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Attenuated familial adenomatous polyposis

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American College of Medical Genetics and Genomics (ACMG) technical standards and guidelines for genetic testing for inherited colorectal cancer


Read the original article in Genetics in Medicine (2013) Hegde et al

Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner. Finally, MYH-associated polyposis is caused by mutations in the MUTYH gene and is inherited in an autosomal recessive manner but may or may not be associated with polyps. There are variants of both familial adenomatous polyposis (Gardner syndrome—with extracolonic features—and Turcot syndrome, which features medulloblastoma) and Lynch syndrome (Muir–Torre syndrome features sebaceous skin carcinomas, and Turcot syndrome features glioblastomas). Although a clinical diagnosis of familial adenomatous polyposis can be made using colonoscopy, genetic testing is needed to inform at-risk relatives. Because of the overlapping phenotypes between attenuated familial adenomatous polyposis, MYH-associated polyposis, and Lynch syndrome, genetic testing is needed to distinguish among these conditions. This distinction is important, especially for women with Lynch syndrome, who are at increased risk for gynecological cancers. Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing. To assist clinical laboratories in developing and validating testing for this group of inherited colorectal cancers, the American College of Medical Genetics and Genomics has developed the following technical standards and guidelines. An algorithm for testing is also proposed.

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Retired Sailor overcomes bleak diagnosis, maintains positive attitude


Retired Sailor overcomes bleak diagnosis, maintains positive attitude

TRIPLER ARMY MEDICAL CENTER, Hawaii, USA – Daniel Shockley, a retired Sailor living on Oahu, meets with Lt. Col. Ronald Gagliano, chief, Colon and Rectal Surgery and director, Surgical Research, TAMC, to discuss recovery and post-operative…

Starting at age 50, it is encouraged that everyone get regular colonoscopies (in the USA), an examination that use a fiber-optic camera to view your lower gastrointestinal tract, to screen for colon cancer.In September 2011 when Daniel Shockley, a retired Sailor living on Oahu, went for his annual physical exam at Spark M. Matsunaga Veterans Affairs Medical Center, he thought besides a little weight loss, he had a clean bill of health.Since Shockley had just turned 50, he was referred to a Hawaii Pacific Health clinic in downtown Honolulu for his first colonoscopy.

Due to his hectic work schedule, Shockley rescheduled the screening a couple times and it wasn’t until May 8, 2012, when he got the colonoscopy.

“They usually schedule colonoscopies for 1-hour blocks of time, but they found so much wrong during mine that he had to spend a lot of time documenting and taking pictures,” Shockley explained. “What they found was approximately 100 polyps embedded throughout my colon, rectum and anus. And at the traverse colon, the junction between the large and small intestine, they found a large tumor that was creating an 80 percent blockage.”

Shockley was referred to Tripler Army Medical Center’s general surgery clinic, and the week following the screening, he met with Susan Donlon, a certified genetic counselor at Tripler.

Donlon performed DNA tests on Shockley and within three weeks the tests had come back confirming that Shockley has a gene mutation known as Adenomatous Polyposis Coli, which increases a person’s risk of developing colorectal cancer. As a result of the mutation, Shockley was diagnosed with Attenuated Familial Adenomatous Polyposis, a condition in which numerous polyps form mainly in the large intestine.

“I knew surgery was inevitable and I was willing to accept the worst case scenario the whole time,” Shockley said.

On July 13, Shockley underwent a total proctocolectomy with ileostomy surgery, which removed portions of his large intestine to include the entire colon, rectum and anus.

Shockley spent about two weeks in Tripler’s general inpatient surgery ward recovering before he was able to go home. It was nine weeks before he was able to go back to work.

Lt. Col. Ronald Gagliano, chief, Colon and Rectal Surgery and director, Surgical Research, TAMC, performed Shockley’s surgery and has followed up with him to ensure he is not only well-informed, but also well-educated.

