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.

Genetic testing refers to searching for mutations in known cancer susceptibility genes using a variety of techniques. Comprehensive genetic testing includes sequencing the entire coding region of a gene, the intron-exon boundaries (splice sites), and assessment of rearrangements, deletions or other changes in copy number (with techniques such as multiplex ligation-dependent probe analysis [MLPA], or Southern blot). Despite extensive accumulated experience that helps distinguish pathogenic mutations from benign variants and polymorphisms, genetic testing sometimes identifies variants of uncertain significance that cannot be used for predictive purposes.

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] In a prospective study of patients with FAP undergoing surveillance with esophagogastroduodenoscopy (EGD), FGPs were detected in 88% of the patients. Low-grade dysplasia was detected in 38% of these patients, whereas high-grade dysplasia was detected in 3% of these patients.[53]

Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming proton pump inhibitors (PPIs).[51,54] 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%.[55-58] 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.[59-62] 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,[63] 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.[45,46,64] There is a 4% to 12% lifetime incidence of duodenal adenocarcinoma in FAP patients.[11,61,65,66] 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.[67]

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.[68] 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.[65] 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.[69,70]

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.[14,66,71,72] 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.[72] According to this system, 36% of patients with the most advanced stage will develop carcinoma.[66] 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.[66]

A baseline upper endoscopy should be performed between ages 25 and 30 years in FAP patients.[62] 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.[61,62] 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;[69,70,73] 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.[74] Pancreaticoduodenectomy and pancreas-sparing duodenectomy are appropriate surgical therapies that are believed to substantially reduce the risk of developing periampullary adenocarcinoma.[74-77] 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.[78] However, a recent study [79] 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.[80] 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.[81] 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.[81] 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.[82-91] Some series have also demonstrated LOH of APC in these tumors.[83,85,92] No specific genotype-phenotype correlations have been identified in FAP patients with hepatoblastoma.[93]

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.[94]

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 [95] 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.[96] The addition of MLPA and analysis of allelic mRNA expression with single nucleotide primer extension (SNuPE) improves the detection rate for APC mutations.[97]

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.[98] 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.[99,100] 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.[101] MYH gene testing may be considered in APC mutation–negative affected individuals.[102] (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]).[103] 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.[104]

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.[105-107] 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.[105,108]

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.[114] 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.[115] 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.[116]

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.[117-120] 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.[115] 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.[121-127] 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.[126,117,127,128] 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.[129,130] Although they are rare, carcinomas have been reported in the ileal pouch and anal transition zone after restorative proctocolectomy in FAP patients.[131] 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.[132]

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.[133-135] 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.[136]

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.[135]

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.[137] A previous randomized study of 24 FAP patients treated with sulindac for 6 months showed a nonsignificant trend in the reduction of duodenal polyps.[138] 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).[137]

Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib,[139-142] 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.[143]

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.[66]

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.[144] 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.[145-147] 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:[145,146,148-150]

• 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.[108] It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided.[108] The role for and timing of risk-reducing colectomy in AFAP is controversial.[151] If germline APC mutation testing is negative in suspected AFAP individuals, genetic testing for MYH mutations may be warranted.[99]

Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[152,153] 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) [154-160] with or without magnification, or possibly newer imaging techniques, such as narrow band imaging,[161] 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).[102,162] 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.[104]

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.[102,104,162,163] 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.[162] 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.[164-167] Mutation detection was limited to the two major variants (Y165C and/or G382D) in most of these studies.[165,167] A Finnish population-based study of 1,042 patients with colorectal cancer found four patients (0.4%) with biallelic MYH mutations.[165] In addition to the colorectal cancer, these four patients had between 5 and 100 adenomas,[165] 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.[167] 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.[168] 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.[164] Only two patients (0.6%) had biallelic MYH mutations, one with four adenomas and one with ten adenomas.[164] 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).[169] These data support the hypothesis that monoallelic mutations are a low penetrance risk factor for colorectal cancer.[168,170]

In Lynch syndrome,[171-173] 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.[174] 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.[175] 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.[174,176] 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.[177] 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.[177] Other computer models predict the probability of a MMR gene mutation. PREMM and the MMRPro models are easy to use and have been validated.[178,179] 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.[180] 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.[181-184] 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.[185] 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.[174]

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,[186,187] and clinical variability is common. Some families with Muir-Torre syndrome have been found to have mutations in the hMSH2 and hMLH1 genes.[188-190]

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.[191]

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.[192,193]

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.[194]

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.[195] 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.

*Lynch syndrome-associated tumors include colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.[195,196]

Research has included colorectal cancer families who do not meet Amsterdam criteria for Lynch syndrome and/or in whom the colorectal tumors are microsatellite stable (MSS). A number of these families have been found to have mutations, both truncating and missense, in hMSH6.[197-201] While the clinical significance and implications of these findings are not clear, these observations suggest that germline mutations in hMSH6 may predispose to late-onset familial colorectal cancers that do not meet Amsterdam criteria for Lynch syndrome.

