Introduction
Background
A GI polyp is defined as a mass of the mucosal surface protruding into the lumen of the bowel. Polyps can be neoplastic, nonneoplastic, or submucosal. GI polyposis is characterized by multiple polyps within the GI tract.
A variety of polyposis syndromes can affect the GI tract. These polyposis syndromes may be classified as familial inherited (autosomal dominant) or nonfamilial.
The inherited polyposis syndromes can be further subdivided into 2 groups depending on whether the polyps are adenomas or hamartomas. The adenomatous polyposis syndromes include the classic familial adenomatous polyposis (FAP), Gardner syndrome, and Turcot syndrome. Hamartomatous familial polyposis syndromes include Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden disease, and Ruval-Caba-Myhre-Smith syndrome.
The noninherited polyposis syndromes include Cronkhite-Canada syndrome and a variety of miscellaneous nonfamilial polyposis.
From a prognostic viewpoint, these syndromes must be recognized, because the adenomatous polyps are premalignant. These syndromes should be considered when an intestinal polyp is recognized in the young, when 2 or more polyps are seen in any patient, when colon carcinoma is discovered in patients younger than 40 years, and when extraintestinal manifestations associated with these syndromes are discovered.
GI polyps may be asymptomatic, but they may also occur with rectal bleeding and diarrhea. The urgency of case tracing and genetic counseling is related not so much to the symptoms of the disease but to the potential for the development of a colon carcinoma. It is probable that patients with familial polyposis, if untreated, will develop a colon carcinoma.1,2,3
Colon, polyposis syndromes. Polyposis coli. Left lateral decubitus image obtained as part of a barium enema study shows numerous small polyps in the transverse and descending colon.
Colon, polyposis syndromes. Polyposis coli. Double-contrast enema study in a man with a family history of familial colonic polyposis shows a solitary polyp with malignant change.
Colon, polyposis syndromes. Polyposis coli, differential diagnosis. Left, Left lateral decubitus image from a double-contrast barium enema study shows numerous polyps throughout the colon. Right, Contrast-enhanced CT scan through the upper abdomen shows massive splenomegaly, retroperitoneal lymphadenopathy, and multiple polypoid lesions in the transverse colon; these distort the colonic mucosa. The histologic diagnosis was a mantle lymphoma.
Pathophysiology
FAP coli
FAP coli is characterized by polyposis of the colon and the eventual development of colon carcinoma. The syndrome is transmitted in an autosomal dominant manner. Some have suggested that Gardner syndrome may represent a spectrum of the same genetic disease as FAP, with a shared locus at 5q21-q22. Therefore, diagnosis is possible by means of linked DNA markers in the asymptomatic patient.
Approximately two thirds of patients with this disease have a family history of FAP or colon cancer. In a third of the patients, the disease occurs as spontaneous mutation. The colonic polyps are numerous and present as a carpet of polyps ranging from 1-2 mm to 1 cm or larger. In all cases, large numbers of adenomas carpet the colon, occurring initially in the left colon and then eventually spreading to involve the entire colon.
The number of polyps markedly varies between kindreds and even between affected individuals within 1 family with the same germline mutation. All affected family members exhibit polyps by the age of 35 years. The number of polyps ranges from 150 to over 1000. The disease is usually diffuse, but segmental involvement may occur.
FAP is associated with hamartomatous polyps in the stomach (49%), adenomatous polyps of the duodenum (25%), and periampullary carcinomas. Histologically, the polyps are adenomatous lesions that are indistinguishable from sporadic nonfamilial colonic polyps. Colon cancers usually develop in all patients with FAP within 20 years after the diagnosis.
Another variant of FAP is attenuated adenomatous polyposis coli syndrome. This variant is associated with fewer polyps (<100), and patients may present with as few as 5-10 polyps. Patients with this syndrome have mutations in the extreme 5' and 3' ends of the APC gene.
Gardner syndrome
Gardner syndrome probably has the same genotype as FAP coli. FAP and Gardner syndrome may occur in the same family. As in FAP, the colonic polyps are histologically adenomatous, and malignant transformation occurs in 100% of patients.
Fibrous tissue in patients with Gardner syndrome has a desmoplastic tendency resulting in desmoid tumors, keloids, mesenteric fibrosis, peritoneal adhesions, retroperitoneal fibrosis, and mammary fibromatosis. Fibroblast cultures derived from skin biopsy specimens in patients with Gardner syndrome have shown abnormalities that may predate the onset of the characteristic features of the disease elsewhere.4 A diffuse form of spontaneous mesenteric fibrosis may occur and is thought to be a response to surgery or unrecognized trauma. It may result in an inoperable bowel obstruction.
A variety of benign and malignant neoplasms and abnormal dentition are associated with Gardner syndrome, including the following:
- Soft tissue tumors
- Epidermoid inclusion cysts of the skin
- Dermoid tumors
- Fibroma
- Lipoma
- Lipofibroma
- Neurofibroma
- Leiomyoma
- Mammary fibromatosis
- Intra-abdominal desmoid tumors and peritoneal fibromas
- GI tumors
- Colonic polyposis (100%) (Colon carcinoma eventually develops.)
- Gastric adenomatous polyps (5-68%)
- Gastric hamartomatous polyps
- Duodenal adenomatous polyps (90%) (Malignant transformation occurs in 12% of patients.)
- Periampullary carcinoma (2-12%)
- Hepatoblastoma
- Pancreatic carcinoma
- Lymphoid hyperplasia of the terminal ileum
- Osseous abnormalities
- Usually involve the membranous bones (50%), mandible (81%), calvarium, maxilla, ribs, and long bones
- Self-limited benign exostosis
- Bone islands and periosteal thickening
- Endocrine tumors
- Thyroid carcinoma (This is commonly papillary, and it may be multicentric with a female preponderance. This may predate other manifestation of Gardner syndrome.)
