Steven H. Erdman and Edward J. Hoffenberg
The most common gastrointestinal tumor in children is the benign single juvenile polyp. Single juvenile polyps are relatively common and do not infer an increased risk of colorectal cancer at any age. In contrast, findings of 5 or more hamartomatous polyps, one or more adenomas, or abnormal dysplastic histology suggest a diagnosis of one of the rare hereditary colorectal cancer syndromes. A family history of early cancer or polyps affecting multiple relatives over several generations is also consistent with a hereditary cancer syndrome.
The manifestations or expression of hereditary colorectal cancer/polyposis syndromes can be highly variable within a given family. Most of these syndromes are autosomal dominant, with cancer-related symptoms expected in other family members. The age of presentation, polyp number, and distribution or the age of cancer development can differ among affected family members who carry the same gene mutation. New spontaneous germline mutations are seen in up to one third of newly diagnosed pediatric polyposis patients.
Adenomas are either sessile or pedunculated and can be difficult to differentiate from hamartomas by appearance at endoscopy Adenomas are by definition dysplastic having disorganized epithelial proliferation, loss of goblet cells, cellular and nuclear atypia, and represent the early formative stages of adenocarcinoma. Finding an adenomatous polyp in a child or adolescent suggests the diagnosis of a hereditary adenomatous polyposis syndrome, all of which are associated with a substantial risk of colon or other cancers, so further evaluation and surveillance are mandatory.
BENIGN JUVENILE POLYPS
Juvenile polyps are the most common gastrointestinal tumor during childhood and can be seen in up to 2% of children under the age of 10 years.1,2 These lesions can present with painless rectal bleeding during defecation, or may only present when the polyp prolapses through the anus. Colonic juvenile polyps can also present with colic-like abdominal pain, diarrhea, or unexplained iron deficiency anemia. Juvenile polyps typically present from 2 to 4 years of age but can be found at any time during childhood or adolescence. Most juvenile polyps are solitary and are found in the rectosigmoid colon. Smaller polyps appear as flat sessile mucosal elevations that with time grow into mushroom-like pedunculated lesions. Juvenile or inflammatory polyps are classified as hamartomas. Pathology reveals an overgrowth of mature orderly epithelium with dilated mucus-filled glands, varying numbers of inflammatory cells, and surface ulceration. At times, the inflammation seen in juvenile polyps described as reactive atypia can be indistinguishable from early dysplasia.
HEREDITARY HAMARTOMATOUS POLYPOSIS SYNDROMES
JUVENILE POLYPOSIS SYNDROME
The diagnostic criteria for juvenile polyposis syndrome (JPS) include: the cumulative development of 5 or more colonic juvenile polyps; the presence of juvenile polyps in the stomach or small intestine (excluding other polyposis syndromes); or the presence of any juvenile polyp with a positive family history of JPS.3,4 JPS is classified as 1 of 4 presentations: JPS of infancy, juvenile polyposis coli, generalized JPS, or hereditary hemorrhagic telangiectasia-JPS (HHT-JPS) (Table 414-1). JPS of infancy is the most severe form of this disease with juvenile polyps forming throughout the digestive tract. Infants present with rectal bleeding, chronic diarrhea, protein-losing enteropathy, failure to thrive, and decreased survival. Juvenile polyposis coli has polyps limited to the large intestine, whereas those of generalized JPS can be found throughout the gastrointestinal (GI) tract.5,6 HHT-JPS presents with both vascular dysplasias of the respiratory, digestive tracts, brain, and skin, as well as gastrointestinal hamartomas.7
Table 414-1. Inherited Polyposis Syndromes—Hamartomatous Syndromes
JPS has been associated with at least 2 specific genes that involve the transforming growth factor (TGF)-β signaling pathway. Germline mutations or large genomic deletions of SMAD4, BMPR1A, and rarely ENG or PTEN, have been identified in patients with JPS.8,9 Affected, mutation-positive family members can develop polyps from early childhood to late adulthood or not at all. Patients with JPS, either with or without a known genetic mutation, have a cumulative lifetime risk of colorectal cancer approaching 50% beginning in the third decade of life.12,13 These families also show an increased risk of gastric cancer with a risk of pancreatic cancer or duodenal cancer of less than 1%.
