Familial Adenomatous Polyposis

Content

Introduction ……………………………………………………………………………3

Actuality of the thesis ……………………………………………………………….3

Purpose of the thesis …………………………………………………………………4

Objectives of the thesis ………………………………………………………………4

Theoretical importance and value of the work ……………………………………4

Chapter 1 ………………………………………………………………………………5

1.1 general information …………………………………………………………….5

1.1.1 Anatomy of the colon …………………………………………………………5

1.1.2 Blood and nerve supply ……………………………….……………..………10

1.1.3 Function of the colon …………………………………………………………12

1.2 Familial adenomatous polyposis ………………………………………….…15

1.2.1 Etiology ………………………………………………………………………..16

1.2.2 Epidemiology …………………………………………………………………18

1.2.3 Clinical presentation and manifestation ……………………………………19

1.2.4 Diagnosis ………………………………………………………………….…..24

1.2.5 Management …………………………………………………………….……27

1.2.5 Prognosis ………………………………………………………………….…..30

Chapter 2

2.1 bibliographic analysis of the thesis …………………………………………………………31

2.2 material and research methods ………………………………………………..32

2.3 case reports ………………………………………………………………………32

2.4 discussions and personal results ………………………………………………35

2.5 conclusion ………………………………………………………………………..38

2.6 bibliographic references …………………………………………………………43

Introduction

Actuality of thesis

Familial adenomatous polyposisا (FAP) is an inherited condition in which numerous adenomatous polypsا اform mainly in the epithelium of the large intestine. While these اpolyps اstart out benign, malignant transformation اintocolon اcancer occurs اwhen they are left untreated. Three variants are known اto exist, FAP اand attenuated FAP (originally called “hereditary اflat adenoma اsyndromeا) are caused by APC gene defects on chromosome 5 اwhileautosomal recessiveا FAP (or MYH-associated polyposis) is caused by defectsا in the MUTYH geneا on chromosome 1. Of the three, FAP itself is the most severeا and most common; اalthough for all three, the resulting colonic polyps and cancers areا confined to اthe colon wall and removal can greatly reduce the spreadا of cancer.

The root causeا of FAP is understoodا اto be a genetic mutation—a flaw in the body's tumour اsuppressor genes that اprevent development of tumours. The flaw allows numerous cells اof the intestinal اwall to develop into potentially cancerous polyps when they اwould usually reach اthe end of their life; inevitably one or more will eventually اprogress and give اrise to cancer (7% اrisk by age 21, rising to 87% by age 45 and 93% اby age 50). اThe flawed اgenes do not trigger cancer, but rather, they reduce the اbody's ability to اprotect against the risk of aged cells becoming cancerous. Even اwith the اflawed gene, it may still take time before a cell actually does develop اthat is cancerous اas a result, and the gene may in some cases still partially operate اto اcontrol tumours, therefore cancer from FAP takes many years to اdevelop and is اalmost always اan adult-onset disease.

Purpose of thesis

Reveal the modern methodology used in diagnosis and treatment of familial adenomatous polyposis

Objectives of thesis

1. Study the morphopathological pattern of transforming polyps into malignancies

2. Study the etiology of colorectal polyps and the most common risk factors for developing the disease

3. Studying the most recent strategies used in detection and diagnosing the disease

4. The importance of early detection and prevention of progression

Value of the work

1. To present a contemporary algorithm which reveal the modern methods of diagnosis and treatment

2. I reviewed the experience of the surgical department and their approach to patients suffering from colorectal polyps

Theoretical importance

1. To reveal the frequent etiologies of the disease according to the recent researches

2. To participate in the modern surgeries at the surgical department of the hospital and acquire an experience

3. To establish the relation between polyps and cancerogenesis and their incidence

Chapter 1

General information

Anatomy of the colon :

The large اintestine, also اcalled the اcolon or the large bowel, is the last part of the digestive systemا in اvertebrates. Water ااis absorbed here and the remaining waste material is اstored اas feces before اbeing اremoved by defecation.[1]

Terminologia اAnatomica, اMedscape, اdefine اthe large intestine as the combination of the اcecum, اcolon, rectum, اand اanal canal. Other sources, such as Mosby's Medical اDictionary and the اOxford اDictionaries of Medicine and Biology exclude اthe analا canal. In اhumans, it اbegins in the right iliac region of the pelvis, just at اor belowا the waist, اwhere itا is joined to the end of the small intestine. It then اcontinuesا up the اabdomen, اacross the width of the abdominal cavity, and then اdown اto its endpoint اat the اanus. Overall, in humans, the large intestine is اabout ا1.5 metres (4.9 ft) long, اwhichا اis about one-fifth of the whole length of the اgastrointestinalا اtract.

اSections

Sections اof theا colon

In mammalsا, the اcolon consists of four sections: the ascending colon, the transverseا colon, the descendingا colon, and the sigmoid colon (the proximal اgut usually refersا to the ascending colon and transverse colon, and distal اgut refers to the descendingا colon). The cecum, colon, rectum اand anal canal make up the largeا intestine.

Sections of اthe colonا are:

The اcecum and theا appendix

Theا اascending اcolon

The right اcolic flexure ا(hepatic)

The اtransverse اcolon

The اtransverse اmesocolon

The left اcolic flexure ا(splenic)

The اdescending اcolon

The sigmoidا colon – the v-اshaped region of the large intestine

The parts of theا colon are اeither intraperitoneal or behind it in the اretroperitoneum. Retroperitoneal اorgans in general do not have a complete covering ofا peritoneum, so they are fixed اin location. Intraperitoneal organs are completely اsurrounded by peritoneum اand are therefore mobile. Of the colon, the ascending اcolon, descending colon اand rectum are retroperitoneal, while the caecum, اappendix, transverseا colon and sigmoid اcolon are intraperitoneal.

This is important as اit affects which اorgans can اbe easily accessed during surgery, such as اa اlaparotomy.

Cecum and appendix

The cecum is the اfirst section of the colon andا involved in the digestion, while the appendix which اdevelops embryologically اfrom it, is a structure of the colon, not involved in اdigestion and considered to beا part of the gut-associated lymphoid tissue. The اfunction of the appendix is اuncertain, but some sources believe that the appendix اhas a role in housing اa sample of the colon's microflora, and is اable to help to repopulate اthe colon with bacteria if the microflora has been اdamaged during the اcourse of an immune reaction.

Ascending اcolon

The ascending اcolon is one part of four اsections of the large intestine. This first section of the large intestine اis connected to اthe small intestine by a section of bowel called the cecum. اThe ascending colon runs through the abdominal cavity, upwards toward the اtransverse colon for approximately اeight inches (20 cm).

One of the main اfunctions of the colon is to اremove theا water and other key nutrients from waste اmaterial and recycle it back intoا the body. As the waste material exits the small intestine اit will move into اthe cecum and then to the ascending colon where this اprocess of extraction اstarts. The unwanted waste material is moved upwardsا toward the transverse اsection of the colon by the action of peristalsis. The اascending colon is sometimes attached to the appendix via Gerlach's valve. The اappendix traditionally seen اas a vestigial organ has been shown to have a high اconcentration of lymphatic اcells. In ruminantsا, the ascending colon اis known as the اspiral colon.[13] The cecum receives the solid wastes of digestionا from the ileum via theileocecalا valve.[14][15]

اTransverse اcolon

The transverse colon اis the part of the colon fromا the hepatic flexure to the splenic flexure ا(the turn of the colonا by the spleen). The transverse colon hangs off the اstomach, attached to it by a large fold of peritoneum called the greater اomentum. On the اposterior اside, the transverseا colon is connected to the posterior اabdominal wall by a mesentery known اas the transverse mesocolon.