- Carcinoid tumors of the small bowel
- Parathyroid adenoma
- Adrenal adenoma/carcinoma
- Pituitary chromophobe adenoma
- Central nervous system medulloblastoma
- Abnormal dentition
- Supernumerary teeth
- Impacted teeth
- Odontoma
- Hypercementosis
- Teeth more prone to caries
Peutz and Jeghers independently described a syndrome consisting of multiple intestinal hamartomatous polyps associated with mucocutaneous melanotic pigmentation. The skin lesions are 2-5 mm, black or brown macules that sometimes coalesce on the lips, oral mucosa, nose, fingers, cheek, palms, toes, forehead, and abdomen. Although the mucosal pigmentation is permanent, the skin lesions may fade at puberty. The hamartomatous polyps have a smooth muscle core, which arises from the muscularis mucosa and extends into the polyp.
Mutation analysis of the STK11 gene (with a chromosomal locus at 19p13.3) reveals disease-causing mutations in about 70% of familial cases and 30-70% of sporadic cases (depending on the study). Such testing is available clinically.
Regarding the distribution of GI polyps and non-GI polyps, the stomach and duodenum are involved in 25% patients; the involvement is usually diffuse, with multiple polyps. The small bowel is involved in more than 95% of patients. The polyps may be broad-based and separated by wide areas of normal mucosa; a carpet of polyps may occur, with individual polyps varying from millimeters to several centimeters in diameter. Some of the polyps may be large and multilobulated.
Colonic and rectal polyps represent 25% of the polyps. They are usually multiple, varying from millimeters to 3 cm in size. Carpeting usually does not occur in the colon and rectum. Polyps may occur in the nose, larynx, and bronchial tree. Polyps and/or adenomas may occur within the urinary tract, particularly the urinary bladder. Polyps in the gallbladder and bile ducts are rare.
Malignant degeneration of these polyps is rare, but the risk of developing other neoplasm is reported to be 18 times greater than that of the general population. A variety of malignant tumors are associated with Peutz-Jeghers syndrome.
The risk of carcinoma in the pancreaticoduodenal region is 2-3% and is not necessarily associated with polyps. Pancreatic carcinoma is a complication of the disease in 13% of cases. Breast carcinoma develops in a minority of patients and is commonly bilateral and ductal. The risk of ovarian cysts and a variety of ovarian neoplasms (5%), including ovarian sex cord tumor, mucinous cystic tumor, cystadenoma, and granulosa cell tumor, is increased. Other non-GI neoplasms include neoplasms of the thyroid, lung, skin, uterus (endometrial cancer, adenoma malignum of cervix), and testicles (feminizing Sertoli cell tumor).5
Turcot syndrome
Turcot et al first described an association between colonic polyps and tumors. The colonic/rectal polyps are adenomatous, usually multiple, and measure 1-30 mm in diameter. Most central nervous system tumors are supratentorial glioblastomas; medulloblastomas occasionally occur. Other reported abnormalities include sebaceous cysts, papillary carcinoma of the thyroid, leukemia, and spinal cord tumors.
A recent study of 14 families with a history of both colon tumors and brain tumors revealed mutations in 2 types of genes known to cause inherited forms of colon cancer. Ten of the families had alterations of the APC gene, a tumor suppressor gene associated with FAP. In 2 additional families, a mutation of 1 of 2 mismatch repair genes, hMLH1 and hPMS2, were identified. Those who inherit a defective mismatch repair gene tend to be mutation prone, and they are at higher risk of developing cancer. Both hMLH1 and hPMS2 are involved in the development of hereditary nonpolyposis colorectal cancer, which is believed to be the most common inherited disease in humans.6
Recent studies have revealed that patients with FAP are about 90 times more likely to develop brain tumors than the general population. Turcot syndrome may be more prevalent then previously thought. Recently, Turcot syndrome was subdivided into 2 groups. In the first group, the association of adenomatous polyposis with malignant brain tumors constitutes the rare disease of Crail syndrome; patients with this disease usually have mutations in the APC gene. A second group of patients have mutations in the DNA repair genes; these patients have hereditary nonpolyposis colon cancer (Turcot syndrome).7,8
Cronkhite-Canada syndrome
Cronkhite-Canada syndrome includes generalized GI polyposis in association with neuroectodermal changes consisting of alopecia, hyperpigmentation, and atrophy of the nails. Electron microscopic studies of the skin reveals increased numbers of melanin granules in keratinocytes, increased numbers of melanosomes in melanocytes, increased melanocyte numbers, compact hyperkeratosis, and perivascular inflammation and exocytosis. A number of hematologic, neurologic, and metabolic abnormalities are associated with Cronkhite-Canada syndrome (see Clinical Details).
Juvenile polyposis syndrome
Juvenile polyposis syndrome is a rare disease, but it is the most common cause of colonic polyposis in children. Inherited in an autosomal dominant manner with variable penetrance, it may be familial or nonfamilial. The 3 forms of juvenile polyposis are determined on the basis of the location of the polyps: familial juvenile polyposis coli, in which the polyps are confined to the colon; familial juvenile polyposis, which occurs in of the stomach; and generalized juvenile polyposis, in which polyps are distributed throughout the GI tract in any age group. Juvenile polyposis syndrome is associated with variable penetrance; one affected family member may have 200 polyps, whereas another affected member may only have a single hamartomatous polyp.
The syndrome is associated with hamartomatous GI polyps, but adenomas may coexist. The polyps are solitary in 75% of patients, but they may be multiple. Most of the polyps are located in the rectosigmoid (80%); polyps in the stomach and small bowels are rare. The polyps are smooth with rounded contour; they may vary from 1 mm in size to several centimeters in diameter.
The polyps are invariably on stalks of differing lengths. Histologically, the polyps are characterized by hyperplasia of mucous glands, retention cysts, and obstruction of the gland orifices associated with an edematous, inflamed, and expanded lamina propria but little or no smooth muscle.
Cowden is the family name of the original reported patient, Rachel Cowden. Cowden syndrome is a rare disorder that is inherited in an autosomal dominant manner with intrafamilial and interfamilial differences in the expressivity of symptoms. Germline mutations in a candidate tumor suppresser gene, PTEN, have been identified with Cowden syndrome. PTEN is involved in a wide variety of cancers, including those of the brain, breast, and prostate.
