polyposis syndrome. Once a polyp has been identified at endoscopy, a carefully targeted family history must be obtained to determine if there are family members who have or have had cancer, the site of the cancers, and the age of onset. It is of particular importance to ascertain if cancer or polyps have occurred in first- or second-degree relatives before the age of 50 years. Box 41-2 summarizes key historical and physical examination findings in a patient with a suspected gastrointestinal polyp. Taking such a history to develop a detailed family cancer pedigree may require the expertise of a multidisciplinary familial cancer clinic or polyposis registry.
History
- •
Nature of bleeding and frequency
- •
Painful or painless rectal bleeding
- •
History of gastrointestinal obstructive symptoms
- •
Detailed family history exploring early deaths or diagnosis of gastrointestinal cancer, including history of non-gastrointestinal malignancies
- •
Weight loss, anorexia (tumor)
- •
Learning difficulties (JPS or PTEN hamartoma)
Examination
- •
Mucosal pigmentation (PJS)
- •
Dysmorphic features (JPS)
- •
Edema (hypoalbuminemia in infantile JPS)
- •
Extraintestinal manifestations of FAP *
* See Table 41-2 .
—e.g., subcutaneous cysts, exostosis, congenital hypertrophy of the retinal pigment epithelium
- •
Hepatic mass (FAP)
- •
Genitourinary abnormalities (JPS)
- •
Cutaneous telangiectasia (HHT with JPS)
- •
Thyroid mass (FAP or Cowden)
The Single Hamartomatous Polyp (The Juvenile Polyp)
The single hamartomatous (or juvenile) polyp has been reported to have a prevalence of 0.1% to 3.7%. The most common presentation is painless bright red rectal bleeding with blood seen on wiping or mixed in the stool. Occasionally, parents will report seeing the polyp prolapsing out of the rectum at defecation, or passing into the diaper after spontaneous auto-amputation. Polyps measuring 0.5 to 5 cm and should be removed at pancolonoscopy and polypectomy.
Seventy percent of juvenile polyps are found in the rectum, or rectosigmoid. The remainder are found more proximally and hence the need for pancolonoscopy. Single or solitary juvenile polyps are benign and confer no future risk of malignancy. Dysplasia has rarely been described in children with solitary juvenile polyps. However, it is unknown whether children who present with a single polyp in childhood may continue to form polyps over time. One series suggests recurrence of a juvenile polyp after removal of a solitary hamartomatous polyp in up to 16% of patients.
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 should be sufficient treatment. After polypectomy, parents must be made aware that juvenile polyps may be the first feature of a hamartomatous polyposis syndrome. If fresh symptoms arise, the child should be reinvestigated. If multiple juvenile polyps are found (more than 3 to 5) or there is a positive family history (e.g., colonic polyps or early onset CRC), a hamartomatous or juvenile polyposis syndrome should be considered and an alternative approach taken.
Hamartomatous Polyposis Syndromes
Hamartomatous polyposis syndromes are a rare group of hereditary autosomal dominant disorders. The polyps themselves are benign, but the polyposis syndromes confer significant potential for developing CRC and extracolonic cancers mediated through a hamartoma–carcinoma sequence. The hamartomatous polyposis syndromes include juvenile polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS) and PTEN hamartoma tumor syndrome, which includes Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS).
Juvenile Polyposis Syndrome
Juvenile polyposis syndrome (JPS) is rare, with an estimated prevalence of 1 in 100,000 individuals presenting with multiple hamartomatous polyps and an increased risk of gastrointestinal malignancies. A family history of juvenile polyps is found in 20% to 50% of patients with an autosomal dominant inheritance pattern of variable penetrance. Affected individuals develop multiple gastrointestinal polyps, which are predominantly in the colon, although other areas of the gastrointestinal tract can also be involved. The condition should be considered in any patient with more than five juvenile polyps in the colon, any juvenile polyps found in other parts of the gastrointestinal tract, or if any juvenile polyp is found in a child with a positive family history.
There are three phenotypic forms:
- 1.
Juvenile polyposis of infancy characterized by diarrhea, protein-losing enteropathy, bleeding, and rectal prolapse.
- 2.
Juvenile polyposis coli where polyp growth involves only the colon.
- 3.
Generalized juvenile polyposis in which polyp growth can affect the colon, stomach, and small bowel.
