Introduction
Familial Adenomatous Polyposis (FAP)
        Density of colonic polyposis
        Extracolonic tumors
        Genetic testing for FAP
        Interventions/FAP
Attenuated FAP (AFAP)
MYH-Associated Neoplasia
Lynch Syndrome
        Genetic/Molecular testing for Lynch syndrome
        Interventions/Lynch syndrome
        Screening for endometrial cancer in Lynch syndrome families
        Risk-reducing surgery in Lynch syndrome
Familial Colorectal Cancer (FCC)
        Familial colorectal cancer Type X
        Interventions/Family history of colorectal cancer
Rare Colon Cancer Syndromes
        Peutz-Jeghers syndrome
        Juvenile polyposis syndrome
        Hereditary mixed polyposis syndrome
        CHEK2
        Hyperplastic polyposis
        Interventions/Rare colon cancer syndromes

Introduction

A number of familial syndromes are associated with a high risk of colorectal adenocarcinoma and are summarized in Table 3. The absolute lifetime risk of colorectal adenocarcinoma is highest in familial adenomatous polyposis (FAP), where the large intestines of affected patients are studded with hundreds to thousands of adenomatous polyps. The absolute risks are lower in Peutz-Jeghers syndrome and juvenile polyposis syndrome than in Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]) or FAP, and these syndromes differ in that the intestinal polyps are hamartomatous although the transformation to adenocarcinoma may be preceded by adenomatous change. Colorectal cancer screening and surveillance recommendations are established for Lynch syndrome and FAP, and have been proposed for Peutz-Jeghers and juvenile polyposis families.

FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes.[1,7,8] It is an autosomal dominant condition, and the reported incidence varies from 1 in 7,000 to 1 in 22,000 live births, with the syndrome being more common in Western countries.[9] Autosomal dominant inheritance means that affected persons are genetically heterozygous, such that each offspring of a patient with FAP has a 50% chance of inheriting the disease gene. Males and females are equally likely to be affected.

Classically, FAP is characterized by multiple (>100) adenomatous polyps in the colon and rectum developing after the first decade of life. Variant features in addition to the colonic polyps may include polyps in the upper gastrointestinal tract, extraintestinal manifestations such as congenital hypertrophy of retinal pigment epithelium (CHRPE), osteomas and epidermoid cysts, supernumerary teeth, desmoid formation, and other malignant changes such as thyroid tumors, small bowel cancer, hepatoblastoma, and brain tumors, particularly medulloblastoma. For additional information, refer to Table 4.

FAP is also known as familial polyposis coli, adenomatous polyposis coli (APC), or Gardner syndrome (colorectal polyposis, osteomas, and soft tissue tumors). Gardner syndrome has sometimes been used to designate FAP patients who manifest these extracolonic features. However, Gardner syndrome has been shown molecularly to be a variant of FAP, and thus the term Gardner syndrome is essentially obsolete in clinical practice.[16]

Most cases of FAP are due to mutations of the APC gene on chromosome 5q21. Individuals who inherit a mutant APC gene have a very high likelihood of developing colonic adenomas; the risk has been estimated to be more than 90%.[1,7,8] The age at onset of adenomas in the colon is variable: By age 10 years, only 15% of FAP gene carriers manifest adenomas; by age 20 years, the probability rises to 75%; and by age 30 years, 90% will have presented with FAP.[1,7,8,17,18] Without any intervention, most persons with FAP will develop colon or rectal cancer by the fourth decade of life.[1,7,8] Thus, surveillance and intervention for APC gene mutation carriers and at-risk persons have conventionally consisted of annual sigmoidoscopy beginning around puberty. The objective of this regimen is early detection of colonic polyps in those who have FAP, leading to preventive colectomy.[19,20]

The early appearance of clinical features of FAP and the subsequent recommendations for surveillance beginning at puberty raise special considerations relating to the genetic testing of children for susceptibility genes.[21] Some proponents feel that the genetic testing of children for FAP presents an example in which possible medical benefit justifies genetic testing of minors, especially for the anticipated 50% of children who will be found not to be mutation carriers and who can thus be spared the necessity of unpleasant and costly annual sigmoidoscopy. The psychological impact of such testing is currently under investigation and is addressed in the Psychosocial Issues in Hereditary Colon Cancer Syndromes: Hereditary Nonpolyposis Colon Cancer and Familial Adenomatous Polyposis section of this summary.

A number of different APC mutations have been described in a series of FAP patients. (Refer to the Colon Cancer Genes section of this summary for more information.) The clinical features of FAP appear to be generally associated with the location of the mutation in the APC gene and the type of mutation (i.e., frameshift mutation vs. missense mutation). Two features of particular clinical interest that are apparently associated with APC mutations are (1) the density of colonic polyposis and (2) the development of extracolonic tumors.

Researchers have found that dense carpeting of colonic polyps, a feature of classic FAP, is seen in most patients with APC mutations, particularly those mutations that occur between codons 169 and 1393. At the other end of the spectrum, sparse polyps are features of patients with mutations occurring at the extreme ends of the APC gene or in exon 9. (Refer to the Attenuated FAP section of this summary for more information.)