Cowden syndrome is characterized by multiple hamartomas and neoplasms of endodermal, ectodermal, and mesodermal origin. The associated GI polyps may be juvenile; hamartomatous; and hyperplastic; lymphomatous; inflammatory; or adenomatous (rare). Cowden syndrome is associated with Lhermitte-Duclos disease and Down syndrome. It is also associated with increased severity and earlier onset of symptoms in subsequent generations.9
A variety of lesions have been associated with the syndrome, including the following:
- Mucocutaneous lesions
- Multiple facial papules; papillomatosis of the lips, gums, and tongue; and oral fibromas
- Acral keratosis, palmoplantar keratosis, acral verrucoid lesions, skin tags, dermal fibromas, lipomas, and skin malignancies
- Soft tissue tumors, including lipomas, fibroangiomas, angiolipomas, and cavernous hemangiomas
- Head and neck abnormalities
- Macrocephaly, hypoplasia of the mandible and maxilla associated with microstomia
- Cysts of the scalp
- Cataracts, angioid streaks, myopia and congenital blood vessel anomalies, and glaucoma
- Goiter, thyroid adenoma, hyperthyroidism, hypothyroidism, thyroiditis, thyroglossal duct cyst, and follicular thyroid carcinoma (3-4%).
- Vocal cord polyps
- Breast lesions
- Fibrocystic disease, fibroadenomas, virginal hyperplasia, and benign gynecomastia (in males)
- Breast cancer (often bilateral, ductal in 20-30%)
- GI lesions
- GI polyps
- Diverticula of the colon
- Ganglioneuromas, neuromas, epithelioid leiomyoma of the rectosigmoid, and adenocarcinoma of the colon
- Hamartoma of the liver
- Genitourinary involvement
- Menstrual irregularity, miscarriages, and still births
- Ovarian cysts
- Uterine leiomyomas
- Vaginal and vulvar cysts
- Adenocarcinoma of the uterus
- Cervical carcinoma
- Ovarian cancer
- Transitional cell carcinomas of the renal collecting system and bladder
- Varicoceles
- Central nervous system involvement
- Reduced intellect
- Seizures
- Intention tremors
- Cutaneous nerve neuromas
- Neurofibromas
- Meningiomas
- Hearing loss
- Musculoskeletal involvement
- Supernumerary digits
- Pectus excavatum
- Scoliosis/kyphosis
- Bone cysts
Ruval-Caba-Myhre-Smith syndrome
Ruval-Caba-Myhre-Smith syndrome is inherited in an autosomal dominant manner, with some sporadic cases. The syndrome is characterized by macrocephaly, pigmented genital lesions, subcutaneous and visceral lipomas, and hemangiomas and GI hamartomatous polyps. Mesodermal hamartomas can affect the subcutaneous, intracranial, visceral, intestinal, thoracic, and osseous tissues. Hydrocephalus and diffuse thickening of the corpus callosum have also been described.
Frequency
United States
FAP is inherited in an autosomal dominant manner with 80% penetrance, but sporadic occurrence has been recorded in one third of patients. The gene for FAP is located on chromosome 5. The prevalence is quoted as 1 in 7,000-24,000 live births.
Gardner syndrome probably has the same genotype as FAP coli. It is transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. The estimated prevalence is 1 in 14,000 population.10
Peutz-Jeghers syndrome has a prevalence of 1 in 7,000 live births with a half familial and half sporadic distribution. Cronkhite-Canada syndrome has no hereditary factors; 100 cases have been published as of 1994. Turcot syndrome is inherited in an autosomal recessive manner. Approximately 100 cases of Cowden's syndrome have been reported in the literature. Ruval-Caba-Myhre-Smith syndrome is rare, and the exact incidence is not known.
International
To the authors' knowledge, no available data suggest that the frequency of polyposis syndromes in other countries is different from that in the United States.
Mortality/Morbidity
In FAP, malignant transformation may occur in the stomach; small bowel; or colon, the most common site. Cancers develop in 12% of patients 5 years after the diagnosis, in 30% at 10 years, and in 100% at 20 years. The carcinomas are multiple in 48%. Carcinomas develop in patients aged 20-40 years. Periampullary carcinoma is the leading cause of death in patients with FAP who have undergone prophylactic colectomy.
- In Gardner syndrome, colonic carcinoma develops in all patients by the age of 41 years.
- Peutz-Jeghers syndrome is often associated with abdominal cramps caused by subacute obstruction or small-bowel intussusception. The incidence of non-GI cancer is 18 times higher than that of the general population. The life expectancy is decreased, with the risk of cancer approaching 40% by the age of 40 years.
- The prognosis for patients with Turcot syndrome is poor because of its association with supratentorial glioblastomas. Death from brain tumor occurs in the second or third decade of life. Malignant transformation of the colonic polyps occurs in almost all patients.
- Cronkhite-Canada syndrome is rapidly fatal in women within 6-18 months of the onset of cachexia; there is a tendency toward remission in men.
- Regarding patients with Cowden syndrome, by the time women reach their 40s, 50-75% develop breast cancer.
Race
There is no racial predilection for colonic polyps.
- The international incidences of colon cancer reflect dietary differences in fat and fiber intake rather than racial differences.
- When the population of a developing country adopts a Western diet, rates of colon cancer increase.
- Similarly, among immigrants from a low-incidence country, the incidence rate soon approximates the rate of their adopted country.
Sex
No sex predominance is reported in FAP coli, Gardner syndrome, or Peutz-Jeghers syndrome. However, the papillary thyroid carcinoma associated with Gardner syndrome has a female preponderance.
- Cronkhite-Canada syndrome is more common in males, although the exact male-to-female ratio is unknown.
- For juvenile polyposis of infancy, the male-to-female ratio is 3:2.
- Cowden syndrome mostly affects women; 50-75% of women with Cowden syndrome develop breast cancer by they reach their 40s.
Age
In FAP, the polyps are not present at birth and usually appear at puberty, although the age at onset varies greatly. In all cases, large numbers of adenomas carpet the colon, occurring initially at an average age of 15 years in the left colon. Eventually, these polyps spread to involve the entire colon. The average patient age at the onset of symptoms is 32 years, but the first symptoms may appear at any age between 5 and 55 years. A gap of 10 years usually occurs between the recognition of disease and the onset of symptoms.
- Patients with Gardner syndrome are typically aged 15-30 years. The average patient age at presentation of Peutz-Jeghers syndrome is 25 years.