Most patients with JPS are identified because of symptoms. At colonoscopic surveillance, all significant polyps should be removed and retrieved for histologic examination. Repeat surveillance colonoscopy with polypectomy should be done yearly until no additional polyps are found, at which time surveillance colonoscopy can be decreased to every 3 years. In some patients, the polyp burden or the presence of dysplastic changes may necessitate the need for subtotal colectomy. For asymptomatic mutation-positive patients, surveillance endoscopy should begin at 15 years of age.12,14
Peutz-Jeghers Syndrome (PJS) is characterized by the presence of mucocutaneous macular pigmentation, gastrointestinal polyps, and a dramatically increased lifetime risk of cancer (Table 414-1). The distinctive blue-black macules are most commonly seen at the vermillion border of the lips (95%), buccal mucosa (65% to 85%), and the hands and feet (Fig. 414-1 and eFig. 414.1 ). The classic lesions tend to fade with age, and PJS has been described without mucocutaneous pigmentation. The polyps of PJS are multiple and commonly found in the small intestine (64%), colon (53%), and stomach (49%) (eFig. 414.2 ).6,15 However, polyps can also be found in the nasopharynx, bronchi, and urinary tract. These pedunculated lesions can vary from being diminutive to 5 cm in diameter and can cause gastrointestinal hemorrhage, iron-deficiency anemia, protein-losing enteropathy, or intestinal intussusception.16,17Although described as hamartomas, the polyps of PJS are histologically distinct from juvenile polyps because of their arborizing abundant smooth muscle extending throughout the polyp toward the surface. PJS is associated with an 11-fold lifetime increased risk for malignancy in multiple organ systems (Table 414-1). During childhood, cancers may develop, including unique ovarian sex cord and testicular Sertolli cell tumors; sexual precocity and male gynecomastia may be the presenting features. Recent studies suggest a cumulative lifetime risk of any cancer exceeding 90% by the age of 65 years.6,18,19
PJS management in children focuses on the control of small intestinal and gastric polyps that cause significant morbidity from bleeding, intussusception, and bowel obstruction.20 Recent advances in capsule endoscopy, double balloon enteroscopy, and other imaging techniques offer new diagnostic and therapeutic options (Fig. 414-2). The appropriate role of these newer technologies in the diagnosis and management of PJS in children is not yet certain.
FIGURE 414-1. Macular pigmentation of the lips with Peutz-Jeghers syndrome.
PTEN HAMARTOMA TUMOR SYNDROME
The PTEN hamartoma tumor syndrome (PHTS) encompasses a spectrum of disorders associated with a germline mutation of the PTEN tumor suppressor gene. Inheritance is autosomal dominant with variable penetrance and expression. The disorders include Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and Proteus syndrome (PS).6,21 The clinical features of CS, BRRC, and PS are listed in Table 414-1. The gastrointestinal polyps of the PHTS can show marked histologic variation displaying features of adenomatous, hamartomatous, and ganglioneuromatous polyps. CS is associated with an increased lifetime cancer risk; however, the risk for gastrointestinal cancers is not clear.21 Colorectal cancer has been described in an adolescent with CS.22 Guidelines recommend that all CS patients with germline PTEN mutations should undergo surveillance screening. Current diagnostic criteria and surveillance guidelines for CS are available through the National Comprehensive Cancer Network Web site (http://www.nccn.org).23
OTHER RARE HAMARTOMATOUS POLYPOSIS SYNDROMES
Neurofibromatosis Type 1 This disorder, also known as Recklinghausen disease, is associated with neurofibromas of the skin and other organs, cutaneous café au lait spots, and skeletal abnormalities. Patients with neurofibromatosis Type 1 can develop intramural or subserosal neurofibromas, throughout the gastrointestinal tract and mesentery in up to 25% of patients.24 Along with gastrointestinal neurofibromas, inflammatory fibroid polyps or ganglioneuromatosis can also develop resulting in abdominal pain, constipation, protein-losing enteropathy, intussusception, and intestinal obstruction or bleeding. Hormone-secreting duodenal carcinoid tumors, pheochromocytomas, gastrointestinal stromal tumors, and mesenteric arterial vasculopathy are associated lesions and findings.25,26,27
Tuberous Sclerosis Complex This disorder can be associated with hamartomas of the liver, pancreas, and intestinal tract—most commonly the rectosigmoid colon. Colonic papillomas, leiomyomas, adenomas, and adenocarcinomas have also been described in adolescents with tuberous sclerosis complex.28,29
Basal Cell Nevus Syndrome This disorder is known for the development of multiple cutaneous basal cell carcinomas and uncommon development of incidental gastric hamartomas.30,31
FIGURE 414-2. Small intestinal hamartomas in a patient with Peutz-Jeghers syndrome as seen during double balloon enteroscopy.