Desmoid tumors are proliferative, locally invasive, nonmetastasizing, fibromatous tumors in a collagen matrix. Although they do not metastasize, they can grow very aggressively and be life threatening.[22] Desmoids may occur sporadically, as part of classical FAP, as part of the clinical variant Gardner syndrome, or in a hereditary manner without the colon findings of FAP.[13,23] Desmoids have been associated with hereditary APC gene mutations even when not associated with typical adenomatous polyposis of the colon.[23,24]

Most studies have found that 10% of FAP patients develop desmoids, with reported ranges of 8% to 38%. The incidence varies with the means of ascertainment and the location of the mutation in the APC gene.[23,25,26] APC mutations occurring between codons 1445 and 1578 have been associated with an increased incidence of desmoid tumors in FAP patients.[24,27-29] Desmoid tumors with a late onset and a milder intestinal polyposis phenotype (hereditary desmoid disease) have been described in patients with mutations at codon 1924.[23]

The natural history of desmoids is variable. Some authors have proposed a model for desmoid tumor formation whereby abnormal fibroblast function leads to mesenteric plaque-like desmoid precursor lesions, which in some cases occur prior to surgery and progress to mesenteric fibromatosis after surgical trauma, ultimately giving rise to desmoid tumors.[30] It is estimated that 10% of desmoids resolve, 50% remain stable for prolonged periods, 30% fluctuate, and 10% grow rapidly.[31] Desmoids often occur after surgical or physiological trauma, and both endocrine and genetic factors have been implicated. Approximately 80% of intra-abdominal desmoids in FAP occur after surgical trauma.[32,33]

The desmoids in FAP are often intra-abdominal, may present early, and can lead to intestinal obstruction or infarction and/or obstruction of the ureters.[26] In some series, desmoids are the second most common cause of death after colorectal cancer in FAP patients.[34,35] A staging system has been proposed to facilitate the stratification of intra-abdominal desmoids by disease severity.[36] The proposed staging system for intra-abdominal desmoids is as follows: stage I for asymptomatic, nongrowing desmoids; stage II for symptomatic, nongrowing desmoids of 10 cm or less in maximum diameter; stage III for symptomatic desmoids of 11 to 20 cm or for asymptomatic, slow-growing desmoids; and stage IV for desmoids larger than 20 cm, or rapidly growing, or with life-threatening complications.[36]

These data suggest that genetic testing could be of value in the medical management of patients with FAP and/or multiple desmoid tumors. Those with APC genotypes, especially those predisposing to desmoid formation (e.g., at the 3’ end of APC codon 1445), appear to be at high risk of developing desmoids following any surgery, including risk-reducing colectomy and surgical surveillance procedures such as laparoscopy.[25,31,37]

The management of desmoids in FAP can be challenging and can complicate prevention efforts. Currently, there is no accepted standard treatment for desmoid tumors. Multiple medical treatments have generally been unsuccessful in the management of desmoids. Treatments have included anti-estrogens, nonsteroidal anti-inflammatory drugs (NSAIDs), chemotherapy, and radiation therapy, among others. Studies have evaluated the use of raloxifene alone, tamoxifen or raloxifene combined with sulindac, and pirfenidone alone.[38-40] There are anecdotal reports of using imatinib mesylate to treat desmoid tumors in FAP patients; however, further studies are needed.[41] Significant desmoid tumor regression was reported in seven patients who had symptomatic, unresectable, intra-abdominal desmoid tumors and failed hormonal therapy when treated with chemotherapy (doxorubicin and dacarbazine) followed by meloxicam.[42]

Thirteen patients with intra-abdominal desmoids and/or unfavorable response to other medical treatments, who had expression of estrogen alpha receptors in their desmoid tissues, were included in a prospective study of raloxifene, given in doses of 120 mg daily.[38] Six of the patients had been on tamoxifen or sulindac before treatment with raloxifene, and seven patients were previously untreated. All 13 patients with intra-abdominal desmoid disease had either a partial or a complete response 7 months to 35 months after starting treatment, and most desmoids decreased in size at 4.7 ± 1.8 months after treatment. Response occurred in patients with desmoid plaques as well as with distinct lesions. Study limitations include small sample size, and the clinical evaluation of response was not consistent in all patients. Several questions remain concerning patients with desmoid tumors not expressing estrogen alpha receptors who have received raloxifene and their outcome, as well as which patients may benefit from this potential treatment.

A second study of 13 patients with FAP-associated desmoids, who were treated with tamoxifen 120 mg/day or raloxifene 120 mg/day in combination with sulindac 300 mg/day, reported that ten patients had either stable disease (n = 6) or a partial or complete response (n = 4) for more than 6 months and that three patients had stable disease for more than 30 months.[39] These results suggest that the combination of these agents may be effective in at least slowing the growth of desmoid tumors. However, the natural history of desmoids is variable, with both spontaneous regression and variable growth rates.

A third study reported mixed results in 14 patients with FAP-associated desmoid tumors treated with pirfenidone for 2 years.[40] In this study, some patients had regression, some patients had progression, and some patients had stable disease.

These three studies illustrate some of the problems encountered in the study of desmoid disease in FAP patients:

• The definition of desmoid disease has been used inconsistently.
• In some patients, desmoid tumors do not progress or are very slow growing and may not need therapy.
• There is no consistent, systematic way to evaluate the response to therapy.
• There is no single institution that will enroll enough patients to perform a randomized trial.

No randomized clinical trials using these agents have been performed and their use in clinical practice is based on anecdotal experience only.