“He knew nothing of his disease and its many facets before we met and our team (at Tripler) began his personal education in order to promote effective counseling regarding his diagnostic and therapeutic options,” Gagliano explained. “Finally we educated him regarding his genetic situation so that he could choose (how to best) inform his family. By giving him great care, we essentially treat an entire family cohort.”

“(Dr. Gagliano and his team) have passion for what they do, and my care was phenomenal,” Shockley expressed. “I cannot say enough good things about my stay and the care they provided.”

Gagliano is very pleased with Shockley’s recovery thus far and attributes it to his attitude.

“I tend not to think about things I can’t control,” Shockley explained. “Medical issues are not something I can control, but what I can control is my attitude and after 51 years on God’s green earth my positive attitude has gotten me this far and I am not going to change it.”

Because of Shockley’s surgeries, he now has an ostomy pouching system, a prosthetic medical device that provides a means for the collection of waste. Nina Lum, certified wound, ostomy and continence nurse, TAMC, who helped care for Shockley throughout his recovery, echoed Gagliano’s remarks.

“Shockley’s resilience in the face of challenges including his tremendous enthusiasm for life, regardless of setbacks, certainly played a huge role in his recovery,” Lum said. “He has always maintained a positive outlook, been fully engaged in his care from the beginning, reached out to the ostomy community not only for support, but also to offer support and advise based on his personal experience.

“He is selfless in trying to reach out to others,” Lum added.

Shockley has embraced his diagnosis and challenged it from the start. He acts as a patient advocate and an ambassador for colon cancer awareness.

“(I want to) share my story with others on behalf of those patients that have gone before me and who were unable to share their story,” Shockley explained. “My catchphrase is ‘AFAP-Seize the disease!'”

Shockley wants to spread the information about his diagnosis and experience so he can inspire others to get the screening and be aware of the condition. Additionally, there is not a lot of information about AFAP available, so he hopes that talking about his diagnosis will help the medical community.

“By maintaining a positive attitude, the opportunity for a success story is much higher,” Shockley said. “This in turn allows me a better chance of overcoming adversities I am faced with during my lifetime.”

Read More;

Polyposis Syndromes – Information for Patients

 

Squaring Genetic vs Clinical Findings in Familial Polyposis


Journal CoverPrevalence and Phenotypes of APC and MUTYH Mutations in Patients With Multiple Colorectal Adenomas

Grover S, Kastrinos F, Steyerberg EW, et al

JAMA. 2012;308:485-492

Summary

Familial adenomatous polyposis (FAP) is caused by mutations in the APC gene and 2 different, or biallelic mutations, in the MUTYH gene. However, not all patients with colorectal polyposis are found to carry mutations on these genes. In addition, it is unclear how the extent of polyp burden or the age at development of the first adenoma corresponds to the likelihood of finding mutations in either of these 2 genes.

In an effort to better characterize the mutation frequency in patients with multiple colorectal adenomas, this study tested for APC and MUTYH mutations in 8676 individuals over 8 years. Each person’s cancer history, adenoma count, and family history of cancer or colorectal adenomas was reported by clinicians ordering the genetic testing.

The study found that patients with classic polyposis were very likely to carry an APC mutation: 80% of those with ≥ 1000 colorectal adenomas and 56% of those with 100-999 adenomas carried an APC mutation. APC mutations were prevalent even in individuals with fewer than 100 adenomas, with mutations seen in 10% of those with 20-99 adenomas and in 5% of those with 10-19 adenomas.

With regard to MUTYH mutations, the frequency was low in individuals with≥ 1000 adenomas (2%) but was fairly consistent in those with 10 colonic adenomas, those who present with multiple adenomas at an unusually young age, or those who have a family history consistent with FAP. The findings of the current study support testing in these individuals and demonstrate that the greater the number of polyps, the greater the likelihood of identifying a mutation.