- Patients with juvenile polyposis of infancy are aged 4-6 years, with an age range of 1-10 years, whereas patients with colonic or generalized polyposis usually present at 20 years of age.
- Patients with Turcot syndrome are symptomatic during the second decade. Cronkhite-Canada syndrome affects patients with an average age of 62 years (age range, 42-75 y). The age of onset of Cowden syndrome is in the first to third decades.
Anatomy
Presentation
The groups of symptoms that are shared by all polyposis syndromes include vague abdominal pain, rectal bleeding, mild diarrhea, passage of mucus, intussusception, rectal prolapse, and bowel obstruction.
GI symptoms of rectal bleeding and abdominal pain usually develop in the third decade in FAP.
Turcot syndrome
The presentation is that of FAP associated with café-au-lait spots and central nervous system tumors. Patients may present with seizures and diarrhea.
Gardner syndrome
Gardner syndrome is characterized by early mild diarrhea associated with a small amount of mucus and blood. Some patients are asymptomatic. Within 15-20 years after the onset of GI symptoms, the polyps undergo malignant transformation, and the associated symptoms are then those of an underlying GI malignancy.
A variety of other tumors can develop, including bone tumors and soft tissue tumors, such as multiple epidermoid cysts, dermoid tumors, fibromas, and neurofibromas. Patients can also have benign exostosis; osteomatosis, which is mostly confined to the face and skull; and multiple impactions of the supernumerary teeth.
Gardner syndrome is frequently associated with retinal pigment epithelium hypertrophy. Patients with Gardner syndrome often seek medical advice because of facial cosmetic deformity associated with soft tissue or bony abnormality. The diagnosis may be first suggested when dental abnormalities are detected or when patients present with sinusitis secondary to osteomas that affect the paranasal sinuses.
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome is associated with brown or black freckles of the lips, buccal mucosa, face, palms, and soles. Hamartomatous polyps occur in the entire GI tract, where they may cause recurrent abdominal pain, rectal bleeding, and anemia. The polyps may form a nidus for intussusception and rectal prolapse. Malignant degeneration within the polyps is rare, but the incidence of both GI and non-GI neoplasms in patients with this syndrome is 18 times that of the general population.
Cronkhite-Canada syndrome
Cronkhite-Canada syndrome may occur with loss of the sense of taste and with xerostomia, glossitis, anorexia, dysphagia, vomiting, abdominal pain, protein-losing enteropathy, and diarrhea.
A number of hematologic and metabolic abnormalities are associated with Cronkhite-Canada syndrome. These include anemia, thromboembolic episodes, hypocalcemia, hypomagnesemia, hypokalemia, electrolyte depletion, and weight loss. With fatty degeneration, liver function test results may be abnormal. Cronkhite-Canada syndrome is also associated with transient ischemic episodes, tetany, cataracts, peripheral neuropathy, systemic lupus erythematosus, finger clubbing, and hypothyroidism. The GI polyps are hamartomatous and have no malignant potential.
Symptoms appear in middle and old age. A rare infantile form has been described; this is characterized by macrocephaly, finger clubbing, alopecia, dystrophic nails, hypotonia, anemia, hepatosplenomegaly, and protein-losing enteropathy. Most polyps are seen in the stomach and colon (100%); the small bowel is affected in over 50% of patients.
Juvenile polyposis syndrome
Juvenile polyposis syndrome can subdivided into 2 types. The first is juvenile polyposis, which affects children aged 4-6 years; patients usually present with protein-losing enteropathy, diarrhea, hemorrhage rectal prolapse, and intestinal obstruction caused by intussusception. The second type is colonic and generalized polyposis. The average age of presentation is by 20 years. Patients present with rectal bleeding, rectal prolapse, and anemia.
The most common presenting symptom may be anemia. The average age at presentation is 18 years. Another typical presentation is a child who has a rectal polyp and presents with bleeding, obstruction, or intussusceptions. The syndrome may be associated with macrocephaly, mental retardation, and breast lesions, including fibroadenomas. Approximately one half of the patients who present with juvenile polyposis have no family history of the disease. The risk of colorectal cancer in juvenile polyposis is approximately 40%; however, some families develop gastric cancer rather than colon cancer.
Cowden syndrome
Patients with Cowden syndrome present with a birdlike facies, a small mandible and maxilla, and microstomia. The palate is high and arched. Skin lesions are common and are seen as multiple facial papules, keratosis, and a scrotal tongue. Female patients may present with menstrual irregularities, miscarriages, and stillbirths. Central nervous system symptoms may predominate and include an intention tremor and seizure often associated with impaired intellect. Cataracts, myopia, hearing loss, and thyroid disorders are well-recognized features. A variety of tumors has been described (see Pathophysiology).
Ruval-Caba-Myhre-Smith syndrome
Patients with Ruval-Caba-Myhre-Smith syndrome may present with macrocephaly, increased birth weight, and postnatal growth retardation. Central nervous system symptoms may be the dominant symptoms. These include a delay in achieving the milestones of development, impaired intellect, speech delay, prolonged drooling, seizures, strabismus, and amblyopia. The palate is arched, and the syndrome is associated with pectus excavatum and hyperextensibility of joints. The presentation may reflect the effects of a colonic polyp or subcutaneous, intracranial, visceral, thoracic, or skeletal hamartomas.
Preferred Examination
Imaging examinations
For polyps larger than 1 cm, the sensitivity of single- and double-contrast barium enema (DCBE) examination is 90-95%. DCBE is more sensitive in the detection of polyps smaller than 1 cm.
When combined with a sodium chloride enema technique, sonography can be used to detect colonic polyps as small as 7 mm in 91% of patients. However, the technique is cumbersome and is not widely practiced. At present, this approach cannot replace a barium enema study or colonoscopy. Still, ultrasonography is an invaluable tool in the screening of patients with polyposis syndromes and in the screening of their families for associated cancers, such as those of the thyroid, breast, liver, ovaries, and uterus.
