Colon and Rectal Cancer (Inherited): Part 4

Medically reviewed by: Gary H. Hoffman, MD



Part III of this series looked at Familial Adenomatous Polyposis (FAP) and the genetics underlying the disease. Part IV will examine the ways in which this knowledge can be used to diagnose and treat patients and family members affected by FAP.

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Genotype To Diagnosis: From Appearance To Discovery

The Laboratory Story: Unraveling The Alphabet Soup Of Genetic Mutations

As ninety six percent of Adenomatous Polyposis Coli (APC) gene mutations in FAP result in a truncated protein product, the protein truncation test (PTT) has been developed to identify the area of the mutant APC gene which produces the abnormal protein. The APC gene mutation causes a premature termination of translation. Translation is the process whereby the nucleic code is translated into amino acids. The protein truncation test is also known as in vitro synthesized protein assay (IVSP). The DNA to be tested is extracted from lymphocytes in whole blood. The PTT has been found to be successful in confirming a diagnosis in eighty five percent of cases. Failure to diagnose FAP by PTT does not exclude the diagnosis and the clinician should not rely on a negative test result and falsely reassure the patient at this point. (27) In those fifteen percent of mutations missed by PTT, electrophoretic migration is used to find the undiscovered mutation. This sequential testing using two techniques has become commonplace and has a high sensitivity and high specificity. (28) If testing is successful in identifying a mutant APC protein, the mutated nucleotides causing the truncation can be precisely identified with gene sequence analysis. This may provide valuable information as to both diagnosis and phenotypic expression of the disease. The mutational information can also be used for comparison with family members being tested for the same mutation.

Predictive gene testing of unaffected family members has become an important tool in the screening of families with members at risk for FAP. PTT, electrophoretic migration testing or direct gene sequencing tests of DNA from whole blood samples can identify and confirm the diagnosis in both symptomatic and asymptomatic patients with a family history of the disease. This is especially useful in young patients or in those who do not wish to undergo an intensive clinical screening process.

Genetic Testing For Individuals And Family Members With Clinically Proven FAP

Prior to embarking on genetic testing, genetic counseling and informed consent should be given to patients and appropriate family members. In individuals affected with the clinical stigmata of FAP, the PTT is the first step toward making a definitive diagnosis (figure 1(28)). Electrophoretic migration testing may be used to further study the APC gene if the PTT fails uncover a mutation. If either test is APC mutation-positive, surveillance is started as outlined below. If possible, genetic sequencing should be performed so as to further elucidate the phenotype risk. The mutant codon location information is used in genetic testing of family members to determine if they have the identical mutation. First degree family members are at a fifty percent risk of carrying the mutation and should be counseled.

If no mutation is identified in a patient with the phenotypic appearance of FAP, the patient is APC mutation-negative. As the PTT and electrophoretic migration tests are highly sensitive for an APC mutation, patients with polyposis or related manifestations of the disease should be evaluated for a mutation in a different gene on a chromosome other than chromosome five. An MYH mutation should be suspected and gene analysis using DNA sequencing techniques can be performed to evaluate for this. No matter the result, continued intensive surveillance of the patient is performed because malignant degeneration of the polyps may occur. Additionally, the negative tests have no predictive value for family members, and further family testing for an APC mutation is likely to be unrewarding. However, as there may be a mutation on a different chromosome, first degree relatives should undergo colorectal surveillance every year between the ages of 12 and 25, every other year between the ages of 25 and 35, and every third year between the ages of 35 and 50. After age 50, healthy family members are considered to be unaffected… (29)

Genetic Testing For Clinically Normal Family Members Under Age 50, With Clinically Proven FAP In A Relative.

With respect to family members without observable disease, who are under the age of fifty, and who belong to an FAP kindred, a genetic evaluation should be performed (figure 2(28)). Genetic counseling should be recommended, with informed consent obtained prior to any genetic testing.

In individuals with a known mutation previously identified in a family member, a PTT is performed. Electrophoretic migration testing can be performed if the PTT is negative. If either test is positive, the patient is an FAP mutation carrier and is at high risk for colorectal cancer. FAP surveillance is instituted. All first degree relatives have a fifty percent risk of carrying the mutation, and they should be evaluated.

If all testing is APC mutation-negative in family members whose relative(s) has a known mutation, the patient and all other mutation- negative family members are not at risk for FAP and surveillance is as for the general population.

In patients of an FAP kindred whose family mutation status is unavailable, PTT and if necessary, electrophoretic migration testing is performed. In those testing positive, germline analysis is performed and surveillance is as for patients with FAP. Family members of this newly diagnosed patient should be evaluated. It should be noted that thirty percent of FAP patients have a new, spontaneous mutation, and the parents of this patient will not be carriers of the mutation. They will test APC mutation-negative. However, descendents of the patient are at a fifty percent risk for carrying the mutant gene and should be tested even though their grandparents may have tested negative.