Multiple Endocrine Neoplasia Type 2B In this disorder approximately 40% of affected individuals will develop symptomatic gastrointestinal ganglioneuromatosis32 manifested by thickening of the myenteric plexi and hypertrophy of the ganglion cells of the digestive tract. Motility disruption occurs resulting in diffuse motility disorders of the GI tract (see also Chapter 537).33,34
INHERITED ADENOMATOUS POLYPOSIS SYNDROMES
APC GENE-ASSOCIATED POLYPOSIS SYNDROMES
Multiple related syndromes including familial adenomatous polyposis (FAP), attenuated FAP (AFAP), Gardner syndrome, and Turcot syndrome are all associated with mutation of the APC gene (Table 414-2). A common feature of these disorders is the development of colon adenomas in varying numbers by the age of 35 years and in up to 95% of affected individuals (Fig. 414-3 and eFig. 414.3 ). The development of colorectal cancer in untreated patients approaches 100% by the fifth decade of life.35,36 The age of first symptoms can vary from early childhood to the sixth decade of life, and the number of adenomas present at diagnosis demonstrates great variability among family members possessing the same APC mutation. Roughly one quarter of patients with FAP will lack a family history and are thought to represent new or de novo APC mutations.37 Congenital hypertrophy of the retinal pigment epithelium is a distinctive eye finding that can be seen in affected infants during the first months of life.
Adenomas of the duodenum, ampulla, and stomach may progress to cancer, but hamartomatous fundic gland polyps rarely become malignant.38 Although rare, colon cancer has been reported in FAP children under the age of 12 years. Cancer risk in adolescents and young adults increases with adenoma burden, aggressive APC gene phenotypes, and severe dysplasia. These patients show an increased incidence of hepatoblastoma, follicular thyroid, and pancreatic cancer.39
Table 414-2. Inherited Polyposis Syndromes—Adenomatous Syndromes
Attenuated FAP is associated with a genotype involving either end of the APC gene. This results in fewer adenomas (less than 100) that develop at an older age and tend to cluster in the right colon. Patients with AFAP can present with fundic gland polyps or ampullary adenomas prior to the formation of colon adenomas, and rarely develop extraintestinal findings. Patients with AFAP carry a significant colon cancer risk that approaches that of FAP. Gardner syndrome describes those patients with FAP with prominent extraintestinal findings, including skeletal and jaw osteomas, supernumerary teeth,40 soft tissue tumors including desmoid tumors, sebaceous and epidermoid cysts, lipomas, and subcutaneous fibromas (Table 414-2). Turcot syndrome (brain tumor polyposis syndrome type 2) describes malignant central nervous system (CNS) tumors that develop with FAP. These lesions are typically medulloblastomas and can present prior to the development of colon adenomas.41
FIGURE 414-3. Numerous colon polyps of various sizes in a patient with familial adenomatous polyposis syndrome. (From Fauci AS, Braunwald E, Kasper DL et al (eds). Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill, 2008.)
Diagnosis and Management
The diagnosis of an APC-associated syndrome is suggested by the presence of colonic, gastric, or duodenal adenomas and confirmed through genetic testing. Current genetic testing can identify APC gene mutations in up to 90% of FAP families. The presence of a known family mutation enables the identification of affected family members with a high degree of accuracy prior to the development of symptoms. This allows for the application of preventive strategies to the affected, while avoiding unnecessary procedures in unaffected family members. The age at which to begin genetic testing of at-risk children remains controversial. Early genetic screening may identify infants and young children for hepatoblastoma surveillance.