CT and magnetic resonance (MR) colonography (virtual colonoscopy) are new techniques being developed for the imaging of colorectal polyps and cancer.11,12,13,14,15,16,17 The limited data presently available show that the sensitivity of both CT and MR colonography for polyps larger than 1 cm is 75-90%; however, the detection rate decreases precipitously for smaller polyps. Both CT and MR colonography allow an analysis in both the cross-sectional and virtual endoscopic formats. New developments, such as fecal tagging, are likely to increase the sensitivity of the techniques, and the noninvasive nature of the procedures increase patient acceptability.18,19,20,21,22
CT and MR techniques have the added advantage that both offer the capability of imaging extraintestinal disease associated with many of the colon polyposis syndromes.23
Genetic counseling, screening, and surveillance
Identified genes
In the majority of patients, colon cancer is sporadic, and patients have no family history of bowel cancer. However, a growing number of genes have been identified; these increase the risk of colon cancer. Three genes with a strong link with colon cancer include the gene for FAP and two genes associated with hereditary nonpolyposis colorectal cancer; these are designated MSH2 and MLH1.24,25,26
The FAP gene is best understood because of the mode of its autosomal dominant inheritance and complete penetrance. Although polyp formation usually begins in the second decade of life, genetic testing is available for the APC gene, which is located on chromosome 5q. Current assays detect approximately 82% of cases tested. The FAP gene, known as APC, has been localized to the long arm of chromosome 5; mutations are usually associated with the progressive development of multiple colonic polyps that have a potential for malignant transformation.27,28,29
For patients with inherited FAP, the lifetime risk of developing colon cancer is almost 100%. Genetic detection and counseling is available to families at risk and can significantly improve the lives of noncarriers. Therefore, a person found not to carry the FAP gene can be spared further surveillance, which is usually undertaken in individuals at high risk.30
Testing for potentially affected families usually starts with analysis of an affected family member, to identify the mutation responsible for the disease. Importantly, 20-30% of patients newly diagnosed with adenomatous polyposis have de novo mutations; such patients are the first patients in the family to present with colonic polyposis.
In patients who have inherited the disease, the condition is treatable and even curable with screening colonoscopy and surgical resection.31,32,33,34,35,36
Screening and surveillance for patients with adenomatous polyposis syndromes
Screening and surveillance in this group includes flexible sigmoidoscopy of first-degree relatives starting at puberty (10-12 y), or sooner in symptomatic patients. Families should be screened annually for polyposis until adenomas are detected, until they have undergone genetic testing along with the index patient, or until they are found not to have the mutant gene that caused the disease in the index case. Genetic testing can be performed as early as age 10 years. If genetic testing is not available or not performed, first-degree relatives who have no evidence of polyps by the age of 25 years may undergo flexible sigmoidoscopy every 2 years until the age of 35 years.
Because FAP has 100% penetrance, virtually all affected members will exhibit polyps by 35 years of age. Upper GI polyps develop in the majority of patients with FAP. Most common are benign polyps in the stomach, as well as adenomas that develop in the duodenum and ampulla.
The risk of gastric or nonduodenal small-bowel cancers appears to be low (0.5%) in patients with FAP. However, the lifetime risk of duodenal, ampullary, and/or pancreatic cancer is increased, at 5-10%. For this reason, most authorities recommend upper GI side-viewing endoscopy every 1-4 years in patients with FAP, starting at 20-25 years of age. Patients should be evaluated for polyps of the stomach or duodenum at least once a year, and biopsy samples of suspicious lesions should be obtained. No screening is usually recommended for first-degree relatives in whom polyposis has not been diagnosed.
Surveillance for extra-GI tumors can be performed by means of yearly physical examination supplemented by laboratory examination. Desmoid tumors affect 10% of patients with FAP. Although these tumors are benign, they have an aggressive behavior and can be lethal, as they encase and constrict the abdominal organs and vessels. Desmoids are more common in women than in men, and they appear to cluster in families. The tumors are provoked by surgery and childbirth.
In patients with FAP, the lifetime risk of thyroid cancer is increased by 2-3%; patients usually present in the third decade. Some authorities recommend thyroid screens, perhaps by means of ultrasonography, whereas others regard physical examination as sufficient.
Patients with Crail syndrome and their potentially affected family members should undergo screening similar to that used in FAP. However, in addition, careful neurologic assessment is indicated. Screening for brain tumors may include CT but preferably MRI of the head. Hepatoblastomas and embryonal liver tumors are known to be associated with FAP in young children. Because these liver cancers are potentially curable, screening with serum alpha-fetoprotein testing and with a consideration of liver imaging (perhaps sonography) may be warranted in children younger than 5 years.
Ophthalmic examinations are performed to evaluate for congenital hypertrophy of the retinal pigment epithelium (CHRPE) in the index patient with FAP. If the index patient has CHRPE, it may be a useful clinical marker of Gardner syndrome in other first-degree relatives; when present, CHRPE has a predictive value of 100%. In screening first-degree relatives of a patient with Gardner syndrome, the absence of non-GI manifestations, such as bone or skin tumors, does not rule out Gardner syndrome.37
In Ashkenazi Jews, a single mutation in the APC gene (I1307K) has been identified. This mutation seems to be associated with a 20-30% lifetime risk of colorectal cancer, but at this point, it is not associated with FAP. This mutation has been found in 28% of Ashkenazi Jews with a family history of colon cancer and in 6% of those with a negative family history of colorectal cancer. For carriers of the mutation who have a positive family history of colorectal cancer, the lifetime risk may approach 50%. Ashkenazi Jews with a family history of colon cancer may benefit from genetic testing for I1307K. If the results are positive for the mutation, individuals may be followed up with colonoscopy every 2 years, beginning at age 35 years. Genetic testing is available.38
A unified policy of screening may be applied to hamartomatous polyposis, with some changes for individual syndromes such as juvenile polyposis, Cowden disease, and Peutz-Jeghers syndrome.
Peutz-Jeghers syndrome is inherited in an autosomal dominant manner. About one half of the patients have an affected parent, and one half of the cases appear to be sporadic. The LKB1/STK11 gene located on chromosome region 19p is associated with Peutz-Jeghers syndrome; however, genetic testing for this condition is not yet available. Of the sporadic cases, many appear to be caused by de novo mutations in STK11. Because the frequency of subtle signs of the disorder has not been thoroughly evaluated and because the molecular genetic data are insufficient to rule out Peutz-Jeghers syndrome in supposedly sporadic cases, parents should be advised that they might be at risk for having Peutz-Jeghers syndrome.
