Major Genetic Syndromes

Introduction
Familial Adenomatous Polyposis (FAP)
        Density of colonic polyposis
        Extracolonic tumors
        Genetic testing for FAP
        Interventions/FAP
Attenuated Familial Adenomatous Polyposis (AFAP)
MYH-Associated Polyposis (MAP)
Lynch Syndrome (LS)
        Criteria for defining LS families
        Genetic/Molecular testing for LS
        Interventions/LS
        Chemoprevention in LS
        Screening for endometrial cancer in LS families
        Risk-reducing surgery in LS
Advances in Endoscopic Imaging in Hereditary CRC
Familial CRC
        Familial CRC type X
        Interventions/family history of CRC
Rare Colon Cancer Syndromes
        Peutz-Jeghers syndrome (PJS)
        Juvenile polyposis syndrome (JPS)
        Hereditary mixed polyposis syndrome (HMPS)
        CHEK2
        Hyperplastic polyposis syndrome (HPPS)
        Interventions/rare colon cancer syndromes

Introduction

Originally described in the 1800s and 1900s by their clinical findings, the colon cancer susceptibility syndrome names often reflected the physician or patient/family associated with the syndrome (e.g., Gardner syndrome, Turcot syndrome, Muir-Torre syndrome, Lynch I and II syndromes, Peutz-Jeghers syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Cowden syndrome). These syndromes were associated with an increased lifetime risk of colorectal adenocarcinoma. They were mostly thought to have autosomal dominant inheritance patterns. Adenomatous colonic polyps were characteristic of the first five, while hamartomas were found to be characteristic in the last three.

With the development of the Human Genome Project and the identification in 1990 of the Adenomatous Polyposis Coli gene on chromosome 5q, overlap and differences between these familial syndromes became apparent. Gardner syndrome and familial adenomatous polyposis (FAP) were shown to be synonymous, both caused by mutations in the APC gene. Attenuated FAP (AFAP) was recognized as a syndrome with less adenomas and extraintestinal manifestations as having FAP mutation on the 3’ and 5’ ends of the gene. Turcot syndrome families were shown to genetically be part of FAP with medulloblastomas and Lynch syndrome (LS) with glioblastomas. Muir-Torre and LS were shown to have genetic similarities. MYH-associated polyposis (MAP) was recognized as a separate adenomatous polyp syndrome with autosomal recessive inheritance. Once the mutations were identified, the absolute risk of colorectal cancer (CRC) could be better assessed for mutation carriers (Table 4).

Table 4. Absolute Risks of Colorectal Cancer for Mutation Carriers in Hereditary Colorectal Cancer Syndromes

Syndrome	Absolute Risk in Mutation Carriers
FAP	90% by age 45 y [1]
Attenuated FAP	69% by age 80 y [2]
Lynch	40% to 80% by age 75 ya [3,4]
MYH-associated polyposis	35% to 53% [5]
Peutz-Jeghers	39% by age 70 y [6]
Juvenile polyposis	17% to 68% by age 60 y [7,8]

FAP = familial adenomatous polyposis.

aRefer to the Lynch syndrome section of this summary for a full discussion of risk.

With these discoveries genetic testing and risk management became possible. 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 amplification [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.

Familial Adenomatous Polyposis (FAP)

FAP is one of the most clearly defined and well understood of the inherited colon cancer syndromes.[1,9,10] 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.[11] 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, 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. Refer to Table 5 for more information.

Table 5. Extracolonic Tumor Risks in Familial Adenomatous Polyposis

Malignancy	Relative Risk	Absolute Lifetime Risk (%)
Desmoid	852.0	15.0
Duodenum	330.8	5.0–12.0
Thyroid	7.6	2.0
Brain	7.0	2.0
Ampullary	123.7	1.7
Pancreas	4.5	1.7
Hepatoblastoma	847.0	1.6
Gastric	—	0.6a

Adapted from Giardiello et al.,[12] Jagelman et al.,[13] Sturt et al.,[14] Lynch et al.,[15] Bülow et al.,[16] Burt et al.,[17] and Galiatsatos et al.[18]

aThe Leeds Castle Polyposis Group.

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.[19]

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%.[1,9,10] 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.[1,9,10,20,21] Without any intervention, most persons with FAP will develop colon or rectal cancer by the fourth decade of life.[1,9,10] 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.[22,23]

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.[24] 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: Lynch Syndrome 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.

Density of colonic polyposis

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 Familial Adenomatous Polyposis (AFAP) section of this summary for more information.)

Extracolonic tumors

Desmoid tumors

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.[25] Desmoids may occur sporadically, as part of classical FAP, or in a hereditary manner without the colon findings of FAP.[15,26] Desmoids have been associated with hereditary APC gene mutations even when not associated with typical adenomatous polyposis of the colon.[26,27]

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.[26,28,29] APC mutations occurring between codons 1445 and 1578 have been associated with an increased incidence of desmoid tumors in FAP patients.[27,30-32] 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.[26]

A desmoid risk factor scale has been described in an attempt to identify patients who are likely to develop desmoid tumors.[33] The desmoid risk factor scale was based on gender, presence or absence of extracolonic manifestations, family history of desmoids, and genotype, if available. By utilizing this scale, it was possible to stratify FAP patients into low-, medium-, and high-risk groups for developing desmoid tumors. It was concluded that the desmoid risk factor scale could be used for surgical planning. Validation of the risk factors comprising this scale were recently supported by a large, multiregistry, retrospective study from Europe.[34]

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.[35] It is estimated that 10% of desmoids resolve, 50% remain stable for prolonged periods, 30% fluctuate, and 10% grow rapidly.[36] 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.[37,38]

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.[29] In some series, desmoids are the second most common cause of death after CRC in FAP patients.[39,40] A staging system has been proposed to facilitate the stratification of intra-abdominal desmoids by disease severity.[41] 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.[41]

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.[28,36,42]

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 antiestrogens, 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.[43-45] There are anecdotal reports of using imatinib mesylate to treat desmoid tumors in FAP patients; however, further studies are needed.[46] 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.[47]

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.[43] 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 and 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 and 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.[44] 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.[45] 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.[48] A recent review of one hospital's experience suggested that surgical outcomes with intra-abdominal desmoids may be better than previously believed.[48,49] Issues of subject selection are critical in evaluating surgical outcome data.[49] Abdominal wall desmoids can be treated with surgical resection, but the recurrence rate is high.

Stomach tumors

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.[16,18,50-54] These polyps consist of distorted fundic glands containing microcysts lined with fundic-type epithelial cells or foveolar mucous cells.[55,56]

The hyperplastic surface epithelium is, by definition, nonneoplastic. 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.[18,57] In one FAP series, focal dysplasia was evident in the surface epithelium of FGPs in 25% of patients versus 1% of sporadic FGPs.[56] In a prospective study of patients with FAP undergoing surveillance with esophagogastroduodenoscopy, 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. In the author's view, if a polyp with high-grade dysplasia is identified, polypectomy can be considered with repeat endoscopic surveillance in 3 to 6 months. Consideration for treatment with daily proton-pump inhibitors also may be given.[58]

Complicating the issue of differential diagnosis, FGPs have been increasingly recognized in non-FAP patients consuming proton pump inhibitors (PPIs).[56,59] 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%.[60-63] 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.[64-67] 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

Duodenum/small bowel tumors

Whereas the incidence of duodenal adenomas is only 0.4% in patients undergoing upper gastrointestinal (GI) endoscopy,[68] 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.[50,51,69] There is a 4% to 12% lifetime incidence of duodenal adenocarcinoma in FAP patients.[13,66,70,71] 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.[16] 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.[72-74] One study of computed tomography (CT) duodenography found that larger adenoma size could be accurately measured but smaller, flatter adenomas could not be accurately counted.[75]

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.[76] 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.[70] 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.[77,78]

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.[16,71,79,80] 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.[80] According to this system, known as the Spigelman Classification (see Table 6), 36% of patients with the most advanced stage will develop carcinoma.[71]

Table 6. Spigelman Classification

Points	Polyp Number	Polyp Size (mm)	Histology	Dysplasia
Stage I, 1–4 points; Stage II, 5–6 points; Stage III, 7–8 points; Stage IV, 9–12 points[80]
1	1–4	1–4	Tubular	Mild
2	5–20	4–10	Tubulovillous	Moderate
3	>20	>10	Villous	Severe

A baseline upper endoscopy, including side-viewing duodenoscopy, should be performed between ages 25 and 30 years in FAP patients.[67] The subsequent intervals between endoscopy vary according to the findings of the previous endoscopy, often, based on Spigelman stage. Recommended intervals are based on expert opinion although the relatively liberal intervals for stage 0-II disease are based in part on the natural history data generated by the Dutch/Scandinavian duodenal surveillance trial.[16] Refer to Table 7 for more information.

The main advantages of the Spigelman Classification are its long-standing familiarity to and usage by those in the field, which allows reasonable standardization of outcome comparisons across studies.[63,81] However, there are several limitations on attempted application of the Spigelman Classification:

• Most pathologists do not currently employ the term moderate dysplasia, preferring a simpler low- versus high-grade dysplasia system.
• Because of the villous nature of normal duodenal epithelium, pathologists commonly disagree over the classification of “tubular,” “tubulovillous,” and “villous.”
• Spigelman staging requires biopsy, which is not always essential when only a few small plaques are present; conversely, for larger adenomas, sampling variation leads to understaging.[82,83]

Table 7. Recommended Screening Intervals by Spigelman Stage

Spigelman Stage	NCCN [84]	Groves et al. [71]
0 (no polyps)	Endoscopy every 4 y	Endoscopy every 5 y
I	Endoscopy every 2–3 y	Endoscopy every 5 y
II	Endoscopy every 1–3 y	Endoscopy every 3 y
		CP + ET
III	Endoscopy every 6–12 mo	Endoscopy every 1–2 y
		CP + ET (+/- GA)
IV	Surgical referral	Surgical resection
	Complete mucosectomy or duodenectomy or Whipple procedure if duodenal papilla is involved
	OR	OR
	Endoscopy every 3–6 mo	Endoscopy every 1–2 y
		CP + ET (+/- GA)

CP = chemoprevention; ET = endoscopic therapy; GA = general anesthetic; NCCN = National Comprehensive Cancer Network.

Refer to the Interventions/FAP section in the Major Genetic Syndromes section of this summary for more information about chemoprevention.

Refer below for additional information about the use of surgical resection in Spigelman stage IV disease.