Level of evidence: 4

Because of the high rates of morbidity and recurrence, in general, surgical resection is not recommended in the treatment of intra-abdominal desmoid tumors. However, some have advocated a role for surgery given the ineffectiveness of medical therapy, even when the potential hazards of surgery are considered, and recognizing that not all desmoids are resectable.[43] A recent review of one hospital's experience suggested that surgical outcomes with intra-abdominal desmoids may be better than previously believed.[43,44] Issues of subject selection are critical in evaluating surgical outcome data.[44] Abdominal wall desmoids can be treated with surgical resection, but the recurrence rate is high.

The most common FAP-related gastric polyps are fundic gland polyps (FGPs). FGPs are often diffuse and not amenable to endoscopic removal. The incidence of FGPs has been estimated to be as high as 60% in patients with FAP, compared with 0.8% to 1.9% in the general population.[14,15,45-49] These polyps consist of distorted fundic glands containing microcysts lined with fundic-type epithelial cells or foveolar mucous cells.[50,51]

The hyperplastic surface epithelium is, by definition, non-neoplastic. Accordingly, FGPs have not been considered precancerous; in Western FAP patients the risk of stomach cancer is minimally increased, if at all. However, case reports of stomach cancer appearing to arise from FGPs have led to a reexamination of this issue.[15,52] In one FAP series, focal dysplasia was evident in the surface epithelium of FGPs in 25% of patients versus 1% of sporadic FGPs.[51]

Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming proton pump inhibitors (PPIs).[51,53] FGPs in this setting commonly show a “PPI effect” consisting of congestion of secretory granules in parietal cells, leading to irregular bulging of individual cells into the lumen of glands. To the trained eye, the presence of dysplasia and the concomitant absence of a characteristic PPI effect can be considered highly suggestive of the presence of underlying FAP. The number of FGPs tends to be greater in FAP than that seen in patients consuming PPIs, although there is some overlap.

Gastric adenomas also occur in FAP patients. The incidence of gastric adenomas in Western patients has been reported to be between 2% and 12%, whereas in Japan, it has been reported to be between 39% and 50%.[54-57] These adenomas can progress to carcinoma. FAP patients in Korea and Japan are reported to have a threefold to fourfold increased gastric cancer risk compared with their general population, a finding not observed in Western populations.[58-61] The recommended management for gastric adenomas is endoscopic polypectomy. The management of adenomas in the stomach is usually individualized based on the size of the adenoma and the degree of dysplasia.

Level of evidence: None assigned

Whereas the incidence of duodenal adenomas is only 0.4% in patients undergoing upper gastrointestinal (GI) endoscopy,[62] duodenal adenomas are found in 80% to 100% of FAP patients. The vast majority are located in the first and second portions of the duodenum, especially in the periampullary region.[45,46,63] There is a 4% to 12% lifetime incidence of duodenal adenocarcinoma in FAP patients.[11,60,64,65] In a prospective multicenter surveillance study of duodenal adenomas in 368 northern Europeans with FAP, 65% had adenomas at baseline evaluation (mean age, 38 years), with cumulative prevalence reaching 90% by age 70 years. In contrast to earlier beliefs regarding an indolent clinical course, the adenomas increased in size and degree of dysplasia during the 8 years of average surveillance, though only 4.5% developed cancer while under prospective surveillance.[14] While this study is the largest to date, it is limited by the use of forward-viewing, rather than side-viewing, endoscopy and the large number of investigators involved in the study. Another modality through which intestinal polyps can be assessed in FAP patients is capsule endoscopy.[66]

A retrospective review of FAP patients suggested that the adenoma-carcinoma sequence occurred in a temporal fashion for periampullary adenocarcinomas with a diagnosis of adenoma at a mean age of 39 years, high-grade dysplasia at a mean age of 47 years, and adenocarcinoma at a mean age of 54 years.[67] A decision analysis of 601 FAP patients suggested that the benefit of periodic surveillance starting at age 30 years led to an increased life expectancy of 7 months.[64] Although polyps in the duodenum can be difficult to treat, small series suggest that they can be managed successfully with endoscopy but with potential morbidity—primarily from pancreatitis, bleeding, and duodenal perforation.[68,69]

FAP patients with particularly severe duodenal polyposis, sometimes called dense polyposis, or with histologically advanced duodenal adenomas appear to be at the highest risk of developing duodenal adenocarcinoma.[14,65,70,71] Because the risk of duodenal adenocarcinoma is correlated with the number and size of polyps, and the severity of dysplasia of the polyps, a stratification system based on these features was developed in order to attempt to identify those individuals with FAP at highest risk of developing duodenal adenocarcinoma.[71] According to this system, 36% of patients with the most advanced stage will develop carcinoma.[65] Individuals with dense polyposis, large adenomas, or histologically advanced adenomas are considered for endoscopic or surgical treatment of the polyps because approximately one-third of these patients will develop duodenal cancer.[65]

A baseline upper endoscopy should be performed between ages 25 and 30 years in FAP patients.[61] The subsequent intervals between endoscopy vary according to the findings of the previous endoscopy. Endoscopy every 4 to 5 years has been recommended for patients with no duodenal adenomas and every 6 to 12 months for those with more advanced adenomas or with multiple larger adenomas.[60,61] In the absence of prospective randomized studies, the surveillance recommendations are based on expert opinion.

