Hereditary colon cancer is a heterogeneous conglomeration of genetic defects that are mostly autosomal dominant in nature and lead to variable risk of colon cancer and other associated cancers. Some of these syndromes are characterized by the formation of traditional adenomas and are caused by defects in tumor suppressor genes and others are in mismatch repair genes. The most common of these include mutations in the tumor suppressor adenomatous polyposis coli (APC) gene that is associated with familial polyposis. Genetic defects in tumor mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) are also associated with the development of adenomas, and these occur in multiple genes that are associated with tumors that have high levels of microsatellite instability (MSI). Finally, there is a group of less common genetic defects that result in hamartomatous polyposis syndromes such as juvenile polyposis and Peutz-Jeghers syndrome, to name the two most common. We will outline the genetic defects, epidemiology, diagnosis, clinical manifestations, and clinical management for these syndromes.

Introduction

Familial adenomatous polyposis (FAP) is an inherited condition characterized by thousands of polyps in the colon. FAP occurs with a frequency of about 1:10,000 to 1:18,000 live births in Northern Europe and other similar Caucasian populations.^1-3 It accounts for less than 1% of all colorectal cancers. Males and females are affected equally.

Genetics

FAP is an autosomal dominant colorectal cancer syndrome caused by a germline mutation in the APC gene, located on chromosome 5q21-22. The APC gene is a tumor suppressor gene that functions by suppressing the formation of adenomas in the colon and tumors elsewhere in the body. Approximately 10% to 25% of germline APC mutations are new in individuals without a family history of FAP.^3-5 There is nearly 100% penetrance of the colonic manifestations of FAP but variable penetrance of the extracolonic manifestations of the disease.⁶

Patients with FAP who inherit a single APC mutation acquire a somatic mutation (or “second hit”) in the second allele of the APC gene. A cell with this functional loss of the APC gene has no functional APC protein. This leads to defects in the Wnt signaling pathway, abnormal intracellular accumulation of beta-catenin, unregulated cell growth and division, and formation of adenomas.^7,8 Over 1000 different mutations in the APC gene associated with FAP have been described, and the location of the mutation may influence the phenotypic expression. In other words, there is variable phenotypic expression depending on the location of the mutation in the gene.⁹

For example, patients with mutations near codon 1300 generally develop particularly severe disease with over 1000 polyps and earlier cancer onset.^9,10 Attenuated FAP (<100 colorectal adenomas) is associated with mutations before codon 157 and after codon 1595.¹⁰ Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is associated with mutations between codons 311 and 1444. Mutations after codon 1444 have been linked to the development of desmoid tumors.^10,11

Clinical Manifestations

In addition to the numerous colorectal adenomas that characterize FAP, there are a variety of extracolonic manifestations with variable phenotypic expression. Initially, most patients with FAP are asymptomatic. Patients who develop cancer may present with rectal bleeding, abdominal pain, and loose stools. Patients with desmoids can have abdominal pain or bowel obstruction. Finally, patients can develop symptoms from duodenal adenomas and various skin lesions as well.

COLONIC

Classic FAP is characterized by >100 colorectal adenomatous polyps prior to age 40. Nearly 100% of people with FAP will develop colorectal cancer because of the sheer number of adenomas that develop at an early age. One or more of these polyps usually progresses to form a cancer. Polyps usually start appearing in the late teens to early twenties, and progress to cancer by age 40.

Attenuated FAP is characterized by at least 10 to 20 adenomas, but fewer than 100. Patients usually present later in life than those with classic FAP, and have later onset of colorectal cancer (mean age 55).¹² In attenuated FAP the polyps are found more frequently proximal to the splenic flexure.