Genetic risk assessment of Lynch syndrome generally considers the cancer family history and age at diagnosis of colorectal cancer in the patient. Studies of gene testing using DNA sequencing in suspected Lynch syndrome probands from a cancer risk assessment clinical setting found that approximately 25% test positive for an informative hMSH2 or hMLH1 mutation. This means that genetically informed management strategies could be developed for the family.[202,203] An attractive, cost-effective strategy is to first perform an MSI assay on the affected family member’s colorectal tumor, if available.[204,205] Colonoscopy surveillance is often recommended empirically for subjects with strong family histories but no prior genetic or tumor testing. In this instance, only an adenoma may be found. This raises the question of whether using adenomas for MSI and IHC testing is informative. One study found 8 of 12 adenomas to have both MSI and IHC protein loss.[206] All of the patients had prior colorectal cancer and known MMR mutations; however, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude Lynch syndrome.

If a colorectal tumor (adenocarcinoma or adenoma) is found to exhibit MSI, then the patient or family may consider germline testing of an affected patient for the three MMR genes, hMSH2, hMLH1, and hMSH6, for which commercial genetic tests are available. A complementary approach is to test the tumor by IHC for protein expression of hMSH2, hMLH1, and hMSH6. If protein expression is absent, then proceed directly to genetic testing. Meta-analysis suggests that, while combinations of clinical criteria (such as the Bethesda guidelines) and MSI/IHC are imperfect, use of MSI does improve detection sensitivity and specificity.[207] The loss of expression of hMSH2, hMLH1, or hMSH6 suggests the possibility of germline mutations in those genes and indicates individuals who could be considered for MMR gene mutation analysis.[208]

Although regional practice patterns vary, it is reasonable to begin a molecular diagnostic evaluation of suspected Lynch syndrome with both MSI and IHC testing. Using these tests together increases the sensitivity of the initial screen and, through the information provided by the IHC testing, provides information regarding the gene most likely to harbor a germline mutation.[209-212] MSI and IHC results indicative of a MMR defect both lead to further germline testing. Because of the generally concordant results, this combination of testing provides reassurance. Although most laboratories assess both MSI and IHC initially, arguments for a sequential approach to increase efficiency have been made. A German consortium has proposed an algorithm suggesting a sequential approach; this is likely to depend on the different costs of MSI and IHC and the prior probability of a mutation.[213] Data from a large U.S. study support IHC analysis as the primary screening method, emphasizing its ease of performance in routine pathology laboratories.[209]

Consistent with the Bethesda guidelines, certain histopathologic features are strongly suggestive of MSI phenotype including the presence of tumor infiltrating lymphocytes, mucinous histology, absence of dirty necrosis, and histologic heterogeneity. Together these features have been combined into computational scores that have high predictive value in identifying MSI colorectal cancers.[214,215]

Other somatic changes in colon cancers that appear to have negative predictive value for identifying individuals who have germline mutations in one of the MMR genes are BRAF mutations and hMLH1 promoter methylation. Aberrant methylation of hMLH1 is responsible for causing approximately 90% of sporadic MSI colon cancers.[216] It has also been detected in Lynch syndrome colon cancers in individuals with germline mutations in either hMLH1 or hMSH2, less frequently ranging from 10% to 50% of cancers.[216-218] Thus, detection of aberrantly methylated hMLH1 in the colon cancer is more suggestive of a sporadic MSI tumor.

BRAF mutations have been detected predominantly in sporadic MSI tumors.[219-222] These BRAF mutations are likely important in the serrated adenoma pathway which may include those cases that appear to have hyperplastic polyposis syndrome. This suggests that somatic BRAF V600E mutations may be useful in excluding individuals from germline mutation testing; however, there are limitations to the current studies that preclude this conclusion at this time. None of the studies clearly define the clinical criteria used to diagnose the families with Lynch syndrome, limiting the general application of the results to patients seen in the clinic setting. Furthermore, at least one person with a germline mutation in hMLH1 (mutation not described) had a colon cancer with a BRAF mutation. Recommendations on the use of somatic BRAF mutations for stratifying individuals for germline mutation testing can be made once a study is performed using a population of individuals who meet borderline clinical criteria for Lynch syndrome and who have had subsequent germline mutation testing. Correlation of BRAF mutation testing with the germline mutation testing in this population will define the test characteristics in the appropriate patient population to which such a test would be applied.