Many factors, including severity of polyposis, comorbidities of the patient, patient preferences, and availability of adequately trained physicians, determine whether surgical or endoscopic therapy is selected for polyp management. Endoscopic resection or ablation of large or histologically advanced adenomas appears to be safe and effective in reducing the short-term risk of developing duodenal adenocarcinoma;[68,69,72] however, patients managed with endoscopic resection of adenomas remain at substantial risk of developing recurrent adenomas in the duodenum. The most definitive procedure for reducing the risk of adenocarcinoma is surgical resection of the ampulla and duodenum, though these procedures also have higher morbidity and mortality associated with them than do endoscopic treatments. Duodenotomy and local resection of duodenal polyps or mucosectomy have been reported, but invariably, the polyps recur after these procedures.[73] Pancreaticoduodenectomy and pancreas-sparing duodenectomy are appropriate surgical therapies that are believed to substantially reduce the risk of developing periampullary adenocarcinoma.[73-76] If such surgical options are considered, preservation of the pylorus is of particular benefit in this group of patients because most will have undergone a subtotal colectomy with ileorectal anastomosis or total colectomy with ileal pouch anal anastomosis. Chemoprevention studies for duodenal adenomas in FAP patients are currently under way and may offer an alternate strategy in the future.

Level of evidence: 3diii

The spectrum of tumors arising in FAP is summarized in Table 4.

Papillary thyroid cancer has been reported to affect 1% to 2% of patients with FAP.[77] However, a recent study [78] of papillary thyroid cancers in six females with FAP failed to demonstrate loss of heterozygosity (LOH) or mutations of the wild-type allele in codons 545 and 1061 to 1678 of the six tumors. In addition, four out of five of these patients had detectable somatic RET/PTC chimeric genes. This mutation is generally restricted to sporadic papillary thyroid carcinomas, suggesting the involvement of genetic factors other than APC mutations. Further studies are needed to show whether other genetic factors such as the RET/PTC chimeric gene are independently responsible for or cooperative with APC mutations in causing papillary thyroid cancers in FAP patients.

Adrenal tumors have been reported in FAP patients, and one study demonstrated LOH in an adrenocortical carcinoma in an FAP patient.[79] In a study of 162 FAP patients who underwent abdominal computed tomography for evaluation of intra-abdominal desmoid tumors, 15 patients (11 females) were found to have adrenal tumors.[80] Of these, two had symptoms attributable to cortisol hypersecretion. Three of these patients underwent subsequent surgery and were found to have adrenocortical carcinoma, bilateral nodular hyperplasia, or adrenocortical adenoma. The prevalence of an unexpected adrenal neoplasia in this cohort was 7.4%, which compares with a prevalence of 0.6% to 3.4% (P < .001) in non-FAP patients.[80] No molecular genetic analyses were provided for the tumors resected in this series.

Hepatoblastoma is a rare, rapidly progressive, and usually fatal childhood malignancy that, if confined to the liver, can be cured by radical surgical resection. Multiple cases of hepatoblastoma have been described in children with an APC mutation.[81-90] Some series have also demonstrated LOH of APC in these tumors.[82,84,91] No specific genotype-phenotype correlations have been identified in FAP patients with hepatoblastoma.[92]

The constellation of colorectal cancer and brain tumors has been referred to as Turcot syndrome; however, Turcot syndrome is molecularly heterogeneous. Molecular studies have demonstrated that colon polyposis and medulloblastoma are associated with mutations in APC, while colon cancer and glioblastoma are associated with mutations in mismatch repair genes.[93]

There are several reports of other extracolonic tumors associated with FAP, but whether these are simply coincidence or actually share a common molecular genetic origin with the colonic tumors is not always evident. Some of these reports have demonstrated LOH or a mutation of the wild-type APC allele in extracolonic tumors in FAP patients, which strengthens the argument for their inclusion in the FAP syndrome.

APC gene testing is now commercially available and has led to changes in management guidelines, particularly for those whose tests indicate they are not mutation carriers. Presymptomatic genetic diagnosis of FAP in at-risk individuals has been feasible with linkage [18] and direct detection [94] of APC mutations. These tests require a small sample (<10 cc) of blood in which the lymphocyte DNA is tested. If one were to use linkage analysis to identify gene carriers, ancillary family members, including more than one affected individual, would need to be studied. With direct detection, fewer family members’ blood samples are required than for linkage analysis, but the specific mutation must be identified in at least one affected person by DNA mutation analysis or sequencing. The detection rate is approximately 80% using sequencing alone.[95] The addition of multiplex ligation-dependent probe amplification (MLPA) and analysis of allelic mRNA expression with single nucleotide primer extension (SNuPE) improves the detection rate for APC mutations.[96]

These mutation search methods, however, can be difficult to perform in routine clinical laboratory settings. More widespread use of a simpler procedure that tests for the truncated protein product using in vitro transcription of the APC gene obtained from lymphocyte RNA is possible.[97] APC protein truncation testing considerably enhances the feasibility of testing at-risk individuals without requiring DNA from multiple affected family members (as linkage requires). In particular, it is useful for testing in small families or in patients with de novo, or spontaneous, mutations (the first occurrence of FAP in a kindred), which may account for as much as one-third of incident cases.[1,7,8] Only about 80% of APC mutations can be detected by this method. In addition, the protein truncation assay (PTT) does not characterize the precise location or character of the mutation. PTT is no longer used in the United States as a commercial test for APC mutations and has been largely replaced with direct end-to-end sequencing. This still carries approximately 80% sensitivity for the mutation. Studies have reported whole exon deletions in 12% of FAP patients with previously negative APC testing.[98,99] For this reason, deletion testing has been added as an optional adjunct to sequencing of APC. Furthermore, mutation detection assays that use MLPA are being developed and appear to be accurate for detecting intragenic deletions.[100] MYH gene testing may be considered in APC mutation–negative affected individuals.[101] (Refer to the Colon Cancer Genes section of this summary for more information.)