The transverse اcolon is encased in اperitoneum, and is therefore mobile (unlike the parts of the colon اimmediately before and اafter it). Cancers form more frequently further along the large intestine اas the contents become more solid (water is removed) اin order to اform feces.

The proximalا two-thirds of the transverse اcolon is perfused by the middle colic artery, a branch of the اsuperior mesenteric artery (SMA), while اthe latter third is supplied by branches اof the inferior mesenteric اartery (IMA). The "watershed" area between these اtwo blood supplies, which اrepresents the embryologic division between اthe midgut and hindgut, is an اarea sensitive to ischemia.

Descending ااcolon

The descending colon اis the part of the colon fromا the splenic flexure to the beginning of the اsigmoid colon. One function of the اdescending colon in the digestive system اis to store faeces that will be اemptied into the rectum. It is retroperitoneal اin two-thirds of اhumans. In the other third, it has a (usually short) اmesentery. The arterial supply comes via the اleft colic artery. The descending colon is اalso called the distal gut, as it isا further along the gastrointestinal tract اthan the proximal gut. Gut اflora are very dense in this region.

Sigmoid اcolon

The sigmoid colon اis the part of the large intestine اafter the descending colon and before the اrectum. The name sigmoid means اS-shaped (see sigmoid; cf. sigmoid sinus). The walls اof the sigmoid اcolon are muscular, and contract to increase the pressure inside اthe colon, causing اthe stool to move into the rectum.

The sigmoid colon is اsupplied with blood اfrom several branches (usually between 2 and 6) ofا the sigmoid arteries, a اbranch of the IMA. The IMA terminates as the اsuperiorا rectal artery.

Sigmoidoscopy is اa common diagnostic technique اused to examine the sigmoid colon.

Rectum

The اrectum اا(from the Latin rectumا intestinum, اmeaning straight intestine) is the final straight اportion of the large intestine in some اmammals, and the gut in others. The human اrectum is about 12ا centimetres (4.7 in) long, and begins at the rectosigmoid اjunction (the end of اthe sigmoid colon), at the level of the third sacral vertebra or اthe sacral promontory اdepending upon what definition is used. Its caliber اis similar to that of the sigmoid اcolon at its commencement, but it is dilated near اits termination, forming اthe rectal ampulla.

Blood اsupply:

Arterialا supply toا the اcolon comes from branches of the اsuperior mesenteric artery (SMA) and اinferior اmesenteric اartery (IMA). Flow اbetween these two systems اcommunicates اvia a "marginal اartery" that runsا parallel to the colon for its entireا length. ااHistorically, it has been اbelieved اthat the arc of Riolan, or the meandering اmesenteric artery (of ااMoskowitz), is a variable vessel connecting the proximal اSMA اto the proximal IMA اthat can اbe extremely important if either vessel is occluded. اHowever, recent اstudies اconducted with improved imaging technologyا have اquestioned the اactual اexistence of this vessel, with some experts calling اfor the اabolition اof the terms اfrom future اmedical literature.

Venous اdrainage اusually mirrors اcolonic arterial اsupply, with the inferior mesenteric اvein اdraining into اthe اsplenic vein, and اthe superior mesenteric vein joining the اsplenic vein to form اthe hepatic اportal vein that اthen enters the اliver.

Innervations:

Theا large intestine اis innervated اby intrinsic and extrinsic sources. Theا vagus nerve ا(CNX) enterا اthe abdominal اcavity via the esophageal اhiatus of the diaphragm اto اprovide parasympathetic اinnervation to اthe large intestines. The اpelvic splanchnic اnerves ا(S2-4) also اcontribute to the large intestines’ parasympatheticا اsupply. The اparasympathetic اfibers are اresponsible for increasing اsecretomotor اactivity along اthis اsegment of the digestive اtract. The vagusا nerve اfulfil this role in the gut to اthe point of the transverse colon, while the pelvic اsplanchnic nerves carry on اthis functionا from the left colic flexure onwards. اThe اT10-L2ا thoracolumbar اoutflow of sympathetic fibers is responsible اfor اthe اinhibitory اactivity along اthe large intestines. Theyا form synapsesا at the اsuperior اand اinferior mesenteric, and اthe inferior hypogastric plexuses. The اsuperiorا mesenteric اplexus provides اsympathetic innervations to the cecum, appendix, اascending and transverse ااcolon (near to the left colic flexure), while the ااinferior اmesenteric اplexus innervates the colon from the left colic flexure to the اrectum. اThe inferior اhypogastric اplexus also اinnervates the rectum.

In additionا to the اextrinsic nerve اsupply to the اgut, there are networks of nerve fibers اoccupying اspace between the longitudinal اand circular اmuscle layers (mesenteric اplexus اof Auerbach), اand in اthe submucosal اlayer (اsubmucosal plexus of Meissner). اIn اaddition to اAuerbach’s اand اMeissner’s plexuses, there are additionalا intrinsic اplexuses اthat collectively form the enteric nervous system. Although اااthese networks receive ااpostganglionic inhibitory and preganglionic اexcitatory اfibers, they are اfully ااfunctional in the اabsence of those اcontributions.

Function:

The large اintestineا اtakesا about 16 hours to اfinish the digestion of the food. It اremoves اwater and اany remaining اabsorbableا nutrients from the food before sending the indigestible اmatter to the اrectum. اThe colon اabsorbs vitamins that are created by the colonicا bacteria, such asا vitamin اK (especially important as the daily ingestion ofا vitamin K is not اnormally اenough to اmaintain adequate blood اcoagulation), vitaminا اB12, thiamine اand riboflavin. It also compacts feces, اand stores fecal اmatter in اthe rectum اuntil it can be discharged via the anus in اdefecation. The اlargeا intestine also secretes K+ and Cl-. Chloride secretion increases ااin cystic fibrosis. اRecycling of various nutrients takes place in colon. Examples ااinclude اfermentation of carbohydrates, short chain fatty acids, andا urea اcycling.

The large intestine اdiffers اin physical form اfrom the اsmall intestine in being much wider اand in اshowing the اlongitudinal layer of the muscularis have been reduced to 3 اstrap-like structures known اas the taeniae coli. اThe wall of the large intestine is lined اwith simple columnar اepithelium. Instead of having the evaginations اof the اsmall intestine ا(villi), the large intestine has invaginations ا(the intestinal glands). اWhile both the اsmall intestine and the large intestine اhave اgoblet cells, they are اabundant in اthe large intestine.

The appendix is اattached to اthe inferior surface اof the cecum, and contains a small amount of اmucosa-associated lymphoid اtissue which gives the appendix an undetermined اrole in immunity. However, the اappendix is known to be important in fetal اlife as اit contains endocrine اcells that release biogenic amines and peptide اhormonesا important for homeostasis اduring early growth and development. The اappendix اcan be removed اwith no apparent damage or consequence toا اthe patient.

The large intestine اextends اfrom the ileocecal junction اto the anus and is about 1.5 m long. On the اsurface, اbands of longitudinal اmuscle fibers called taeniae coli, each about ا1/5 in اwide, can be identified. اThere are three bands, and they start at the base اof اthe appendix and اextend from اthe cecum to the rectum. Along theا sides of the اtaeniae, tags اof peritoneum filled with fat, called epiploic appendages ا(or appendices epiploicae) are اfound. The sacculations, called haustra, are اcharacteristicا features of the اlarge intestine, and اdistinguish it from the smallا اintestine.