If a mutation is identified in an affected person, then testing for that same mutation could be offered to at-risk family members. If no mutation is identified in the affected family member, then testing would be considered uninformative for the at-risk family members. This would not exclude an inherited susceptibility to colon cancer in the family, but rather could indicate that current gene testing technology is not sensitive enough to detect the mutation in the hMSH2 or hMLH1 gene. The current sensitivity of testing is between 50% and 95%, depending on the methodology used. Clinically available tests may not detect large genomic rearrangements in hMSH2 or hMLH1 that may be present in a significant number of Lynch syndrome probands.[223-225] An assessment of 365 probands with suspected Lynch syndrome showed 153 probands with germline mutations in hMLH1 or hMSH2, 12 of 67 (17.9%) and 39 of 86 (45.3%) of which were large genomic alterations in hMLH1 and hMSH2, respectively.[226] In this group of patients, other techniques such as Southern blotting or MLPA [227,228] may be necessary to rule out a disease-causing mutation in these genes. Recent studies have also shown that a subset of Lynch syndrome families who do not have detectable hMLH1, hMSH2, or hMSH6 germline mutations will have mutations in PMS2. The incidence of PMS2 germline mutations has been underappreciated.[229-231] One study reported an incidence of 2.2% for PMS2 mutations in 184 patients with suspected Lynch syndrome.[232] In this same study, patients with PMS2 mutations presented with colorectal cancer 7 to 8 years later than those with hMLH1 and hMSH2 mutations. These families were small and did not fulfill Amsterdam criteria.[232]

Alternatively, the family could have a mutation in one of the other Lynch syndrome-associated genes for which clinical testing is not currently available, or the pedigree may have a mutation in a yet-unidentified gene that causes Lynch syndrome or a predisposition to colon cancer. For example, deleterious mutations in the hMSH6 gene have been reported in fewer than 5% of patients suspected of Lynch syndrome.[201,233] Another explanation for a negative mutation test is that, by chance, the individual tested in the family has developed colon cancer through a nongenetic mechanism (i.e., it is a sporadic case), while the other cases in the family are really due to a germline mutation. Finally, failure to detect a mutation could mean that the family truly is not at genetic risk in spite of a clinical presentation that suggests a genetic basis. If no mutation can be identified in an affected family member, testing should not be offered to at-risk members. They would remain at increased risk of colorectal cancer by virtue of their family history and should continue with recommended intensive screening. (Refer to the Interventions/Lynch syndrome section of this summary for more information.)

There is overlap in the phenotype of families with Lynch syndrome and attenuated FAP as both syndromes can present with multiple colonic adenomas and extracolonic cancers.[234] (Refer to the Attenuated FAP section of this summary for more information.) A clinical finding that would suggest AFAP over Lynch syndrome is fundic gland polyposis of the stomach. The presence of uterine, gastric, urinary, and/or ovarian cancers within a family would favor the diagnosis of Lynch syndrome. Genetic counseling for the affected individual is suggested to determine the best options for genetic testing.[72]

An interest in noninvasive methods of screening has led to evaluation of new screening techniques, including computed tomography (CT) colography (also known as virtual colonoscopy or CT colonography) and detection of DNA mutations in stool. One study of 78 individuals with Lynch syndrome, all of whom underwent CT colography and colonoscopy, showed that CT colography had good sensitivity for large polyps but poor sensitivity for small polyps.[235] Therefore, CT colography was not recommended as a primary tool for Lynch syndrome surveillance. These findings are of particular importance in Lynch syndrome screening, since neoplasms in this setting begin as subtle flat lesions. The stool DNA mutation tests detect somatic mutations derived from the tumor tissue and cannot replace germline mutation testing. This method has not been adequately evaluated in high risk populations such as patients with FAP or Lynch syndrome. (Refer to the PDQ summary on Colorectal Cancer Screening for more information on these methods.)

Several aspects of the biologic behavior of Lynch syndrome suggest how the approach to surveillance should differ from that for average-risk people:

1. Colorectal cancers in Lynch syndrome occur earlier in life than do sporadic cancers. For hMLH1 and hMSH2 mutation carriers, the estimated risks for colorectal cancer at age 40 years are 31% and 32% for females and males, respectively, and at age 50 years , the estimated risks are 52% and 57%, respectively.[3] This suggests that screening should begin earlier in life.



2. A larger proportion of Lynch syndrome colorectal cancers (60%–70%) occur in the right colon, suggesting that sigmoidoscopy alone is not an appropriate screening strategy and that a colonoscopy provides a more complete structural examination of the colon.



3. The progression from normal mucosa to adenoma to cancer is accelerated,[236,237] suggesting that screening should be done at shorter intervals (every 1–2 years) and with colonoscopy.[237,238] Because patients with Lynch syndrome have an ordinary, or slightly increased, frequency of polyps but a substantially increased rate of cancer, it is clear that a larger proportion of polyps progress to cancer. It has been demonstrated that MMR gene mutation carriers develop adenomas at an earlier age than noncarriers.[175] The mean age at diagnosis of adenoma in carriers was 43.3 years (range, 23–63.2 years), and the mean age at diagnosis of carcinoma was 45.8 years (range, 25.2–57.6 years).[175]



4. Incidence of colorectal cancer through life is substantially higher, suggesting that the most sensitive test available should be used.



