Adenomatous polyps are found on screening colonoscopy in 22.5% to 58.2% of the adult population and therefore represent a common problem. Patients with multiple adenomatous polyps are of unique interest because a proportion of these patients have an inheritable form of colorectal cancer. This article discusses the history and clinical features, genetic testing, surveillance, and treatments for the condition.
Adenomatous polyps are found on screening colonoscopy in 22.5% to 58.2% of the adult population and therefore represent a common problem. Patients with multiple adenomatous polyps are of unique interest because a proportion of these patients have an inheritable form of colorectal cancer.
Patients with adenomatous polyps are categorized into 6 groups. The first 2 groups are autosomal dominant syndromes, namely, familial adenomatous polyposis (FAP) and its less virulent subtype, attenuated FAP (AFAP). The third group is Lynch syndrome, which is also transmitted in an autosomal dominant fashion and caused by a mutation in a mismatch repair (MMR) gene. Another group is familial colorectal cancer syndrome X (FCC X), which includes patients with a strong family history of colorectal cancer, also transmitted in an apparent autosomal dominant fashion, but who do not have a detectable mutation. The fifth group, MUTYH-associated polyposis (MAP), is transmitted in an autosomal recessive manner and is caused by mutations in the MUTYH gene. Some patients may not meet the criteria for a known polyposis syndrome and may not have a detectable mutation but nevertheless present with multiple adenomatous polyps. In this article, the authors review the presentation, options for genetic testing, surveillance recommendations, medical therapies, and timing and choice of surgical procedures for patients with multiple adenomatous polyps.
History and clinical features
Patients with multiple adenomatous polyps may be asymptomatic. Alternatively, they may present with abdominal pain, rectal bleeding, anemia, mucous discharge, or a change in bowel habits as a result of polyps or a colorectal cancer. Patients may also present because of a known family history of polyps or colorectal cancer. A detailed personal and family history taking along with a careful physical examination may reveal other features suggestive of a polyposis syndrome.
A complete colonoscopy of the cecum with adequate bowel preparation is essential for the accurate determination of polyp burden and distribution. The size, number, and distribution of polyps should be noted, and their histopathology carefully reviewed. Hamartomatous and hyperplastic polyposis should be ruled out because patients with these conditions may be managed differently from those with multiple adenomatous polyposis. Although there may be more than one type of histopathological finding present, the predominant subtype should be adenomatous.
Classic FAP
Classic FAP may be characterized by hundreds to thousands of adenomatous colorectal polyps and accounts for less than 1% of all colorectal cancers. Although most patients with FAP have a family history of the condition, up to 25% represent the first-recognized mutation in the family. These patients are likely to have colorectal cancer at the time of presentation. The median age for adenoma development in patients with FAP is 17 years. Untreated patients develop colorectal cancer at a median age of 40 years, and death occurs by age 44 years. In patients with FAP, an upper endoscopy may reveal gastric fundic gland polyps and gastric and duodenal adenomas. Extraintestinal manifestations of FAP on history or physical examination may include congenital hypertrophy of the retinal pigment epithelium (CHRPE), osteomas, fibromas, lipomas, epidermoid cysts, supernumerary teeth, and desmoid tumors. Other cancers such as medulloma, papillary thyroid cancer, or pediatric hepatoblastoma may also be associated with FAP.
AFAP
Patients with AFAP may have between 1 and 100 adenomatous polyps (usually<50), and the polyps tend to be smaller and flatter. As in classic FAP, there can be a wide variation in the number of polyps between members of the same kindred. The distribution of polyps tends to be more right sided, and rectal sparing is more likely. Polyps and colorectal cancer occur later than in classic FAP, at mean ages of 44 and 56 years, respectively. Patients with AFAP may have gastric fundic gland polyps, gastric or duodenal adenomas, and periampullary tumors. CHRPE, osteomas, and desmoids are rarely reported in patients with AFAP.
Lynch Syndrome
Lynch syndrome is more common than FAP and accounts for 2% to 3% of all colorectal cancers. Patients who meet the Amsterdam Criteria ( Box 1 ) and have an MMR mutation are referred to as having the Lynch syndrome. Those patients who meet the Amsterdam Criteria but do not have an MMR mutation are referred to as having FCC X.