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;[77,78,85] however, patients managed with endoscopic resection of adenomas remain at substantial risk of developing recurrent adenomas in the duodenum.[82] 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.[86] In a series of 47 patients with FAP and Spigelman stage III or stage IV disease who underwent definitive radical surgery, the local recurrence rate was reported to be 9% at a mean follow-up of 44 months. This local recurrence rate is dramatically lower than any local endoscopic or surgical approach from the same study.[82] Pancreaticoduodenectomy and pancreas-sparing duodenectomy are appropriate surgical therapies that are believed to substantially reduce the risk of developing periampullary adenocarcinoma.[83,86-88] 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. As noted in a Northern European study,[16] and others,[89,90] the vast majority of patients with duodenal adenomas will not develop cancer and can be followed with endoscopy. However, individuals with advanced adenomas (Spigelman stage III or stage IV disease) generally require endoscopic or surgical treatment of the polyps. Chemoprevention studies for duodenal adenomas in FAP patients are currently under way and may offer an alternate strategy in the future.

The endoscopic approach to larger and/or flatter adenomas of the duodenum depends on whether the ampulla is involved. Endoscopic mucosal resection (EMR) following submucosal injection of saline, with or without epinephrine and/or dye, such as indigo carmine, can be employed for nonampullary lesions. Ampullary lesions require even greater care including endoscopic ultrasound evaluation for evidence of bile or pancreatic duct involvement. Stenting of the pancreatic duct is commonly performed to prevent stricturing and pancreatitis. The stents require endoscopic removal at an interval of 1 to 4 weeks. Because the ampulla is tethered at the ductal orifices, it typically does not uniformly “lift” with injection, so injection is commonly not used. Any consideration of EMR or ampullectomy requires great experience and judgment, with careful consideration of the natural history of untreated lesions and an appreciation of the high rate of adenoma recurrence despite aggressive endoscopic intervention.[78,82,83,87,91-94] The literature uniformly supports duodenectomy for Spigelman stage IV disease. For Spigelman stage II and III disease, there is a role for endoscopic treatment invariably focusing on the one or two worst lesions that are present.

Reluctance to consider surgical resection has to do with short-term morbidity and mortality and long-term complications related to surgery. Although these concerns are likely overstated,[82,83,88,91,95-101] fear of surgical intervention can lead to aggressive and somewhat ill-advised endoscopic interventions. In some circumstances, endoscopic resection of ampullary and/or other duodenal adenomas cannot be accomplished completely or safely by endoscopic means, and duodenectomy cannot be accomplished without risking a short-gut syndrome or cannot be done at all because of mesenteric fibrosis. In such cases, surgical transduodenal ampullectomy/polypectomy can be performed. This is, however, associated with a high risk of local recurrence similar to that of endoscopic treatment.

Level of evidence: 3diii

Other tumors

The spectrum of tumors arising in FAP is summarized in Table 5.

Papillary thyroid cancer has been reported to affect 1% to 2% of patients with FAP.[102] However, a recent study [103] 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. Although level 1 evidence is lacking, a consensus opinion recommends annual thyroid examinations beginning in the late teenage years to screen for papillary thyroid cancer in patients with FAP. The same panel suggests clinicians could consider the addition of annual thyroid ultrasounds to this screening routine.[84,104,105]

Adrenal tumors have been reported in FAP patients, and one study demonstrated LOH in an adrenocortical carcinoma in an FAP patient.[106] In a study of 162 FAP patients who underwent abdominal CT for evaluation of intra-abdominal desmoid tumors, 15 patients (11 females) were found to have adrenal tumors.[107] 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.[107] 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.[108-117] Some series have also demonstrated LOH of APC in these tumors.[109,111,118] No specific genotype-phenotype correlations have been identified in FAP patients with hepatoblastoma.[119] Although lacking level 1 evidence, a consensus panel has recommended abdominal examination, abdominal ultrasound, and measurement of serum alpha fetoprotein every 3 to 6 months for the first 5 years of life in children with a predisposition to FAP.[84,120]

The constellation of CRC 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 (MMR) genes.[121]

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.

Genetic testing for FAP

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 [21] and direct detection [122] 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.[123]

Studies have reported whole exon deletions in 12% of FAP patients with previously negative APC testing.[124,125] 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.[126] MYH gene testing may be considered in APC mutation–negative affected individuals.[127] (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 AFAP and MYH-associated colorectal neoplasia (also reported as MYH-associated polyposis or MAP).[128] AFAP can be diagnosed by testing for germline APC gene mutations. (Refer to the Attenuated Familial Adenomatous Polyposis (AFAP) section in the Major Genetic Syndromes section of this summary for more information.) MYH-associated neoplasia is caused by germline homozygous recessive mutations in the MYH gene.[129]

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,[20] though all experts agree that at least one flexible sigmoidoscopy or colonoscopy examination should be performed in early adulthood (by age 18–25 years).[20,21] 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.

Interventions/FAP

Individuals at risk of FAP, because of a known APC mutation in either the family or themselves, are evaluated for onset of polyposis by flexible sigmoidoscopy or colonoscopy. Once an FAP family member is found to manifest polyps, the only effective management to prevent CRC is eventual colectomy. In patients with classic FAP identified very early in their course, the surgeon, endoscopist, and family may choose to delay surgery for several years in the interest of achieving social milestones. In addition, in carefully selected patients with AFAP (those with minimal polyp burden and advanced age), deferring a decision about colectomy may be reasonable with surgery performed only in the face of advancing polyp burden or dysplasia.

The recommended age at which surveillance for polyposis 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, CRC 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 has consisted of either flexible sigmoidoscopy or colonoscopy every year.[84,130,131] If flexible sigmoidoscopy is utilized and polyps are found, colonoscopy should be performed. Historically, sigmoidoscopy may have been a reasonable approach at the time in identifying early adenomas in a majority of the patients. However, colonoscopy must be considered the tool of choice in light of (a) improved instrumentation for full colonoscopy, (b) safer and deeper sedation (Propofol), (c) recognition of AFAP, in which the disease is typically most manifest in the right colon, and (d) the growing tendency to defer surgery for a number of years. Individuals who have tested negative for an otherwise known family mutation do not need FAP-oriented surveillance at all. They are recommended to undergo average-risk population screening. In the case of families in which no family mutation has been identified in an affected person, then clinical surveillance is warranted. Colon surveillance should not be stopped in persons who are known to carry an APC mutation but who do not yet manifest polyps, since adenomas occasionally are not manifest until the fourth and fifth decades of life. (Refer to the Attenuated Familial Adenomatous Polyposis (AFAP) section of this summary for more information.) (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.[84,132]

Table 8 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance of FAP.

Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP)

Organization	APC Gene Test Recommended	Age Screening Initiated	Frequency	Method	Comment
American Cancer Society [133]	NA	Puberty	NA	Endoscopy	Referral to a center specializing in FAP screening suggested.
American Society of Colon and Rectal Surgeons [134-136]	Yes	NA	NA	NA
GI Societiesa [130]	Yes	10–12 y	Annual	FS
NCCN [84]	Yes	10–15 y	Annual	FS or C	Consider MYH mutation testing if APC testing is negative and family history is compatible with recessive inheritance; in families in which no mutation is found, offspring of those affected are screened as if they were carriers.

C = colonoscopy; FS = flexible sigmoidoscopy; GI = gastrointestinal; NA = not addressed; NCCN = National Comprehensive Cancer Network.

aGI Societies – American Academy of Family Practice, American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy.

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.[137] 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.[138] 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.[139]

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 of 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 and by case reports of adenocarcinoma in the ileoanal pouch and anal canal after restorative proctocolectomy.[140-143] 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.[138] 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, and the duration of follow-up after IRA.[144-150]

In most cases, the clinical polyp burden in the rectum at the time of surgery dictates the type of surgical intervention, namely restorative proctocolectomy with IPAA versus IRA. Patients with a mild phenotype (<1,000 colonic adenomas) and fewer than 20 rectal polyps may be candidates for IRA at the time of prophylactic surgery.[151] In some cases, however, the polyp burden is equivocal, and in such cases, investigators have considered the role of genotype in predicting subsequent outcomes with respect to the rectum.[152] 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.[149,140,150,153] 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.[154,155] Although they are rare, carcinomas have been reported in the ileal pouch and anal transition zone after restorative proctocolectomy in FAP patients.[156] 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.[157]

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.[158-160] 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 CRC 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.[161]

A small, randomized, placebo-controlled, dose-escalation trial of celecoxib in a pediatric population (aged 10–14 years) demonstrated the safety of celecoxib at all dosing levels when administered over a 3-month period.[162] This study found a dose-dependent reduction in adenomatous polyp burden. At a dose of 16 mg/kg/day (which approximates the approved dose of 400 mg twice daily in adults), the reduction in polyp burden paralleled that demonstrated with celecoxib in adults.

Omega-3-polyunsaturated fatty acid eicosapentaenoic acid in the free fatty acid form has been shown to reduce rectal polyp number and size in a small study of patients with FAP post subtotal colectomy.[163] Although not directly compared in a randomized trial, the effect appeared to be similar in magnitude to that previously observed with celecoxib.

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.[160]

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.[164] A previous randomized study of 24 FAP patients treated with sulindac for 6 months showed a nonsignificant trend in the reduction of duodenal polyps.[165] 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).[164]

Because of reports demonstrating an increase in cardiac-related events in patients taking rofecoxib and celecoxib,[166-169] it is unclear whether this class of agents will be safe for long-term use for patients with FAP and in the general population. Also, because of the short-term (6 months) 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, CRC incidence.[170]

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.[9,22] The severity of duodenal polyposis detected appears to correlate with risk of duodenal adenocarcinoma.[71] (Refer to the Duodenum/small bowel tumors section and the Other tumors section in the Major Genetic Syndromes section of this summary for more information about screening for extracolonic malignancies in patients with FAP.)

Attenuated Familial Adenomatous Polyposis (AFAP)

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.[171] Adenomas in AFAP are believed to form in the mid-twenties to late twenties.[57] Similar to classic FAP, the risk of CRC is higher in individuals with AFAP; the average age at diagnosis, however, is older than classic FAP at 56 years.[172-174] Extracolonic manifestations similar to those in classic FAP also occur in AFAP. These manifestations include upper GI polyps (fundic gland polyps, duodenal adenomas, and duodenal adenocarcinoma), osteomas, epidermoid cysts, and desmoids.[57]

AFAP is associated with particular subsets of APC mutations, including missense changes. Three groups of site-specific APC mutations causing AFAP have been characterized:[172,173,175-178]

• 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 GI 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.[132] It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided.[132] The role for and timing of risk-reducing colectomy in AFAP is controversial.[179] If germline APC mutation testing is negative in suspected AFAP individuals, genetic testing for MYH mutations may be warranted.[124]

Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[180,181] In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MAP), LS, or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or LS.