5. Patients with Lynch syndrome are at an increased risk of other cancers, especially those of the endometrium and ovary. The cumulative risk of extracolonic cancer has been estimated to be 20% by age 70 years in 1,018 women in 86 families, compared with 3% in the general population.[183] There is some evidence that the rate of individual cancers varies from kindred to kindred.[182,239,240] Expert consensus suggests consideration of endometrial cancer screening by age 25 years.[241]

Evidence-based reviews of surveillance colonoscopy in Lynch syndrome have been reported.[242,243] There is only one controlled trial of colorectal cancer screening in Lynch syndrome.[237,238] In a study from Finland, 252 at-risk members of 22 families with Lynch syndrome were offered screening for 15 years. One hundred thirty-three individuals accepted screening by either colonoscopy or barium enema and sigmoidoscopy, and 123 of the at-risk members (93%) completed screening. One hundred nineteen did not accept advice to be screened, although 24 (20%) had screening examinations outside the study. Once genetic testing was performed in these families (starting in 1996, 14 years after the beginning of screening), screening was recommended for mutation-positive controls, 63% of whom chose to begin active screening. The screened group had 62% fewer cancers (P < .03) and 65% fewer colorectal cancer deaths (10 vs. 26, P = .003). All of the colorectal cancers detected in the screened population were local and caused no deaths, compared with nine deaths from colorectal cancer in the control group. The results, while biologically plausible, are of limited validity, primarily because the main comparison was between compliant and noncompliant patients, and compliant patients have been shown to have an inherently better prognosis, independent of intervention.[244] This assertion is supported by the observed low rates of all causes of mortality. It is noteworthy, however, that these differences were observed in spite of the fact that most mutation-positive controls ultimately entered a screening program.

The data from this Finnish trial were recently updated.[245] Over the course of the study (early 1980s to present) the approach to colonoscopy surveillance has evolved. Colonoscopy is now limited to MMR mutation carriers when this information is obtainable and the interval between exams was shortened from 5 years to 3 years to 2 years. The current series limited its attention to subjects with no prior diagnosis of adenoma or cancer. The 420 mutation carriers, at a mean age of 36 years, underwent an average of 2.1 colonoscopies, with a median follow-up of 6.7 years. Adenomas were detected in 28% of subjects. Cumulative risk of one or more adenomas by age 60 years was 68.5% in men and 48.3% in women. Notably, risk of detecting cancer in those free of cancer at baseline exam, and thus regarded as interval cancers, by age 60 years was 34.6% in men and 22.1% in women. The combined cumulative risk of adenoma or cancer by age 60 years was 81.8% in men and 62.9% in women. For both adenomas and carcinomas, about half were located proximal to the splenic flexure. While the rates for colorectal cancer despite colonoscopy surveillance appear high, it must be emphasized that the recommended short intervals were not regularly adhered to in this nonrandomized series. These authors concluded by recommending surveillance at 2-year intervals. The appropriate colonoscopy surveillance interval remains every 1 to 2 years according to most consensus guidelines. (Refer to Table 6 of this summary for more information.)

In other series, the risk of developing adenomas in a MMR gene mutation carrier has been reported to be 3.6 times higher than the risk in noncarriers.[175] By age 60 years, 70% of the carriers developed adenomas, compared with 20% of noncarriers. As previously mentioned, these mutation carriers developed adenomas at an earlier age than noncarriers. Most of the adenomas in carriers had absence of MMR protein expression and were more likely to have dysplastic features, compared with adenomas from control subjects.[175] Given that colonoscopy is the accepted measure for colon cancer surveillance, preliminary data suggest that the use of chromoendoscopy, such as with indigo carmine, may increase the detection of diminutive, histologically advanced adenomas.[155,246]

Although screening the intact colon is usually recommended for at-risk Lynch syndrome family members, some patients, faced with the high risk of colorectal cancer and the fallibility of screening, elect to undergo risk-reducing colectomy. However, there is a risk of developing cancer in the remaining rectum.[247]

Level of evidence: 3a

Table 6 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance for Lynch syndrome.

Note: A separate PDQ summary on Endometrial Cancer Screening in the general population is also available.

Cancer of the endometrium is the second most common cancer observed in Lynch syndrome families with initial estimates of cumulative risk in Lynch syndrome carriers of 30% to 39% by age 70 years.[182,184] In a large Finnish study of 293 putative Lynch syndrome gene carriers, the cumulative lifetime risk for endometrial cancer was 43%. Endometrial cancer risk was directly related to age, ranging from 3.7% at age 40 years to 42.6% by age 80 years, compared with a 3% endometrial cancer risk in the general population. The maximal risk for endometrial cancer in Lynch syndrome families occurs 15 years earlier than in the general population, with the highest risk occurring between ages 55 and 65 years. In a community study of unselected endometrial cancer patients in central Ohio, at least 1.8% (95% CI, 0.9%–3.5%) of newly diagnosed patients had Lynch syndrome.[249]

In the general population, the diagnosis of endometrial cancer is generally made when women present with symptoms including abnormal or postmenopausal bleeding. An office endometrial sampling, or a dilatation and curettage (D&C), is then performed, providing a histologic specimen for diagnosis. Eighty percent of women with endometrial cancer present with stage I disease due to the presenting symptoms. There is no data suggesting the clinical presentation in women with Lynch syndrome differs from the general population.