At least 3 relatives who have a hereditary nonpolyposis colorectal cancer (HNPCC)-associated cancer (colorectal, endometrial, ureter, renal pelvis, small bowel)
One is a first-degree relative of the other two
At least 2 generations are affected
At least 1 relative was diagnosed at 50 years of age or earlier
FAP has been excluded
The phenotype of a patient with Lynch syndrome may include multiple adenomatous polyps and early age of onset of colorectal, endometrial, and other cancers. Colorectal cancer occurs at an average age of 45 years, and the adenoma to carcinoma sequence may be accelerated. The history may reveal multiple HNPCC-associated cancers in the individual or family. Colorectal cancers tend to be right sided in Lynch syndrome, in contrast to the sporadic colorectal cancer, which shows a left-sided predominance. Histologic evaluation of the adenoma or cancer may show lymphocytic infiltration. Cancers are more likely to be poorly differentiated, heterogeneous, and of the medullary, mucinous, or signet-ring cell types.
FCC X
Patients with FCC X may appear similar to patients with Lynch syndrome because their family history meets the Amsterdam Criteria. However, the major distinguishing feature of patients with FCC X from those with Lynch syndrome is the absence of a detectable MMR mutation. In addition, those with FCC X are more likely to have left-sided cancer and present at a slightly older age (55 vs 41 years). Overall, FCC X tumors tend to be better differentiated, more often aneuploid, and less mucinous compared with the microsatellite unstable tumors in Lynch syndrome.
MAP
Estimations of the prevalence of MAP are from 26% to 50% in patients with 10 to 100 adenomatous polyps and 7% to 29% in patients with 100 to 1000 polyps. Adenomas or colorectal cancers tend to be detected between the fourth and seventh decade of life. However, because MAP has an autosomal recessive pattern of inheritance with variable penetrance, the family history is more likely to be negative or subtle compared with that for the autosomal dominant syndromes. In some studies, the extraintestinal manifestations of this syndrome are not clearly defined but appear to include an increased risk of duodenal polyposis; ovarian, bladder, and sebaceous skin cancers; and an increased risk of breast cancer. Gastric adenomas and fundic gland polyps have also been described. There are no pathologic features specifically associated with MAP polyps or cancers. However, cancers have been disproportionately found in the proximal colon.
Because family history may not be well known and extracolonic manifestations may not be evident, genetic testing is often required in patients with multiple adenomatous polyps.
Genetic testing
An important component of genetic testing is both pre- and posttest genetic counseling. Unfortunately, this testing is not always performed. Genetic testing begins with a family member who is known to express the phenotype of the syndrome being tested to establish that the test will be informative in the family. The phenotype and clinical presentation can guide the testing for polyposis syndromes. A family history of extensive polyposis transmitted in an autosomal dominant fashion may suggest testing for an APC mutation first, whereas a family history of multiple early-age-of-onset colorectal and other cancers may suggest testing for Lynch syndrome initially. It has been suggested by some investigators that patients with more than 10 to 20 adenomatous polyps should be considered for APC and MUTYH mutation testing. APC and MUTYH testing use the DNA obtained from peripheral leukocytes for gene sequencing.
When the phenotype and history suggest Lynch syndrome and cancer tissue is available, testing may begin with immunohistochemical (IHC) staining for the loss of MMR proteins. The MMR genes, MLH1 , MSH2 , MSH6 , and PMS2 , code for proteins that repair base mismatches in DNA. IHC staining uses antibodies to the MMR proteins produced by the MMR genes. A lack of staining for a particular protein indicates a possible mutation of that gene. Although the sensitivity and specificity of IHC testing is excellent when performed on cancer tissue, only 70% of adenomas have an abnormal IHC in patients with a known MMR mutation.
An alternative and equally effective option to IHC testing is microsatellite instability (MSI) testing. MSI refers to the expansion or contraction of areas of DNA that are composed of short repeating sequences of nucleotides. MSI testing compares the length of microsatellites in tumor DNA to that in normal DNA from blood or normal tissue. The Bethesda Guidelines ( Box 2 ) were established to determine which patients with colorectal cancer should undergo MSI testing. However, only 58% of adenomatous polyps demonstrate MSI in patients with known MMR mutations. Because the yield for MSI and IHC testing is lower in adenomatous polyps than in cancer, gene sequencing should be performed on the patient who presents with multiple adenomatous polyps when Lynch syndrome is suspected. If the involved gene is known from another affected family member or based on the loss of a specific MMR protein detected on IHC testing, only that gene needs to be sequenced. Otherwise, the entire gene may need to be sequenced unless the patient is from a family that meets the Amsterdam Criteria and is of Ashkenazi Jewish descent, in which case rapid single-amplicon testing for a specific mutation in the MSH2 gene may be pursued. When a tumor does not show loss of MMR proteins on IHC testing or is MSI stable and there are multiple polyps present, testing for MUTYH or APC mutations may be pursued.