However, multiple factors can complicate the value of genetic testing in clinical practice. The clinical phenotype of biallelic MUTYH mutations is quite varied; reports show that some mutation carriers can have hundreds of polyps, whereas others with colon cancer have no reported polyps.[2] Also, overlap among the clinical phenotypes of Lynch syndrome, MUTYH-associated disease, and attenuated FAP or other polyposis conditions may require clinical expertise for appropriate diagnosis and management. Finally, some controversy remains with regard to risk (if any) for colon cancer in persons with only 1 MUTYH mutation, and management in these patients is uncertain.[3]

At the same time, not all individuals manifesting colonic polyposis harbor a mutation in APC or MUTYH, and management is not straightforward in patients with polyposis but no identified mutation. Clearly, there are cases of unknown etiology, and there are probably as-yet unidentified genes that may predispose to adenomatosis. But changing technologies and testing standards can also affect interpretation of genetic test results. For example, polyposis testing was once only pursued in persons with > 20 polyps, whereas guidelines now recommend that testing be done in all patients who have ≥ 10 adenomas,[1] so historically “negative” tests may need to be revisited in the future.

Similarly, individuals tested before the availability of APC deletion/duplication analysis and MUTYH testing must be reassessed. Indeed, in the past few months, new and more efficient molecular testing modalities, so-called next-generation sequencing, have allowed the commercial launch of several cost-efficient gene panels that can test multiple genes at once for polyposis and nonpolyposis mutations. This may prove particularly helpful in evaluating patients with low polyp counts.

Current recommendations note that individuals with multiple adenomas or a family history of colon cancer be referred for genetic counseling. However, a lack of family history does not exclude the possibility of FAP, because an individual can harbor a de novo mutation; genetic testing for a hereditary cancer syndrome can thus be pursued on the basis of age, polyp count, and family history. In the absence of an identified mutation, family history as well as clinical presentation can be used to determine whether the individual may be at increased risk for other syndromes, and an empiric screening and prevention protocol can be established.

via Squaring Genetic vs Clinical Findings in Familial Polyposis.

MUTYH-associated polyposis (MAP)


MUTYH-associated polyposis (MAP)

Clinical characteristics

MUTYH-associated polyposis (MAP), caused by biallelic mutations in MUTYH (formerly known as MYH), is characterized by a greatly increased lifetime risk of colorectal cancer (43% to almost 100% in the absence of timely surveillance). Although typically associated with ten to a few hundred colonic adenomatous polyps that are evident at a mean age of about 50 years, colonic cancer develops in some individuals with biallelic MUTYH mutations in the absence of polyposis (Wang et al. 2004). Duodenal adenomas are found in 17%-25% of individuals with MAP; the lifetime risk of duodenal cancer is about 4%. Also noted are a modestly increased risk for rather late-onset malignancies of the ovary, bladder, and skin, and some evidence for an increased risk for breast and endometrial cancer. More recently, thyroid abnormalities (multinodular goiter, single nodules, and papillary thyroid cancer) have been reported in some studies. Some affected individuals develop sebaceous gland tumors.

Biallelic mutations in MUTYH have been found to account for approximately 10% of polyposis patients, but <1% of all colorectal cancer (Halford et al. 2003; Wang, Baudhuin et al. 2004).  The largest population study to date indicates that approximately 0.2% of all colorectal cancer is caused by biallelic mutations in MYH (Webb et al. 2006).  It was demonstrated in the same study that monoallelic MUTYH mutations are not associated with an increased risk of colorectal cancer.  The MAP phenotype is similar AFAP, with extra-colonic manifestations consisting of duodenal polyps but not intra-abdominal desmoids although occasionally patients may have up to several thousand polyps.  Among Caucasians approximately 80% of mutations in MUTYH causing MAP are Y165C or G382D (Sieber, Lipton et al. 2003).  https://familyhistorybowelcancer.files.wordpress.com/2012/08/myh.png

The E466X mutation is a common founder mutation among Pakistani populations.  The family tree above shows 2 Pakistani brothers who were affected with colorectal cancer and polyps in their 30s due to this founder mutation.  Y90X is a founder mutation in Indian populations (Sieber, Lipton et al. 2003).