MYH-Associated Polyposis (MAP)

MAP is an autosomal recessive inherited polyposis syndrome. The MYH gene was first identified in 2002 in three siblings with multiple colonic adenomas and CRC but no APC mutation.[129] MAP has a broad clinical spectrum. Most often it resembles the clinical picture of AFAP, but it has been reported in individuals with phenotypic resemblance to classical FAP and LS.[182] MAP patients tend to develop fewer adenomas at a later age than patients with APC mutations [127,183] and also carry a high risk of CRC (35%–53%).[5] This broad clinical presentation results from the MYH gene's ability to cause disease in its homozygous or compound heterozygous forms. Based on studies from multiple FAP registries, approximately 7% to 19% of patients with a FAP phenotype and without a detectable APC germline mutation carry biallelic mutations in the MYH gene.[5,127,184,185]

Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients. The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC.[186] The Mallorca group and NCCN have established clinical management guidelines based on available literature. These guidelines are generally consistent but have some differences related to age at initiation of surveillance. NCCN recommends beginning initiation at age 25 to 30 years repeated at 3 to 5 year intervals,[84] while the Mallorca group recommends surveillance beginning at age 18 to 20 years with upper-tract surveillance beginning at age 25 to 30 years.[187] The recommended surveillance interval can be based on the burden of involvement according to Spigelman criteria.[187] Total colectomy with ileorectal anastomosis may be appropriate for patients with MYH-associated polyposis, provided that they have no rectal cancer or severe rectal polyposis at presentation and that they undergo yearly endoscopic surveillance thereafter.[188]

Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, and thyroid and skin cancers including melanoma, squamous epithelial, and basal cell carcinomas.[189,190] Additionally, extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[127,190-192] Female MAP patients have an increased risk of breast cancer.[193] These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or LS.[194,195]

Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying a biallelic MYH mutation and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.

The clinical phenotype of monoallelic MYH mutations is less well characterized with respect to incidence and associated clinical phenotypes, and their role in pathogenesis of polyposis coli and colorectal carcinoma remains controversial. Approximately 1% to 2% of the general population carry a deleterious mutation in MYH.[5,127,129] In one cohort of 215 APC mutation-negative patients, eight monoallelic MYH mutation carriers had a later mean age at diagnosis (average 48 years compared with 43 years in MAP) and a high CRC incidence rate of 50%.[185] Monoallelic mutations were found in four patients with polyposis coli with 10 to 100 adenomas and in four patients with fewer than 10 adenomas; none of the monoallelic MYH mutation carriers had manifestation in the upper GI tract.[185] This is in contrast to past reports of extracolonic polyposis in 22% of monoallelic MYH mutation carriers.[196,197] The literature reports up to 4.4% frequency of monoallelic MYH carriers in CRC patients.[198] This incidence rate is above the carrier frequency in the general population (0%–2.1%),[199] suggesting a causative involvement in CRC. The risk of CRC in heterozygous carriers of single MYH mutations who are relatives of patients with MAP is comparable with that of first-degree relatives of patients with sporadic CRC.[183] Screening measures for monoallelic carriers could be based on this modest increase in risk (standardized incidence ratio [SIR] = 2.12; 95% confidence interval [CI], 1.30–3.28).[183] However, a 2007 meta-analysis of all previous case-control studies failed to support an increased risk of CRC in monoallelic MYH mutation carriers.[200]

MMR genes may interact with MYH and increase the risk of CRC. An association between MYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 mutations in monoallelic MYH mutation carriers with CRC compared to noncarriers (11.5% vs. 0%; P = .037).[201]

Lynch Syndrome (LS)

Between 1900 and 1990, numerous case reports of families with apparent increases in CRC were reported. As series of such reports accumulated, certain characteristic clinical features emerged: early age at onset; high risk of second primary tumors; preferential involvement of the right colon; improved clinical outcome; and a range of associated extracolonic sites including the endometrium, ovaries, other sites in the GI tract, uroepithelium, brain, and skin (sebaceous tumors). Terms such as Lynch 1 (families with CRC only), Lynch 2 (families with CRC and extracolonic tumors), cancer family syndrome, and later, hereditary nonpolyposis colorectal cancer (HNPCC), were commonly employed.

By 1990, the need for enhanced surveillance (colonoscopy at an early age and repeated frequently) was recognized. However, the need to limit this aggressive regimen to families most likely to have an inherited susceptibility or “true” HNPCC led to development of the so-called Amsterdam criteria: three or more cases of CRC over two or more generations, with at least one diagnosed before age 50, and no evidence of FAP.

At about this same time, a chromosomal abnormality on 5q led to detecting genetic linkage between FAP and this genomic region, from which the APC gene was eventually cloned. This led to searches for similar linkage in HNPCC. The APC gene was one of several genes (along with DCC and MCC) evaluated and to which no HNPCC linkage was found. An extended genome-wide search resulted in the recognition of a candidate chromosome 2 susceptibility locus in large HNPCC families in 1993. Once the first HNPCC gene was sequenced, MSH2, it was evident (from the somatic mutation patterns in the tumors) that a family of genes, the MMR family, was likely involved. Shortly thereafter, additional MMR genes were identified, including MLH1, MSH6, and PMS2.

Concurrent with the linkage studies, somatic genetic studies of HNPCC tumors showed evidence of characteristic mutations in microsatellite regions of numerous genes, which appeared to be a molecular marker of MMR deficiency. This was characterized with synonyms such as ubiquitous somatic mutations, replication errors, and eventually, the currently-employed term microsatellite instability (MSI). In HNPCC-related tumors showing MSI, there is typically loss of immunohistochemical expression for one or more of the proteins associated with the MMR genes. Since immunohistochemistry (IHC) is relatively easy to perform, it can serve to complement or even supplant MSI screening of suspected HNPCC cases. Although MSI characterizes nearly all HNPCC tumors, it can also occur sporadically in about 12% of CRCs. These cases clearly do not have the inherited disorder HNPCC, since further studies have shown that the MSI is caused by somatic inactivation of the MLH1 protein by hypermethylation of the MLH1 promoter; the sporadic nature of these cases can be confirmed by concurrent detection of somatic BRAF mutations in CRC tumor tissue.

Mutational testing for germline alterations has been somewhat disappointing, as no more than half of suspected HNPCC cases have detectable pathologic mutations. Because of this, and the lack of sufficiently specific clinical features, various genetic screening strategies have emerged to improve the yield of genetic testing. A sufficiently compelling family history, ideally complemented by the presence of MSI, warrants mutational testing, and most clinical practice guidelines provide for such an approach. The Bethesda guidelines are a combination of clinical, pathologic, and family history features that are sufficiently predictive to warrant MSI/IHC screening. Computer risk-assessment profiles have been developed to do this same work more quantifiably and can estimate mutation risk likelihood with or without the intermediate step of using MSI/IHC.

Against this background of potential clinical selection criteria for mutation testing, population studies have emerged that can estimate HNPCC frequency (1%–3%) and determine the performance characteristics of these same selection tools when implemented in otherwise unselected cases.

The combination of genetic counseling/testing strategies with clinical screening/treatment measures has led to the development of consensus clinical practice guidelines. These guidelines can be used by providers and patients alike to better understand the available options and key decision-points that exist. Refer to Table 9 for more information about practice guidelines for diagnosis and colon surveillance in LS.

Terminology related to familial CRC has certainly evolved. Most in the field use the term Lynch syndrome (LS) as a preferred synonym over HNPCC, since HNPCC is both excessively wordy and misleading—many patients do have polyps and many others have tumors other than CRC. In addition, entities such as Muir-Torre syndrome are now recognized as phenotypic variants of LS. Even Turcot syndrome, which was initially thought to only be an FAP variant, is now known to be an LS variant when it presents with glioblastomas and an FAP variant when it presents with medulloblastomas. It has been suggested that the term Lynch syndrome be applied to cases in which the genetic basis can be confidently linked to a germline mutation in a DNA MMR gene (either a germline mutation is present or can be confidently inferred based on the clinical presentation combined with MSI/IHC).[202]

The term familial colorectal cancer type X was coined to refer to families who meet Amsterdam criteria but lack MSI/IHC abnormalities. Maybe a better term will emerge—there are many conditions with “X” in them—but it survives for now since workers in the field at least agree to use it to describe these cases.

In LS,[203-205] unlike FAP, most patients do not have an unusual number of polyps. LS accounts for about 3% to 5% of all CRCs. LS is an autosomal dominant syndrome characterized by an early age of onset of CRC, excess synchronous and metachronous colorectal neoplasms, right-sided predominance, and extracolonic tumors. LS is caused by mutations in the DNA MMR genes, namely MLH1, MSH2, MSH6, and PMS2. Mutations of the EPCAM gene that result in hypermethylation and silencing of MSH2 have also been described. (Refer to the MSI section in the Major Genetic Syndromes section of this summary for more information.) The average age of CRC diagnosis in LS mutation carriers is 44 to 52 years[206-208] and 71 years in sporadic CRC.[209] Even though LS is characterized by an early age of onset of CRC, in mutation-positive families when probands were excluded and both affected and non-affected relatives were ascertained, the average age at diagnosis of CRC was reported to be 61 years.[210]

The lifetime risk of CRC in MLH1 and MSH2 mutation carriers was 68.7% in males and 52% in females.[210] However, in a meta-analysis of three population-based studies and one clinic-based study, the lifetime risk of CRC in MLH1 and MSH2 mutation carriers was reported to be 53% in males and 33% in females.[211,212] In a study of 113 families with MSH6 mutation carriers, the estimated cumulative risk of CRC in males was 22% and 10% in females.[213] PMS2 lifetime CRC risk to age 70 years has been reported to be 20% in males and 15% in females.[214] A large registry-based study from France estimated CRC risk at age 70 years to be 41% for MLH1 mutation carriers, 48% for MSH2 mutation carriers, and 12% for MSH6 mutation carriers.[215]

These data have been largely retrospective and potentially include some biases for that reason. Some prospective data do exist, however. The Colon Cancer Family Registry program followed 446 carriers prospectively and found a 10-year risk of CRC of 8%.[216]

Patients with LS can have synchronous and metachronous colorectal neoplasms and other primary extracolonic malignancies. LS mutation carriers 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 in nonmutation carriers from the same families.[217] Unlike patients with sporadic cancers, whose cancer develops most often in the left side of the colon, approximately two-thirds of LS cancers develop in the right side of the colon, defined as proximal to the splenic flexure.