EXTRACOLONIC

Extracolonic manifestations of FAP include upper gastrointestinal polyps that occur in nearly all patients with FAP. Fundic gland polyps occur in most patients with FAP; they are small and rarely progress to cancer.^13,14 In contrast, gastric adenomas are much less common in patients with FAP, are typically located in the antrum, and have a relatively low risk of cancer progression.¹⁵

Around 90% of patients with FAP will develop duodenal adenomas; however, only about 5% progress to duodenal cancer.¹⁶ Approximately half of duodenal cancers are ampullary or periampullary.¹⁷

DESMOID TUMORS

After colorectal cancer and duodenal cancer, desmoid disease is the third leading cause of death in FAP patients.¹⁸ Desmoid tumors are usually found in an intra-abdominal location, especially in the small bowel mesentery and in the abdominal wall. Risk factors for development include trauma, prior surgery, and female sex.¹⁹ In fact, delay of prophylactic colectomy is advocated in patients at high risk for intra-abdominal desmoid disease, if safe. Surgery is to be avoided if possible for intra-abdominal desmoids as the majority are in the small bowel mesentery and can lead to extensive loss of bowel and bleeding. The primary treatment is medical, and includes NSAIDs and antiestrogen therapy.¹⁹ More aggressive regimens include vinblastine/methotrexate and doxorubicin/dacarbazine, and imatinib.^19-21

OTHER EXTRA-INTESTINAL MALIGNANCIES

These include thyroid cancer, which is usually papillary, and presents in the second or third decade of life. Lifetime risk is about 2%. Annual physical exam with or without neck ultrasound is generally recommended.¹⁹ Other associated tumors such as pancreatic adenocarcinoma, hepatoblastoma, medulloblastoma, and adrenal and biliary cancers have risks <2% in FAP patients, and therefore surveillance tests are not generally recommended unless there is a strong family history.^19,22,23

CHRPEs are characterized by hyper- or hypopigmentation of the retinal epithelium that have no effect on vision. They are present in over 75% of FAP patients and can act as a screening tool or marker for FAP.²⁴

Gardner syndrome was a term used to describe the constellation of colonic polyposis with a number of extracolonic manifestations including sebaceous or epidermoid cysts, lipomas, osteomas, fibromas, supernumerary teeth, gastric fundic gland polyps, desmoid tumors, juvenile nasopharyngeal angiofibromas, and CHRPE.^6,25 Now that it is clear that mutations in the APC gene are the underlying cause of both Gardner syndrome and FAP, the term “Gardner syndrome” is obsolete as it is not a distinct entity.⁶

Diagnosis

FAP should be suspected in any patient who is found on colonoscopy to have ten or greater colorectal adenomas. The diagnosis of attenuated FAP (AFAP) should be suspected in any patient who has ten or greater colorectal adenomas over a lifetime. In addition, FAP should be suspected if a patient has a history of colorectal adenomas plus extra-intestinal features of FAP such as duodenal/ampullary adenomas, papillary thyroid cancer, CHRPE, desmoid tumors, epidermal cysts, or osteomas.

The National Comprehensive Cancer Network (NCCN) recommends APC gene testing for persons with a personal history of 20 or greater adenomas, or a known deleterious APC mutation in the family. Per the NCCN guidelines (version 2; 2016) APC and MUTYH gene testing should be considered for patients with a personal history of desmoid tumor, hepatoblastoma, cribiform morular variant of papillary thyroid cancer, or multifocal/bilateral CHRPE. Patients who also have between 10 to 20 adenomas should also be tested for APC and MUTYH mutations.

If a mutation is found, mutation-specific genetic testing should be offered to at-risk family members. This includes all first-degree relatives of the index case and all first-degree relatives of those found to have the APC mutation. The age of testing generally begins around age 10 to 12 years, but may be earlier if the age of onset of polyps in the family is younger. If the familial mutation is found and an individual does not have it, that person can be discharged from surveillance, as they do not have FAP.²² If a mutation is not found in an affected patient, then the patient and at-risk family members must be under regular surveillance. Genetic counseling should be offered prior to any genetic testing.

Screening

NCCN Guidelines (version 2; 2016) recommends that patients with a positive APC mutation should have a colonoscopy every 12 months beginning at age 10 to 15 years. Patients should continue to undergo colonoscopic surveillance while awaiting colectomy. Esophagogastroduodenoscopy (EGD) screening and thyroid ultrasound screening begin around age 20.