Patients who develop fewer than 100 colorectal adenomatous polyps are a diagnostic challenge. The differential diagnosis should include attenuated FAP (AFAP) and MYH-associated colorectal neoplasia (also reported as MYH polyposis or MYH-associated polyposis [MAP]).[102] AFAP can be diagnosed by testing for germline APC gene mutations. (Refer to the Attenuated FAP [AFAP] section of this summary for more information.) MYH-associated neoplasia is caused by germline homozygous recessive mutations in the MYH gene.[103]

Presymptomatic genetic testing removes the necessity of annual screening of those at-risk individuals who do not have the gene mutation. For at-risk individuals who have been found to be definitively mutation-negative by genetic testing, there is no clear consensus on the need for or frequency of colon screening,[17] though all experts agree that at least one flexible sigmoidoscopy or colonoscopy examination should be performed in early adulthood (by age 18–25 years).[17,18] Colon adenomas will develop in nearly 100% of persons who are APC gene mutation positive; risk-reducing surgery comprises the standard of care to prevent colon cancer after polyps have appeared.

Individuals at risk of FAP, because of a known APC mutation in either the family or themselves, are evaluated for polyps by flexible sigmoidoscopy or colonoscopy. The recommended age at which surveillance should begin involves a trade-off. On the one hand, someone who waits until the late teens to begin surveillance faces a remote possibility that a cancer will have developed at an earlier age. Although it is rare, colorectal cancer can develop in a teenager who carries an APC mutation. On the other hand, it is preferable to allow people at risk to develop emotionally before they are faced with a major surgical decision regarding the timing of colectomy. Therefore, surveillance is usually begun in the early teenage years (age 10–15 years). Surveillance should consist of either flexible sigmoidoscopy or colonoscopy every year.[104-106] If flexible sigmoidoscopy is utilized and polyps are found, colonoscopy should be performed. Although many clinicians have suggested that surveillance can be stopped in midlife, this recommendation is based on experience with individuals who had a 50% risk of inheriting the mutation, thus including noncarriers. Colon surveillance should not be stopped in persons who are known to carry an APC mutation because polyps occasionally are not manifest until the fourth and fifth decades of life. (Refer to the Attenuated FAP [AFAP] section of this summary for more information.) An interest in noninvasive methods of screening has led to the evaluation of new screening techniques, including virtual colonoscopy and the detection of DNA mutations in stool. These methods have not been adequately evaluated in high-risk populations such as FAP and Lynch syndrome. The stool DNA mutation tests detect somatic mutations derived from the tumor tissue and are not appropriate for germline mutation testing. (Refer to the PDQ summary on Colorectal Cancer Screening for more information on these methods.)

In some circumstances, full colonoscopy may be preferred over the more limited sigmoidoscopy. Among pediatric gastroenterologists, tolerability of endoscopic procedures in general has been regarded as improved with the use of deeper intravenous sedation.[104,107]

Table 5 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance of FAP.

Once an FAP family member is found to manifest polyposis, the only effective management is colectomy. Patient and doctor should enter into an individualized discussion to decide when surgery should be done. It is useful to incorporate into the discussion the risk of developing desmoid tumors following surgery. Timing of risk-reducing surgery usually depends on the number of polyps, their size, histology, and symptomatology.[113] Once numerous polyps have developed, surveillance colonoscopy is no longer useful in timing the colectomy because polyps are so numerous that it is not possible to biopsy or remove all of them. At this time, it is appropriate for patients to consult with a surgeon who is experienced with available options, including total colectomy and postcolectomy reconstruction techniques.[114] Rectum-sparing surgery, with sigmoidoscopic surveillance of the remaining rectum, is a reasonable alternative to total colectomy in those compliant individuals who understand the consequences and make an informed decision to accept the residual risk of rectal cancer occurring despite periodic surveillance.[115]