Patients with juvenile polyposis coli and generalized juvenile polyposis develop 50 to 200 polyps in their lifetime. The total number of polyps needed to make the diagnosis remains controversial at between three and five. Patients present with chronic and acute gastrointestinal bleeding, anemia, prolapsed rectal polyps, abdominal pain, and diarrhea. These hamartomatous polyps occur throughout the gastrointestinal tract including the colon, rectum, stomach, and small bowel. A significant proportion of patients with juvenile polyposis have been reported to have other morphologic abnormalities including digital clubbing, polydactyly, macrocephaly, alopecia, cleft lip or palate, congenital heart disease, double renal pelvis and ureter, bifid uterus and vagina, undescended testes, supernumerary teeth, and mental retardation.
Cancer Risk in Juvenile Polyposis Syndrome
There is little doubt that juvenile polyposis is a premalignant condition. There is a 15% incidence of colorectal carcinoma occurring in patients younger than age 35 years, leading to a cumulative lifetime risk of colorectal cancer of 38% to 68% with a mean age of colonic neoplasia onset between 38 and 44 years. Neoplastic changes have been documented both in the polyps and in flat, apparently normal colonic mucosa. There have been numerous case reports documenting gastric and pancreatic adenocarcinomas. The risk of neoplastic change is more likely to occur in patients with the generalized form of polyposis compared with those with colorectal polyposis alone.
Genetics of Juvenile Polyposis
JPS is a fully penetrant condition with variable expression. Sixty percent of cases are familial, and the others occur sporadically. Germline mutations in SMAD4, BMPR1A , and ENG1 cause JPS. All are part of the transforming growth factor β (TGF-β) superfamily of proteins. Whether a PTEN gene mutation is associated with JPS is controversial. Approximately 54% of JPS cases will have a detectable mutation.
SMAD4 on chromosome 18q21.2 is a tumor suppressor gene in the TGF-β signal transduction pathway and mutation will be found in about 20% of patients with JPS. SMAD4 mutations predispose to hamartomas and cancer through disruption of the TGF-β signaling pathway. The most common mutation is a four base-pair deletion of exon 9, although other missense and nonsense, deletions, and insertions have been described. Patients with the SMAD4 mutation appear to have a higher risk of gastric polyps and hereditary hemorrhagic telangiectasia (HHT). The latter condition is characterized by cutaneous telangiectasia and risk of arteriovenous malformations. Patients found to have the SMAD4 mutation should be screened for cerebral and pulmonary arteriovenous malformations associated with HHT.
BMPR1A is located on chromosome 10q22.3 and accounts for another 20% of patients with JPS. BMPR1A gene is a serine/threonine kinase receptor protein involved in the TGF-β signaling pathway upstream of SMAD4 , responsible for phosphorylation of SMAD proteins that then bind to SMAD4 . ENG1 mutation on gene 9q34.1 has recently been described in JPS patients without HHT. ENG encodes the protein endoglin, which is an accessory protein of the TGF-β signaling pathway.
When consulting with a family known to have JPS, it is beneficial to isolate the specific family gene mutation so that predictive genetic testing can be employed to test other at-risk family members, enabling appropriately timed screening colonoscopies.
Screening and Follow-up
Once the gene mutation has been identified in the index patient, other at-risk family members should be tested. Approximately 75% of patients will have an affected parent. If this is the case, all children of that proband will have a 50% chance of inheriting the mutation, and if the family mutation is known, children should undergo genetic screening.
Proposed guidelines suggest that affected children should undergo colonoscopic surveillance every 2 years or earlier if symptoms arise. In those families in which the gene mutation is not known, first-degree relatives of patients with JPS should be screened by a single colonoscopy starting at age 12 to 15 years, even when the subject is asymptomatic ( Figure 41-1 ).
Full colonoscopy is necessary, as right-sided polyps are the most common. All polyps should be resected. Annual colonoscopy is performed until all polyps have been resected after which the screening interval is stretched to every 2 to 3 years. Gastroscopy is commenced from the mid-teens. Colectomy is warranted for patients with cancer, dysplasia, or high polyp burden with symptoms that cannot be controlled endoscopically. It should also be considered in patients who fail to turn up for screening and in those with polyps showing adenomatous change, severe diarrhea with hypoproteinemia, or persistent bleeding with anemia.