The large intestine ااcomes after the small intestine in the digestive tract and measures approximately ا1.5 meters in length in اadult humans. There are differences in the largeا intestine between اdifferent organisms. The large intestine is mainly responsible for اstoring waste, اreclaiming water, maintaining the water balance, absorbing some اvitamins, such اas vitamin K, and اproviding a location for اflora-aidedا fermentation.

By the time the ااchyme has reached this tube, most اnutrients and 90% of the water has been اabsorbedا by the body. At this point some electrolytes like اsodium, magnesium, اand chloride are left as well as indigestible parts اofا ingested food (e.g., a اlarge part of اingested amylase, starch which has been shielded ااfrom digestion اheretofore, and اdietary fiber, which is largely اindigestible اcarbohydrate اin either soluble اor insoluble form). Asا the chyme moves اthrough اthe large اintestine, most of the اremaining water is removed, while the اchymeا is mixed with mucus اand bacteria (known as gut flora), and becomes اfeces. The ascending اreceives fecal material as a liquid. The muscles of the colon اthen move the watery waste اmaterial forward and slowly absorb all the excess اwater. The stools gradually اsolidify as they move along into the اdescending اcolon.

The bacteria break اdown some of the fiber اfor their own nourishment and create acetate, اpropionate, and butyrate as اwaste products, اwhich in turn are used by the cell lining اof the colon for nourishment. No اprotein is made available. In اhumans, perhaps 10% of the undigested اcarbohydrate thus becomes available, though اthis may vary with diet;  in other اanimals, including other apes and primates, who اhave proportionally larger اcolons, more is made available, thus permitting a اhigher portion of plant material اin the diet. The large intestine produces no digestive اenzymes — chemical اdigestion is completed in the small intestine before the اchyme reaches the large اintestine. The pH اin the colon varies betweenا 5.5 and ا7 (slightly acidicto neutral)

Familial adenomatous polyposis

Familial adenomatous اpolyposis (FAP) is an اautosomal-dominant colorectal cancer syndrome, اcaused by a germline mutation اin the adenomatous polyposis coli (APC) gene, on اchromosome 5q21. It is اcharacterized by hundreds of adenomatous colorectal اpolyps, with an almostا inevitable progression to colorectal cancer at an اaverage age of 35 to 40 yr. اAssociated features include upper gastrointestinal اtract polyps, congenital اhypertrophy of the retinal pigment epithelium, اdesmoid tumors, and other اextracolonic malignancies. Gardner syndrome اis more of a historical اsubdivision of FAP, characterized by osteomas, dental اanomalies, epidermal cysts, اand soft tissue tumors. Other specified variants include اTurcot syndrome (اassociated with central nervous system malignancies) اand hereditary desmoid اdisease. Several genotype–phenotype اcorrelations have اbeen observed. اAttenuated FAP is a phenotypically distinct entity, presenting اwith fewer اthan 100 adenomas. Multiple colorectal adenomas can also be اcaused by mutations اin the human MutY homologue (MYH) gene, in an اautosomal recessive اcondition referred to as MYH associated polyposis (MAP). اEndoscopic screening اof FAP probands and relatives is advocated as early as اthe ages of 10–12 yr, اwith the objective of reducing the occurrence of اcolorectal cancer. Colectomy اremains the optimal prophylactic treatment, while اthe choice of procedure (اsubtotal vsproctocolectomy) is still controversial. اAlong with identifying betterا chemopreventive agents, optimizing screening of extracolonic اcancers and applyingا new radiological and endoscopic technology to the اdiagnosis and management اof extracolonic features are the major challengesا for اthe future.

Etiology

APC gene اmutationا variants

The APC is a اtumour suppressor gene اresponsible for the production of adenomatous اpolyposis coli (APC), a large اmultifunction tumour-suppressing protein which acts اas a "gatekeeper" to prevent اdevelopment of tumours. (APC regulates β-catenin, اa protein that plays a crucial اrole in cell communication, signalling, growth, and اcontrolled destruction, اbut which left uncontrolled also gives rise to numerous اcancers). A flaw in اthe APC gene means APC is not as effective as it should اbe, اand over time it is اlikely that some cells that should have been controlled by APC اwill not be, اand will instead continue to develop and become cancerous. In اfamiliar polyposis they اusually manifest as polyps—small abnormalities اon the surface of the اintestinal tract.

Although the polyps اare inherently اbenign, the first step of the two-hit hypothesis has already اtaken place: the اinherited APC mutation. Often, the remaining "normal" allele اis mutated or اdeleted, accelerating generation of polyps. Further اmutations (e.g. in p53 or kRAS) to اAPC-mutated cells are much more likely to اlead to cancer than they would اin non-mutated epithelial cells.

The normal function اof the APC gene اproduct is still being investigated; it is present both the cell اnucleus and the اmembrane. The اcanonical tumor-suppressor function اof APC is suppression اof β-catenin, but other tumor-suppressor functions اof APC may be اrelated to cell adherence and cytoskeleton اorganization.

Mutation of APC اalso occurs commonlyا in incident cases of colorectal carcinoma, emphasizing its اimportanceا in this form of cancer.

Figure 6

Relationship betweenا Wnt signaling and the اAPC tumor-suppressor gene in activating the β-catenin to enter the اnucleus (no APC activity) اfor promoting اgenes expression and polyamine metabolism (ODC) اin the colonic اepithelium; اor (with APC activity) اfor the proteasomal degradation in the اcolonicا اepithelium.

MUTYH اgene mutation اvariants

MUTYH encodesا DNA repair enzyme اMYH glycosylase. During اnormal cellular activities, guanine اsometimes becomes altered by اoxygen, which اcauses it to pair with adenine instead اof cytosine. MYH اglycosylase fixes اthese mistakes by base excision اrepair, such thatا mutations do not اaccumulate in the DNA and lead to tumorا formation. When اMYH glycosylase اdoes not اfunction correctly, DNA errors may accrue to اinitiate tumorigenesis with a اclinical presentation similar to that in patients اwith اAPC mutations.

Mutations in the اMUTYH اgene are inherited in an اautosomal recessive pattern, which means two اcopies of the gene must be altered اfor a person to be affected by the disorder. Most اoften, the parents of a child اwith an autosomal recessive disorder are not affected but ااare carriers of one اcopy of the altered gene

Epidemiology

The incidence اof the mutation اis between 1 in 10,000 اand 1 in 15,000 births. By age 35 years, 95% ofا individuals with FAP (>100 اadenomas) have polyps. Without colectomy, اcolon cancer is virtually اinevitable. The mean age of colon cancer in untreated اindividuals is 39 yearsا (range 34–43 years).

Attentuated FAP اarises when APC is defective اbut still somewhat functional. As a result, it retains اpart of its ability to suppress اpolyps. Therefore, attenuated FAP manifests as اcolorectal cancer unusually اlate (age 40–70, average=55[3]), and typically with few, اor at least far اfewer polyps (typically 30[2]), than the more usual version of اFAP, at an age اwhen FAP is no اlonger considered much of a likelihood or riskا according to usual اFAP epidemiology.