Genetic counseling plays a critical role in the diagnosis and management of individuals and families with FAP. Screening should begin by age 12 years with yearly surveillance colonoscopy once adenomas are detected. Total colectomy remains the only proven therapy to reduce the risk of colon cancer and prolong survival. The optimal age for prophylactic colectomy is determined on a case-by-case basis. This decision is influenced by polyp burden, increasing adenoma dysplasia or adenocarcinoma, and the developmental maturity and coping mechanism of the child or adolescent in dealing with the consequences of surgery. In AFAP with fewer adenomas, endoscopic removal of all lesions on a yearly basis may allow postponement of colectomy.42
Because colorectal cancer risk in FAP increases significantly in the second decade of life, prophylactic colectomy should not be postponed beyond the late teenage years. Adenoma chemoprevention remains an area of intense research. Although initially promising, non-steroidal anti-inflammatory drugs (NSAIDs) have not been proven to reduce the risk of cancer. Adolescents and adults with FAP who have undergone colectomy require lifelong surveillance endoscopy of the stomach, duodenum, and rectal surgical site to monitor cancer development. The pediatric care provider should encourage long-term follow-up, and facilitate transfer of care to a qualified physician experienced in the management of hereditary colorectal cancer syndromes.
MutYH-associated polyposis (MAP) is an autosomal recessive disorder requiring biallelic mutation where each asymptomatic heterozygous parent contributes an inactivated gene. As a group, patients typically present in their mid-40s, similar to AFAP.43 However, adenomas and other digestive cancers may occur in children and adolescents with MAP.44 Surveillance guidelines follow the same recommendations as used for FAP.42
Lynch syndrome (LS) or hereditary nonpolyposis colorectal cancer is an autosomal-dominant colorectal cancer syndrome caused by a heterozygous mutation in 1 of 4 genes involved in DNA mismatch repair (MMR).14 This is the most common hereditary colorectal cancer syndrome. It was originally defined by the Amsterdam Criteria as requiring at least 3 relatives with colorectal or other specific cancers: (1) one should be a first-degree relative of the other two, (2) two or more successive generations are involved, and (3) cancer occurs in a family member before the age of 50 years. An updated definition, the Bethesda Criteria, includes tumor histology to identify at-risk individuals and families who should undergo further MMR gene testing. Approximately half of the families that fulfill the Bethesda or Amsterdam criteria do not carry a demonstrable mutation in any of the 4 MMR genes associated with LS. These likely represent one or more unknown hereditary colorectal cancer syndromes. LS patients are at risk for other malignancies (Table 414-1). Although typically thought of as a disease of adulthood, colorectal adenomas and cancers occur in children and adolescents from LS families.45,46,47 Children with biallelic MMR gene mutations (homozygous recessive or compound heterozygous) are rare but develop particularly aggressive cancers including brain tumors, lymphoma, leukemia, and colon cancer.48,49
Surveillance colonoscopy should begin at 20 years of age in individuals with a known or suspected MMR gene mutation. However, this is modified for at-risk children and adolescents from LS families with very early colon cancer (under 30 years of age). Surveillance colonoscopy should begin 10 years earlier than the age of cancer diagnosis in the affected family member or whenever symptoms are present. Surveillance colonoscopy should continue every 1 to 2 years to detect and remove adenomas that can progress to cancer at an accelerated rate compared to sporadic adenomas. 42,50
NONHEREDITARY POLYPOSIS SYNDROMES AND OTHER INTESTINAL TUMORS
As a noninherited disorder predominantly seen in adults, Cronkhite-Canada syndrome is characterized by diffuse polyposis of the small and large intestine, alopecia, onychodystrophy, and brown macular skin lesions. Polyps are usually hamartomas, but adenomas and colorectal cancer can occur in 10% to 20% of cases.51 Prognosis is poor due to severe malabsorption, protein-losing enteropathy, and malnutrition.