Given their substantial increased risk for endometrial cancer, endometrial screening for women with Lynch syndrome has been suggested. Proposed modalities for screening include transvaginal ultrasound (TVUS) and/or endometrial biopsy. Although the Pap test occasionally leads to a diagnosis of endometrial cancer, the sensitivity is too low for it to be a useful screening test. The presence of endometrial cells in a Pap smear obtained from a postmenopausal woman not taking hormone replacement therapy is abnormal and warrants further investigation.[250,251] Two studies have examined the use of TVUS in endometrial screening for women with Lynch syndrome.[252,253] In one study of 292 women from Lynch syndrome or Lynch syndrome-like families, no cases of endometrial cancer were detected by TVUS. In addition, two interval cancers developed in symptomatic women.[252] In a second study, 41 women with Lynch syndrome were enrolled in a TVUS screening program. Of 179 TVUS procedures performed, there were 17 abnormal scans. Three of the 17 women had complex atypical hyperplasia on endometrial sampling, while 14 had normal endometrial sampling. However, TVUS failed to identify one patient who presented 8 months after a normal TVUS with abnormal vaginal bleeding, and was found to have stage IB endometrial cancer.[253] Both of these studies concluded that TVUS is neither sensitive or specific. A study of 175 women with Lynch syndrome that included both endometrial sampling and TVUS, showed that endometrial sampling improved sensitivity over TVUS. Endometrial sampling found 11 of the 14 cases of endometrial cancer. Two of the three other cases were interval cancers that developed in symptomatic women and one case was an occult endometrial cancer found at the time of hysterectomy. Endometrial sampling also identified 14 additional cases of endometrial hyperplasia. Among the group of 14 women with endometrial cancer, ten also had TVUS screening with endometrial sampling. Four of the ten had abnormal TVUS, but six had normal TVUS.[254] While this cohort study demonstrates that endometrial sampling may have benefits over TVUS for endometrial screening, there is no data that predicts screening with any other modality has benefits for endometrial cancer survival in women with Lynch syndrome. Given the favorable survival for endometrial cancer diagnosed by symptoms, it is unlikely that a sufficiently powered screening study will be able to demonstrate a survival advantage. Certainly, women with Lynch syndrome should be counseled that abnormal or postmenopausal vaginal bleeding warrants an endometrial sampling or D&C.

Routine screening for endometrial cancer has not been shown to be beneficial in the general population, but expert consensus suggests that it be considered in women who are members of high-risk Lynch syndrome families. Some studies suggest that women with a clinical or genetic diagnosis of Lynch syndrome do not universally adopt intensive gynecologic screening.[255,256] (Refer to the Gynecologic cancer screening in Lynch Syndrome section of this summary for more information.) Despite absence of a survival advantage, a task force organized by the National Institutes of Health (NIH) has suggested annual endometrial sampling beginning at age 30 to 35 years. TVUS can also be considered annually to evaluate the ovaries.[243,248]

Level of evidence: 5

There have been no controlled studies of the benefit of risk-reducing surgery in at-risk Lynch syndrome mutation carriers. Recommendations based upon expert opinion, however, have been formulated by a panel convened by an NIH research consortium.[241] The expert panel recommended consideration of risk-reducing subtotal colectomy as an option for persons with Lynch syndrome having adenomas at surveillance, because of their risk of additional adenomas and cancer. In addition, the panel recommended presenting risk-reducing subtotal colectomy as an option for persons with Lynch syndrome who are not willing or are unable to undergo periodic colonic surveillance. Patients should be counseled, however, that the efficacy of these interventions is unknown.

The expert panel recommended that risk-reducing hysterectomy (RRH) and bilateral salpingo-oophorectomy (RRSO) be presented as an option for women with Lynch syndrome, and that counseling include thoughtful discussion of childbearing plans, psychosocial effects of risk-reducing surgery, and long term effects of prolonged estrogen replacement therapy, as well as uncertainties concerning the efficacy of risk-reducing surgery as a means to reduce the risk of endometrial or ovarian cancer.

Level of evidence for colon cancer: 5

A retrospective study of 315 female patients with germline mutations associated with Lynch syndrome reported no occurrences of endometrial, ovarian, or primary peritoneal cancers in women who underwent RRH with or without RRSO as compared with women who had no risk-reducing surgery.[257] Sixty-nine of 210 women developed endometrial cancer, and 12 of 223 women developed ovarian cancer in the control group. In the risk-reducing surgery group, 61 and 47 women underwent RRH or RRSO, respectively. The authors suggested that RRH with RRSO is an effective strategy for preventing endometrial and ovarian cancer in women with Lynch syndrome.[257] There were no data on survival benefit from risk-reducing surgical intervention in this study.