Figure 1

Relative and approximate اcontributions of اfamilial causes to the incidence of colorectal cancer. FAP – Familial adenomatous اpolyposis, JP – Familial اjuvenile polyposis, PJ – Peutz-Jeghers syndrome, HNPCC – Hereditary اnonpolyposis colorectal cancer ا(Lynch Syndrome). Note the very small contribution of FAP to اthe etiology of اcancer.

Clinical presentation and اmanifestations

Symptoms اare uncommon in the child اand adolescent until the adenomas are large and numerous اso as to cause rectal اbleeding or even anemia. Other non-specific complaints اsuch as change in اbowel habits, اconstipation, or diarrhea, abdominal pains or اpalpable abdominal masses or weight loss in young patients can lead to recto-sigmoid اexamination andا identification of polyps suggestive of FAP. FAP can present اwith extraintestinal اmanifestations such as osteomas, dental abnormalitiesا (unerupted teeth, congenital absence اof one or more teeth, supernumerary اteeth, dentigerous cysts, and اodontomas), congenital hypertrophy of اthe retinal pigment اepithelium (CHRPE), desmoid tumors, or extracolonic cancers ا(thyroid, liver, bile ducts, central nervous system), (see below). Some اlesions (skull and mandible osteomas, اdental abnormalities, fibromas on the اscalp, shoulders, arms, and back) are indicative of the Gardner variant of FAP. اToday the condition should rarely اpresent as a colonic or even as an اextra-colonic اmalignancy.

Classic FAP is اcharacterized by the presence اof hundreds to thousands of colorectal adenomas اof different sizes. اToday this is rarely seen in countries with well developed اpublic health services. In the اmajority of patients polyps begin to develop during اchildhood, mostly اin the اdistal colon (rectosigmoid) as small intramucosal اnodules (Fig. 2A). By the اtime of adolescence, the polyps are usually identified اthroughout the colon and, اthereafter, increase in size and numbers (Fig. 2B). اAbout half of FAP اpatients develop اadenomas by 15 years of age and 95% by اage 35 years

Figure 2 Panel A اshows the endoscopic اappearance of early FAP اadenomas; panel اB shows the endoscopic appearance اof اestablished, اmultiple, FAP اadenomas.

Other اgastrointestinal manifestations

Individuals with اFAP can also اdevelop a اvariety of extra-colonic اgastrointestinal manifestations

Figure 3

Panel A illustratesا the extracolonic upper gastrointestinal polyp manifestations of FAP (Used with permission and اadapted from the American اGastroenterology Association Institute's Clinical Teaching اUnit 11, copyright). اFig. B is aا schematic illustration of a "J-pouch", formed from the distal small intestine and اattached to the anal اsphincter. The shorter limb of the "J" acting as a fecal reservoir; Fig. C is an اx-ray demonstration of this اpouch (Figures اprovided by Dr. A. Deutsch, Petach Tikva and اreproduced, with permission of the اpublishers, from اreference [70]: Rozen P, Levin B, Young GP: Who are at risk اfor familial colorectal اcancer اand how can they be managed? In Colorectal Cancer in اClinical Practice: اPrevention, Early Detection and اManagement Edited by: Rozen P, Young GP, Levin B, Spann اSJ. اLondon, Ed 2, Taylor اand Francis 2002:55-66).

In the stomach, اfundic gland اpolyps (FGP) develop اin 90% of patients with FAP. They are of اspecial interest since, in contrast to اthe benign nature of sporadic FGP, 40% of these اlesions in individuals اwith FAP have been shown to have adenomatous features, اbut rarely do progress اto cancer. FGPs in FAP patients are pathogenetically اdistinct from sporadic اFGPs. Somatic, second-hit APC gene alterations, which اprecede morphological اdysplasia in many FAP-associated FGPs, indicate that اFGPs arising in the اsetting of FAP are neoplastic lesions.

Adenomatous polyps اin the duodenumا (mainly in the 2nd and 3rd parts) and periampullary اregion. In one series اthey developed in approximately 90% of individuals withا اFAP, 10-20 years after diagnosis اof colorectal polyps. The lifetime risk of اduodenal اadenomas has been اreported to reach 100%. Spigelman's اclassification of duodenal اpolyps is a scale, based on polyp number, size, histology, and severity اof dysplasia. اIt is estimated that about 5% of duodenal, and اspecifically اperiampulary اpolyps, اprogress to cancer within 10 years. While اrare in the اgeneral اpopulation, theا risk of duodenal or periampullary cancer اis increased severalا hundred اfold in FAP patients. Duodenal polyposis اusually progresses اin an orderly اfashion through increasing Spigelman stage, but اcancer can اpresent in patients اunder surveillance with lower Spigelman stages اbeing identified in their اpenultimate examinations. Pancreatitis can be the اresult of اampullary اadenoma or اas a presentation of malignancy

Extra-intestinal اmanifestations

Extraintestinal اmanifestations اof FAP, which اare rarely malignant, include: cutaneous اlesions such asfibromas, اlipomas, sebaceous and epidermoid cysts, and nasopharyngeal اangiofibromas (Fig 4A). Osteomas can be palpated or seen, they can be identifiedا as اoccult radio-opaque jaw lesions, and dental abnormalities which can be اdisfiguring (Fig. 4B). اGardner described the presence of these extraintestinal اlesions and this اphenotypic variant is named after him as "Gardner syndrome" ا.Congenital hypertrophy اof the retinal pigment epithelium (CHRPE) is a patch(s)ا of اdiscoloration in the ocular fundus but is not specific for FAP (Fig. 4C). Almost اall اpatients with CHRPE do not have symptoms and the lesions are found اduring اexamination of the dilated eye. However, when multiple bilateral اlesions اoccur it اcan be a sensitive phenotypic marker and calls for اscreening. اLow-grade اadenocarcinoma has been described in these اlesions

Figure 4

Panel A illustrates the extraintestinal اmanifestations اof FAP (Used with permission and adapted from the American اGastroenterology Association اInstitute's Clinical Teaching Unit 11, copyright). Panel B is اa panoramic jaw X-ray showing اmandibular اareas of osteoslerosis that اcan be found in some FAP patients اbut is not diagnostic of FAP. Panel اC shows retinal pigmentation (CHRPE) that can be foundا in some FAP ااpatients but is not اdiagnostic of FAP.

Attenuated familial اadenomatous اpolyposis (AFAP)

This is a less aggressiveا variant of FAP that is اcharacterized by fewer colorectal adenomatous polyps ا(usually 10 to 100), later age اof adenoma appearance (mean age of polyp diagnosisا is 44 years) and cancer (mean اage 56 years). اClinically, it can be confusing as oftenا there is mainly proximal اcolonic involvement with polyps, and infrequent اrectal involvement. اThus, it can اbe misdiagnosed as occurring in a patient اwith sporadic اadenomas (Figs. 5A-C) however, it can also occur in families with اmembers having اfull clinical اfeatures of FAP.

Although these اindividuals have a smaller اpolyp burden relative to classic FAP, they still have an increased اrisk of cancer that, اin general, occurs approximately 10-15 years later. As ااin FAP the most prominent اextracolonic findings are upper gastrointestinal اpolyps specifically, duodenal and gastric اadenomas and fundic gland polyps. Gastric اand breast adenocarcinomas, as اwell as hepatoblastoma, have also been documentedا اin AFAP. Other اextracolonic manifestationsا of FAP are rare

Panel A shows the endoscopic ااappearance of early FAP and the difficultyا in identifying adenomas; Panel B shows the endoscopic appearance after اspraying with dilute Indian ink contrastا chromoendoscopy; اnote the easier identification of small polyps (Figures reproducedا from reference[85]: P اRozen, F Macrae, Familial اadenomatous polyposis: The practical applications of clinical and molecular اscreening. Familial Cancer, 2006; 5:227-335, اwith kind permission of Springer Science and Business Media). Panel C shows the ااoccasional adenoma seen in attenuated FAP اand the difficulty in makingا the endoscopic diagnosis of FAP.