Prenatal testing is possible. However, prenatal diagnosis of diseases that typically manifest in adulthood poses a difficult situation, and careful genetic counseling is required.
Screening of the first-degree family members consists of colonoscopy and upper GI series with small-bowel follow-through study. Current recommendations for surveillance include colonoscopy, esophagogastroduodenoscopy, and small-bowel follow-through studies every 2 years after diagnosis. Affected individuals should also undergo an annual physical examination, and women should undergo annual mammograms. Some authorities recommend transvaginal ultrasonography for the surveillance of gynecologic or testicular tumors.39,40,41,42,43,44,45,46,47
Screening of families potentially affected by juvenile polyposis
Screening in this group involves careful history taking and colonoscopic examination every 5 years, beginning at age 12 years. For families with familial juvenile polyposis of the stomach, esophagogastroscopy is substituted for colonoscopy. Patients with polyps should undergo endoscopic surveillance every 1-3 year. Colectomy is recommended for patients who have numerous polyps in the colon; however, surveillance of the ileal pouch should be continued because of the risk of malignant change.48,49,50
No commercial genetic testing for juvenile polyposis is currently available. Studies have shown that the DPC4 gene located on chromosome arm 18q is constitutionally mutated in some patients with juvenile polyposis. In addition, chromosome arm 10q (PTEN gene) appears to be mutated in some patients.
Screening and surveillance for Cowden syndrome
Endoscopic screening is not necessary. However, because of the common association of non-GI cancers, the surveillance of affected individuals should include physical examination with special attention to the organs that are at risk, to thyroid function tests and/or scans, and to mammography every 6-12 months. No genetic test for Cowden syndrome is currently commercially available, although the disease has been linked to mutations in the PTEN gene on chromosome arm 10q.
Limitations of Techniques
The false-negative rate for the detection of polyps smaller than 1 cm is 7% with double-contrast barium enema. Small sessile polyps are easily missed. Interpretive problems may occur because of overlapping bowel loops, air bubbles, spasm, diverticula, a poorly prepared bowel, and barium flooding. Diverticula impacted with feces, lobulated diverticula seen en face, and edema of the diverticular neck caused by inflammatory changes can also mimic polyps and contribute to the false-positive rates.
The screening and surveillance of patients with many of the colonic polyposis syndromes include prolonged observation; barium enema studies are less acceptable for surveillance because of concerns about radiation exposure.
Ultrasonography remains operator dependent. Colonic and bowel gas and obesity degrade sonograms. The presence of feces and mucus also prevents the identification of colonic polyps. An assessment of the bowel thickness at the base of a polyp is important in identifying malignant transformation; however, this cannot always be evaluated by using the sodium chloride enema technique. Polyps smaller than 7 mm can be missed during ultrasonographic examination.
The main limiting factor for interpreting CT colonograms is time spent on reading the scans. For virtual colonoscopy to be a clinically feasible tool, the examination must be performed and the results interpreted in a time-efficient manner. For example, a large cohort of patients underwent both 2-dimensional (2D) and 3-dimensional (3D) imaging with antegrade and retrograde 3D navigation of the colon. Patients were in both the supine and prone positions. The median interpretation time for 2 radiologists was 31 minutes (2D imaging) and 27 minutes (3D imaging), respectively. The sensitivity of CT for polyps 10 mm or larger was over 90%.16,51,52
The time issue is especially a problem with multisection CT colonography, with which nearly 1000 images can be obtained per patient, depending on the section collimation and degree of overlap.
MR colonography shares several limitations with its CT counterpart. Inadequate colon distention, contrast opacification, and the presence of air bubbles and fecal masses may potentially cause problems in interpretation.51,53,52,54,55,56
None of the above techniques are useful in differentiating hamartomatous polyps from adenomatous polyps.
Differential Diagnoses
Colon, Adenocarcinoma
Colon, Polyps
Intussusception, Child
Neurofibromatosis Type 1
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References
Beech D, Pontius A, Muni N. Familial adenomatous polyposis: a case report and review of the literature. J Natl Med Assoc. Jun 2001;93(6):208-13. [Medline].
East JE, Saunders BP, Jass JR. Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin North Am. Mar 2008;37(1):25-46. [Medline].
Bougatef K, Krichene A, Marrakchi R, Kourda N, Blondeau Lahely Y, Moussa A, et al. Do we know all there is to know about Familial Adenomatous Polyposis?. Gastroenterol Clin Biol. Dec 2007;31(12):1062-6. [Medline].
Kopelovich L, Conlon S, Pollack R. Defective organization of actin in cultured skin fibroblasts from patients with inherited adenocarcinoma. Proc Natl Acad Sci U S A. Jul 1977;74(7):3019-22. [Medline].
Saranrittichai S. Peutz-jeghers syndrome and colon cancer in a 10-year-old girl: implications for when and how to start screening?. Asian Pac J Cancer Prev. Jan-Mar 2008;9(1):159-61. [Medline].
Harley I, Rosen B, Risch HA, Siminovitch K, Beiner ME, McLaughlin J, et al. Ovarian cancer risk is associated with a common variant in the promoter sequence of the mismatch repair gene MLH1. Gynecol Oncol. Apr 9 2008;[Medline].
Hamilton SR, Liu B, Parsons RE. The molecular basis of Turcot''s syndrome. N Engl J Med. Mar 30 1995;332(13):839-47. [Medline].
Scribano E, Loria G, Ascenti G. Turcot''s syndrome: a new case in the first decade of life. Abdom Imaging. Mar-Apr 1995;20(2):155-6. [Medline].
Marra G, Armelao F, Vecchio FM. Cowden''s disease with extensive gastrointestinal polyposis. J Clin Gastroenterol. Jan 1994;18(1):42-7. [Medline].
Pierce E. Gardner's syndrome: formal genetics and statistical analysis of a large Canadian kindred. Clin Genet. 1970;1:65.
Fenlon HM, Ferrucci JT. Virtual colonoscopy: what will the issues be?. AJR Am J Roentgenol. Aug 1997;169(2):453-8. [Medline].