In addition to CRC, LS patients and their relatives are at risk of a wide variety of other cancers. The most common is endometrial adenocarcinoma, which affects at least one female member in about 50% of LS pedigrees. The lifetime risk of endometrial cancer in MLH1 and MSH2 mutation carriers has been estimated at 44% to 54%.[210-213] Families with a MSH6 mutation have been reported to have an endometrial cancer predominance. Lifetime risk of endometrial cancer in MSH6 mutation carriers in 113 families was estimated to be 26% at age 70 years and 44% at age 80 years.[213] In PMS2 mutation carriers, the endometrial cancer risk at age 70 years has been reported to be 15%.[214] The same prospective data collection in the Colon Cancer Family Registry program yielded 5- and 10-year endometrial cancer risks of about 3% and 10%, respectively, in women from this cohort.[216] Endometrial cancer can be the index cancer in female LS patients. LS-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 LS.[218]

Patients with LS are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis, and cancers of the stomach, small intestine, liver and biliary tract, brain, breast, and ovary.[216,219-223]

Muir-Torre syndrome is considered a variant of LS and includes a phenotype of multiple cutaneous neoplasms (including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas). The skin lesions and CRC define the phenotype,[224,225] and clinical variability is common. Both mutations in the MSH2 and MLH1 genes have been found in Muir-Torre families.[226-228] A study of 1,914 MSH2 and MLH1 unrelated probands found MSH2 to be more common in individuals with the Muir-Torre syndrome phenotype.[229]

Criteria for defining LS families

The research criteria for defining LS families were established by the International Collaborative Group (ICG) meeting in Amsterdam in 1990, and are known as the Amsterdam criteria.[230]

Amsterdam criteria:

1. One member diagnosed with CRC 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 LS families, but they are not considered comprehensive; a number of families who do not meet these criteria, but have germline MMR gene mutations, have been reported.[231,232]

To address these issues and to improve the diagnosis of LS clinically, the ICG developed revised criteria in 1999; these are known as Amsterdam criteria II.[233]

Amsterdam criteria II:

1. There should be at least three relatives with a LS-associated cancer (CRC 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. FAP should be excluded in the CRC cases.
6. Tumors should be verified by pathological examination.

Although these criteria are among the most stringent used to identify potential candidates for microsatellite and germline testing, it must be cautioned that by definition, familial CRC type X includes families meeting Amsterdam criteria but in whom there is no evidence of MSI. (Refer to the Familial CRC type X section in the Major Genetic Syndromes section of this summary for more information.)

A third set of clinical criteria that can be used to identify LS families is the revised Bethesda guidelines.[234] The criteria was expanded to improve sensitivity in identifying families. The Bethesda guidelines are the least stringent for identifying families with germline mutations in one of the MMR genes. Because of lack of specificity for LS, the Bethesda guidelines are utilized to identify individuals whose colorectal tumors should be tested for MSI and/or IHC, rather than to identify families that meet clinical criteria for LS. (Refer to the Genetic/Molecular Testing for LS section in the Major Genetic Syndromes section of this summary for more information about testing for MSI and IHC.)

Revised Bethesda Guidelines for Testing of Colorectal Tumors for MSI:

1. CRC diagnosed in an individual younger than 50 years.

2. Presence of synchronous, metachronous colorectal, or other LS-associated tumors.*

3. CRC with MSI-high (MSI-H) 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. CRC or LS-associated tumor* diagnosed in at least one first-degree relative younger than 50 years.

5. CRC or LS-associated tumor* diagnosed at any age in two first-degree or second-degree relatives.

*LS-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.[234,235]

Research has included CRC families who do not meet Amsterdam criteria for LS and/or in whom the colorectal tumors are microsatellite stable (MSS). A number of these families have been found to have mutations in MSH6.[236-240] While the clinical significance and implications of these findings are not clear, these observations suggest that germline mutations in MSH6 may predispose to late-onset familial CRCs that do not meet Amsterdam criteria for LS and tumors that might not necessarily display MSI.

Genetic/Molecular testing for LS

Genetic risk assessment of LS generally considers the cancer family history and age at diagnosis of CRC and/or other LS-associated cancers in the patient. Studies of gene testing using DNA sequencing in suspected LS probands from a cancer risk assessment clinical setting found that approximately 25% test positive for an informative MSH2 or MLH1 mutation, allowing genetically informed management strategies to be developed for the family.[241,242] Computer models analogous to BRCAPro predict the probability of a MMR gene mutation. PREMM1, PREMM2, PREMM6, and the MMRPro models are easy to use and have been validated.[243-245] Although these models can predict mutation even in the absence of MSI or IHC information, they can incorporate those data as available. All three computer prediction models take family history of endometrial cancer into account. The mutation detection rate is higher for patients with more striking family histories or with informative tumor testing.

In the absence of additional family or personal history suggestive of LS, isolated cases of CRC diagnosed prior to age 36 years are uncommonly associated with MMR gene mutations. One study found MMR mutations in only 6.5% of such individuals.[246] Therefore, isolated cases of very early-onset CRC should be offered tumor screening with MSI/IHC rather than proceeding directly to germline mutation analysis.

MSI/IHC in adenomas

Current practice is to offer colonoscopy surveillance to those with strong family histories but no prior genetic or tumor testing. At times, adenomas are detected during these colonoscopies. In the instance when an adenoma is detected, the question of whether to test the adenoma for MSI/IHC is raised. One study of patients with prior CRC and known MMR mutations found 8 of 12 adenomas to have both MSI and IHC protein loss.[247] However, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude LS.

MSI

Microsatellites are short, repetitive sequences of DNA (often mononucleotides, dinucleotides, or trinucleotides) located throughout the genome, primarily in intronic sequences.[248,249] The term microsatellite instability (MSI) is used when tumor DNA shows alterations in microsatellite regions when compared to normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic or germline mutations or epigenetic alterations.[250] In most instances, MSI is associated with absence of protein expression of one or more of the MMR proteins (MSH2, MLH1, MSH6, and PMS2). However, loss of protein expression may not be seen in all MSI-H tumors.

Certain histopathologic features are strongly suggestive of MSI phenotype including the presence of tumor infiltrating lymphocytes, Crohn-like reaction, mucinous histology, absence of dirty necrosis, and histologic heterogeneity. These histologic features have been combined into computational scores that have high predictive value in identifying MSI CRCs.[251,252]

Because many colon cancers demonstrate frameshift mutations at a small percentage of microsatellite repeats, the designation of an adenocarcinoma showing MSI depends, in part, on the detection of a specified percentage of unstable loci from a panel of dinucleotide and mononucleotide repeats that were selected at a National Institutes of Health Consensus conference.[253] If more than 30% of a tumor's markers are unstable, it is scored as MSI-H; if at least one, but fewer than 30% of markers are unstable, the tumor is designated MSI-low (MSI-L). If no loci are unstable, the tumor is designated MSS. Most tumors arising in the setting of LS will be MSI-H.[253] The clinical relevance of MSI-L tumors remains controversial at this point. The probability of finding a germline mutation in a MMR gene in this setting is very small. One distinction is that people with germline mutations in MSH6 do not necessarily manifest the MSI-H phenotype. One study presented evidence that MSH6 mutations were associated with cancers having an MSI-L phenotype.[238] However, a second study found that 18/21 (86%) of CRCs in MSH6 carriers showed MSI-H.[254] In addition, in sporadic cancers with MSI-L phenotype, MSH6 mutations were not found.[255]

(Refer to the Diagnostic strategies for all individuals diagnosed with CRC section of this summary for information about the utilization of MSI status in the diagnostic work-up of a patient with suspected LS.)

The complexity of aberrant methylation of MMR genes

Aberrant MLH1 methylation in sporadic CRC

The presence of an MSI-H tumor associated with loss of MSH2, MSH6, or PMS2 protein expression strongly supports a diagnosis of LS. However, MSI-H tumors with absent MLH1 protein expression present a more complex scenario. MSI occurs in approximately 10% to 15% of sporadic CRC (generally, patients aged >50 years and with little or no family history). In sporadic CRC, absent MLH1 protein expression is a consequence of aberrant MLH1 methylation, a somatic event confined to the tumor that in the vast majority of cases is not heritable. Since loss of MLH1 protein expression occurs in both LS and sporadic tumors, its specificity for predicting germline MMR gene mutations is lower than for the other MMR proteins.

Because of this uncertainty, additional molecular testing is often necessary to clarify the etiology of MLH1 absence in these cases. Other somatic changes in colon cancers that appear to have negative predictive value for identifying individuals with germline mutations in one of the MMR genes are BRAF mutations and MLH1 promoter methylation.

Aberrant methylation of MLH1 is responsible for causing approximately 90% of sporadic MSI colon cancers.[256] Other mechanisms such as somatic MLH1 mutations may be responsible for the minority of cases where aberrant MLH1 methylation is absent.[256] In most studies, aberrant MLH1 methylation has been detected in only a small percentage of LS colon cancers in individuals with germline mutations in MLH1.[256-259] Thus, detection of aberrantly methylated MLH1 in colon cancer is more suggestive of a sporadic MSI tumor. Since assays of methylation are complex and resource-intensive, surrogate markers of MLH1 methylation have been examined. One study found that loss of immunohistochemical staining for p16 correlated strongly with both MLH1 methylation and BRAF V600E mutations (BRAF mutations are discussed in detail in the following paragraphs). However, only 30% of sporadic tumors examined in this study exhibited loss of p16 expression, limiting the utility of this assay.[260]

BRAF mutations have been detected predominantly in sporadic MSI tumors.[261-264] This suggests that somatic BRAF V600E mutations may be useful in excluding individuals from germline mutation testing; however, limitations of current studies preclude this conclusion. For example, none of the studies clearly define the clinical criteria used to diagnose the families with LS, limiting the general application of the results to patients seen in the clinical setting. Furthermore, at least one person with a germline mutation in MLH1 (mutation not described) had colon cancer with a BRAF mutation. Recommendations for BRAF testing to stratify individuals for subsequent germline MMR testing cannot be made until a study is performed using a population of individuals who meet borderline clinical criteria for LS and who have had germline MMR testing.[265]

(Refer to the Diagnostic strategies for all individuals diagnosed with CRC section of this summary for more information about the clinical role of BRAF and hypermethylation testing.)