Diagnosis

The diagnosis of اclassic اFAP is based on a suggestiveا family history and clinical findings. Whenever اpossible, the clinical diagnosis اshould be اconfirmed by genetic اtesting.

Clinical اdiagnosis

Making the diagnosisا of FAP before the development اof colon cancer is important not just forا the individual, but also for اthe sake of other family members who may اbe affected. Two diagnostic اmethods exist:

Colonoscopy is the اusual diagnostic test of اchoice as it favours اthe common right-side location اof polyps اbetter than sigmoidoscopy اif the mutation is attenuated FAP, اand can confirm or allow (a) the actual اclinical presentation and any change to اthe condition, of the 'at risk' individual, (b) quantification of polyps throughout اthe colon, (c) a اhistologic diagnosis (cell/cancer type detection) and (d) اwhere polyps exist, it اcan suggest whether out patient excision (removal) اis viable or surgery is recommended.

Barium enema and اvirtual اcolonoscopy (a form of medical imaging) can also be used to suggest اthe اdiagnosis of FAP.

Genetic testing اprovides the اultimate diagnosis in 95% of cases; genetic counseling is usually اneeded in اfamilies where FAP has been diagnosed. Testing may also aid اin the diagnosis اof borderline cases in families that are otherwise known toا p34.3 and p32.1 (1p34.3–p32.1). اTesting can only show if an individual is اsusceptible to FAP or rule اit out (i.e., whether or not they inherited the defective ااAPC gene). اIt cannotا determine the actual condition of a patient; this can only اbe found by اdirect physical examination.

NCBI states thatا physicians must ensure اthey understand the "risks, benefits, and limitations" of any اgenetic test done, اsince in 1997 "for almost one third of individuals assessed اfor FAP, the physician اmisinterpreted the test results".[10]

Once the diagnosis ofا FAP is made, close اcolonoscopic surveillance with polypectomy is ااrequired.

Prenatal testing اis possible if a اdisease-causing mutation is identified in an affected family اmember; however, prenatal اtesting for typically adult-onset disorders is uncommonا and requires اcareful genetic counseling.

Ultrasound of the اabdomen and blood اtests evaluating liver function are often performed to rule اout metastasis to اthe liver.

The clinical diagnosisا is dependent on اthe physician's suspicion and awareness. The patient may be اcompletely asymptomatic اand obtaining a detailed family cancer history is اessential for a correct diagnosis, sinceا in most cases some grandparents, اparents and siblings will be affected. اAsking simple questions like "has anyone in اyour family had cancer? اWhich cancer? And اat what age?" is important اinformation. Alternatively, rectal اbleeding or abdominal complaints may develop اdepending on the stage of اdisease i.e., polyp burden or stage of cancer. For the اastute physician, identification اof extra-colonic manifestations can lead to اperforming endoscopic اexamination of the large bowel. For example, identifying a اdesmoid or a mandibular osteoma اin an individual should lead to a work-up for اruling-out FAP. This should اinitially be doneا by taking a detailed extended family اhistory and performing اa sigmoidoscopy or a full colonoscopy depending on اthe age of the patientا or whether اwe suspect FAP or AFAP.

During childhood, اonly diminutive adenomasا may be found, limited mainly to the rectosigmoid اarea of the colon, by a اflexible sigmoidoscopy (Fig. 2A). Random biopsies can visualize اintra-mucosal اadenomas (Fig. 5D). As age progresses, hundreds of اcolorectal adenomas اand, in some patients, adenomas in extracolonic locations اmay be اfound (as described previously) (Figs. 2B and 3A).

The diagnosis of اAFAP is more complex اthan that of classic FAP because of the wide phenotypic اvariation of disease. اTotal colonoscopy, rather than sigmoidoscopy, اhas been advocated اfor screening individuals at risk as the polyps tend to have اa right-sided اdistribution. Chromoendoscopy (Fig. 5A and 5B) is اrecommended to اhighlight the polyp burden. As in FAP, the diagnosis of AFAP اis based on the اcombination of clinical findings and genetic tests.

Genetic testing is اmainly used for screening and اthe presymptomatic early diagnosis of at-risk اfamily members. In اaddition, confirmation of the diagnosis in patients with اobscure clinical findings اis essential. At first, only the index case should be tested اand because of the اlong time it can sometime take to receive the answer to the اinitial mutation اanalysis, and even if no اmutation is identified, first-degree relatives اshould be اmanaged clinically اuntil results are obtained. If the mutation has اbeen identified, it اcan be quickly اand cheaply performed to screen at-risk اrelatives.

Management اof the FAP patient

Cancer prevention اand maintaining good quality of اlife are the main goals in management of patients اwith clinical or genetic اevidence of FAP. Large bowel endoscopy is the most اimportant clinical اexamination since there is almost a 100% chance ofا CRC. However, as discussed اpreviously, the disease is systemic with extracolonic اmanifestations and should اbe looked for by systematic reexaminationsا. CRC is rare in the اasymptomatic youth, so after their genetic diagnosis and اbaseline sigmoidoscopy, they اare systematically followed clinically until اcompleting schooling and اgrowth and maturing. Around ages 16-18 y patients with اFAP should be followed اby annual or less frequent colonoscopic اexaminations (depending on اthe polyp burden at last colonoscopy) and all significant اsized adenomas should be اremoved if surgery is not contemplated at اthat time. In addition, both اforward-viewing and side-viewing upper tract اendoscopies should be performed اprior to surgery or every 1 to 5 years depending اon the polyp burden and اSpigelman stage to detect اgastric but mainly duodenal اand periampullary اadenomas, respectively.

Usually, by the اlate teensا or early twenties, اdue to the increasing number of adenomas, اprophylactic cancer-preventive اcolorectal surgery is advocated. Since this is an elective اprocedure the timing canا be arranged to be the least inconvenient for اthe patient and family. اElective surgery, can at times, be delayed if the اpatient is اcompliant and polyps اare sparse and not large.

Surgical options اinclude subtotal اcolectomy with اileorectal anastomosis (IRA), total proctocolectomy اwith ileostomy, اand proctocolectomy with or without mucosectomy and اileal pouch anal اanastomosis (IPAA) .

Given the substantial اrisk of rectal اcancer developing after colectomy and ileorectal anastomosis, اmost experts advise اtotal اproctocolectomy for the typical FAP patient with multiple اrectal adenomas. اThis surgery includes removal of the entire large bowel and اstriping of the اremaining rectal mucosa down to the dentate line if there areا multiple polyps or اleaving a cuff of rectal mucosa, and forming an internal اpouch from the ileum. اBecause of better bowel control after such surgery, many اcolorectal surgeons اprefer the stapled rather than the hand-sewn anastomosis. اSo, if there is اno severe اrectal polyposis this is the most common pouch اoperation. However, this اrequires careful biannual or annual examination and اremoval of adenomas that can اrecur there. This surgery is called total اproctocolectomy with ileoanalا J-pouch and it is the surgical procedure of اchoice for most patients with اclassical FAP (Figs. 3B and 3C).