As protein testing is highly sensitive, if a mutation is not detected, the patient in question most likely does not have an APC mutation. However, another as of yet undefined mutation may exist, and the patient must not be falsely reassured that he is mutation free or disease free. (28) Colorectal surveillance should be continued. The patient should consider having the originally affected relative tested to evaluate for an APC mutation or other mutation.

Using genetic testing, detection rates in AFAP are almost one hundred percent.

From Diagnosis To Screening And Surveillance

The Physician On The Frontlines

Genetic testing can guide screening and surveillance recommendations. The risk of colorectal disease can be evaluated with genetic testing and shown to be either that of the general population at three percent, or that of patients with untreated FAP at one hundred percent.

Individuals affected with FAP
Figure 1. Individuals affected with FAP

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In patients with known FAP, routine endoscopic surveillance should begin at age eleven with a flexible sigmoidoscopy. The rationale for this limited exam is that polyps usually do not appear until puberty and are most commonly left sided in eighty four percent of patients. Colonoscopic surveillance should be started at age fourteen and continued yearly for life. Patients should be counseled and prepared for a prophylactic colectomy. Genetic counseling should be offered regarding the risks to future offspring. In first-degree relatives without an identified mutation, screening should be performed at the time of initial genetic testing, but no later than age fifteen. As the genetic testing is highly sensitive, an APC mutation negative patient should undergo future surveillance in the same manner as in colorectal cancer surveillance in the general population. The traditional approach with respect performing a prophylactic colectomy for FAP has been that it should be performed by age twenty five in patients with polyps, although the choice this age is arbitrary and many affected individuals have undergone operative prophylaxis by the age of twenty. (30,31) It is now recommended that operative intervention be undertaken as soon as polyposis is discovered. Without treatment, there is close to a one hundred per cent risk for the development of colorectal cancer by age forty. In patients undergoing an early prophylactic procedure, long term survival rates are between eighty seven to ninety four per cent. In patients presenting with an established malignancy, ten year survival rates are forty per cent. (32,33) The pendulum seems to be swinging toward earlier prophylactic colectomy, possibly within two years of the discovery of the disease.

In AFAP, full colonoscopic screening should begin at age twenty as this entity has a later age of onset, with polyps found more commonly in the proximal colon. The screening interval is similar to those in patients with FAP.

Upper gastrointestinal surveillance should begin at age twenty and continue for the lifetime of the patient at intervals between one and five years, depending upon the findings. Alternatively, surveillance can begin at the same time as a diagnosis of FAP is secured. Strict attention must be paid to performing a thorough duodenal inspection using both straight viewing and side viewing endoscopes. Although the lifetime risk of forming duodenal adenomas approaches one hundred percent, less than thirty percent of duodenal adenomas in crease in size, number or histology. If surgical intervention is to be undertaken, the entire gastrointestinal tract must be evaluated prior to the intervention. (34,35)

From Screening And Surveillance To Therapy

The Surgeon On The Frontlines: Surgical Prophylaxis And Treatment

Prior to any operative intervention, histopathological confirmation of FAP is mandatory so as not to confuse FAP with other polyposis syndromes which look like FAP, but which may not require radical operative treatment.

Unaffacted individuals younger than 50 who are members of an FAP kindred

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With operative intervention, the goal is to remove as much of the colorectal mucosa as possible. Currently, three operations are available to treat FAP. None of them cures the underlying disease. The aim of each is to remove as much susceptible tissue as possible, while retaining normal colorectal functioning.

Laparoscopic Or Open Proctocolectomy With An End Ileostomy

A proctocolectomy with an end ileostomy provides the most complete future colorectal cancer risk reduction but requires the creation of a permanent stoma. This is an unpopular option because of the permanent stoma. Young patients are unlikely to choose this approach. However, total abdominal colectomy with a proctectomy is the procedure of choice in patients with a distal rectal carcinoma. It is also an option in patients who cannot undergo a rectal or anal anastomosis because of intraoperative technical difficulties (the planned reconstruction will not reach the anastomotic site due to anatomic considerations or infiltrative mesenteric desmoid disease) or poor sphincter function. A variation on this operation involves creating a continent ileostomy, or Kock pouch. In this procedure, a reservoir is created using the terminal ileum. A nipple valve is constructed and brought out through the abdominal wall. Ideally, there is no need to wear an ostomy appliance as the reservoir holds the intestinal contents until the patient performs a self-catheterization, usually four to six times per day. When not in use, the ostomy is covered with a band aid. The esthetic and cosmetic advantages are obvious. However, the procedure is associated with prolapse of the nipple. The Kock pouch is rarely used.