Germline MLH1 hypermethylation

Reports of patients with germline MLH1 hypermethylation should not be confused with EPCAM mutation-induced hypermethylation of MSH2, as described below. Prior paragraphs have emphasized the issues associated with the common, acquired somatic hypermethylation of the MLH1 promoter. However, examples of hypermethylation of the MLH1 promoter described in the germline have generally not been associated with a stable Mendelian inheritance.

A comprehensive review of MLH1 constitutional epigenetic alterations involving hypermethylation of one MLH1 allele has been published.[266] Such epimutations are seen in patients with early-onset LS and/or multiple tumors of the LS type. Germline sequence variations or rearrangements are not seen in these patients, although the tumors show MSI-H, loss of MLH1 protein expression, and an absence of BRAF V600E mutations. These patients commonly have no family history of LS-like tumors. Interestingly, inheritance appears to be maternal, and therefore non-Mendelian. The constitutional monoallelic hypermethylation may appear as a mosaic, involving different tissues to a varying extent. In addition, the constitutional epimutation is typically reversible in the course of meiosis, such that offspring are usually unaffected. Because inheritance has been demonstrated in very few families, performing genetic counseling and genetic testing (which requires specialized research techniques) is particularly challenging.

EPCAM/TACSTD1

Tumors with MSI and loss of MSH2 protein expression are generally indicative of an underlying MSH2 germline mutation (inferred MSH2 mutation). Unlike the case with MLH1, MSI with MSH2 loss is rarely associated with somatic hypermethylation of the promoter. Nevertheless, in at least 30% to 40% of these cases of inferred MSH2 mutation, no germline mutation can be detected with state of the art technology. One Chinese family with tumors showing MSH2 loss was found to have allele-specific hypermethylation that appeared to have been an inherited phenomenon.[267] Another study of a family with MSH2-deficient MSI-high tumors employed the commonly used diagnostic MLPA analysis of MSH6 and also showed reduced expression of MSH6. In doing so, a decrease in signal was observed for exon 9 of the EPCAM (TACSTD1) gene, which is near MSH2. Use of additional MLPA probes located between exon 3 of EPCAM and exon 1 of MSH2 demonstrated that the deletion spanned most 3’ exons of EPCAM, but spared the MSH2 promoter.[268] The mutation in EPCAM was found to induce the observed methylation of the MSH2 promoter by transcription across a CpG island within the promoter region. The presence of EPCAM mutations showing similar methylation-mediated MSH2 loss was found at about the same time in families from Hungary.[269]. On the strength of these observations, EPCAM testing has already been introduced clinically for patients with loss of MSH2 protein expression in their CRCs who lack detectable MSH2 germline mutation.

IHC

A complementary and perhaps even alternative approach to MSI is to test the tumor by IHC for protein expression using monoclonal antibodies of the MSH2, MLH1, MSH6, and PMS2 proteins. Loss of expression of these proteins appears to correlate with the presence of MSI and may suggest which specific MMR gene is altered in a particular patient.[270-273]

Tumor testing for suspected LS

Either MSI or IHC can be used as a tumor-based screen for LS.[206,274,275] The choice of whether to use MSI, IHC, or both depends on local availability and expertise.

It appears that clinical practice has shifted from reliance on MSI in the early days of tumor testing to increasing, and in many cases exclusive, reliance on IHC currently. Using both of these tests increases the sensitivity of the initial screen and improves quality assurance; therefore, many laboratories assess both MSI and IHC initially. However, because these tests are so commonly regarded as simple alternatives, cost-effectiveness considerations seem to support IHC and account for its preferential use. Part of this rationale is that the information provided by IHC may direct testing toward a specific MMR gene (the one with loss of protein expression) as opposed to comprehensive testing that would be necessitated by the use of MSI alone.[206,207,275-278] 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.[274] Data from a large U.S. study support IHC analysis as the primary screening method, emphasizing its ease of performance in routine pathology laboratories.[206]

If greatest weight is given to clinical selection considerations (i.e., Bethesda guidelines being met), then IHC combined with MSI may be appropriate. In fact, in a truly high-risk population (Amsterdam criteria being met), any strategy may be acceptable, including germline testing without the benefit of tumor testing first. (Refer to the Genetic/Molecular Testing for LS section of this summary for information about models.) However, as more institutions are adopting universal testing using MSI or IHC, perhaps in part based on some of the outlier (older, family history-negative) cases reported [206,274,275] or in part based on prognostic considerations (MSI-H having better prognosis), concerns about cost effectiveness of screening commonly dictate a more truncated approach. Thus, in a relatively low-risk population of patients with CRC, a screen with IHC or MSI alone may be adequate in cases of normal staining or MSS tumor.

Other techniques

In instances where tumor is not available from individuals to test for MSI and/or MMR protein IHC, germline mutation analysis of MLH1, MSH2, and MSH6 may be considered. This approach is, however, time consuming and expensive. Strategies to screen for mutations using heteroduplex analysis-based techniques have been explored. These techniques are limited by the need to perform DNA sequencing as a subsequent step on all aberrant samples detected in screening. Additionally, such techniques frequently detect numerous variants of uncertain significance. They cannot, therefore, be recommended for routine clinical use at this time.[279]

Genetic testing

Genetic testing for germline mutations in MLH1, MSH2, MSH6, and PMS2 can help formulate appropriate intervention strategies for the affected mutation-positive individual and at-risk family members.

If a mutation is identified in an affected person, then testing for that same mutation could be offered to at-risk family members (referred to as predictive testing). Family members who test negative for the familial mutation are generally not at increased risk of CRC or other LS-associated malignancies and can follow surveillance recommendations applicable to the general population. Family members who carry the familial mutation should follow surveillance and management guidelines for LS. (Refer to the Interventions/LS section of this summary for more information.)

If no mutation is identified in the affected family member, then testing is considered uninformative for the individual and 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 genes tested. The current sensitivity of testing is between 50% and 95%, depending on the methodology used. Mutation testing utilizing sequencing alone will not detect large genomic rearrangements in MSH2 or MLH1 that may be present in a significant number of LS probands.[280-282] An assessment of 365 probands with suspected LS showed 153 probands with germline mutations in MLH1 or MSH2, 12 of 67 (17.9%) and 39 of 86 (45.3%) of which were large genomic alterations in MLH1 and MSH2, respectively.[283] Such mutations can be detected by MLPA or Southern blotting (MLPA has largely replaced Southern blotting).[284,285] MLPA analysis of MLH1, MSH2, and MSH6 is commercially available and should be performed in cases where no mutation is detected by sequence analysis.

Alternatively, the family could have a mutation in a yet-unidentified gene that causes LS or a predisposition to colon cancer. 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. If this scenario is suspected, testing another affected individual is recommended. Finally, failure to detect a mutation could mean that the family truly is not at genetic risk despite 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 CRC by virtue of their family history and should continue with recommended intensive screening. (Refer to the Interventions/LS section of this summary for more information.)

MLH1

Prevalence

MLH1 and MSH2 make up the majority of LS mutations. Up to 50% of mutation-positive LS families harbor a MLH1 mutation, with some geographic variation.[286]

Genotype-phenotype correlations

MLH1 mutations have been associated with the entire spectrum of malignancies associated with LS.[286] The lifetime risk of CRC in MLH1 mutation carriers is estimated to be 41% to 68%.[210,215,287] The lifetime risk of endometrial cancer is estimated to be approximately 40%.[3,215] Muir-Torre syndrome is less commonly associated with MLH1 mutations than are MSH2 mutations.[229]

Practices and pitfalls in testing

In contrast to the scenario of MSI associated with loss of expression of MSH2, MSH6 or PMS2, absence of MLH1 expression is not specific to LS. Most instances of absence of MLH1 expression are caused by the sporadic hypermethylation of the MLH1 promoter. Therefore, absent MLH1 expression is less specific for LS than absence of the other MMR proteins. In addition, rare instances of inherited germline MLH1 methylation have added additional complexity to the interpretation of MSI associated with absence of MLH1 expression. (Refer to the Microsatellite instability (MSI) section for more information about germline MLH1 hypermethylation.)

MSH2

Prevalence

The prevalence of MSH2 mutations in individuals or families with LS has varied across studies. MSH2 mutations were reported in 38% to 54% of LS families in studies including large cancer registries, cohorts of early-onset CRC (<55 years), and registries around the world.[212,244]

Genotype-phenotype correlations

The lifetime risk of colon cancer associated with MSH2 mutations is estimated to be between 48% and 68%.[210,215,287] In a case series of LS patients, those carrying germline MSH2 mutations (49 individuals, 45% females) had a lifetime (cutoff of age 60 years) risk of extracolonic cancers of 48% compared with 11% for MLH1 carriers (56 individuals, 50% females).[288] In addition, the same group reported a significantly higher prevalence of poorly differentiated CRCs (44% for MSH2 carriers vs. 14% for MLH1 carriers; P = .002) and Crohn-like reaction (49% for MSH2 carriers vs. 27% for MLH1 carriers; P = .049). Another study reported no significant differences between the prevalence of colorectal and extracolonic cancers in 22 families with germline MLH1 mutations and in 12 families with germline MSH2 mutations.[289]

Multiple groups have reported that MSH2 and MSH6 carriers have a greater chance of presenting with endometrial cancers before CRCs than do MLH1 carriers.[3,236,290] The average age at diagnosis of endometrial cancers differed with genotype in two studies: age 41 years for MSH2 , age 49 years for MLH1, and age 55 years for MSH6 carriers.[291,292]

Practices and pitfalls in testing

In patients with absence of MSH2 and MSH6 protein expression who have undergone genetic testing with no mutation found by the currently available standard techniques, germline mutation testing for EPCAM/TACSTD1 should be considered. It has been reported that approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC and no MSH2 or MSH6 mutation identified will have germline deletions in EPCAM/TACSTD1.[293] The latter mechanism accounts for approximately 5% of all LS cases.[293] (Refer to the EPCAM/TACSTD1 section of this summary for more information.)

MSH6

Prevalence

Most series show a prevalence of germline MSH6 mutations in approximately 10% of LS families. However, the reported range (5%–52%) is large.[236,239,240,294-297] This wide variation is likely a result of small sample sizes, referral bias, and ascertainment bias.

Genotype-phenotype correlations

The lifetime risk of colon cancer associated with MSH6 mutations is estimated to be between 12% and 22%.[213,215] It appears that the lifetime risk of CRC might be lower in MSH6 carriers than in MSH2 and MLH1 carriers. Initial studies have suggested that inactivating germline mutations of MSH6 might be more frequent in persons with a later average age at onset of CRC whose tumors exhibit a non-MSI-high phenotype.