Around 2530% of polyposis cases with more than 20 polyps and without evidence of a dominant inheritance pattern, in whom genetic analysis has not identified an APC mutation, are due to bi-allelic mutations in the base excision repair (BER) gene, MUTYH. Polyps can be exclusively adenomatous or mixed adenomatous/hyperplastic. Since the mode of inheritance is autosomal recessive, lack of vertical transmission of the polyposis phenotype in the family should raise the possibility of MUTYH-associated polyposis  (MAP). Siblings are at 25% risk of carrying bi-allelic deleterious mutations. Children of a bi-allelic carrier are at high risk if the other parent also carries at least one mutant allele. Large, systematic studies of MUTYH mutation frequency in colorectal cancer cases and controls suggest penetrance in bi-allelic carriers is very high, and probably >90%.

The heterozygote carrier frequency in the UK is around 2% and around 1:10 000 homozygous or compound heterozygotes for two MUTYH mutations. The proportion of polyposis syndromes due to MUTYH in clinical practice is less clear because studies have so far focused on selected research case series of multiple polyps that have been screened negative for APC mutations. In one study 4% of multiple polyp cases (3100) and 8% of APC mutation negative polyposis cases carry MUTYH mutations.

Molecular Pathogenesis

Damaged DNA is repaired by several mechanisms, one of which involves a family of enzymes involved in base-excision repair (BER). The MUTYH gene (also known as MYH) encodes a DNA glycosylase involved in the repair of the oxidative lesion 8-oxoguanine, a by-product of cellular metabolism and oxidative damage of DNA.

(8-oxoG, left), in syn conformation, forming a...

(8-oxoG, left), in syn conformation, forming a with (dATP, right). Created using ACD/ChemSketch 10.0 and . (Photo credit: Wikipedia)

(8-oxoG, left), in syn conformation, forming a with (dATP, right). Created using ACD/ChemSketch 10.0 and . (Photo credit: Wikipedia)

The products of three BER repair genes, OGG1, MTH1 and MYH work together to prevent 8-oxo-G induced mutagenesis.  Mutations in MUTYH cause an autosomal recessive colorectal cancer and polyposis syndrome MYH-associated polyposis (MAP; OMIM 608456) (Al-Tassan et al. 2002).  Somatic mutations in the APC gene in polyps from individuals affected with MAP are almost invariably G to T transversions (Sieber et al. 2003), and it was by understanding the underlying DNA repair mechanism of this mutation, base-excision repair, that MUTYH was identified as a candidate-predisposition

English: Schematic of base excision repair

English: Schematic of base excision repair (Photo credit: Wikipedia)

Schematic of base excision repair (Photo credit: Wikipedia)

gene. G to T transversion mutations were also identified in KRAS in codon 12 (Lipton et al. 2003).  The adenoma to carcinoma pathway in MAP does not involve BRAF V600E, SMAD4 or TGFBIIR mutations, or microsatellite instability, and the cancers are near-diploid (Lipton, Halford et al. 2003).  Thus, tumours with germline MUTYH mutations tend to follow a distinct pathway.

Colorectal surveillance & screening

Treatment of manifestations: Suspicious polyps identified on colonoscopy should be removed until polypectomy alone cannot manage the large size and density of the polyps, at which point either subtotal colectomy or proctocolectomy is performed. Duodenal polyps showing dysplasia or villous changes should be excised during endoscopy. Abnormal findings on thyroid ultrasound examination should be evaluated by a thyroid specialist to determine what combination of monitoring, surgery, and/or fine needle aspiration (FNA) is appropriate. Surveillance: Individuals with biallelic MUTYH germline mutations: Evaluation of relatives at risk: Offer molecular genetic testing for the familial mutations to all siblings of an individual with genetically confirmed MAP in order to reduce morbidity and mortality through early diagnosis and treatment.

Counselling: MAP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier with a small increased risk of CRC, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified.