In cases with اfew rectal polyps, IRA can اbe a suitable alternative procedure providing there اis acceptance of life-long rectal اsurveillance. Many prefer this procedure اfor women with a low polyp اburden اsince it has been reported that pouch اprocedures can reduce fertility. Later اconversion of an ileorectal anastomosis اto a J-pouch can اbe performed, but اmay be difficult because of desmoid اformation in اthe اoperated area.

Post-colectomy اsurveillance

It is important to اemphasize that follow-up is اvital after surgical procedures are completed. Initially, اit should be at short intervals to asses the psychological and physical adaptation اto surgery and identify اdesmoid tumor formation in its earliest stage. The اinitial follow-up should اinclude a thorough physical examination, اbaseline abdominal اultrasound (US) or computed tomography or magnetic resonance اimaging (CT or MRI) to aid اin detecting existing or future changes suspicious اof a desmoid tumor. Patients اafter stapled and hand sewn IRA are at risk for rectal اadenomas and carcinomas. اTherefore, the physician needs to stress the اimportance of endoscopic اannual surveillance of the pouch. Many studies have اshown that adenomas اand occasionally even adenocarcinomas haveا been found in theا ileo-anal pouch after restorative proctocolectomy ا.Therefore, surveillance of اthe pouch [80, 81, 83] and transitional anal اzone is اessential

Figure 9

Panel A shows اflat and elevated duodenal adenomas in a FAP patient. These were proven by biopsy and endoscopic اultrasound to be free of اcancer. Panel B – the اpolyps were اremoved by submucosal resection اand polypectomy. Panel C – the polyp اremnants had been destroyed by argon plasma coagulation ا(figures provided by Dr. M. Santo, اTel Aviv). اPanel D showsا اa large polyp اthat developed,

Prognosis

Prior اto reaching اthe advanced stages of colorectal اcancer, the polyps are confined to the inner اwall and thickness of theا intestinal اtract and do not metastatise اor 'spread'. So provided FAP is detected اand controlled either at the pre-cancerous stage اor when any cancerous polypsا are still internal to the intestinal tract, surgery اhas a very high success rate اof preventing or اremoving cancer, without اrecurrence, since the locations اgiving rise to cancer are physically اremoved اin toto by the اsurgery.

Following اsurgery, اif a partial اcolectomy has been اperformed, colonoscopic surveillance of the اremaining colon is necessary as the اindividual still has a risk of developing اcolon cancer. However, if this اhappened, it would be a fresh incident from اpolyps developing anew in the اunremoved part of the colon subsequent to اsurgery, اrather اthan a return or metastasis اof any cancer removed by the اoriginal اsurgery.

Since surgery اis an elective اprocedure in FAP, the treating اspecialist has the opportunity to educateا اthe patient regarding the specific اprocedure and quality of life that should اbe اexpected post-surgery so as toا minimize fear and reduce expectations. This اcan be facilitated by meeting اpatients of the اsame sex and similarا age group اwho have had a similar اprocedure performed, and occasionally a sympathetic اpsychologist can be helpful اin overcoming fear .There are many reports showing اthat most patientsا are satisfied following an IPAA procedure .However, اpatients should be اadvised that although fecal elimination via the anus will be اpreserved, functional اoutcome may vary and is not comparable with اbowel اelimination priorا to surgery.

Chapter 2

Bibliographic analysis of the thesis

There are two major اissues that need to اbe addressed. Firstly, there is a significant minority اof patients with clinical FAP that don't have their genetic mutation identified اeven with the more اsophisticated genetic testing. This issue means that first-degreeا relatives cannot be اscreened genetically اand will require life-time repeated clinical اevaluation to اexclude being a اcarrier of the disorder. Secondly, there is some اclinical evidence اsupporting the possibility of influencing the manifestation اof disease اby chemoprevention اand lifestyle changes. These issues اrequire further اresearch and اevaluation.

The majority of اpatients with FAP develops اadenomatous polyps and requires preventive surgery اduring their late teens or اearly twenties. These years are the main reproductive اyears and maintaining sexual اfunction is of major concern. Sexual impairment اfollowing proctectomy is largely اtechnique-dependent and this should be اdiscussed with the surgeon performing اthe procedure. For men, denervation of ااthe pelvic plexus is the اmajor cause of erectile اand ejaculation اdysfunction. اFollowing an IPAA, erectile اdysfunction is reported to اoccur in 0-1.5% of اpatients, while اejaculation dysfunction اoccurs in 3-4% of these individuals

To summarize, اthe اoptimal management strategy اfor desmoid tumors in patients with FAP should beا individualized, taking اinto consideration the extent of disease, morbidity اand potential benefit versus اrisk of the different اtreatment modalities.

Material and اresearch methods

Caseا 1

Based on اcolonoscopically confirmed multiple polypsا in the colon and rectum at the age of 11 coupled اwith a family history, a maleا patient underwent subtotal colectomy with اileorectal anastomosis. At 39 years اof age, the patient underwent restorative proctectomy اwith ileal pouch-anal اanastomosis. Histopathology revealed hundreds اof polyps with two اadenocarcinomas found in the specimen – both Dukes A, اAstler Coller B1 and G2 – and اmultiple polyps with low- to high-grade dysplasia ا(fig. ​(fig.1,) In 2010, at اthe age of 41, the patient was referred for genetic testing اfrom the Oncology اDepartment where he was receiving 5-fluoropirimidineا/leucovorin and اradiation as adjuvant treatment after Miles procedure for recurrentا rectal اcancer (a tumor 3 cm in diameter was found on ileoanal اanastomosis, with 3 positive اlymph nodes out of 4 isolated). The 2-year follow-up CT showed اmultiple lung اand liver metastases and the patient was treated with a اcapecitabine-irinotecan ا(XELIRI) plus bevacizumab protocol as first-line اchemotherapy for metastatic اcolorectal cancer.

Figا. 1

Countless اpolyps اcarpeting اthe mucosal surface of the اresected rectum.

Caseا 2

The first clinically اconfirmed family member was patientا No. 1's mother. In 1972, the Caucasian female, اwho was 24 years old at اthe time, underwent her first procedure, which was اMiles procedure for اrectal cancer located at 13 cm from the anal verge. On اpathology specimen, several polyps اwith high-grade dysplasia were اfound in the rectal ampulla. At اthe age of 33, a correction of sigmoidostomy was اperformed due to a prolapse اof the stoma, and multiple polyps were found اin the specimen. Clinical اdiagnosis of FAP was established. At the age of 42, اtotal colectomy with Kock's reservoir اwas performed (around 50 polyps with low- to اhigh-grade dysplasia were اrecorded on pathology report). Further follow-up اwas carried out اaccording to FAP protocols, and at the age of 55, polyps were اdetected in the gastric اantrum and duodenum and a biopsy revealed اadenoma. At اthe age of 57, 4 large اperiampullar polyps were removed, one of which اcomprised اadenocarcinoma in situ. At the age of 63 and 65, another 2 polyps, gastric اand duodenal, were اremoved. At the اage of 45, adenoma of the parathyroid hadا اbeen removed.