In patients with a known familial positive APC gene for attenuated FAP, colonoscopy begins in the late teens and continues every 2 to 3 years, unless polyps are identified. Upper endoscopy should start at age 20 to 25 years as well as an annual thyroid exam. If genetic testing is uninformative or a patient has not been gene tested, screening should still be performed.

Management and Surveillance

In a patient with FAP, colorectal cancer is usually inevitable, so the goal is prevention with either colectomy or proctocolectomy. The timing of surgery and type of operation is individualized based on the patient’s polyp burden, family history of age of cancer/polyp formation, and risk of desmoid formation. Most patients with classical FAP undergo surgery between the ages of 16 and 20 years.

Total abdominal colectomy (TAC) with ileorectal anastomosis can be considered if the rectal polyps are amenable to endoscopic surveillance and resection. It is technically simpler than a proctectomy, has a good functional outcome, avoids a permanent stoma, and avoids the risk of sexual or bladder dysfunction and decreased fecundity that can occur following proctectomy. The disadvantage, however, is risk of cancer in the remaining rectum.^26,27 The rectum must be closely surveyed at least annually.

Total proctocolectomy (TPC) with or without ileoanal pouch (ileal pouch-anal anastomosis [IPAA]) is recommended for patients with profuse polyposis or rectal cancer. While TPC with end ileostomy eliminates the risk of colorectal cancer, TPC with IPAA leaves a risk of cancer in the pouch and anal transition zone, and thus requires surveillance. The disadvantages of a rectal dissection include risk of sexual or bladder dysfunction, need for temporary or permanent ileostomy, and variable function (with IPAA).

If the polyps are controlled endoscopically in patients with attenuated FAP, then they may not need a colectomy. If cancer occurs or the polyp burden becomes too great, TAC with ileorectal anastomosis is usually sufficient, as the polyps are most often right-sided. Of course, if polyps are found more distally, then TPC must be entertained.

Surveillance following colectomy or TPC includes endoscopic evaluation of the rectum or ileal pouch every year and of the ileostomy, if present, every 2 years.¹⁷ Chemoprevention has been entertained to manage the rectum postop. There are currently no FDA-approved medications for this indication. While there are data to suggest that Sulindac is the most potent polyp regression medication, it is not known if the decrease in polyp burden decreases cancer risk.

UPPER GI POLYPOSIS

In patients with classic or attenuated FAP, the American College of Gastroenterology recommends screening for gastric and proximal small bowel tumors using an upper endoscopy including duodenoscopy starting at age 25 to 30 years.¹⁷ The Spigelman staging system of duodenal polyps (based on polyp number, size, histology, and degree of dysplasia) allows for an objective assessment of duodenal polyposis and thus recommended surveillance intervals.²⁸ Surveillance should be repeated every 0.5 to 4 years depending on the Spigelman stage of duodenal polyposis: 0 = 4 years, I = 2 to 3 years, II = 1 to 3 years, III = 6 to 12 months, IV = surgical evaluation. Examination of the stomach should include random sampling of fundic gland polyps. Low-grade dysplasia is common in fundic gland polyps, and surgery should be reserved for high-grade dysplasia or cancer.¹⁷

Treatment for duodenal polyposis includes endoscopic and surgical options; pharmacologic agents, namely, NSAIDs, have been used for early disease, although benefits have not been proven.¹⁹ Endoscopic resection with polypectomy or endoscopic mucosal resection for more advanced polyps, and endoscopic thermal ablation of duodenal polyps are all options, although these may have high rates of recurrence.¹⁹ According to the NCCN guidelines (version 2; 2016), surgery is recommended for invasive carcinoma as well as for dense polyposis or high-grade dysplasia that cannot be managed endoscopically. Premalignant lesions may be locally excised via duodenotomy if possible, otherwise pancreas-sparing duodenectomy or pancreaticoduodenectomy is needed, as they are for invasive cancer.^19,29

THYROID CANCER

Annual thyroid screening by ultrasound is recommended for patients with FAP and attenuated FAP starting in the late teens.¹⁷