UK Recommendations: Large bowel surveillance colonoscopy every 23 years is recommended from age 25 years for patients who are biallelic MUTYH carriers (or homozygous carriers of other BER gene defects). Colonoscopy is the preferred modality because of the likelihood of polyps requiring polypectomy.

Experience is limited because the role of MUTYH and other BER genes has only relatively recently been demonstrated. Hence, available evidence comes from pooled descriptive experience and opinion. However, there is a substantial colorectal cancer risk for those who are bi-allelic carriers.  Although indirect evidence suggests colonoscopic surveillance and polypectomy may be effective in colorectal cancer control, this has yet to be definitively determined. Indeed, we are not aware in the literature to date of any control subjects with bi-allelic MUTYH mutations who have reached the age of 55 years without developing colorectal cancer or polyposis . Hence, the risk may be sufficiently high to merit at least considering prophylactic colectomy and ileorectal anastomosis or even proctocolectomy and ileo-anal pouch if dense rectal polyposis is a feature. The patient should be counselled about the limited evidence available to guide decisions on either surveillance or pre-emptive surgical strategies

Familial adenomatous polyposis (FAP)


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Familial adenomatous polyposis (FAP)

Multiple polyp patients are a clinically heterogeneous group. Classical familial adenomatous polyposis (FAP; OMIM 175100) is caused by a germline mutation of the APC gene (at the locus 5q22-21) which activates the Wnt pathway (Bodmer et al. 1987; Groden et al. 1991; Clevers 2006). APC is also somatically mutated in approximately 70% of sporadic colorectal cancer.  However these cases are not caused by inherited mutations in the gene.

Polyposis (carpeting the rectum 20 years following a previous ileorectal anastamosis)

FAP is characterised by over a hundred colonic adenomas, and a high penetrance of colorectal cancer with an average age of cancer presentation of 39 years. There are also extra-colonic manifestations including intra-abdominal desmoids, duodenal adenomas and congenital hypertrophy of the retinal pigment epithelium(CHRPE).

In classical FAP, the risk of developing colorectal cancer exceeds 90% by age 70 years without prophylactic surgery.  The risk of gastroduodenal cancer is about 7%.  Around 25% of all cases are due to new mutations in the APC gene and so there is no previous family history. Nonetheless, children of individuals with a new mutation are at 50% risk of inheriting the condition.

The population prevalence of FAP is estimated at 1:14 000.  Owing to highly effective surgical prophylaxis, FAP accounts for only 0.07% of incident colorectal cancers in modern practice.  As registries and genetic services improve detection of at-risk family members, the proportion of colorectal cancer cases due to FAP should reduce, limited only by the proportion due to new mutations, which account for 25% of cases.

In attenuated FAP (AFAP) there is a later age of onset of colorectal cancer with a lower penetrance. The polyps number 10-100 in affected individuals. This arbitrary distinction is based on clinical characteristics, merely representing different ends of the same phenotypic spectrum of FAP. Germline mutations in APC account for up to 15% of patients with 5–100 adenomas and can be categorised AFAP.

English: CHRPE - congenital hypertrophy of the...

English: CHRPE – congenital hypertrophy of the retinal pigment epithelium (Photo credit: Wikipedia)

English: CHRPE – congenital hypertrophy of the retinal pigment epithelium (Photo credit: Wikipedia)

Somatic mutations in the APC gene

With regard to APC mutations, the most important functional domains of the APC gene appear to be the first serine alanine methionine proline (SAMP) (axin binding) repeat at codon 1580(Smits et al. 1999) and the first, second and third 20-amino acid repeats (20AARs) involved in ß-catenin binding and degradation. The great majority of pathogenic APC mutations truncate the protein before the first SAMP repeat and leave a stable, truncated protein that encodes 0-3 20AARs.

The ‘just-right’ model. The figure shows the multiple domains of the APC protein and the correlation between the position of the germline mutation and that of the somatic mutation. (a) Germline mutations between the first and the second 20AAR are associated with LOH. (b) Germline mutations before the first 20AAR are associated with somatic mutations between the second and third 20AAR. (c) Germline mutations after the second 20AAR are associated with somatic mutations before the first 20AAR(Segditsas and Tomlinson 2006).