Caseا 3

After the clinical اdiagnosis was established in اthe family, other family members were screened. اIn 2010, patient No. 1's 13-year-اold daughter was routinely followed by اcolonoscopy. One year later, after high-grade اdysplasia was confirmed byا a polyp biopsy, total proctocolectomy اwith ileoanal anastomosis was performedا (pathology اexamination of the اspecimen revealed more than 50 polyps, with one اcomprising adenocarcinoma in اsitu). In 2012, اthe patient underwent اtotal thyroidectomy due to papillary اthyroid cancer and duodenal polypectomy for اduodenal tubular adenoma. No اother extracolonic disease or intestinal اrecurrences اwere found.

The اFamily

Retrospectively, اthe family history revealed that اpatient No. 2's اmother had had colon cancer at the اage of 41 and that her father had died of اgastric cancer at the age of 69. However, اmedical records could not be اretrieved. Patient No. 1's 31-year-old brother and اhis older daughter (14 years old) اhad 2 and 3 polyps on colonoscopy, اrespectively (adenomas on biopsy), while اhis younger daughter (12 years old) had اnegative اcolonoscopy.

Figا. 3

Family اpedigreeا chart

Mutationsا

A family اpedigree chart (fig. ​(fig.3)3) was then constructed اand genetic testing was offered to the اentire family: patients No. 1–3, patientا No. 1's brother and his daughters. In patients اNo. 1–3, a 2805C>G substitution اwas detected. The mutation causes اpremature APC protein termination اat the position 935Y>X. The other family ااmembers were اmutation-free.

Discussion and personal results

Herein a اthree-generation case of FAP in a single family اis presented, in which the grandmother, اher son and her granddaughter had a اclinical presentation of FAP. The grandmother اand granddaughter remained اdisease-free after they had undergone total اproctocolectomy, but the son اdeveloped recurrent colon cancer on ileoanal anastomosis اand later metastatic disease. They اwere all subjected to the screening and follow-up اrecommended for FAP اpatients, and genetic testing revealed a 2805C>G اsubstitution, which results in اa truncated protein.

Most individuals with اFAP will develop colon اcancer by the age of 40; therefore, prophylactic surgery اis generally recommended before اthe age of 25. There are 3 main surgical options اfor patients with FAP: (1) اtotal proctocolectomy with Brooke ileostomy; (2) اsubtotal colectomy with اileorectal anastomosis, and (3) restorative proctocolectomy اwith the formation اof an ileal reservoir and ileoanal anastomosis [5, 6]. The اtreatment of choice is اtotal colectomy; however, the removal or preservation اof the rectum is اa matter of controversy. The decision to remove the rectum is اinfluenced by the number اof polyps in the rectum as well as by the family اhistory. If there are only few اpolyps in the rectum, total colectomy with ileorectal اanastomosis may اbe recommended. If the rectum is involved, then restorative اproctocolectomy اwith ileal pouch-anal anastomosis is the treatment of اchoice [7]. Prophylactic surgery اsignificantly improves the outcome of patients ااwith FAP.

In the granddaughter's اresected colon, numerous اpolyps were found, microscopically اdemonstrating high-grade اepithelial dysplasia as the last stage in the multistep process اof colorectal carcinogenesis. اThese features probably displayed a more اaggressive mutation phenotype اsince she was only 14 years old at the time of اsurgery. Generally, prophylactic اcancer-preventive colorectal surgery is recommended اby the late teens or اearly twenties [8]. Half of FAP patients develop اadenomas by 15 years of age اbut cancer development at this age is uncommon. اGenerally, cancer starts to اdevelop a decade after the appearance of the اpolyps [9]. The optimal اsurgical procedure is proctocolectomy with pouch formation and اileoanal anastomosis اsince it completely removes all large bowel mucosa as اpotential origin of cancer اand thereby minimizes the risk of malignancy, while اpreserving bowel function. For اmost patients, this is the procedure of choice [10]. On اthe other hand, patients اwho undergo ileorectal anastomosis are at risk, اvarying from 13 to 59%, of اdeveloping rectal adenomas and carcinomas after 25 اyears and they demand اlifelong rectal surveillance [5]. Moreover, in a subset اof patients having اundergone proctocolectomy, endoscopic annual اsurveillance of the اpouch and transitional anal zone is essential since many اstudies have demonstrated اthat premalignant changes and invasive adenocarcinomas اare found in the اileoanal pouch اeven after restorative proctocolectomyا [11, 12, 13].

Patient No. 1 Cاomitted colonoscopic surveillance اbetween the last two surgical procedures, which اmight explain the extent of local اrecurrence. Colonoscopy and prophylactic colectomy اare the primary اstrategies to prevent colon cancer or detect it at an early اstage. The American اGastroenterology Association recommends annual اsigmoidoscopy in patients اwith classic FAP and at-risk relatives starting at اthe age of 10–12 years. اPatients with adenomatous polyps found on sigmoidoscopy اshould undergo a full اcolonoscopy and random biopsies to اestablish the severity of the اpolyposis [14]. The family members who are mutation-free will اbe surveyed by the protocols اfor the general population. Implementation of اgenetic testing that would result in اstandard protocols is still a matter of debate, اsince the tests are still not اwidely available and patients are not referred when indicated, اleaving room اfor improvement in FAP treatment.

The reason why the اgrandmother did not haveا a regular follow-up or a more aggressive surgical اtreatment remained obscure اeven after a careful review of her history. We believeا it might both be due to اthe unawareness of this syndrome at the time اof the first operation and اsurgery planning based on sigmoidoscopy. On اthe other hand, the patient had not اbeen compliant with regular follow-up until اthe diagnosis of FAP was madeا and its implication explained. This issue اstresses the critical importance ofا lifelong follow-up and responsibility for both اpatients and physicians to adhereا to when dealing with FAP. Several studies have اdemonstrated that a regular اuse of nonsteroidal anti-inflammatory drugs and اselective COX-2 inhibitors can اreduce the polyp number and size in اpatients with FAP. Upon these results, اcelecoxib was approved as اadjunctive preventive treatment in patients اwith FAP, besides inevitable endoscopic اsurveillance and surgical اintervention. The successful management of colonic اdisease implies a اcontinuous surveillance of extracolonic disease. Patient No. ا2 had surgery for parathyroid اadenoma and patient No. 3 for thyroid cancer, اwhile patient No. 2 had ampullar اcancer endoscopically removed. اMultidisciplinarity اand, again, long-term اsurveillance is essential for these اpatients.

Conclusion

Patient compliance اwith regular and strict surveillanceا is an important factor when deciding on اthe optimal type of prophylactic اsurgery. Patients who are not adherent to اsurveillance should undergo proctocolectomy اwith ileal pouch-anal anastomosis. Timing اand type of preventive surgery as اwell as compliance with preventive strategies اand strict follow-up are essential اfor minimizing the risk of cancer development اin patients اwith FAP.

Effectiveness اof اscreening

The usefulness اof screening asymptomaticا FAP patients for all of its possible manifestations is اunproven. For children, to اidentify hepatoblastoma, some recommend annual اalpha-fetoprotein and اabdominal ultrasound from birth until the age of 10 years. For اall FAP patients, اan annual physical examination should include an evaluation for اsoft tissue or اbone lesions, and a thorough thyroid examination with a low اthreshold for اperforming an ultrasound of any suspicious اlesion.

Symptomatic اpatients (abdominal pain, new onset اdiabetes mellitus or acute pancreatitis) اrequire evaluation which could includeا computed tomography of the abdomen to rule اout desmoid tumors of the اmesentery or pancreatic adenocarcinomas ا(or intraductal papillary and اmucinous tumors (IPMT) of the pancreas. اIf theا CT is not اdiagnostic, then اmagnetic resonance imaging is indicated, it can outline اvascular involvement اof a desmoid tumor and may predict its اgrowth. CT of the brain can also beا used in symptomatic اpatients to search for a اmedulloblastoma.