Laparoscopic Or Open Total Abdominal Colectomy With An Ileorectal Anastomosis.

A total abdominal colectomy with an ileorectal anastomosis may be used in patients with few rectal adenomas or in patients with AFAP, as AFAP usually spares the rectum. A total abdominal colectomy with an ileorectal anastomosis is relatively easy to perform, usually does not require a temporary protective ileostomy, restores intestinal continuity and achieves good functional results. The risks of erectile and ejaculatory dysfunction that may occur in a more extensive operation secondary to operative nerve trauma during the pelvic dissection are largely avoided. Female fertility is preserved as well. Patients must submit to regular, lifelong endoscopic surveillance with removal of any new rectal polyps. However, repeated endoscopic polyp removal may lead to rectal scarring, stenosis and poor rectal functioning.

The risk of developing a malignancy in the remaining rectal mucosa is estimated to be between zero percent (36) and thirty two percent. (37) This development would require a completion proctectomy. Factors that seem to be associated with this risk are having greater than twenty polyps in the rectum or colon cancer resected before or during the colectomy. In a St. Mark’s series, the cumulative risk of developing a malignancy in the retained rectum was ten percent at twenty years, increasing to greater than thirty percent at thirty five years. The report concluded that the means of surveillance must be improved or that the patients must undergo a complete proctocolectomy at an earlier age. (38) Even with increased surveillance, other studies have echoed these results, thus calling into question the use of the total abdominal colectomy with ileorectal anastomosis for treatment of FAP. Given that the more aggressive and complete proctocolectomy with a restorative ileal pouch-anal anastomosis (IPAA) is associated with a greater morbidity, studies have looked at features that might guide the surgeon in choosing to perform a total abdominal colectomy with an ileorectal anastomosis, rather than a proctocolectomy with an IPAA. The two factors which helped exclude patients from having an ileorectal anastomosis were the severity of colorectal polyposis, (39) and the location of the mutation on the APC gene. The risk of the development of a second carcinoma was greater if the mutation was located between codons 1250 and 1500, especially at codon 1309, a known “hot spot”. None of the patients with AFAP and mutations in codons 0 to 200, or greater than 1500 required a secondary proctectomy. (40) These studies conclude that it is reasonable to perform a total abdominal colectomy with ileorectal anastomosis in young patients with less than twenty rectal adenomas, less than one thousand colonic adenomas (considered to be mild disease), and in FAP with mutations in codons 0 to 200 or greater than 1500. Lifetime surveillance is required with the understanding that a future proctectomy may be required.

Laparoscopic Proctocolectomy with an ileal pouch-anal anastomosis

The third treatment option for FAP is a laparoscopic total abdominal proctocolectomy with an ileal pouch-anal anastomosis (IPAA), with or without a rectal mucosectomy. This type of pouch is also known as a J-pouch. Potential advantages include restored intestinal continuity with a new rectal reservoir, or neo-rectum, in those patients who do not want an end ileostomy, and an almost complete removal of the at-risk colorectal tissue. This approach is favored in situations where there is extensive polyposis, greater than twenty rectal polyps, polyps that cannot be controlled endoscopically, adenomatous dysplasia or carcinoma at any location in the large intestine, in patients with a history of desmoid tumors in whom the operative risk is higher due to the desmoid disease and in whom another operative procedure would potentially be fraught with problems, or in those patients with APC mutations associated with an increased rectal cancer risk. However, patients must be carefully selected as those with poor preoperative sphincter function, especially the elderly, may have poor functional results after IPAA. Additionally, anatomic considerations or infiltrative mesenteric desmoid disease may make the creation of an IPAA technically difficult or impossible, requiring a temporary or permanent ileostomy. Preoperatively, the patient must be prepared for this eventuality.

The operation itself is associated with a greater blood loss and an increased risk of immediate postoperative sepsis. Local sepsis is associated with pouch failure requiring excision of the pouch. A longer hospital stay is not uncommon. Longer term complications include the possibility of postoperative anal stenosis with troublesome functional symptoms, and increased stool frequency both during the day and nighttime. Stool frequency is often associated with perianal skin irritation. Urinary and sexual functioning may be compromised after this extensive dissection due to disruption of the autonomic pathways.

Other disadvantages include the unsuspected retention of rectal mucosa and the new, potentially occult development of rectal polyps. In patients undergoing an IPAA, continued endoscopic surveillance is mandatory as pouch adenomas can develop in the small intestinal pouch mucosa in thirty per cent of patients. Additionally, a small, but unknown number of patients may develop cancer in the pouch, at the site of the anastomosis or in the anal transition zone. The carcinomas can be locally advanced (T4) or not (T1, T2). (41) Continued lifetime surveillance is mandatory.