Lymphonodular hyperplasia (LNH) is characterized by small, 1- to 5-mm, submucosal lymphoid lesions that cluster in the duodenal bulb, ileocecal region, or rectosigmoid colon. Although generally considered a benign and self-limited lesion in children, colonic LNH may cause rectal bleeding, especially in young children. In the ileum, the nodules are rare lead points for intussusception and may be seen through the teenage years without causing symptoms.
LNH probably represents a normal nonspecific response of intestinal lymphoid tissue to an immune or inflammatory stimulus but may also be present in discrete entities such as food allergy and celiac disease.54 Recognition of this entity is important to prevent confusion with lymphoma, polyposis syndromes, or inflammatory bowel disease. Diagnosis is confirmed by the histologic features of lymphoid aggregates of mature lymphocytes, normal overlying mucosa, and a lack of tissue destruction. An increase in density of intraepithelial gamma/delta+ T-cells on the mucosa in patients with LNH is of unclear significance.55 Usually, no therapy is required, with symptoms resolving over several weeks to months.
INFLAMMATORY POLYPS OR PSEUDOPOLYPS
Reactive polyps or pseudopolyps can be associated with severe colitis of any cause. They usually are small, less than 1 cm in diameter, and require biopsy to differentiate from a carcinoma, especially in patients with long-standing inflammatory bowel disease. Other diseases that may give rise to inflammatory polyps include amebiasis and chronic bacterial infections.
COLITIS CYSTICA PROFUNDA
This rare entity is characterized by one or more mucin-filled cysts in the submucosa of the colon. The cause is unknown but it is associated with inflammatory and infectious conditions, as well as trauma. Lesions must be differentiated from adenocarcinoma and sessile polyps. Magnetic resonance imaging may assist in the diagnosis.56 Biopsy demonstrates thickened mucosa with mucus-filled cysts. Treatment depends on the underlying cause.
Leiomyoma are the most common benign tumors of smooth muscle in the small intestine of adults but are rare in children, usually found in the upper gastrointestinal tract. Tumors may cause obstruction, intussusception, or intermittent intestinal bleeding. Multiple lesions have been reported in children later in the course of HIV infection and are associated with Epstein-Barr virus infection. Esophageal leiomyomas are associated with Alport disease(nephropathy, deafness, and cataracts),57 whereas gastrointestinal leiomyomas may be associated with Carney triad (extra-adrenal paragangliomas, gastrointestinal stromal tumors, and pulmonary chondroma).58
HEMANGIOMAS AND OTHER VASCULAR LESIONS
Bleeding is the most common gastrointestinal manifestation of vascular lesions. Intestinal obstruction or intussusception may occur with larger hemangiomas. The most common type of hemangioma contains ectatic vascular channels that involve mucosa and submucosa and protrude into the lumen. Often, children with GI hemangiomas have external manifestations suggesting the diagnosis if they present with GI bleeding or anemia.
Hereditary hemorrhagic telangiectasia (HHT) (also known as Osler Weber Rendu) is an auto-somal dominant multisystem vascular dysplasia with multiple AVMs. The diagnosis is made by the presence of 3 of 4 criteria: (1) recurrent epistaxis; (2) multiple telangiectasias on the tongue, face, or hands; (3) visceral involvement, and (4) family history.59,60 HHT is caused by a mutation in one of several genes. HHT1 is caused by mutation in the endoglin gene on 9q34, whereas HHT2 is caused by mutation in the ALK1 gene on 12q1. Klippel-Trénaunay syndrome consists of large cutaneous hemangiomas plus skeletal and soft tissue hypertrophy with rare GI bleeding.61,62Turner syndrome is also associated with telangiectasias that may involve the intestinal tract. Blue rubber bleb nevus syndrome is characterized by distinctive cutaneous and gastrointestinal malformations, generally presenting with gastrointestinal bleeding.
Primary adenocarcinoma of the intestine is rare during childhood and adolescence. Most are of the mucin-producing or the signet-ring histo-logic varieties, which account for only 5% of tumors in adults. Carcinoembryonic antigen is not a reliable tumor marker for screening, and other markers have not yet been identified. Risks factors include any of the familial polyposis syndromes, inflammatory bowel disease, cystic fibrosis, and ureterosigmoidostomy. Because colon cancer develops in 5% of patients with ureterosigmoidostomies, endoscopic surveillance should be performed every 2 to 3 years.