PTEN Hamartoma Tumor Syndrome
This group comprises three rare genetic syndromes: Cowden syndrome, BRRS syndrome, and Proteus syndrome. All are associated with a mutation in the PTEN gene located at 10q23.3. The PTEN gene is a tumor suppressor gene that regulates the Akt/PKB signaling pathway and is additionally involved in regulating cell cycle and apoptosis. All three syndromes are characterized more by extraintestinal manifestations than intestinal polyposis.
Cowden syndrome rarely presents in childhood. Clinical manifestations include macrocephaly, papillomatous papules, mucocutaneous lesions (such as facial trichilemmoma), and acral keratosis. It carries a 50% risk of breast cancer in adult women, and a 10% lifetime risk of epithelial thyroid cancer. Between 30% and 90% of patients have small hamartomatous colonic polyps distal to the hepatic flexure.
BRRS presents in childhood with gastrointestinal hamartomas, particularly in the ileum and colon, which cause intussusception, rectal bleeding, and hypoalbuminemia. There are additional characteristics including macrocephaly, developmental delay, abnormal metacarpal and phalanges, pectus excavatum, scoliosis, genital pigmentation, lipomatosis, and hemangiomatosis.
Proteus syndrome is characterized by hemi-hypertrophy and congenital malformations. It has few gastrointestinal implications but is included in the PTEN group as it shares the PTEN gene mutation.
The PTEN mutation can be detected in 80% of patients with Cowden, 60% with BRRS, and 50% with Proteus syndrome. All offspring of an affected individual have a 50% chance of inheriting the mutation.
BRRS presents prior to adolescence and there is value in genetic testing in early childhood in a family where the mutation has been identified. Patients with BRRS need regular colonoscopy and small bowel surveillance as they are at risk of anemia, intussusception, and hypoalbuminemia from the polyposis. They carry a probable lifetime increased risk of cancer, and surveillance is recommended from age 18 to 25 years focusing on renal, thyroid, and breast cancer. For those patients with Cowden syndrome, the risk of adenocarcinoma of the breast is between 30% and 50%, and there is a risk in male breast tissue. There is a lifetime 10% risk of thyroid cancer, and up to 10% risk of endometrial cancer. Guidelines presently recommend screening for breast, thyroid, endometrial, and kidney cancer starting from the age of 18 to 25 years.
Peutz-Jeghers Syndrome
Clinical Features and Diagnosis
PJS is a rare autosomal dominant condition with a prevalence of 1 in 50,000 to 1 in 200,000 live births. It is characterized by mucocutaneous pigmentation and the presence of hamartomatous polyps throughout the gastrointestinal tract. Polyps arise primarily in the small bowel and to a lesser extent in the stomach and colon. Polyps are most commonly found in the jejunum and cause bleeding and anemia, or intussusception and obstruction from an early age. Presumptive diagnosis can be made in those with a positive family history and typical PJS freckling.
Pigmentation tends to arise in infancy, occurring around the mouth, nostrils, perianal area, fingers, toes, and the dorsal and volar aspects of hands and feet ( Figure 41-2 ). It may fade after puberty but tends to persist in the buccal mucosa, this being present in 95% of cases. Lip freckling is not unique to PJS.
The primary concern to the pediatrician is the risk of small bowel intussusception causing intestinal obstruction, vomiting, and pain. In addition, intestinal bleeding—with melena, hematemesis, and rectal bleeding—can occur, leading to anemia. In a child or adolescent, the clinical diagnosis of PJS may be made when any one of the following are present:
- 1.
Two or more histologically confirmed PJ polyps
- 2.
Any number of PJ polyps detected in one individual who has a family history of PJS in close relative(s)
- 3.
Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in close relative(s)
- 4.
Any number of PJ polyps in an individual who also has characteristic mucocutaneous pigmentation.
Genetics of Peutz-Jeghers Syndrome
As with other hamartomatous syndromes, PJS has an autosomal dominant pattern of inheritance and many cases may be sporadic new mutations. The mutated gene STK11(LKB1), located on chromosome 19p 13.3 and encoding a serine/threonine kinase, is associated with PJS. It appears that STK11 is a tumor suppressor gene that might act as a gatekeeper, regulating the development of hamartomas and adenocarcinomas in PJS. The gene has an essential role in cell cycle arrest, cell polarity, and p53-dependent apoptosis.