Individuals who meet any of the following criteria:
Colorectal cancer diagnosed at 50 years of age or earlier
Two HNPCC-related cancers (synchronous or metachronous)
Colorectal cancer with MSI-high histology at 60 years of age or earlier
First-degree relative who has HNPCC-related cancer, one of the cancers diagnosed at 50 years of age or earlier
Colorectal cancer in 2 or more first- or second-degree relatives with HNPCC-related tumors
Approximately 40% of patients meeting the Amsterdam Criteria may test negative for genetic abnormalities in the MMR genes. These patients fall into the category of FCC X. In these cases, it is difficult to assess patients’ risk of extraintestinal manifestations. The largest study to date found no statistically increased risk for other cancers. However, other studies have shown a potential for association with a variety of other tumors.
MAP is caused by variants in the base excision repair gene, MUTYH. In North America, the carrier frequency has been reported to be 2%. MAP represents the only known colorectal cancer syndrome with autosomal recessive inheritance; this inheritance pattern can make a family colorectal cancer history more difficult to detect. For example, parents and offspring of the proband patient may not be affected, whereas siblings of the proband have a 25% chance of carrying biallelic mutations. Testing the other unaffected parent helps to assess if the children are at risk. Testing for MUTYH mutations may be done when the result of APC testing is negative; some laboratories test for both APC and MUTYH mutations simultaneously.
Some patients present with multiple adenomatous polyps but without a family history suggestive of a colorectal cancer syndrome and test negative for a known genetic mutation. These patients may harbor a de novo mutation, may be a member of a not-yet-identified kindred, or may harbor a mutation that is not detected by currently available testing technology. If the results of a clinical genetic workup are negative, patients can be counseled that the potential for an underlying inherited predisposition to developing colorectal cancer cannot be ruled out and that they should continue to undergo close surveillance if the colon can be cleared of polyps. If colonoscopic polypectomy cannot clear the colon, the patient should be offered a prophylactic colectomy.
Genetic testing
An important component of genetic testing is both pre- and posttest genetic counseling. Unfortunately, this testing is not always performed. Genetic testing begins with a family member who is known to express the phenotype of the syndrome being tested to establish that the test will be informative in the family. The phenotype and clinical presentation can guide the testing for polyposis syndromes. A family history of extensive polyposis transmitted in an autosomal dominant fashion may suggest testing for an APC mutation first, whereas a family history of multiple early-age-of-onset colorectal and other cancers may suggest testing for Lynch syndrome initially. It has been suggested by some investigators that patients with more than 10 to 20 adenomatous polyps should be considered for APC and MUTYH mutation testing. APC and MUTYH testing use the DNA obtained from peripheral leukocytes for gene sequencing.
When the phenotype and history suggest Lynch syndrome and cancer tissue is available, testing may begin with immunohistochemical (IHC) staining for the loss of MMR proteins. The MMR genes, MLH1 , MSH2 , MSH6 , and PMS2 , code for proteins that repair base mismatches in DNA. IHC staining uses antibodies to the MMR proteins produced by the MMR genes. A lack of staining for a particular protein indicates a possible mutation of that gene. Although the sensitivity and specificity of IHC testing is excellent when performed on cancer tissue, only 70% of adenomas have an abnormal IHC in patients with a known MMR mutation.
An alternative and equally effective option to IHC testing is microsatellite instability (MSI) testing. MSI refers to the expansion or contraction of areas of DNA that are composed of short repeating sequences of nucleotides. MSI testing compares the length of microsatellites in tumor DNA to that in normal DNA from blood or normal tissue. The Bethesda Guidelines ( Box 2 ) were established to determine which patients with colorectal cancer should undergo MSI testing. However, only 58% of adenomatous polyps demonstrate MSI in patients with known MMR mutations. Because the yield for MSI and IHC testing is lower in adenomatous polyps than in cancer, gene sequencing should be performed on the patient who presents with multiple adenomatous polyps when Lynch syndrome is suspected. If the involved gene is known from another affected family member or based on the loss of a specific MMR protein detected on IHC testing, only that gene needs to be sequenced. Otherwise, the entire gene may need to be sequenced unless the patient is from a family that meets the Amsterdam Criteria and is of Ashkenazi Jewish descent, in which case rapid single-amplicon testing for a specific mutation in the MSH2 gene may be pursued. When a tumor does not show loss of MMR proteins on IHC testing or is MSI stable and there are multiple polyps present, testing for MUTYH or APC mutations may be pursued.