GASTROINTESTINAL STROMAL TUMORS
These mesenchymal sarcomas are rare in children and may be associated with Carney triad (extra-adrenal paragangliomas, gastrointestinal stromal tumors, and pulmonary chondroma).58Gastrointestinal stromal tumors (GISTs) are most commonly found as submucosal masses in the stomach but occur throughout the gastrointestinal tract. Symptoms, related to the size and location of the tumor, include abdominal pain, ulceration, bleeding, and perforation.63GISTs in children may be less likely to express the cell surface transmembrane receptor kit, CD117 (c-kit) and thus may not respond to imatinib mesylate.64 Surgical resection is the treatment of choice.
The most common malignant tumors of the small intestine in children are primary intestinal lymphomas. Lymphoma is discussed in more detail in Chapter 451. They most frequently occur in the second decade of life and usually are non-Hodgkin lymphoma of the Burkitt type; a small number of diffuse histiocytic lymphomas, lymphoblastic lymphomas, and malignant histiocytoses of the intestine also are reported. Clinical findings and small bowel contrast studies may suggest an initial diagnosis of Crohn disease. Children with lymphoma may present with abdominal pain, distension, vomiting, a palpable abdominal mass, and intussusception. The most common sites of involvement for all small bowel lymphomas are the terminal ileum, cecum, and appendix. Helicobacter pylori infection is a risk factor for gastric lymphoma. Celiac disease is associated with small intestinal lymphomas. Post-transplant lymphoproliferative disease can be associated with Epstein-Barr virus infection.
Carcinoid tumors are usually benign and are rare in children.65 Most are found incidentally in the tip of the appendix at the time of appendectomy (Fig. 414-4).66 Increased blood levels of 5-hydroxytryptamine (serotonin) and histamine cause symptoms known as the carcinoid syndrome— periodic flushing, diarrhea, cyanosis, and bronchoconstriction. Urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) is often elevated. Malignant carcinoid tumors are rare in children. The primary tumor may locally infiltrate the intestinal wall of the ileum or colon, cause massive hepatic enlargement, or rarely reside within duplications or teratomas. Pancreatic and bronchial carcinoids also occur. Metastases may be extensive and are associated with a poor prognosis. Surgical resection offers the best hope, and appendectomy may be curative. Right hemicolectomy is reserved for uncertain margins, tumors larger than 2 cm, or local infiltration. Symptoms may be controlled with octreotide.
FIGURE 414-4. Colonoscopy showing a carcinoid tumor located in the cecum, adjacent to the appendiceal orifice. (Courtesy of www.gastrolab.net, with permission.)
Gastrinomas are usually small gastrin-secreting tumors of the upper abdomen. The high levels of gastrin cause excess production of gastric acid, leading to ulcers, abdominal pain, and diarrhea, and this is known as the Zollinger-Ellison syndrome. The majority of children with gastrinomas have high basal acid output and markedly elevated fasting gastrin levels, with values frequently above 500 ng/L.67
The diagnosis can be confirmed by the secretin stimulation test. Vitamin B12 deficiency may be associated with high gastrin levels. Gastrinomas generally are small tumors that are most commonly found in the duodenum but may be found in the pancreas or stomach. Tumor localization may be difficult and require selective angiography, endoscopic ultrasound, or 111 In-octreotide scintigraphy. Acid overproduction may be controlled with high-dose proton pump inhibitors or total gastrectomy.69 Approximately 25% of patients with gastrinoma have multiple endocrine neoplasia type I (MEN-I), and autosomal dominant disorder caused by mutation in the menin gene on 11q13. This disorder includes pancreatic, anterior pituitary, and parathyroid tumors as well as gastrinomas. Patients should be evaluated for hyperparathyroidism and adrenal tumors.
Leiomyosarcomas are rare slow-growing tumors in children discussed in Chapter 455. Recurrent intestinal bleeding, abdominal pain, and palpable abdominal mass are the most common clinical features. Diagnosis may occur during surgery for obstruction or on evaluation of intussusception. Multiple leiomyosarcomatous lesions have been reported in children with HIV infection.