The gene mutation can be identified in up to 90% of patients. Once the mutation has been identified, at risk family members can be tested for the family specific mutation. Parents of apparently isolated PJS cases should be carefully assessed, and all siblings should be tested if a parent is found to be affected. After appropriate genetic counseling and informed consent, testing at-risk family members may be performed early in childhood so that gastrointestinal surveillance can commence before gastrointestinal complications arise.
There is marked inter- and intrafamily phenotypic variability in PJS. In studies of larger PJS cohorts, no difference was seen between individuals with missense and truncating mutations, nor between familial and sporadic cases. It was, however, suggested that there was a higher risk of cancer in individuals with mutations in exon 3 of the gene. In a group of 419 PJS patients in the 297 with documented mutations, the type and site of mutation did not influence cancer risk.
If the gene mutation is known in previous affected cases in the family, there is value in presymptomatic genetic testing in those patients with no pigmentation or even potential prenatal diagnosis.
Screening, Management, and Complications
Individuals at risk of PJS should be evaluated in infancy for pigmented lesions and gastrointestinal symptoms. Asymptomatic at-risk children should undergo genetic testing for the family proband mutation if the STK11 / LKB1 mutation is known, soon after infancy, so the family can access medical care early if the child develops symptoms consistent with small bowel obstruction.
The management of a young child with mid-gut PJS polyps is controversial but recommended guidelines have been published. In a retrospective review, 68% of children had undergone a laparotomy for bowel obstruction by the age of 18 years, and many of these proceeded to a second laparotomy within 5 years. There is a high re-operation rate after initial laparotomy for small bowel obstruction.
Children who present with mid-gut complications need polypectomy by either laparotomy and intraoperative enteroscopy (IOE) ( Figure 41-3 ) or single- or double-balloon enteroscopy (SBE or DBE). An IOE is recommended in any patient with PJS undergoing laparotomy, as careful endoscopy via an enterotomy in the small bowel allows identification and removal of polyps, thus avoiding multiple enterotomies and the risk of short bowel syndrome associated with resection. This technique is superior to palpation and transillumination in identifying polyps, and removal of all detected polyps (“clean sweep”) reduces relaparotomy rate significantly.
Balloon enteroscopy with polypectomy of PJS polyps in the small bowel carries a significant risk of perforation and should be performed only by those who are expert in polypectomy. Muscularis mucosa commonly invaginates into the large pedunculated stalk increasing the risk of perforation at electrocautery ( Figure 41-4 ). SBE or DBE can be combined with laparoscopy to assess perforations that may arise at polypectomy.
Endoscopic evaluation of the upper and lower gastrointestinal tract and imaging of the small bowel should be performed from the age of 8 years ( Figure 41-5 ). Screening should start earlier if symptoms are present before this. The development of video capsule endoscopy (VCE) has replaced barium enterography as the preferred technique for assessing the small bowel. VCE is more sensitive, preferred by patients, and reduces the lifetime risk from cumulative radiation exposure. Children younger than 6 years may require the VCE to be placed endoscopically, and the risk of capsule retention is less than 1%. An acceptable alternative to VCE is magnetic resonance imaging (MRI) enterography, with a close correlation between the two modalities, especially with polyps larger than 15 mm.
The advantages and disadvantages of prophylactic polypectomy for asymptomatic patients should be discussed with the family. Management is influenced by the size of the polyps and their location. Prophylactic polypectomy of larger small bowel polyps (greater than 1.5 cm) by intraoperative or DBE should be performed to reduce the incidence of subsequent complications and the requirement for emergency laparotomy. For children who are asymptomatic with small polyps (less than 1.0 cm), the parents should be counseled about the risk of intussusception. No single pharmacologic agent has been shown to impact the clinical course of PJS.
Malignancy Risk
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 boys. A meta-analysis to assess the risk of cancer in PJS identified a relative risk for all cancers in PJS patients (ages 15 to 64) of 15.2 compared to the normal population, with tumors reported throughout the gastrointestinal tract including colon (39%), pancreas (36%) and stomach (29%), and extraintestinal tumors of the lung, testes, breast (54%), uterus, ovary, and cervix. The risk of developing any cancer by age 70 years is documented as 76%.
Clinicians caring for adolescents with PJS should be aware of unusual symptoms—for example, those occurring due to a feminizing testicular tumor—and have a low threshold for investigating potential malignancies. A recommended screening program for PJS patients after adolescence is shown in Box 41-3 , although it is not yet proven that such a program will reduce morbidity or mortality.
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