Individuals with aا family history of FAP should اbe screened. When a specific APC mutation اhas been identified in اan index patient all 1st degree relatives carry a 50% اrisk of FAP and should be اreferred for genetic counseling and offered APC اmutation testing. A family member اwho is found to carry the mutation has ا100% chance of developing FAP and itsا complications. It is recommended اthat these individuals have a colonoscopy اand follow specific surveillanceا recommendation that have been outlined forا FAP patients. Children that have been identified اas carrying an APC mutation اshould have a flexible sigmoidoscopy performedا by the age of early adolescence اunless symptoms develop at an earlier اstage. When polyps are detected, اdiscussion with the patient and parents اshould take placeا regarding further اsurveillance and timing of surgery as اdescribed above.

If genetic testing اcannot be performed in a 1st degreeا relative of a known mutation carrier, اthen the asymptomatic 1st degree اfamily member has a 50% chance of harboring اthe mutation and should be اscreened as if they have the APC mutation. اAll adults should have اcolonoscopies performed and all children should اundergo a flexible sigmoidoscopy اaround the age of 10-12 years. Adenomas اdevelop withا the child's growth, and اtherefore are easier to identify at adolescence. If polyps اare not found, then there اshould be annual clinical visits for physical or ophthalmic اevidence of FAP اand to assess suspicious symptoms. Sigmoidoscopy should be اrepeated at اsuitable intervals, minimizing its psychological trauma and اmaximizing اcooperation of the growing child, until polyps emerge. If by the اage of 25 years polyps اare not detected, then biennial sigmoidoscopy or, اpreferably colonoscopy, can be اdone since the likelihood of developing adenomas اdecreases as the patient's اage increases. From the age of 35 years, an examination اevery third year is اrecommended until the individual is 50 years old. If polyps اhave not been detected اby then, the individual most likely, but not absolutely, اdoesn't have FAP, اand screening is recommended according to guidelines for the اgeneral اpopulation.

When an individual اin a family with a اknown mutation اtests negative, then routine colorectal اscreening is recommended, as اfor the general population, beginning at اage ا50 years.

In approximately ا25-30% of patients with clinically اevident FAP a mutation cannot be اidentified. If available, MUTYH testing اand more complete DNA analyses are اperformed in specialized laboratories. اIf these are also negative, then such individuals اare considered to have FAP اand should be treated as such. Gene testing can exclude اFAP only if a mutation is اidentified in a family member and this mutation اdoes not exist in a اgiven individual.

Diet and اlifestyle

The evidence اfor being able to modulate the اclinical manifestations of a dominant genetic اdisease is indirect and based اon observations in animal models and humans. Caloric اrestriction or diet with اolive oil, fruits and vegetables significantly reduced اthe number of polyps اin the genetically manipulated APC Min اmice model. In the اsame model, low اdosage ursodiol together with sulindac اprevented adenomas with اless toxicity than if each had been given alone inا full اdosage 

Clinical observation اof FAP families showed that the اseverity of disease varied between affected اfamily members or between families اcarrying the same mutation. This اwould suggest that not only اare there genetic-genetic/endogenous اmodulating factors, but اthere could be genetic-exogenous modulating factors اat play. Adenoma expression and اgrowth occurs with aging, effect of growth اfactors, hormones, weight gain, diet, اtobacco use. As an example, in two اtwin boys with FAP there was a اclear correlation between obesity in one twin اand adenoma expression as اcompared to the other twin (Rozen, personnel اcommunication).

So, it would be wise اto recommend a "balanced" CRC-preventive اlifestyle and diet from childhood in اanticipation of modulating the اclinical expression of FAP.

The goal is pre-اsymptomatic genetic diagnosis of APC اmutation-carriers that can lead to improved clinical اcare and prevent premature اmortality from cancer or other FAP complications. اMost patients with اclinical FAP can be identified and have their اdiagnosis confirmed اby genetic testing. اIndividuals with FAP carry a 100% risk of colorectal اcancer that is reduced almost اabsolutely when patients enter a screening-treatment اprogram as outlined اearlier. Once proctocolectomy has been performed, the اrisk of ampullary and اduodenal cancer is significant and requires lifelong اupper gastrointestinal اsurveillance that has been shown to save lives of FAP اpatients. Desmoids need to beا identified early while small and not causing local اperturbations. They اshould be اmanaged as described above. Duodenal cancer اand desmoids are the two mainا causes of mortality after total colectomy has removed اthe risk for CRC. The اsociological, psychological and physiological issues اrelated to the diagnosis and اtreatment of FAP need to be addressed. The colectomy اand ensuing change in اbowel habits, frequently lead to dietary changes that canا اbe unbalanced and اlead to vitamin-mineral deficiencies. Notable isا the possibility of vitaminا B12 deficiency due to rapid intestinal transit, ileal اresection and ascending اbacterial overgrowth. All these problems require اsystematic follow-up and اsupportive care.

Bibliographic references

Rosai J. Rosai and Ackerman's Surgical Pathology. ed 9. St. Louis: CV Mosby; 2004.

Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis.2009;12:4–22. [PMC free article] [PubMed]

Bisgaard ML, Fenger K, Bülow S, Niebuhr E, Mohr J. Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat. 1994;3:121–125.[PubMed]

Anaya DA, Chang GJ, Rodriguez-Bigas MA. Extracolonic manifestations of hereditary colorectal cancer syndromes. Clin Colon Rectal Surg. 2008;21:263–372.[PMC free article] [PubMed]

Aziz O, Athanasiou T, Fazio VW, Nicholls RJ, Darzi AW, Church J, Phillips RK, Tekkis PP. Meta-analysis of observational studies of ileorectal versus ileal pouch-anal anastomosis for familial adenomatous polyposis. Br J Surg. 2006;93:407–417. [PubMed]

Bülow C, Vasen H, Järvinen H, Björk J, Bisgaard ML, Bülow S. Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis.Gastroenterology. 2000;119:1454–1460. [PubMed]

Ziv Y, Church JM, Oakley JR, McGannon E, Schroeder TK, Fazio VF. Results after restorative proctocolectomy and ileal pouch anal anastomosis in patients with familial adenomatous polyposis and coexisting colorectal cancer. Br J Surg. 1996;83:1578–1580.[PubMed]

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Familial adenomatous polyposis

Efficacy of endoscopic and surgical treatment for advanced duodenal adenomas

Fabricio J. Alarcon

, Carol A. Burke

, James M. Church

, Rosalind U. van Stolk

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Laparoscopic Surgery for Colorectal Cancer

Robotic Approaches to Colorectal Surgery
Howard Ross (Editor), Sang W. Lee (Editor), Bradley J. Champagne (Editor

Colon Polyps and the Prevention of Colorectal Cancer
Omer Engin

Surgical Treatment of Colorectal Problems
Alberto Pena

Colorectal Cancer Screening: Quality and Benchmarks

Farquharson's Textbook of Operative General Surgery, 10th Edition

http://www.cancer.net/cancer-types/familial-adenomatous-polyposis

http://www.macmillan.org.uk/information-and-support/diagnosing/causes-and-risk-factors/genetic-testing-and-counselling/fap.html

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http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1098-2388(200006)18:4%3C314::AID-SSU6%3E3.0.CO;2-9/abstract