APC is a classic tumour suppressor gene, requiring two hits for inactivation (Knudson 1971). In colorectal tumours from FAP patients, the germline wild-type allele either undergoes loss of heterozygosity (LOH) or acquires a protein-truncating mutation. Most somatic mutations occur in a restricted region of the gene, the mutation cluster region (MCR) (Miyoshi, Nagase et al. 1992). The reason for the MCR and relatively low frequency of LOH at APC was discovered from studies of FAP (Lamlum et al. 1999). It was found that LOH is strongly associated with germline mutations between the first and second 20AAR (codons 1285-1379). Germline mutations before codon 1280 are associated with somatic mutations between the second and third 20AAR (codons 1400 and 1495); and germline mutations after codon 1400 are associated with somatic mutations before codon 1280 (Lamlum, Ilyas et al. 1999; Albuquerque et al. 2002; Crabtree et al. 2003), Most tumours end up with APC alleles that encode a total of two 20AARs(Figure 1‑4). Similar associations exist for sporadic colorectal cancers. This association has been proposed to cause an optimal level of Wnt signalling/ß-catenin activation (Lamlum, Ilyas et al. 1999; Albuquerque, Breukel et al. 2002). Whatever the case, it is clear that selective constraints act on colorectal tumours such that some combinations of APC mutations provide a superior growth advantage for the tumour cell. This is known as the ‘just right’ hypothesis.

Germline APC mutation and phenotype

There is a genotype-phenotype relationship determined by the precise location of the APC mutation. AFAP is associated with germline mutations in three regions of APC: 5’ (codon 1580); and the alternatively spliced region of exon 9 (Knudsen et al. 2003). Mutations close to codon 1300 are the most commonly found and are associated with a severe phenotype, typically producing over 2000 polyps and earlier-onset colorectal cancer (Nugent et al. 1994; Debinski et al. 1996). De novo mutations of APC occur in approximately 20% of FAP. In a small study de novo mutations of APC were found to be more commonly of paternal origin (Aretz 2004).

Somatic mutations in the Wnt signalling pathway in genes other than APC

Figure 1. Wnt doesn't bind to the receptor. Ax...

Figure 1. Wnt doesn’t bind to the receptor. Axin, GSK and APC form a “destruction complex,” and β-Cat is destroyed. Compare to Figure 2. See the article main text for details. (Photo credit: Wikipedia)

Figure 1. Wnt doesn’t bind to the receptor. Axin, GSK and APC form a “destruction complex,” and β-Cat is destroyed. Compare to Figure 2. See the article main text for details. (Photo credit: Wikipedia)

The Wnt signalling pathway is activated in approximately 75% of colorectal cancer, and is one of the key signalling pathways in cancer, regulating cell growth, motility and differentiation. APC binds to the ß-catenin protein which functions in cell adhesion andas a downstream transcriptional activator in the Wnt signallingpathway (Wong and Pignatelli 2002). Somatic mutations in ß-CATENIN usually delete the whole of exon 3 or target individual serine or threonine residues encoded by this exon (Ilyas et al. 1997; Morin et al.). These residues are phosphorylated by the degradation complex that contains APC, and hence their mutation causes ß-catenin to escape from proteosomal degradation. These mutations are particularly associated with HNPCC tumours (but not sporadic MSI tumours) (Johnson et al. 2005). However, less than 5% of all sporadic colorectal cancer has mutation in ß-CATENIN. In addition somatic mutations have been reported in AXIN1 (Webster et al. 2000) and AXIN2 (Suraweera et al. 2006), the importance of which is uncertain.
Screening and Managment of FAP

Establishment of FAP registries

Families with FAP should be referred to the regional clinical genetics service or other specialist service that can facilitate risk assessment, genetic testing and screening of family members. Some regional services have specific FAP registers that facilitate regular follow-up. FAP registries have been shown to improve outcomes by systematic and structured delivery of management, monitoring interventions and surveillance, as well as serving as a focus for audit.