Hawes RH. Does virtual colonoscopy have a major role in population-based screening?. Gastrointest Endosc Clin N Am. Jan 2002;12(1):85-91. [Medline].
Macari M. Virtual colonoscopy: clinical results. Semin Ultrasound CT MR. Oct 2001;22(5):432-42. [Medline].
Mendelson RM, Forbes GM. Computed tomography colonography (virtual colonoscopy): review. Australas Radiol. Mar 2002;46(1):1-12. [Medline].
Rex DK. Considering virtual colonoscopy. Rev Gastroenterol Disord. Summer 2002;2(3):97-105. [Medline].
Rex DK. CT and MR colography (virtual colonoscopy): status report. J Clin Gastroenterol. Oct 1998;27(3):199-203. [Medline].
Schoenfelder D, Debatin JF. [Virtual reality in MR colonography]. Radiologe. Mar 2000;40(3):283-9. [Medline].
Lauenstein TC, Goehde SC, Debatin JF. Fecal tagging: MR colonography without colonic cleansing. Abdom Imaging. Jul-Aug 2002;27(4):410-7. [Medline].
Lauenstein TC, Debatin JF. Magnetic resonance colonography for colorectal cancer screening. Semin Ultrasound CT MR. Oct 2001;22(5):443-53. [Medline].
Macari M, Milano A, Lavelle M. Comparison of time-efficient CT colonography with two- and three- dimensional colonic evaluation for detecting colorectal polyps. AJR Am J Roentgenol. Jun 2000;174(6):1543-9. [Medline].
Macari M, Lavelle M, Pedrosa I. Effect of different bowel preparations on residual fluid at CT colonography. Radiology. Jan 2001;218(1):274-7. [Medline].
Macari M, Bini EJ, Xue X. Colorectal neoplasms: prospective comparison of thin-section low-dose multi-detector row CT colonography and conventional colonoscopy for detection. Radiology. Aug 2002;224(2):383-92. [Medline].
Jasperson KW, Blazer KR, Lowstuter K, Weitzel JN. Working through a diagnostic challenge: colonic polyposis, Amsterdam criteria, and a mismatch repair mutation. Fam Cancer. Jan 6 2008;[Medline].
Groden J, Thliveris A, Samowitz W. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. Aug 9 1991;66(3):589-600. [Medline].
Groden J. Colon-cancer genes and brain tumors. N Engl J Med. Mar 30 1995;332(13):884-5. [Medline].
Howe JR, Roth S, Ringold JC. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. May 15 1998;280(5366):1086-8. [Medline].
Nishisho I, Nakamura Y, Miyoshi Y. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. Aug 9 1991;253(5020):665-9. [Medline].
Nugent KP, Phillips RK, Hodgson SV. Phenotypic expression in familial adenomatous polyposis: partial prediction by mutation analysis. Gut. Nov 1994;35(11):1622-3. [Medline].
Rustgi AK. Hereditary gastrointestinal polyposis and nonpolyposis syndromes. N Engl J Med. Dec 22 1994;331(25):1694-702. [Medline].
Lynch ED, Ostermeyer EA, Lee MK. Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet. Dec 1997;61(6):1254-60. [Medline].
Loftus WK, Metreweli C, Sung JJ. Ultrasound, CT and colonoscopy of colonic cancer. Br J Radiol. Feb 1999;72(854):144-8. [Medline].
Cruz-Correa M, Giardiello FM. Diagnosis and management of hereditary colon cancer. Gastroenterol Clin North Am. Jun 2002;31(2):537-49, x. [Medline].
Drenth JP, Nagengast FM, Oyen WJ. Evaluation of (pre-)malignant colonic abnormalities: endoscopic validation of FDG-PET findings. Eur J Nucl Med. Dec 2001;28(12):1766-9. [Medline].
Offerhaus GJ, Giardiello FM, Krush AJ. The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology. Jun 1992;102(6):1980-2. [Medline].
Kwak EL, Chung DC. Hereditary colorectal cancer syndromes: an overview. Clin Colorectal Cancer. Jan 2007;6(5):340-4. [Medline].
Spits C, De Rycke M, Van Ranst N, Verpoest W, Lissens W, Van Steirteghem A, et al. Preimplantation genetic diagnosis for cancer predisposition syndromes. Prenat Diagn. May 2007;27(5):447-56. [Medline].
Gelisken O, Yucel A, Guler K. Ocular findings in familial adenomatous polyposis. Int Ophthalmol. 1997-98;21(4):205-8. [Medline].
Laken SJ, Petersen GM, Gruber SB. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet. Sep 1997;17(1):79-83. [Medline].
Brown SR, Baraza W, Hurlstone P. Chromoscopy versus conventional endoscopy for the detection of polyps in the colon and rectum. Cochrane Database Syst Rev. Oct 17 2007;CD006439. [Medline].
Byers T, Levin B, Rothenberger D. American Cancer Society guidelines for screening and surveillance for early detection of colorectal polyps and cancer: update 1997. American Cancer Society Detection and Treatment Advisory Group on Colorectal Cancer. CA Cancer J Clin. May-Jun 1997;47(3):154-60. [Medline].
Glick S, Wagner JL, Johnson CD. Cost-effectiveness of double-contrast barium enema in screening for colorectal cancer. AJR Am J Roentgenol. Mar 1998;170(3):629-36. [Medline].
Lindgren G, Liljegren A, Jaramillo E. Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer. Gut. Feb 2002;50(2):228-34. [Medline].
Screening for colorectal cancer. In. DHH Services, eds. Guide to clinical preventive services. 2nd Ed. Report of the U.S. Preventive Services Task Force. Washington, DC: U.S. Preventive Services Task Force;. 1995.
Winawer SJ, Fletcher RH, Miller L. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology. Feb 1997;112(2):594-642. [Medline].
van Stolk RU. Familial and inherited colorectal cancer: endoscopic screening and surveillance. Gastrointest Endosc Clin N Am. Jan 2002;12(1):111-33. [Medline].
Desai TK, Barkel D. Syndromic colon cancer: lynch syndrome and familial adenomatous polyposis. Gastroenterol Clin North Am. Mar 2008;37(1):47-72. [Medline].
Frank TS. Hereditary cancer syndromes. Arch Pathol Lab Med. Jan 2001;125(1):85-90. [Medline].