Surgical options include restorative proctocolectomy with ileal pouch anal anastomosis (IPAA), subtotal colectomy with ileorectal anastomosis (IRA), or total proctocolectomy with ileostomy (TPC). TPC is reserved for patients with low rectal cancer in which the sphincter cannot be spared or for patients on whom an IPAA cannot be performed because of technical problems. Following TPC, there is no risk for developing rectal cancer because the whole mucosa at risk has been removed. Whether a colectomy and an IRA or a restorative proctocolectomy is performed, most experts suggest that periodic and lifelong surveillance of the rectum or the ileal pouch be performed to remove or ablate any polyps. This is necessitated by case series of rectal cancers arising in the rectum of FAP patients who had subtotal colectomies with an IRA in which there was an approximately 25% cumulative risk of rectal adenocarcinoma 20 years after IRA, as well as case reports of adenocarcinoma in the ileoanal pouch and anal canal after restorative proctocolectomy.[116-119] The cumulative risk of rectal cancer after IRA may be lower than that reported in the literature, in part because of better selection of patients for this procedure, such as those with minimal polyp burden in the rectum.[114] Other factors that have been reported to increase the rectal cancer risk after IRA include the presence of colon cancer at the time of IRA, the length of the rectal stump, the duration of follow-up after IRA, and the genotype of the patients.[120-126] Mutations reported to increase the rectal cancer risk and eventual completion proctectomy after IRA include mutations in exon 15 codon 1250, exon 15 codons 1309 and 1328, and exon 15 mutations between codons 1250 and 1464.[125,116,126,127] In patients who have undergone IPAA, it is important to continue annual surveillance of the ileal pouch because the cumulative risk of developing adenomas in the pouch has been reported to be up to 75% at 15 years.[128,129] Although they are rare, carcinomas have been reported in the ileal pouch and anal transition zone after restorative proctocolectomy in FAP patients.[130] A meta-analysis of quality of life following restorative proctocolectomy and IPAA has suggested that FAP patients do marginally better than inflammatory bowel disease patients in terms of fistula formation, pouchitis, stool frequency, and seepage.[131]

Specific cyclooxygenase II (COX-2) inhibitors such as celecoxib and rofecoxib, or nonspecific COX-2 inhibitors, such as sulindac, have been associated with a decrease in polyp size and number in FAP patients, suggesting a role for chemopreventive agents in the treatment of this disorder. Celecoxib is currently approved by the U.S. Food and Drug Administration as an adjunct to endoscopic surveillance following subtotal colectomy in patients with FAP.[132-134] Celecoxib reduced the number of polyps by 28% from baseline, and the sum of the polyp diameters by 30.7% in patients with FAP; however, it is unknown whether this will translate into reductions in colorectal cancer incidence or mortality, or improvements in quality of life. Rofecoxib has also been shown to modestly reduce the number of polyps in patients after subtotal colectomy. Rofecoxib (25 mg/day) reduced the number of polyps by 6.8% from baseline in 21 patients after 9 months of treatment.[135]

It is unclear at present how to incorporate COX-2 inhibitors into the management of FAP patients who have not yet undergone risk-reducing surgery. A double-blind placebo-controlled trial in 41 APC mutation carrier children and young adults who had not yet manifested polyposis demonstrated that sulindac may not be effective as a primary treatment in FAP. There were no statistically significant differences between the sulindac and placebo groups over 4 years of treatment in incidence, number, or size of polyps.[134]

Consistent with the effects of COX-2 inhibitors on colonic polyps, in a randomized, prospective, double-blind, placebo-controlled trial, celecoxib (400 mg, administered orally twice daily) reduced, but did not eliminate, the number of duodenal polyps in 32 patients with FAP after a 6-month course of treatment. Of importance, a statistically significant effect was seen only in individuals who had more than 5% of the duodenum involved with polyps at baseline and with an oral dose of 400 mg, given twice daily.[136] A previous randomized study of 24 FAP patients treated with sulindac for 6 months showed a nonsignificant trend in the reduction of duodenal polyps.[137] The same issues surrounding the use of COX-2 inhibitors for the treatment of colonic polyps apply for their use for the treatment of duodenal polyps (e.g., only partial elimination of the polyps, complications secondary to the COX-2 inhibitors, and loss of effect after the medication is discontinued).[136]

Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib,[138-141] it is unclear whether this class of agents will be safe for long-term use for patients with FAP, as well as the general population. Also, because of the short-term (6-month) nature of these trials, there is currently no clinical information about cardiac events in FAP patients taking COX-2 inhibitors on a long-term basis.

Level of evidence for celecoxib study: 1

One cohort study has demonstrated regression of colonic and rectal adenomas with sulindac (an NSAID) treatment in FAP. The reported outcome of this trial was the number and size of polyps, a surrogate for the clinical outcome of main interest, colorectal cancer incidence.[142]

Level of evidence for sulindac study: 1

Patients who carry APC germline mutations are at increased risk of other types of malignancies, including thyroid cancer, small bowel cancer, hepatoblastoma, and brain tumors. The risk of these tumors, however, is much lower than that for colon cancer, and the only surveillance recommendation by experts in the field is upper endoscopy of the gastric and duodenal mucosa.[7,19] The severity of duodenal polyposis detected appears to correlate with risk of duodenal adenocarcinoma.[65]

Attenuated FAP (AFAP) is a heterogeneous clinical entity characterized by fewer adenomatous polyps in the colon and rectum than in classic FAP. It was first described clinically in 1990 in a large kindred with a variable number of adenomas. The average number of adenomas in this kindred was 30, though they ranged in number from a few to hundreds.[143] Adenomas in AFAP are believed to form in the midtwenties to late twenties.[52] Similar to classic FAP, the risk of colorectal cancer is higher in individuals with AFAP; the average age of diagnosis, however, is older than classic FAP at 56 years.[144-146] Extracolonic manifestations similar to those in classic FAP also occur in AFAP. These manifestations include upper gastrointestinal polyps (fundic gland polyps, duodenal adenomas, and duodenal adenocarcinoma), osteomas, epidermoid cysts, and desmoids.[52]

AFAP is associated with particular subsets of APC mutations, including missense changes. Three groups of site-specific APC mutations causing AFAP have been characterized:[144,145,147-149]

• Mutations associated with the 5’ end of APC and exon 4 in which patients can manifest 2 to more than 500 adenomas, including the classic FAP phenotype and upper gastrointestinal polyps.
• Exon 9–associated phenotypes in which patients may have 1 to 150 adenomas but no upper gastrointestinal manifestations.
• 3’ region mutations in which patients have very few adenomas (<50).