Level of evidence: 3di

The surgical management of a patient with Lynch syndrome must be individualized.[258] Management of these patients can be subdivided into patients with newly diagnosed colorectal cancer, those with colorectal cancer treated with segmental resection, and those who are at risk of developing colorectal cancer or who are mutation carriers. Because of the increased incidence of synchronous and metachronous colorectal neoplasms, many experts have advocated that the treatment of choice for a Lynch syndrome patient with newly diagnosed colon cancer is a subtotal colectomy with anastomosis of the ileum to either the sigmoid colon or the rectum. The risk of metachronous colorectal cancers has been estimated to be as high as 40% at 10 years after less than a subtotal colectomy, and up to 72% at 40 years after the diagnosis of colorectal cancer.[184,259] There are no prospective data, however, to suggest a survival benefit from a subtotal colectomy over a segmental resection. In a decision analysis model, one study showed that performing a subtotal colectomy at a young age (27 and 47 years) led to an increased life expectancy of 1 to 2.3 years compared with a segmental resection.[260] In this model, the potential benefit in life expectancy depended on the age of the patient and stage of the cancer at diagnosis. The older the patient and/or the more advanced cancer at diagnosis, the less theoretical benefit in terms of life expectancy from a subtotal colectomy as opposed to a segmental resection.[260]

When considering the surgical options, it is important to recognize that a subtotal colectomy will not eliminate the rectal cancer risk. The lifetime risk of developing cancer in the rectal remnant following a subtotal colectomy has been reported to be 12% at 12 years postcolectomy.[247] In addition to the general complications of surgery, there are the potential risks of urinary and sexual dysfunction and diarrhea following a subtotal colectomy, with these risks being greater the more distal the anastomosis. Therefore, the choice of surgery must be made on an individual basis by the surgeon and the patient. In all Lynch syndrome patients who have undergone a partial surgical resection of the colon, endoscopic surveillance should be the mainstay of follow-up.

An estimated 7% to 10% of people have a first-degree relative with colorectal cancer,[261,262] and approximately twice that many have either a first-degree or a second-degree relative with colorectal cancer.[262,263] A simple family history of colorectal cancer (defined as one or more close relatives with colorectal cancer in the absence of a known hereditary colon cancer) confers a twofold to sixfold increase in risk. The risk associated with family history varies greatly according to the age of onset of colorectal cancer in the family members, the number of affected relatives, the closeness of the genetic relationship (e.g., first-degree relatives), and whether cancers have occurred across generations.[261,264] A positive family history of colorectal cancer appears to increase the risk of colorectal cancer earlier in life such that at age 45 years, the annual incidence is more than three times higher than that in average-risk people; at age 70 years, the risk is similar to that in average-risk individuals.[261] The incidence in a 35- to 40-year-old is about the same as that of an average-risk person at age 50 years. There is no evidence to suggest that colorectal cancer in people with one affected first-degree relative is more likely to be proximal or is more rapidly progressive.

A personal history of adenomatous polyps confers a 15% to 20% risk of subsequently developing polyps [265] and increases the risk of colorectal cancer in relatives.[266] The RR of colorectal cancer, adjusted for the year of birth and sex, was 1.78 for the parents and siblings of the patients with adenomas as compared with the spouse controls (95% CI, 1.18–2.67). The RR for siblings of patients in whom adenomas were diagnosed before age 60 years was 2.59 (95% Cl, 1.46–4.58), as compared with the siblings of patients who were 60 years or older at the time of diagnosis and after adjustment for the sibling's year of birth and sex, as well as a parental history of colorectal cancer.

While familial clusters of colorectal cancers account for approximately 20% of all colorectal cancer cases in developed countries,[267] the rare and highly penetrant Mendelian colorectal cancer diseases contribute to only a fraction of familial cases, which suggests that other genes and/or shared environmental factors may contribute to the remainder of the cancers. Two studies attempted to determine the degree to which hereditary factors contribute to familial colorectal cancers.

The first study utilized the Swedish, Danish, and Finnish twin registries that cumulatively provided 44,788 pairs of same-sex twins (for men: 7,231 monozygotic [MZ] and 13,769 dizygotic [DZ] pairs; for women: 8,437 MZ and 15,351 DZ pairs) to study the contribution of heritable and environmental factors involved in 11 different cancers.[268] The twins included in the study all resided in their respective countries of origin into adulthood (>50 years). Cancers were identified through their respective national cancer registries in 10,803 individuals from 9,512 pairs of twins. The premise of the study was based on the fact that MZ twins share 100% and DZ twins share 50% of their genes on average for any individual twin pair. This study calculated that heritable factors accounted for 35%, shared environmental factors for 5%, and nonshared environmental factors for 60% of the risk for colorectal cancer. For colorectal cancer, the estimated heritability was only slightly greater in younger groups than in older groups. This study revealed that though nonshared environmental factors constitute the major risk for familial colorectal cancer, heredity plays a larger-than-expected role.

The second study utilized the Swedish Family-Cancer Database, which contained 6,773 and 31,100 colorectal cancers in offspring and their parents, respectively, from 1991 to 2000.[269] The database included 253,467 pairs of spouses, who were married and lived together for at least 30 years, and who were used to control for common environmental effects on cancer risk. The overall standardized incidence ratio (SIR) for cancers of the colon, rectum, and colon and rectum combined in the offspring of an affected parent was 1.81 (95% CI, 1.62–2.02), 1.74 (95% CI, 1.53–1.96), and 1.78 (95% CI, 1.53–1.96), respectively. The risk conferred by affected siblings was also significantly elevated. Because there was no significantly increased risk of colorectal cancer conferred between spouses, the authors concluded that heredity plays a significant role in familial colorectal cancers; however, controls for shared environmental effects among siblings were absent in this study.