Becker JM, McGrath KM, Meagher MP. Late functional adaptation after colectomy, mucosal proctectomy, and ileal pouch-anal anastomosis. Surgery. Oct 1991;110(4):718-24; discussion 725. [Medline].
Erbe RW. Inherited gastrointestinal-polyposis syndromes. N Engl J Med. May 13 1976;294(20):1101-4. [Medline].
Pillai RB, Tolia V. Colonic polyps in children: frequently multiple and recurrent. Clin Pediatr (Phila). Apr 1998;37(4):253-7. [Medline].
Chen SC, Lu DS, Hecht JR. CT colonography: value of scanning in both the supine and prone positions. AJR Am J Roentgenol. Mar 1999;172(3):595-9. [Medline].
Fletcher JG, Johnson CD, Welch TJ. Optimization of CT colonography technique: prospective trial in 180 patients. Radiology. Sep 2000;216(3):704-11. [Medline].
Dachman AH, Kuniyoshi JK, Boyle CM. CT colonography with three-dimensional problem solving for detection of colonic polyps. AJR Am J Roentgenol. Oct 1998;171(4):989-95. [Medline].
Hara AK, Johnson CD, Reed JE. Colorectal polyp detection with CT colography: two- versus three- dimensional techniques. Work in progress. Radiology. Jul 1996;200(1):49-54. [Medline].
Johnson CD, Dachman AH. CT colonography: the next colon screening examination?. Radiology. Aug 2000;216(2):331-41. [Medline].
Lauenstein TC, Herborn CU, Vogt FM. Dark lumen MR-colonography: initial experience. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr. Sep 2001;173(9):785-9. [Medline].
Yoshida H, Nappi J, MacEneaney P. Computer-aided diagnosis scheme for detection of polyps at CT colonography. Radiographics. Jul-Aug 2002;22(4):963-79. [Medline].
Yasuda S, Fujii H, Nakahara T. 18F-FDG PET detection of colonic adenomas. J Nucl Med. Jul 2001;42(7):989-92. [Medline].
Oriuchi N, Endo K, Watanabe N. Semiquantitative SPECT tumor uptake of technetium-99m-labeled anti-CEA monoclonal antibody in colorectal tumor. J Nucl Med. Apr 1995;36(4):679-83. [Medline].
Macari M, Megibow AJ. Pitfalls of using three-dimensional CT colonography with two- dimensional imaging correlation. AJR Am J Roentgenol. Jan 2001;176(1):137-43. [Medline].
Power NP, Pryor MD, Martin A. Optimization of scanning parameters for CT colonography. Br J Radiol. May 2002;75(893):401-8. [Medline].
Rex DK, Cutler CS, Lemmel GT. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology. Jan 1997;112(1):24-8. [Medline].
Rogalla P, Meiri N, Ruckert JC. Colonography using multislice CT. Eur J Radiol. Nov 2000;36(2):81-5. [Medline].
Wessling J, Fischbach R, Domagk D. Colorectal polyps: Detection with multi-slice CT colonography. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr. Dec 2001;173(12):1069-71. [Medline].
Whiting BR, McFarland EG, Brink JA. Influence of image acquisition parameters on CT artifacts and polyp depiction in spiral CT colonography: in vitro evaluation. Radiology. Oct 2000;217(1):165-72. [Medline].
Yee J, Akerkar GA, Hung RK. Colorectal neoplasia: performance characteristics of CT colonography for detection in 300 patients. Radiology. Jun 2001;219(3):685-92. [Medline].
Yee J, Hung RK, Akerkar GA. The usefulness of glucagon hydrochloride for colonic distention in CT colonography. AJR Am J Roentgenol. Jul 1999;173(1):169-72. [Medline].
Yee J, Akerkar GA, Hung RK. Colorectal neoplasia: performance characteristics of CT colonography for detection in 300 patients. Radiology. Jun 2001;219(3):685-92. [Medline].
Pickhardt PJ, Choi JR, Hwang I, Butler JA, Puckett ML, Hildebrandt HA, et al. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. N Engl J Med. Dec 4 2003;349(23):2191-200. [Medline].
Semelka RC, Marcos HB. Polyposis syndromes of the gastrointestinal tract: MR findings. J Magn Reson Imaging. Jan 2000;11(1):51-5. [Medline].
Baldisserotto M, Spolidoro JV, Bahu Mda G. Graded compression sonography of the colon in the diagnosis of polyps in pediatric patients. AJR Am J Roentgenol. Jul 2002;179(1):201-5. [Medline].
Limberg B. Diagnosis of large bowel tumours by colonic sonography. Lancet. Jan 20 1990;335(8682):144-6. [Medline].
Ling UP, Chen JY, Hwang CJ. Hydrosonography in the evaluation of colorectal polyps. Arch Dis Child. Jul 1995;73(1):70-3. [Medline].
de Barros N, Cerri GG, de Souza Rocha M. Sonographic appearances of conglomerated polyps (giant polyposis) in patients with Crohn''s disease. J Clin Ultrasound. May 2000;28(4):199-205. [Medline].
Giardiello FM, Hamilton SR, Krush AJ. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. May 6 1993;328(18):1313-6. [Medline].
Further Reading
Keywords
familial polyposis coli, familial adenomatous polyposis, FAP, intestinal polyposis type I, attenuated adenomatous polyposis coli syndrome, Gardner syndrome, Gardner's syndrome, bone tumor, epidermoid cyst, polyposis, multiple familial colon polyposis, osteomatosis, polyposis intestinal III, GRS, Turcot syndrome, Turcot's syndrome, colon polyposis, brain tumor, glioma polyposis, Turcot-Després-St Pierre syndrome, Crail syndrome, Peutz-Jeghers syndrome, intestinal polyposis, Hutchinson-Weber-Peutz syndrome, Jeghers' syndrome, melanoplakia, Peutz-Touraine syndrome, Cronkhite-Canada syndrome, juvenile polyposis syndrome, Cowden disease, multiple hamartoma neoplasia syndromes, Ruval-Caba-Myhre-Smith syndrome, Bannyan-Riley-Rual-Caba syndrome, Bannyansyndrome, Riley-Smith syndrome