One study reported on 146 MSH6 carriers (59 men and 87 women) from 20 families, all of whom had truncating mutations in MSH6. While the prevalence of CRCs by age 70 years was not significantly different between MSH6 and MLH1 or MSH2 carriers (P = .0854), the mean age at diagnosis for colorectal carcinoma in male MSH6 mutation carriers was 55 years (n = 21; range, 26–84 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively. The prevalence of CRC was significantly lower in women with MSH6 germline mutations than in MLH1 or MSH2 carriers (P = .0049). The mean age at diagnosis for colorectal carcinoma in female MSH6 mutation carriers was 57 years (n = 15; range, 41–81 years) versus 43 years and 44 years in MLH1 and MSH2 mutation carriers, respectively.[254]

In addition, endometrial cancer has been reported to be more common in MSH6 families. In the same study, the cumulative risk of uterine cancer was significantly higher in MSH6 mutation carriers (71%) than in MLH1 (27%) and MSH2 (40%) mutation carriers (P = .02). The mean age at diagnosis of endometrial carcinoma was 54 years in MSH6 mutation carriers (n = 29; range, 43–65 years) versus 48 years and 49 years in MLH1 and MSH2 mutation carriers, respectively.[254] A group of researchers reported on ten MSH6 kindreds with LS in which 70% of females had been diagnosed with endometrial cancer compared with 31% and 29% in MLH1 and MSH2 carriers, respectively.[290] One study found the prevalence of endometrial carcinoma to be 58% in 12 MSH6 families with a mean age at diagnosis of 57 years.[295]

One group of researchers assembled the largest series of MSH6 mutation carrier families to estimate penetrance of cancers.[213] A total of 113 families of MSH6 mutation carriers from five countries were ascertained through family cancer clinics and population-based cancer registries. The families contained an estimated 1,043 mutation carriers. By age 70 years, 22% (95% CI, 14%–32%) of male MSH6 mutation carriers developed CRC compared with 10% (95% CI, 5%–17%) of female MSH6 mutation carriers. By age 80 years, 44% (95% CI, 28%–62%) of male MSH6 mutation carriers were diagnosed with CRC, compared with 20% (95% CI, 11%–35%) of female MSH6 mutation carriers. For all MSH6 mutation carriers, the increased risk of CRC, relative to that of the general population, across all age groups was statistically significantly elevated (HR, 7.6; 95% CI, 5.4–10.8; P < .001). By ages 70 years and 80 years, 26% (95% CI, 18%–36%) and 44% (95% CI, 30%–58%), respectively, of women would be diagnosed with endometrial cancer. Female MSH6 mutation carriers had an endometrial cancer risk that was about 25 times higher than women in the general population (HR, 25.5; 95% CI, 16.8–38.7; P < .001).

In the same study, female MSH6 mutation carriers had a cumulative risk of other Lynch cancers (i.e., ovarian, stomach, small intestine, kidney, ureter, or brain) of 11% (95% CI, 6%–19%) by age 70 years and 22% (95% CI, 12%–38%) by age 80 years.[213] The risk of LS cancers, excluding colorectal and endometrial cancers, was six times that of the general population (HR, 6.0; 95% CI, 3.4–10.7; P < .001). Male MSH6 mutation carriers showed no evidence of an increased risk of these cancers (HR, 0.8; 95% CI, 0.1–8.8; P = .9). The authors estimated that 24% (95% CI, 16%–37%) of men and 40% (95% CI, 32%–52%) of women harboring deleterious MSH6 mutations would be diagnosed with any LS cancer by age 70 years and that these values will increase to 47% (95% CI, 2%– 66%) of men and 65% (95% CI, 53%–78%) of women by age 80 years.

Practices and pitfalls in testing

One study reported that of 42 population-based probands harboring deleterious MSH6 germline mutations who were ascertained independent of their family cancer history, 30 (71%) had a family cancer history that did not meet the Amsterdam II criteria.[213]

MSH6 colorectal tumors can be MSI-high, MSI-low, or MSS. This pitfall illustrates the utility of IHC for the MMR protein expression. Eighteen of 21 (86%) of the colorectal tumors showed an MSI-high phenotype. Of the 16 endometrial tumors tested, 11 were MSI-high (69%); four were MSI-low (25%), and one was microsatellite stable (6%).[254]

In endometrial cancers with germline MSH2 mutations, loss of MSH6 frequently occurs with loss of MSH2.[292,298]

PMS2

Prevalence

The prevalence of PMS2 germline mutations has been underappreciated for many reasons. It is the most recent of the major genes to be identified, probably has the lowest prevalence, was not felt to be worthy of serious investigation, and commercial testing is not widely available.[299-301] One registry study reported an incidence of 2.2% for PMS2 mutations in 184 patients with suspected LS.[302] A population-based study reported a prevalence of approximately 5% (1 of 18).[207]

Genotype-phenotype correlations

A meta-analysis of three population-based studies and one clinic-based study estimated that for carriers of PMS2 mutations, the risk of CRC to age 70 years was 20% among men and 15% among women, and the risk of endometrial cancer was 15%.[211]

In one study, patients with PMS2 mutations presented with CRC 7 to 8 years later than did those with MLH1 and MSH2 mutations. However, these families were small and did not fulfill Amsterdam criteria.[302]

Diagnostic strategies for all individuals diagnosed with CRC

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a project developed by the Office of Public Health Genomics at the Centers for Disease Control and Prevention, formed a working group to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice. The Working Group was commissioned to address the following question: Do risk assessment and MMR gene mutation testing in individuals with newly diagnosed CRC lead to improved outcomes for the patient or relatives, or are they useful in medical, personal, or public health decision-making?[303,304] The Working Group constructed economic models to assist in analyzing available evidence on clinical utility in estimating how various testing strategies might function in practice. These included mutation frequency, sensitivity and specificity of both IHC and MSI testing, and the cost of these tests. The performance of these tests is based on the risk of positivity of carrying a mutation including family history, age at diagnosis, and extracolonic cancers. In 2009, the Working Group reported that there was sufficient evidence to recommend offering genetic testing for LS to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives. They concluded that there was insufficient evidence to recommend a specific gene-testing strategy among the following four strategies tested:[303,304]

1. All individuals with CRC tested for germline mutations in MSH2, MLH1, and MSH6. The average cost per LS detected was estimated to be $111,825.

2. All tumors tested for MSI, followed by germline mutation analysis of MSH2, MLH1, and MSH6 offered to those with MSI-H tumors. The average cost per LS detected was estimated to be $47,268.

3. All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2, followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. The average cost per LS detected was estimated to be $21,315.

4. All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2 followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. If there was absence of MLH1, testing was offered for BRAF mutation–negative tumors. The average cost per LS detected was estimated to be $18,863.[304]

The EGAPP analysis made several assumptions, including (1) IHC and MSI will not detect all LS patients and (2) not all patients with CRC will opt for testing.

Results are available from a Markov model that incorporated the risks of colorectal, endometrial, and ovarian cancers to estimate the effectiveness and cost-effectiveness of strategies to identify LS among persons with newly diagnosed CRC.[305] The strategies incorporated in the model were based on clinical criteria, prediction algorithms, and tumor testing or up-front germline mutation testing followed by directed screening and risk-reducing surgery. Similar to the EGAPP working group, IHC followed by BRAF mutation testing was the preferred strategy in this study. An incremental cost-effectiveness ratio of $36,200 per life year gained resulted from this strategy. In this model, the number of relatives tested (3 to 4) per proband was a critical determinant of both effectiveness and cost-effectiveness.

A different approach based on risk assessments of 100,000 simulated individuals representative of the U.S. population who were tracked from age 20 and exposed to 20 different screening strategies has been reported.[306] In this study, the strategies involved risk assessment at different ages utilizing the PREMM126 model followed by mutation analysis for MLH1, MSH2, MSH6, and PMS2 in individuals whose mutation risk threshold exceeded 0%, 2.5%, 5%, or 10%. In individuals whose risk assessment (starting at age 25, 30, or 35 years) for carrying a mutation exceeded 5%, colorectal and endometrial cancers in mutation carriers were reduced by 12.4% and 8.8%, respectively. In the whole population, this strategy increased the quality adjusted life-years by 135 years per 100,000 individuals with an average cost-effectiveness ratio of $26,000. The authors suggested that the outlined strategy was more cost effective than current practice and could improve health care outcomes.

Diagnostic strategies for all individuals diagnosed with endometrial cancer

Based on a Markov mathematical model, a strategy of performing IHC for MMR protein expression in all patients with endometrial cancer, irrespective of the age at diagnosis, who have a first-degree relative with endometrial cancer, was reported to be cost-effective in the detection of LS in patients with LS-related cancer.[307] (Refer to the Genetic testing section of this summary for more information about performing IHC for MMR protein expression.) In this study, incremental cost-effectiveness ratio (ICER) was defined as the additional cost of a specific strategy divided by its health benefit compared to an alternative strategy. In this model, the strategy of performing IHC on the tumor from all patients diagnosed with LS-related cancer who have a first-degree relative with endometrial cancer had an incremental cost ratio of $9,126 per year of life gained relative to the least-costly strategy, which was genetic testing on all women diagnosed with endometrial cancer younger than 50 years with at least one first-degree relative with LS-related cancer.

The model predicted that if all endometrial cancers in the United States (estimated to be 45,000 new cases in 2010) underwent IHC screening, 827 women (1.84%) would be diagnosed as LS patients.[307] However, applying the strategy of testing only those endometrial tumors of patients with at least a first-degree relative with LS-related cancer, 755 affected individuals (1.68%) would be identified. If the Amsterdam II criteria were applied, 539 carriers (1.2%) would be identified. The authors stated that the incremental benefit of the most cost-effective strategy was only associated with an average life expectancy gain of 1 day compared with testing by Amsterdam II criteria. However, they argue that this may be significant, as it is comparable to the life expectancy gain from triennial cervical cancer screening, which is a current recommendation from the American College of Obstetricians and Gynecologists for women older than 30 years in the general population.