A Cleveland Clinic prospective study found the risk of developing adenomas in the pouch, anal transition zone or at the anastomotic staple line to be twice as high in a stapled IPAA as in a hand-sewn anastomosis (twenty eight percent versus fourteen percent). The study found that the postoperative development of adenomas was related to the severity of the colonic polyposis prior to operative intervention. However, the incidence of cancer development was minimal in both techniques, although the study stated that this may have been due to a short follow up period. The article concluded that the risk of future neoplasia must be balanced against the relatively better functional outcome with an IPAA. (42)

…And Back Again

A clinician who is knowledgeable in mutational genetics and who cares for patients at the early part of the diagnostic algorithm is in an ideal position to do a tremendous service for those patients and family members presenting with signs and symptoms pointing to a diagnosis of familial adenomatous polyposis. With advances in early detection, and with the concomitant improvement in survival rates and functional outcomes, operative intervention in patients with known or newly diagnosed familial adenomatous polyposis or attenuated familial adenomatous polyposis is gratifying for the patient, the family, any newly diagnosed relatives, the astute physician who first considers and confirms the diagnosis, and the surgeon who performs the preventative or curative operative procedure. Further improvements in early detection will enhance our ability to diagnose and treat this family of genetic disorders.


27. Giardello, F.M., Brensinger, J.D., Peterson, G.M. et al. “The Use And Interpretation Of Commercial APC Gene Testing For Familial Adenomatous Polyposis.” New England Journal Of Medicine 336 (1997): 823-827

28. Wong Et Al., N. “Genetic Counseling And Interpretation Of Genetic Tests In Familial Adenomatous Polyposis And Hereditary Nonpolyposis Colorectal Cander.”Diseases Of The Colon And Rectum 44 (2001): 271-79.

29. Rabelo, R., W. Foulkes, and P. H. Gordon. “Role Of Molecular Diagnostic Testing In Familial Adenomatous Polyposis and Hereditary Nonpolyposis Colorectal Cancer.” Diseases Of The Colon And Rectum 44 (2001): 437-46.

30. Peterson, G. M. “Genetic Counseling And Predictive Testing in Familial Adenomatous Polyposis.” Seminars In Colon And Rectal Surgery 6 (1995): 55-60.

31. Karen, P., Nugent, M.A., “Total Colectomy And Ileorectal Anastomosis.”Pathology: Phillips, R, K., Et Al. London: Edward Arnold, 19954 80-91.

32. Bertario, L., S. Presciuttini, and P. Sala. “Causes Of Death And Postsurgical Survival In Familial Adenomatous Polyposis: Results From The Italian Registry.” Seminars In Surgical Oncology 10 (1994): 225-34.

33. Heiskanen, I. Et Al. “Impact Of Screening Examinations On Survival In Familial Adenomatous Polyposis.” Scandinavian Journal Of Gastroenterology 35 (2000): 1284-287.

34. Burke, C. A., G. J. Beck, J. M. Church, and R. W. Van Stolk. “The Natural History of Duodenal And Ampullary Adenomas In Patients With Familial Adenomatous Polyposis Followed In An Endoscopic Surveillance Program.” Gatrointestinal Endoscopy 49 (1999): 358-64.

35. Brosens Et Al., L. A. “Prevention And Management Of Duodenal Polyps in Familial Adenomatous Polyposis.” Gut 54 (2005): 1034-043.

36. Gingold, B. S., Jagelman, D. J., and R. D. Turnbull, R.D., “Surgical Management OF Familial Adenomatous Polyposis And Gardner’s Syndrome.” American Journal Of Surgery137 (1979): 54-56.

37. Bess, M. A., Adson, L. R. Elveback, A. A., and Moertel, C. G., “Rectal Cancer Following Colectomy For Polyposis.” Archive Of Surgery 115 (1980): 460-67

38. Bussey, H. J., Eyers, S. M. Ritchie, M., and J. M. Thompson. “The Rectum In Adenomatous Polyposis.” British Journal Of Surgery 72. [supplement] (1985): S29-31.

39. Chruch, J. Et Al. “Predicting Polyposis Severity By Proctoscopy: How Reliable Is It?” Disease Of The Colon And Rectum 44 (2001): 1249-254

40. Bulow, C., and H. Vasen Et Al. “Ileorectal Anastomosis Is Appropriate For A Subset Of Patients With Familial Adenomatous Polyposis.” Gastroenterology 119 (2000): 1454-460.

41. Nivatvongs, Santhat. “Part III: Colorectal Disorders.” Principles And Practice of Surgery For The Colon, Rectum and Anus. Informa Healthcare USA. 466-87.

42. Remzi, F. H., J. M. Church, and J. Bast et al. “Mucosectomy vs. stapled ileal pouch—anal anastomosis in patients with familial adenomatous polyposis.” Diseases Of The Colon And Rectum 44 (2001): 1590-596.

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