Summary FAP

Familial polyposis is due to genetic defects in the adenomatous polyposis coli tumor suppressor gene. Depending on the location of the mutation in the gene, there is variable phenotypic expression of the disease. Patients with fullblown FAP generally present in their teens and twenties with hundreds to thousands of polyps, and virtually 100% of these patients end up with colorectal cancer if left untreated by the age of 40. These patients are best managed with TPC with either and ileoanal J pouch or an ileostomy. Patients with attenuated FAP present in their 40s to 60s with tens to a hundred polyps. These patients often have rectal sparing from the polyps and an intermediate operation of TAC with ileorectal anastomosis and surveillance of the retained rectum. Thyroid cancer, desmoids and duodenal and gastric lesions also require close attention.

Introduction

MUTYH-associated polyposis (MAP) is an autosomal recessive condition associated with an increased risk of colorectal cancer and the early development of multiple adenomatous polyps. This is often referred to as the recessive form of familial polyposis, as many of the clinical manifestations are very similar.³⁰ Patients with biallelic MYH mutations account for less than 1% of all colorectal cancer cases.³¹ Some patients will develop fewer than 100 polyps, while others may have hundreds.³⁰

Genetics

MAP is an autosomal recessive polyposis caused by biallelic (homozygous or compound heterozygous) mutations in the MUTYH gene. MUTYH is a base excision repair gene, and thus is involved with correcting the effects of oxidative damage to the DNA.^17,32 This leads to a G:C → A:T transversion in the APC and KRAS genes and hence adenomatous polyposis and serrated polyps. The two most prevalent MUTYH mutations in individuals of European descent with MAP are two missense mutations, Y179C and G396D. Although many other distinct MUTYH mutations have been found, approximately 90% of Western MAP patients have at least one of these two mutations.^17,33

Clinical Manifestations

Colonic and extracolonic manifestations can be present in patients with MUTYH-associated polyposis. The colonic phenotype in patients with MAP can be variable, but patients with MAP usually develop 10 to 100 colorectal polyps.^17,32 Colorectal cancer develops at an average age of 48 years. Although patients with MAP predominantly have adenomas, multiple hyperplastic and/or sessile serrated polyps may occur. Patients with MAP have an approximate lifetime risk of colorectal cancer (CRC) of 70% to 75% while those with a monoallelic MUTYH mutations may only have a marginally increased risk.^17,34,35

Data on extracolonic manifestations of MAP are limited. However, there does appear to be an increased risk of duodenal cancer.³⁶ Other extracolonic findings include gastric polyps, endometrial cancer, breast cancer, ovarian cancer, bladder cancer, various skin cancers, thyroid cancer, sebaceous gland adenomas, lipomas, CHRPE, osteomas, desmoid tumors, and epidermoid cysts.^17,36

Diagnosis

Patients with at least 10 adenomas in their lifetime, a known family germline mutation, or a history of adenomas in combination with extracolonic features associated with MUTYH-associated polyposis (duodenal adenomas, desmoid tumors, thyroid cancer, CHRPE, epidermal cysts, or osteomas) should be considered for genetic testing for MUTYH-associated polyposis.^17,37 The family history follows an autosomal recessive pattern of inheritance. The diagnosis is established by biallelic germline mutations in the MUTYH gene. If the mutation is found, mutation-specific genetic testing should be offered to at-risk relatives of the index case.

Management and Surveillance

Patients at risk for or affected with MAP should undergo yearly colonoscopy starting at puberty.¹⁷ If the polyp burden becomes unmanageable, or if cancer is present, then colectomy is indicated. The type of operation depends on rectal polyp burden. As for AFAP, if the rectum is manageable endoscopically, then total colectomy with ileorectal anastomosis can be entertained. TPC (with or without restoration) may be needed if the rectal polyp burden is unmanageable. Surveillance following colectomy or TPC includes endoscopic evaluation of the rectum or ileal pouch every year, and of the ileostomy, if present, every 2 years.¹⁷

Just as in patients with classic or attenuated FAP, the American College of Gastroenterology recommends MAP patients undergo screening for gastric and proximal small bowel tumors using an upper endoscopy including duodenoscopy starting at age 25 to 30 years.