Individuals who meet any of the following criteria:
Colorectal cancer diagnosed at 50 years of age or earlier
Two HNPCC-related cancers (synchronous or metachronous)
Colorectal cancer with MSI-high histology at 60 years of age or earlier
First-degree relative who has HNPCC-related cancer, one of the cancers diagnosed at 50 years of age or earlier
Colorectal cancer in 2 or more first- or second-degree relatives with HNPCC-related tumors
Approximately 40% of patients meeting the Amsterdam Criteria may test negative for genetic abnormalities in the MMR genes. These patients fall into the category of FCC X. In these cases, it is difficult to assess patients’ risk of extraintestinal manifestations. The largest study to date found no statistically increased risk for other cancers. However, other studies have shown a potential for association with a variety of other tumors.
MAP is caused by variants in the base excision repair gene, MUTYH. In North America, the carrier frequency has been reported to be 2%. MAP represents the only known colorectal cancer syndrome with autosomal recessive inheritance; this inheritance pattern can make a family colorectal cancer history more difficult to detect. For example, parents and offspring of the proband patient may not be affected, whereas siblings of the proband have a 25% chance of carrying biallelic mutations. Testing the other unaffected parent helps to assess if the children are at risk. Testing for MUTYH mutations may be done when the result of APC testing is negative; some laboratories test for both APC and MUTYH mutations simultaneously.
Some patients present with multiple adenomatous polyps but without a family history suggestive of a colorectal cancer syndrome and test negative for a known genetic mutation. These patients may harbor a de novo mutation, may be a member of a not-yet-identified kindred, or may harbor a mutation that is not detected by currently available testing technology. If the results of a clinical genetic workup are negative, patients can be counseled that the potential for an underlying inherited predisposition to developing colorectal cancer cannot be ruled out and that they should continue to undergo close surveillance if the colon can be cleared of polyps. If colonoscopic polypectomy cannot clear the colon, the patient should be offered a prophylactic colectomy.
Surveillance
If surgery is not indicated or desired at the time of the initial evaluation, surveillance of the colon is critical in patients with adenomatous multiple polyps. Patients should be advised about the potential risk of developing colorectal cancer while under surveillance. The age to commence colonoscopic examination and the frequency are determined by the genetic syndrome and phenotype.
Patients with FAP may undergo colonoscopy on an annual basis, beginning at approximately 12 years of age or earlier, if symptoms are present. Multiple biopsies may be obtained from adenomas throughout the colon, particularly of large adenomas. Patients with AFAP may undergo colonoscopies on an annual basis as well.
Patients with multiple adenomas and an MMR mutation may undergo colonoscopy every 1 to 2 years, beginning at age 20 to 25 years or at an age 10 years younger than the youngest age of colorectal cancer diagnosed in the family. However, if the patient is found to have polyps that cannot be managed endoscopically, surgery may be indicated. A prospective trial demonstrated a 63% decrease in the risk of colorectal cancer in patients with Lynch syndrome who underwent colonoscopy at 3-year intervals. A more recent study showed that 1- to 2-year intervals further decreased cancer risk and that cancers were more likely to be detected at an earlier stage with a more frequent regimen.
Individuals with FCC X have a 2-fold risk of developing colorectal cancer compared with the general population but appear to be at a lower risk compared with patients with Lynch syndrome. There are no specific guidelines for colonoscopic surveillance for patients with FCC X. Some investigators suggest a surveillance regimen customized by pedigree and colonoscopic findings. The authors and some other investigators suggest using the guidelines for patients with Lynch syndrome in the population with FCC X.
Some investigators suggest that colonoscopic surveillance for biallelic MUTYH carriers may commence by about age 18 to 20 years and the follow-up interval may be 2 to 3 years. However, this suggestion is not based on any evidence specific to MAP; it is based on the overall lifetime risk and the average age of adenoma and cancer onset. In patients with multiple adenomatous polyps and no specific mutation detected or family history of mutation, regular screening may be individualized based on phenotype.
Polyposis syndromes have associated benign and malignant extracolonic manifestations. FAP is associated with an increased risk for papillary thyroid cancer, desmoid tumors, and duodenal or periampullary adenomas with a risk of carcinoma. Lynch syndrome is associated with the development of a variety of extracolonic cancers, including those of the small bowel, stomach, ureter, renal pelvis, pancreas, biliary tract, endometrium, ovaries, and brain. Some investigators have also suggested associations of the syndrome with breast and prostate cancers. The risks associated with MAP are not as well defined but may include duodenal polyposis; ovarian, bladder, and skin cancers; and possibly an increased risk of breast cancer. Referral for appropriate screening is an important component of managing patients with these syndromes. Patient education is also important to ensure that they pursue appropriate follow-up.
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