Interventions/LS

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

1. CRCs in LS occur earlier in life than do sporadic cancers. For MLH1 and MSH2 mutation carriers, the estimated risk of CRC at age 40 years is 31% for females and 32% for males; 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 LS CRCs (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. Annual colonoscopic surveillance is recommended.[308]

3. The progression from normal mucosa to adenoma to cancer is accelerated,[309,310] suggesting that screening should be done at shorter intervals (every 1–2 years) and with colonoscopy.[310,311] Because patients with LS 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.[217] 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).[217]

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

5. Patients with LS 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.[221] There is some evidence that the rate of individual cancers varies from kindred to kindred.[220,312,313] Expert consensus suggests consideration of endometrial cancer screening by age 25 years.[314]

Evidence-based reviews of surveillance colonoscopy in LS have been reported.[315,316] There is only one controlled trial of CRC screening in LS.[310,311] In a study from Finland, 252 at-risk members of 22 families with LS 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 CRC deaths (10 vs. 26, P = .003). All of the CRCs detected in the screened population were local and caused no deaths, compared with nine deaths from CRC 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.[317] 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 subsequently updated.[318] Over the course of the study (early 1980s to present), the approach to colonoscopy surveillance has evolved. Colonoscopy was the approach used for MMR mutation carriers when this information was obtainable and the interval between exams was shortened from 5 years to 3 years to 2 years. The 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 CRC 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 9 of this summary for more information.) Analysis of surveillance data in 242 patients 10 years after mutation testing shows 95% compliance in surveillance procedures for CRC and endometrial cancer. Although not all CRCs were prevented, mortality was comparable with mutation-negative relatives. However, this may be attributable to the modest sample size of the study.[319]

In other series, the risk of developing adenomas in an MMR gene mutation carrier has been reported to be 3.6 times higher than the risk in noncarriers.[217] 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.[217] 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.[320,321]

Although screening the intact colon is usually recommended for at-risk LS family members, some patients, faced with the high risk of CRC and the fallibility of screening, elect to undergo risk-reducing colectomy. However, there is a risk of developing cancer in the remaining rectum.[322]

Level of evidence: 3a

Table 9 summarizes the clinical practice guidelines from different professional societies regarding diagnosis and surveillance for LS.

Table 9. Practice Guidelines for Diagnosis and Colon Surveillance of Lynch Syndrome

Organization	Tumor MSI	Tumor IHC	MMR Mutation Testing	Age Screening Initiated	Frequency	Method	Comments
American Cancer Society [133]	NA	NA	Counseling to consider genetic testing	21 y	1–2 y until age 40 y, then annually	C
American Society of Colon and Rectal Surgeons [134-136]	Yes	Yes	Yes	NA	NA	NA
Europe Mallorca Group [323]	Yes	Yes	Yes	20–25 y; consider stopping at age 80 y	1–2 y	C	Despite acknowledging that existing data support a 3 y screening interval, this group elected to recommend a shorter screening interval.
GI Societiesa [130]	NA	NA	NA	20–25 y	1–2 y	C
NCCN [84]	Yes	Yes	Yes	20–25 y OR 2–5 y prior to the youngest age at diagnosis in the family if it is before age 25 y; whichever comes first	1–2 y	C	Families in whom a tumor has shown informative IHC and MSI, but no germline mutation found, should have at-risk relatives screened as if they were mutation carriers.

C = colonoscopy; GI = gastrointestinal; IHC = immunohistochemistry; MMR = mismatch repair; MSI = microsatellite instability; NA = not addressed; NCCN = National Comprehensive Cancer Network.

aGI Societies – American Academy of Family Practice, American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American College of Radiology, American Gastroenterological Association, American Society of Colorectal Surgeons, and American Society for Gastrointestinal Endoscopy.

Chemoprevention in LS

The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP2) was a double-blind, placebo-controlled, randomized trial to determine the role of aspirin in preventing CRC in patients with LS who were in surveillance programs at a number of international centers.[324] The study randomly assigned 861 participants to aspirin (600 mg/day), aspirin placebo, resistant starch (30 g/day), or starch placebo for up to 4 years. At a mean follow-up of 55.7 months (range: 1–128 mo), 53 primary CRCs developed in 48 participants (18 of 427 in the aspirin group and 30 of 434 in the aspirin placebo group). Seventy-six patients who refused randomization to the aspirin groups (due to aspirin sensitivity or history of peptic ulcer disease) were randomly assigned to receive resistant starch or resistant starch placebo. The intention-to-treat analysis yielded an HR for CRC of 0.63 (95% CI, 0.35–1.13; P = .12). However, five of the patients who developed CRC developed two primary colon cancers. A Poisson regression was performed to account for the effect of the multiple primary CRCs and yielded a protective effect for aspirin (incidence rate ratio [IRR], 0.56; 95% CI, 0.32–0.99; P = .05). For participants who completed at least 2 years of treatment, the per-protocol analysis yielded an HR of 0.41 (95% CI, 0.19–0.86; P = .02) and an IRR of 0.37 (0.18–0.78; P = .008). An analysis of all LS cancers (endometrial, ovarian, pancreatic, small bowel, gall bladder, ureter, stomach, kidney, and brain) revealed a protective effect of aspirin versus placebo (HR, 0.65; 95% CI, 0.42–1.00; P = .05). There were no significant differences in adverse events between the aspirin and placebo groups, and no serious adverse effects were noted with any treatment. The authors concluded that 600 mg of aspirin per day for a mean of 25 months substantially reduced cancer incidence in LS patients. A limitation of the trial is that the frequency of surveillance studies at the various centers was not reported as being standardized. Earlier CAPP2 trial results for 746 LS patients enrolled in the study were published in 2008 [325] and failed to show a significant preventive effect on incident colonic adenomas or carcinomas (RR, 1.0; 95% CI, 0.7–1.4) with a shorter mean follow-up of 29 months (range: 7–74 mo). The CAPP3 trial, which will evaluate the effect of lower doses of aspirin, is expected to begin in 2013.

Screening for endometrial cancer in LS families

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 LS families with initial estimates of cumulative risk in LS carriers of 30% to 39% by age 70 years.[220,222] In a large Finnish study of 293 putative LS gene carriers, the cumulative lifetime risk of 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.[209] The maximal risk of endometrial cancer in LS 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 LS.[326] Adenocarcinomas of the lower uterine segment may carry a greater risk of manifesting LS.[327]

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 LS differs from the general population.

Given their substantial increased risk of endometrial cancer, endometrial screening for women with LS 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.[328,329] Two studies have examined the use of TVUS in endometrial screening for women with LS.[330,331] In one study of 292 women from LS or LS-like families, no cases of endometrial cancer were detected by TVUS. In addition, two interval cancers developed in symptomatic women.[330] In a second study, 41 women with LS 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.[331] Both of these studies concluded that TVUS is neither sensitive or specific. A study of 175 women with LS, which 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.[332] 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 LS. 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 LS 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 LS families. Some studies suggest that women with a clinical or genetic diagnosis of LS do not universally adopt intensive gynecologic screening.[333,334] (Refer to the Gynecologic cancer screening in LS 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.[316,323]

The published literature on TVUS for endometrial cancer screening has shown it to be insensitive and nonspecific, but because there may still be a role for TVUS in ovarian cancer screening, clinical practice guidelines have been reluctant to date to recommend against TVUS.

Level of evidence: 5

Risk-reducing surgery in LS

There have been no controlled studies of the benefit of risk-reducing surgery in at-risk MMR gene mutation carriers. Recommendations based upon expert opinion, however, have been formulated by a panel convened by an NIH research consortium.[314] The expert panel recommended consideration of risk-reducing subtotal colectomy as an option for persons with LS 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 LS 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 options for women with LS, and that counseling include thoughtful discussion of childbearing plans, psychosocial effects of risk-reducing surgery, long-term effects of prolonged estrogen replacement therapy, and 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 LS reported no occurrences of endometrial, ovarian, or primary peritoneal cancers in women who underwent RRH with or without RRSO compared with women who had no risk-reducing surgery.[335] 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 LS.[335] 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 LS must be individualized.[336] Management of these patients can be subdivided into patients with newly diagnosed CRC, those with CRC treated with segmental resection, and those who are at risk of developing CRC 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 LS 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 CRCs 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 CRC.[222,337-339] 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.[340] 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.[340] This model did not take into account quality of life and was reported in absolute years. In a Markov decision analysis model taking into account both survival and quality of life based on assumptions obtained from published literature, the mean survival of a male aged 30 years with LS was 0.7 years better in an individual who underwent a total abdominal colectomy versus a segmental resection.[341] When quality-adjusted life years (QALYs) were taken into account in this model, patients undergoing segmental resection had 21.5 QALYs, whereas patients undergoing an abdominal colectomy had 21.2 QALYs. Because the data underpinning these models are not likely to be validated and this topic is controversial, most surgeons choose to individualize the surgical decision based on patient-centered considerations.

Aside from the diagnosis of LS, other factors to consider in individualizing the surgical decision are age at diagnosis and the stage of the primary CRC. Most surgeons would consider loss of protein expression or MSI in the tumor in patients younger than age 50 years as evidence of LS even if germline mutational testing is uninformative or cannot be done before surgery. After more extensive resections, younger individuals tend to adapt better in terms of bowel function than older individuals undergoing similar procedures.[342]

Similar results regarding a decrease in the number of metachronous CRCs after subtotal or total abdominal colectomy at the time of diagnosis of first CRC were reported by retrospective studies from Creighton University and the Cancer Family Registries.[339,339] No survival advantage was demonstrated when performing a more extensive procedure compared to a segmental resection in these studies.

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.[322] 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 LS patients who have undergone a partial surgical resection of the colon, endoscopic surveillance should be the mainstay of follow-up.

Summary

The data on a decrease in metachronous CRC, and thus, a decrease in the number of surgeries, support the notion of routine subtotal colectomy in patients with LS. However, it appears that this has not penetrated surgical practice where functional outcomes weigh heavily in decision making. While young patients will in theory live longer and therefore be at a higher risk of metachronous CRC and in general will adapt better functionally than older patients, the majority of young patients with LS and CRC undergo segmental resection.

Advances in Endoscopic Imaging in Hereditary CRC

Performance of endoscopic therapies for adenomas in FAP and LS, and decision-making regarding surgical referral and planning, require accurate estimates of the presence of adenomas. In both AFAP and LS the presence of very subtle adenomas poses special challenges—microadenomas in the case of AFAP and flat, though sometimes large, adenomas in LS.

Modern high-resolution endoscopes improve adenoma detection yield, but use of various vital dyes, in particular indigo carmine dye-spray, have further improved the detection. Several studies have shown that the improved mucosal contrast achieved with the use of indigo carmine can improve the adenoma detection rate. Whether family history is significant or not, careful clinical evaluation consisting of dye-spray colonoscopy (indigo carmine or methylene blue),[320,343-348] with or without magnification, or possibly newer imaging techniques, such as narrow-band imaging,[349] may reveal the characteristic right-sided clustering of more numerous microadenomas. Upper gastrointestinal endoscopy may be informative if duodenal adenomas or fundic gland polyps with surface dysplasia are found. Such findings will increase the likelihood of mutation detection if APC or MYH testing is pursued.