There is no consensus as to whether monoallelic MUTYH mutations warrant increased CRC screening.¹⁷

Summary MUTYH Polyposis

MUTYH polyposis is a defect in an autosomal recessive base excision repair gene. It is often called the recessive familial polyposis. Surgical therapy for the colon is predicated upon the number and distribution of polyps in the colon. It is generally best treated with TPC with ileoanal J pouch for patients with rectal involvement and TAC with ileorectal anastomosis for patients with a spared rectum. Although it is a different genetic defect, the management principles are like those for FAP. The surgeon should also be mindful that carriers of the recessive gene are at increased risk of colorectal cancer as well.

Introduction

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is the most common form of inherited colon and rectal cancer. It is responsible for approximately 3% of all cases of both endometrial and colon cancer. It is inherited in an autosomal dominant fashion. Affected kindreds are characterized by multigenerational involvement, with the offspring of affected individuals having a 50% chance of inheriting the disorder such that in large kindreds several offspring can be affected. Individuals often have more than one index cancer and generally the cancers present before the age of 50 years. The most common cancers with associated lifetime risks without surveillance are colorectal cancer (80%), uterine cancer (50%), ovarian cancer (20%), transitional cell carcinoma (5%), gastric cancer (5%), and cancers of the pancreas (1%), small intestine (1%), and the biliary system (1%). Some families are also affected with prostate and breast cancer. The genetic defects responsible for HNPCC are germ line mutations in a DNA mismatch repair (MMR) gene. For the most part, tumors in affected patients have loss of MMR as well as being high in MSI. The diagnosis of HNPCC requires a high index of suspicion combined with sound interpretation of MSI status and immune-histochemical (IHC) staining in patients at risk. In patients with a suggestive clinical and family history if MSI status and IHC staining indicate HNPCC, germline testing should be undertaken.

Genetics

The most common MMR mutations identified are MLH1 (chromosome 3p21) in 37% of affected individuals, MSH2 (chromosome 2p16) in 41% of affected individuals, MSH6 (chromosome 2p16) in 13% of affected individuals, and PMS2 (chromosome 7p22) in 9% of affected individuals.³⁸ In an even smaller group of patients a genetic defect in the 3′ end of the epithelial cell adhesion molecule (EPCAM) carries over to the neighboring MSH2 gene, silencing the MSH2 gene, resulting in HNPCC. These patients are at increased risk of colon cancer but generally not the extracolonic cancers such as uterine cancer. Defects in the EPCAM gene on chromosome 2 account for less than 3% of cases of HNPCC.³⁹ Dr. Henry T. Lynch of Creighton University first identified two kindreds in 1966 with the clinical features of HNPCC.⁴⁰ The actual responsible genes were finally identified in the 1990s independently and simultaneously by the laboratories of Dr. Richard Kolodner at Dana Farber Cancer Institute and Dr. Bert Vogelstein at Johns Hopkins.

Defects in MMR proteins result in an increased risk for the development of a multitude of cancers. These genes are responsible for repairing erroneously substituted base pairs, and insertions and/or deletions of segments of DNA that occur during cellular replication and division. Affected individuals have a mutation at one allele, and the second allele is usually inactivated by a variety of mechanisms that then results in failure to repair the aforementioned DNA mismatches. The regions most often affected are areas of repetitive nucleotide sequences called microsatellites. Hence a common feature of HNPCC is high levels of MSI. In turn, MSI affects genes that regulate cell death and growth, resulting in unregulated cell growth and/or cell death and thereby cancer.⁴¹ In the last 25 years since the discovery of the MMR genes responsible for HNPCC identification, management and surveillance of affected individuals and their families has dramatically improved. The risk of developing cancer in known MMR carriers by each gene is lower than in the past. Table 48-1 identifies the risk of each cancer depending on which gene is affected. Genetic defects in the PMS gene are rare and hence fewer patients with these mutations were identified and followed prospectively. Generally, it is felt that the risk for each of these cancers is even less in patients with a PMS 2 mutation.⁴²