APC gene testing is an important component of the evaluation of patients suspected of having AFAP.[107] It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided.[107] The role for and timing of risk-reducing colectomy in AFAP is controversial.[150] If germline APC mutation testing is negative in suspected AFAP individuals, genetic testing for MYH mutations may be warranted.[98]

Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[151,152] In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MYH-associated polyposis or MAP), Lynch syndrome, or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or Lynch syndrome. Whether the family history is significant or not, careful clinical evaluation consisting of dye-spray colonoscopy (indigo carmine or methylene blue) [153-159] with or without magnification, or possibly newer imaging techniques, such as narrow band imaging,[160] may reveal the characteristic right-sided clustering of more numerous microadenomas. Upper GI endoscopy may be informative if duodenal adenomas or FGPs with surface dysplasia are found. Such findings will increase the likelihood of mutation detection if APC or MYH testing is pursued.

Homozygous mutations in the MYH gene have been associated with a phenotype of multiple colorectal adenomas with or without cancer. This accounts for a proportion of FAP patients without a pathogenic APC mutation. The syndrome has been referred to as MYH polyposis or MYH-associated polyposis (MAP).[101,161] The original report described three APC mutation–negative affected siblings, two of whom had approximately 50 adenomas at the ages of 55 years and 59 years, and one with colorectal cancer and an unknown number of adenomas at 46 years. Each sibling was found to carry the same biallelic mutations in the MYH gene.[103]

This finding led other investigators to estimate the proportion of APC mutation–negative patients accounted for by germline biallelic MYH mutations. On the basis of studies from multiple FAP registries, approximately 7% to 17% of patients with a FAP phenotype and without a detectable APC germline mutation carry biallelic mutations in the MYH gene.[101,103,161,162] In these individuals, the burden of adenomas ranges from very few to hundreds. MYH-associated neoplasia has been reported to have an autosomal recessive pattern of inheritance. In one study of 64 at-risk siblings of 25 index patients with identifiable biallelic MYH mutations, ten siblings were affected with colon polyposis alone, and seven had polyposis and colorectal cancer. Five of the 17 were tested for MYH mutations and shown to have similar biallelic mutations as their respective index case.[161] Neither MYH testing nor the colorectal phenotype, however, was reported in the other 47 siblings in this study.

Several studies have examined the frequency of MYH mutations in apparently sporadic colorectal cancer patients and in subjects undergoing colonoscopy screening.[163-166] Mutation detection was limited to the two major variants (Y165C and/or G382D) in most of these studies.[164,166] A Finnish population-based study of 1,042 patients with colorectal cancer found four patients (0.4%) with biallelic MYH mutations.[164] In addition to the colorectal cancer, these four patients had between 5 and 100 adenomas,[164] while no biallelic mutations were found in 400 cancer-free control subjects. In a hospital-based series of 400 individuals undergoing screening colonoscopy who had up to three adenomas, 444 patients with colorectal cancer, and 140 patients referred for genetic testing for possible FAP but with negative APC gene testing, 18 of the total individuals (2%) had biallelic MYH mutations. None of the screening patients, 16 (11%) of the APC mutation–negative patients, and two patients with colorectal cancer had biallelic MYH mutations.[166] A similar detection rate of 1% biallelic MYH mutations was found in a population-based study of 1,238 cases from Ontario with colorectal cancer and 1,255 healthy, randomly selected controls.[167] In a multiregister study of 358 unrelated colorectal cancer patients in the United Kingdom diagnosed at age 56 years or younger, the whole coding sequence of the MYH gene was examined.[163] Only two patients (0.6%) had biallelic MYH mutations, one with four adenomas and one with ten adenomas.[163] These studies identified several individuals with monoallelic MYH mutations. The relative risk (RR) of monoallelic mutations has been estimated at 1.27 (95% confidence interval [CI], 1.01–1.61). The RR in biallelic carriers is very high (RR 117, 95% CI, 74–184).[168] These data support the hypothesis that monoallelic mutations are a low penetrance risk factor for colorectal cancer.[167,169]

In Lynch syndrome,[170-172] unlike FAP, most patients do not have an unusual number of polyps. Lynch syndrome accounts for about 3% to 5% of all colorectal cancer. Other designations include HNPCC and cancer family syndrome. Lynch syndrome is an autosomal dominant condition caused by the mutation of one of several DNA mismatch repair (MMR) genes. (Refer to the DNA Mismatch Repair Genes section of this summary for more information.) The average age of colorectal cancer diagnosis in Lynch syndrome mutation carriers is 44 years, compared with 64 years in sporadic colorectal cancer. Individuals with mutations in hMSH6 have been reported to have a mean age at colorectal cancer diagnosis of 55 to 57 years.[173] Lynch syndrome mutation carriers also have an increased risk of developing colon adenomas (hazard ratio = 3.4), and the onset of adenomas appears to occur at a younger age than that seen in nonmutation carriers.[174] Individuals with a Lynch syndrome gene mutation have an estimated 80% lifetime risk of developing colon or rectal cancer.[3] Unlike sporadic cancers, which develop most often in the left side of the colon, Lynch syndrome cancers are most likely to develop in the right side, defined as proximal to the splenic flexure.