Large bowel surveillance for FAP family members Annual flexible sigmoidoscopy and alternating colonoscopy should be offered to mutation carriers from diagnosis until polyp load indicates a need for surgery.198 In a small minority of families where no mutation can be identified and genetic linkage analysis is not possible, family members at 50% risk should have annual surveillance from age 13e15 until age 30 years, and every 35 years thereafter until age 60. Surveillance might also be offered as a temporary measure for people with documented APC gene mutations and a significant polyp load but who wish to defer prophylactic surgery for personal reasons. Such individuals should be offered 6-monthly flexible sigmoidoscopy and annual colonoscopy. As in Lynch syndrome, chromoendoscopy or narrow band endoscopy may have a place in surveillance for attenuated FAP, but the utility of these techniques merits further appraisal and must not replace conventional endoscopic approaches. Surgery can be deferred if careful follow-up is instigated and the patient is fully aware of the risks of cancer. This is especially the case for attenuated FAP but can also be useful in the management of classical FAP for individuals who have a low polyp burden in terms of size, multiplicity and degree of dysplasia. The cancer risk increases substantially after 25 years, and so surgery should be undertaken before then unless polyps are sparse and there is no high-grade dysplasia. If colectomy and ileorectal anastomosis are performed, the rectum must be kept under review annually for life because the risk of cancer in the retained rectum is 1229%.The anorectal cuff after restorative proctocolectomy should also be kept under annual review for life.

Prophylactic colorectal surgery

Patients with typical FAP should be advised to undergo prophylactic surgery between the ages of 16 and 25 years, but the exact timing of surgery should be guided by polyp numbers, size and dysplasia and fully informed patient choice influenced by educational and child-bearing issues. Surgical options include proctocolectomy and ileoanal pouch or a colectomy with ileorectal anastomosis.

People with proven FAP require prophylactic surgery to remove the majority of at-risk large bowel epithelium. Colectomy and ileorectal anastomosis is associated with a 1229% risk of cancer in the retained rectum, whereas restorative proctocolectomy is associated with a very low risk of cancer in the pouch or in the retained mucosa at anorectum. Ileoanal pouch construction may be associated with impaired fertility.  It is clear that case identification and prophylactic surgery have markedly improved survival in FAP.

Upper gastrointestinal surveillance in FAP

Because of the substantial risk of upper gastrointestinal malignancy in FAP, surveillance of this tract is recommended. While gastroduodenal polyposis is well recognised in FAP and surveillance practice is established practice in the overall management, there is limited evidence on which to gauge the potential benefit of surveillance. However, the approach seems reasonable, and 3-yearly upper gastrointestinal endoscopy is recommended from age 30 years with the aim of detecting early curable cancers. Patients with large numbers of duodenal polyps should undergo annual surveillance.

Gastroduodenal and periampullary malignancies account for a small, but appreciable, number of deaths in patients with FAP. Duodenal polyposis occurs in approximately 90% of FAP patients and the overall lifetime risk of periampullary cancer is 35%.Advancing age and mutation location within the APC gene appear to have an effect on duodenal carcinoma risk.  Almost all FAP patients have some abnormality on inspection and biopsy of the duodenum by age 40.  The degree of duodenal polyposis can be assessed using an endoscopic/histological scoring system (Spigelman classification143), which can be helpful in predicting the risk of duodenal cancer. The worst stage (IV) has a 10-year risk of 36% and stage 0 negligible risk.207 Hence, it seems reasonable to offer 3-yearly upper gastrointestinal surveillance from age 30 years and more frequently if there is extensive polyposis. However, it should be noted that the effectiveness of this intervention in reducing mortality is unknown, especially since duodenal polypectomy is unsatisfactory208 and prophylactic duodenectomy is a major undertaking with substantial attendant morbidity and mortality.

 

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