One study from Holland using indigo carmine dye-spray for detection of duodenal adenomas showed an increase in number and size of adenomas, including some large ones. Overall Spigelman score was not significantly affected.[350]

Familial CRC

An estimated 7% to 10% of people have a first-degree relative with CRC,[351,352] and approximately twice that many have either a first-degree or a second-degree relative with CRC.[352,353] A simple family history of CRC (defined as one or more close relatives with CRC 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 CRC 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.[351,354] A positive family history of CRC appears to increase the risk of CRC 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.[351] 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 CRC 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 [355] and increases the risk of CRC in relatives.[356] The RR of CRC, adjusted for the year of birth and sex, was 1.78 (95% CI, 1.18–2.67) for the parents and siblings of the patients with adenomas as compared with the spouse controls. The RR for siblings of patients in whom adenomas were diagnosed before age 60 years was 2.59 (95% CI, 1.46–4.58), 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, with a parental history of CRC.

While familial clusters account for approximately 20% of all CRC cases in developed countries,[357] the rare and highly penetrant Mendelian CRC 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 CRCs.

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.[358] 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 of CRC. For CRC, the estimated heritability was only slightly greater in younger groups than in older groups. This study revealed that although nonshared environmental factors constitute the major risk of familial CRC, heredity plays a larger-than-expected role.

The second study utilized the Swedish Family-Cancer Database, which contained 6,773 and 31,100 CRCs in offspring and their parents, respectively, from 1991 to 2000.[359] 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 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 CRC conferred between spouses, the authors concluded that heredity plays a significant role in familial CRCs; however, controls for shared environmental effects among siblings were absent in this study.

Ten percent to 15% of persons with CRC and/or colorectal adenomas have other affected family members,[351,352,354-356,360-365] but their findings do not fit the criteria for FAP, and their family histories may or may not meet clinical criteria for LS. Such families are categorized as having familial CRC, which is currently a diagnosis of exclusion (of known hereditary CRC disorders). The presence of CRC 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 familial CRC remains a research challenge.

Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in familial CRC families,[366] with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas.[365] A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2.[367] A more recent study has linked three potential loci in familial CRC families on chromosomes 11, 14, and 22.[368]

Familial CRC type X

Families meeting Amsterdam-I criteria for LS 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 LS and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as familial CRC type X,[369-373] and it has been suggested that these families be classified as a distinct group.

Age of CRC onset in LS ranges from 44 years (registry series) to a mean of 52 years (population-based series).[206-208] There are no corresponding population-based data for familial CRC type X, as familial CRC type X by definition requires at least one early-onset case and is not likely to lend itself to any population-based figures in the foreseeable future. Studies that have directly compared age of onset between familial CRC type X and LS have suggested that the age of onset is slightly older in familial CRC type X,[369,370,372] but the lifetime risk of cancer is substantially lower. The SIR for CRC 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 MMR (LS families).[369] The risk of extracolonic tumors was also not found to be elevated for the type X families, suggesting that enhanced surveillance for CRC 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 LS.[371]

Interventions/family history of CRC

There are no controlled comparisons of screening in people with a mild or modest family history of CRC. 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.[130]

A common but unproven clinical practice is to initiate CRC screening 10 years before the age of the youngest CRC 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 CRC.

These issues were weighed by a panel of experts convened by the American Gastroenterological Association before publishing clinical guidelines for CRC screening, including those for persons with a positive family history of CRC.[314] These guidelines have been endorsed by a number of other organizations.

The American Cancer Society and the United States Multi-Society Task Force on Colorectal Cancer have published guidelines for average-risk individuals.[130,374-377] These guidelines address screening issues related to modest family history of CRC or adenomas. Given the heterogeneity of this grouping, it is beyond the scope of this more targeted discussion of major gene conditions.

Rare Colon Cancer Syndromes

Peutz-Jeghers syndrome (PJS)

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.[378-380] Germline mutations in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[381-385] (Refer to the Peutz-Jeghers Gene(s) section in the PDQ summary on Genetics of Colorectal Cancer for more information.) The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancy. A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS.[386] Table 10 shows the cumulative risk of these tumors. The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Clinical Practice Guidelines for the Diagnosis of Cancer in Peutz-Jeghers Syndrome in the PDQ summary on Genetics of Colorectal Cancer.

Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in over-estimates of these risks should be considered.

Table 10. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Age^a

Site	Age (y)	Cumulative Risk (%)b	Reference(s)
Any cancer	60–70	37–93	[6,385,387-390]
GI cancerc,d	60–70	38–66	[6,387,389,390]
Gynecological cancer	60–70	13–18	[6,390]
Per origin
Stomach	65	29	[388]
Small bowel	65	13	[388]
Colorectum	65	39	[6,388]
Pancreas	65–70	11–36	[6,388]
Lung	65–70	7–17	[6,388,390]
Breast	60–70	32–54	[6,388,390]
Uterus	65	9	[388]
Ovary	65	21	[388]
Cervixe	65	10	[388]
Testese	65	9	[388]

GI = Gastrointestinal.

aReprinted with permission from Macmillan Publishers Ltd: Gastroenterology [386], copyright 2010.

bAll cumulative risks were increased compared to the general population (P < .05) with the exception of cervix and testes.

cGI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.

dWesterman et al.: GI cancer does not include pancreatic cancer.[387]

eDid not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.

Juvenile polyposis syndrome (JPS)

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.[391,392] 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 [393] 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.[394,395] The lifetime CRC risk in JPS has been reported to be 39%.[396]

Hereditary mixed polyposis syndrome (HMPS)

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, and colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14.[397,398] 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.

CHEK2

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.[399-401] 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 CRC; however, a specific missense mutation (I157T) was associated with modest increased risk (odds ratio [OR], 1.5; 95% CI, 1.2–3.0) of CRC.[402]

Similar results were obtained in another study conducted in Poland.[403] In this study, 463 probands from LS and LS–related families and 5,496 controls were genotyped for four CHEK2 mutations, including I157T. The missense I157T allele was associated with LS–related cancer only for MMR mutation-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating mutations. Further studies are needed to confirm this finding and to determine whether they are related to familial CRC type X.

Hyperplastic polyposis syndrome (HPPS)

Isolated and multiple hyperplastic polyps (HP) (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 HP occurring proximal to the sigmoid colon (of which at least two are greater than 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.[404]

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 CRC.[405,406] Several studies show that the prevalence of colorectal adenocarcinoma in patients with formally defined criteria for HPPS is 50% or more.[407-414]

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.[405] 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 CRC. 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).[415] 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 CRC 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.[416]

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 (V600E) was found in polyp tissue.[417] Fifty percent (20 of 40) of HPs from these patients demonstrated the V600E 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.[408]

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.[418] BRAF mutations are more commonly associated with the right colon and methylation of p16^INK and MINT31.[417]

Interventions/rare colon cancer syndromes

Individuals with Peutz-Jeghers and juvenile polyposis syndromes are at increased risk of CRC and extracolonic cancers. Because these syndromes are rare, there have been no evidence-based surveillance recommendations. Due to the markedly increased risk of colorectal and other cancers in these syndromes, a number of guidelines have been published based on retrospective and case series (i.e., based exclusively on expert opinion).[131,419-422] One's best clinical judgment must be used in making screening recommendations based on published guidelines.

Table 11. Clinical Practice Guidelines for the Diagnosis of Cancer in Peutz-Jeghers Syndrome

Organization/ Author	STK11 Gene Testing Recommendeda	Age Colon Screening Initiated	Frequency	Method	Extracolonic Screening Recommendations	Comment
ACPGBI		18 y	3 y	C or FS + BE	No mention of extracolonic screening	No mention of genetic testing; need to consider STK11/LKB1 testing
Brosens et al. [422]	Yes, age not specified	Late teens or at symptoms	3 y	C	Breast, Gynecologic (Cervix, Ovaries, Uterus), Pancreas, Small Intestine, Stomach, Testes	Genetic testing at late teens or at symptoms
Giardiello and Trimbath [421]	Yes, at age 8 y	18 y	2–3 y	C	Breast, Gynecologic (Cervix, Ovaries, Uterus), Pancreas, Small Intestine, Stomach, Testes
NCCN [84]	No specific recommendation	Late teens	2–3 y	C	Breast, Gynecologic (Cervix, Ovaries, Uterus), Lungb, Pancreas, Small Intestine, Stomach, Testes	Refer to specialized team
van Lier et al. [386]		25–30 y		C	Breast, Gynecologic (Cervix, Ovaries, Uterus), Pancreas, Small Intestine, Stomach
Zbuk and Eng [423]		18 y	3 y	C	Breast, Gynecologic (Cervix, Ovaries), Pancreas, Small Intestine, Stomach, Testes

ACPGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; FS = flexible sigmoidoscopy; NCCN = National Comprehensive Cancer Network.

a STK11 mutation analysis includes sequencing followed by analysis for deletions (e.g., MLPA), if no mutation found by sequencing.

bLung cancer risk is increased, but there are no recommendations beyond smoking cessation and heightened awareness of symptoms.

Level of evidence: 5

Table 12. Clinical Practice Guidelines for the Diagnosis of Colon Cancer in Familial Juvenile Polyposis Syndrome (JPS)

Organization/ Author	SMAD4/BMPR1A Testing Recommendeda	Age Screening Initiated	Frequency	Method	Comment
ACGBI		15–18 yb	1–2 y	C or FS + BE	Gene carriers and affected surveillance until age 70 y and discussion of prophylactic surgery
Brosens et al. [422]	Yes, genetic testing preferred over colonoscopy	15 y or at symptoms	Yearly until polyp free then every 2–3 y	C	Prophylactic surgery if >50–100 polyps, unable to manage endoscopically, severe GI bleeding, JPS with adenomatous changes, strong family history of CRC
NCCN [84]	No specific recommendation	~15 y	2–3 y or 1 y if polyps are found	C	Refer to specialized team
Zbuk and Eng [423]		15 y	3 y	C, EGD	Some families with SMAD4 mutation also have HHT; these individuals may need to be screened for HHT

ACGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; CRC = colorectal cancer; EGD = esophagogastroduodenoscopy; FS = flexible sigmoidoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; NCCN = National Comprehensive Cancer Network.

a SMAD4/BMPR1A mutation analysis includes sequencing followed by analysis for deletions (e.g., MLPA), if no mutation found by sequencing.[424]

bYounger, if patient has presented with symptoms.

Level of evidence: 5

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