Newer data from a combined set of Lynch syndrome families showed that the average age at diagnosis of colorectal cancer is 61 years among gene carriers when a more rigorous statistical approach is utilized in which all gene carriers (both affected and unaffected) are considered.[173,175] A meta-analysis of population-based or ascertainment-adjusted published results showing that the cumulative lifetime risks of colorectal and endometrial cancer are lower than previously reported, and these estimates have been incorporated into a computer prediction model (MMRPro) for calculating lifetime risk.[176] This meta-analysis suggests the lifetime risk of colorectal cancer is higher in males (60%) than females (30%) among all MLH1 or MSH2 gene mutation carriers, and the risk of colorectal cancer is lower in carriers of MSH6 mutations (30% for men and women) than those who carry mutations in either MLH1 or MSH2.[176] Other computer models predict the probability of a MMR gene mutation. PREMM and the MMRPro models are easy to use and have been validated.[177,178] These models incorporate immunohistochemistry (IHC) for MMR protein expression as well as microsatellite instability (MSI) testing as predictive variables. All three computer prediction models take family history of endometrial cancer into account.

Patients with Lynch syndrome can have synchronous and metachronous colorectal cancers as well as other primary extracolonic malignancies. In addition to colorectal cancer, patients and their relatives are at risk for a wide variety of other cancers. The most common is endometrial adenocarcinoma, which affects at least one female member in about 50% of Lynch syndrome pedigrees. Lynch syndrome-associated endometrial cancer is not limited to the endometrioid subtype. Endometrial adenocarcinoma, clear cell carcinoma, uterine papillary serous carcinoma, and malignant mixed Müllerian tumors are part of the spectrum of uterine tumors in Lynch syndrome.[179] Patients with Lynch syndrome are also at risk for cancers of the stomach, small intestine, liver and biliary tract, brain, and ovary, as well as transitional cell carcinoma of the ureters and renal pelvis.[180-183] The risk of endometrial cancer in hMSH2 and hMLH1 mutation carriers is 61% and 42%, respectively, but the difference is not statistically significant in this small study.[3] A more recent study of 281 families in Germany did not identify any significant differences in the cumulative probability or mean age at onset of endometrial cancers when comparing hMSH2 versus hMLH1 mutation carriers.[184] A cohort study of 146 hMSH6 mutation carriers identified a cumulative risk for colorectal cancer of 69% for men and 30% for women. The cumulative risk for endometrial cancer in women was 71% at age 70 years.[173]

Muir-Torre syndrome is considered a variant of Lynch syndrome, and includes a phenotype of multiple cutaneous adnexal neoplasms (including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas) and tumors in the small and large bowel, stomach, endometrium, kidney, and ovaries. The skin lesions and colorectal cancer define the phenotype,[185,186] and clinical variability is common. Some families with Muir-Torre syndrome have been found to have mutations in the hMSH2 and hMLH1 genes.[187,188]

The research criteria for defining Lynch syndrome families were established by the International Collaborative Group (ICG) meeting in Amsterdam in 1990, and are known as the ICG or Amsterdam criteria.[189]

Amsterdam criteria:

1. One member diagnosed with colorectal cancer before age 50 years.
2. Two affected generations.
3. Three affected relatives, one of them a first-degree relative of the other two.
4. FAP should be excluded.
5. Tumors should be verified by pathological examination.

These criteria provide a general approach to identifying Lynch syndrome families, but they are not considered comprehensive; a number of families who do not meet these criteria, but have germline mismatch repair gene mutations, have been reported.[190,191]

To address these issues and to improve the diagnosis of Lynch syndrome clinically, the ICG developed revised criteria in 1999; these are known as Amsterdam criteria II.[192]

Amsterdam criteria II:

1. There should be at least three relatives with a Lynch syndrome-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis).
2. One should be a first-degree relative of the other two.
3. At least two successive generations should be affected.
4. At least one should be diagnosed before age 50 years.
5. Familial adenomatous polyposis should be excluded in the colorectal cancer cases.
6. Tumors should be verified by pathological examination.

A third set of clinical criteria that can be used to identify Lynch syndrome families is the revised Bethesda guidelines.[193] These criteria are the least stringent for identifying families with germline mutations in one of the MMR genes.

Revised Bethesda Guidelines for Testing of Colorectal Tumors for Microsatellite Instability (MSI)

1. Colorectal cancer diagnosed in an individual younger than 50 years.



2. Presence of synchronous, metachronous colorectal, or other Lynch syndrome-associated tumors (i.e., endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas; and carcinoma of the small bowel), in an individual regardless of age.



3. Colorectal cancer with MSI-high pathologic associated features diagnosed in an individual younger than 60 years.  [Note: Presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.]



4. Colorectal cancer or Lynch syndrome-associated tumor* diagnosed in at least one first-degree relative younger than 50 years.



5. Colorectal cancer or Lynch syndrome-associated tumor* diagnosed at any age in two first-degree or second-degree relatives.