Ten percent to 15% of persons with colorectal cancer and/or colorectal adenomas have other affected family members,[261,262,264-266,270-275] but their findings do not fit the criteria for FAP, and their family histories may or may not meet clinical criteria for Lynch syndrome. Such families are categorized as having FCC, which is currently a diagnosis of exclusion (of known hereditary colorectal cancer disorders). The presence of colorectal cancer in more than one family member may be caused by hereditary factors, shared environmental risk factors, or even chance. Because of this etiologic heterogeneity, understanding the basis of FCC remains a research challenge.

Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in FCC families,[276] with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas.[275] A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2.[277] A more recent study has linked three potential loci in FCC families on chromosomes 11, 14, and 22.[278]

Families meeting Amsterdam-I criteria for Lynch syndrome who do not show evidence of defective MMR by MSI testing do not appear to have the same risk of colorectal or other cancers as those families with classic Lynch syndrome and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as FCC Type X,[279-283] and it has been suggested that these families be classified as a distinct group.

Clinically, the age of onset of colorectal cancer in FCC Type X is older than in Lynch syndrome (55 years vs. 41 years), and the lifetime risk of cancer is substantially lower. The SIR for colorectal cancer among families with intact MMR (Type X families) was 2.3 (95% CI, 1.7–3.0) in one large study, compared with 6.1 (95% CI, 5.7–7.2) in families with defective mismatch repair (Lynch syndrome families).[279] The risk of extracolonic tumors was also not found to be elevated for the Type X families, suggesting that enhanced surveillance for colorectal cancer was sufficient. Although further studies are required, tumors arising within Type X families also appear to have a different pathologic phenotype, with fewer tumor-infiltrating lymphocytes than those from families with Lynch syndrome.[281]

There are no controlled comparisons of screening in people with a mild or modest family history of colorectal cancer. Most experts, if they accept that average-risk people should be screened starting at age 50 years, suggest that screening should begin earlier in life (e.g., at age 35 to 40 years) when the magnitude of risk is comparable to that of a 50-year-old. Because the risk increases with the extent of family history, there is room for clinical judgment in favor of even earlier screening, depending on the details of the family history. Some experts suggest shortening the frequency of the screening interval to every 5 years, rather than every 10 years.[106]

A common but unproven clinical practice is to initiate colorectal cancer screening 10 years before the age of the youngest colorectal cancer case in the family. There is neither direct evidence nor a strong rational argument for using aggressive screening methods simply because of a modest family history of colorectal cancer.

These issues were weighed by a panel of experts convened by the American Gastroenterological Association (AGA) before publishing clinical guidelines for colorectal cancer screening, including those for persons with a positive family history of colorectal cancer.[241] These guidelines have been endorsed by a number of other organizations.

The American Cancer Society (ACS) and the U.S. Multi-Society Task Force on Colorectal Cancer have published guidelines for average-risk individuals.[106,284] The recommendations for screening average-risk persons (asymptomatic, older than 50 years, with no other risk factors) include the following options:

• Fecal occult blood screening each year (Level of evidence: 1) and/or screening flexible sigmoidoscopy every 5 years (Level of evidence: 2), followed by colonoscopy if adenomatous polyps or blood in the stool is found;
• Double contrast barium enema every 5 to 10 years (Level of evidence: 5); or
• Colonoscopy every 10 years (Level of evidence: 3).

Individuals with a first-degree relative diagnosed before age 60 years with colorectal cancer or adenoma should be offered full-colon screening beginning at age 60 years or 10 years prior to the earliest diagnosis in the family (Level of evidence: 5).

Peutz-Jeghers syndrome (PJS) is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, and the perioral and buccal regions, and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[285-287] Germline mutations in the STK11 gene at chromosome 19p13.3, which appears to function as a tumor suppressor gene,[288] have been identified in approximately half of PJS families.[289-292] A study of 419 individuals with PJS (297 of whom had a documented STK11/LKB1 mutation) reported that 85% of individuals developed cancer by age 70. In comparison, the highest cumulative risk of developing noncutaneous cancer by age 70 was for breast cancer (45%), colorectal cancer (39%); uterine, ovarian, cervical and other gynecologic cancers (18%); and pancreatic cancer (11%). No statistical difference in cancer risk was found in individuals according to their mutation status.[4]

Juvenile polyposis syndrome (JPS) is a genetically heterogeneous, rare, childhood-onset, autosomal dominant disease that presents characteristically as hamartomatous polyposis throughout the GI tract and can present with diarrhea, GI tract hemorrhage, and protein-losing enteropathy.[293,294] While most patients with juvenile polyposis appear to represent sporadic illness, this may be due to reduced penetrance. Juvenile polyposis syndrome is due to germline mutations in the MADH4 gene, also known as SMAD4/DPC4, at chromosome 18q21 [295] in approximately 15% to 20% of cases, and to mutations in the gene-encoding bone morphogenic protein receptor 1A (BMPR1A) residing on chromosome band 10q22 in approximately 25% to 40% of cases.[296,297] The lifetime colorectal cancer risk in JPS has been reported to be 39%.[298]

Hereditary mixed polyposis syndrome (HMPS) is a rare cancer family syndrome characterized by the development of a variety of colon polyp types, including serrated adenomas, atypical juvenile polyps, and adenomas, as well as colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14.[299,300] While there is considerable phenotypic overlap between JPS and HMPS, one large family has been linked to a locus on chromosome 15, raising the possibility that this may be a distinct disorder.

Evidence demonstrates that a subset of families with hereditary breast and colon cancer may have a cancer family syndrome caused by a mutation in the CHEK2 gene.[301-303] Although the penetrance of CHEK2 mutations is clearly less than 100%, additional studies are needed to determine the risk of breast, colon, and other cancers associated with CHEK2 germline mutations. One large study showed that truncating mutations in CHEK2 were not significantly associated with colorectal cancer; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR] = 1.5; 95% Cl 1.2–3.0) of colorectal cancer.[304]

Isolated and multiple hyperplastic polyps (typically white, flat, and small) are common in the general population and their presence does not suggest an underlying genetic disorder. The clinical diagnosis of hyperplastic polyposis syndrome (HPPS), as defined by the World Health Organization (WHO), must satisfy one of the following criteria:

• At least five histologically diagnosed hyperplastic polyps (HP) occurring proximal to the sigmoid colon (of which at least two are >10 mm in diameter).
• One HP occurring proximal to the sigmoid colon in an individual who has at least one first-degree relative with hyperplastic polyposis.
• Greater than 30 HPs distributed throughout the colon.[305]

These WHO criteria are based on expert opinion; there is no known susceptibility gene or genomic region that has been reproducibly linked to this disorder, so genetic diagnosis is not possible. Although the vast majority of cases of HPPS lack a family history of HPs, approximately half of HPPS cases have a positive family history for colorectal cancer.[306,307] Several studies show that the prevalence of colorectal adenocarcinoma in patients with formally defined criteria for HPPS is 50% or more.[308-312]

Only one study to date has linked a germline mutation with HPPS. In a recent study of 38 patients with more than 20 HPs, a large (>1 cm) HP, or HPs in the proximal colon, molecular alterations were sought in the base-excision repair genes MBD4 and MYH.[306] One patient was found to have biallelic MYH mutations, and thus was diagnosed with MYH-associated polyposis. No pathogenic mutations were detected in MBD4 among 27 patients tested. However, six patients had single nucleotide polymorphisms of uncertain significance. Only two patients had a known family history of HPPS, and ten of the 38 patients developed colorectal cancer. This series presumably included patients with sporadic HPs mixed in with other patients who may have HPPS.

In a cohort of 40 HPPS patients, defined as having more than five HPs or more than three HPs, two of which were larger than 1 cm in diameter, one patient was found to have a germline mutation in the EPHB2 gene (D861N).[313] The patient had serrated adenomas and more than 100 HPs in her colon at age 58 years, and her mother died of colon cancer at age 36 years. EPHB2 germline mutations were not found in 100 additional patients with a personal history of colorectal cancer or in 200 population-matched healthy control patients.

The EPHB2 gene is a target of the Wnt/beta-catenin signaling pathway and is important in the compartmentalization of intestinal epithelial cell proliferation to the intestinal crypts. When mice with disruption of the Ephb2 gene were bred with Apc^min/+ mice, tumor progression was accelerated suggesting that Ephb2 is a tumor suppressor whose loss of expression in the colon enhances adenoma progression.[314]

Far more is known about the somatic molecular genetic alterations found in the colonic tumors occurring in HPPS patients. In a study of patients with either more than 20 HPs per colon, more than four HPs larger than 1 cm in diameter, or multiple (5–10) HPs per colon, a specific somatic BRAF mutation (V599E) was found in polyp tissue.[315] Fifty percent (20 of 40) of HPs from these patients demonstrated the V599E BRAF mutation. The HPs from these patients also demonstrated significantly higher CpG island methylation phenotypes (CIMP-high), and fewer KRAS mutations than left-sided sporadic HPs. In a previous study from this group, HPs from patients with HPPS showed a loss of chromosome 1p in 21% (16 of 76) versus 0% in HPs from patients with large HPs (>1 cm), or only five to ten HPs.[309]  [Note: The V559E mutation has also been published as V600E due to differences in counting bases.]

Many of the genetic and histological alterations found in HPs of patients with HPPS are common with the recently defined CIMP pathway of colorectal adenocarcinoma. The CIMP pathway (identified molecularly by hypermethylation of specific genes such as CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) is characterized histologically by a hyperplastic polyp-serrated adenoma-adenocarcinoma sequence.[316] BRAF mutations are more commonly associated with the right colon and methylation of p16^INK and MINT31.[315]

There are no data upon which to base recommendations for monitoring individuals for extracolonic cancers in these rare disorders. One must employ one's best clinical judgment in the context of the pattern of disease displayed in each family.

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