Inherited Colorectal Cancer and the Genetics of Colorectal Cancer

PART

FOUR

Neoplastic Disease Inherited Colorectal Cancer and the Genetics of Colorectal Cancer Matthew F. Kalady 

|

  C. Richard Boland 

|

CHAPTER

165 

  James M. Church

C

olorectal cancer (CRC) is a complex heterogeneous disease with a variety of factors influencing genetic and epigenetic changes that drive tumor initiation and progression. Alterations in the intricate system of biological checks and balances can lead to a malignant change of the normal colorectal mucosa. The underlying changes, whether inherited or sporadic, influence the genotype and phenotype of that particular cancer and patient. Understanding CRC in this context, and grouping patients based on the underlying cancer pathway, helps to study the disease and provide more precise clinical management. This chapter provides an overview of the underlying changes in colorectal carcinogenesis and the hereditary CRC syndromes.

GENETIC BASIS OF COLORECTAL CANCER MULTISTEP CARCINOGENESIS IN COLORECTAL CANCER Cancer is fundamentally a genetic disease as tumors develop through genetic or epigenetic somatic alterations in cells. A relatively small proportion of gastrointestinal (GI) cancer, probably less than 5%, develops as a consequence of a highly penetrant germline mutation in one gene, resulting in a familial GI polyposis or cancer syndrome. The tumors that develop in these syndromes then follow the same evolutionary paths as sporadic tumors, but the risk for cancer is greatly elevated in the mutation carrier, the tumors have a substantially earlier median age of onset, and the patients are at risk for multiple metachronous tumors. An understanding of the biological basis of sporadic CRCs has provided insight into the special instances of the familial syndromes, all of which are quite distinct genetically and clinically. There are multiple signaling pathways that regulate cell growth. Consequently, there are multiple possible pathways for tumorigenesis, which explains why CRCs—and the cancer syndromes—are heterogeneous genetically and clinically.1 However, there is a discrete number of parallel regulatory pathways, which crosstalk with one another, and the function of any pathway can be altered by a defect in any one of the serial links.

There are three classes of genes involved in the evolution of cancer: proto-oncogenes, which become activated through mutation, amplification, or chromosomal rearrangement; tumor suppressor genes, which become inactivated through mutation, chromosomal deletion, or promoter methylation; and genes involved in maintaining genomic stability, which become dysregulated—usually by inactivation—leading to genomic instability and the rapid accumulation of more mutations. Moreover, without some form of genomic instability, it would take a very long time to accumulate mutations in these specific genes that drive cancer development.

CLASSIC CHROMOSOMAL INSTABILITY We can classify CRCs into three broad classes of genetic or epigenetic instability, but there is some overlap among them, which can be initially confusing. The first is manifested by chromosomal instability (CIN), and was first proposed in 1990 by Vogelstein in the context of multistep carcinogenesis.2 The first step in the CIN pathway is inactivation of the WNT signaling pathway, followed, in sequence, by activating mutations in key growth-stimulating genes, such as KRAS, CDC4, PIK3CA, and others, followed by disruption of the negative growth regulatory network of transforming growth factor (TGF)-β signaling (typically through inactivation of one or more of the SMAD genes), and the cataclysmic conversion of benign to malignant behavior by mutations and allelic losses of the p53 (TP53) gene, which abrogates the G1/S cell cycle checkpoint and permits the accumulation of chromosomal rearrangement and aneuploidy.3 This pathway is illustrated in Fig. 165.1. More than half of all CRCs develop through this pathway. There is considerable heterogeneity in the evolution of this pathway, and only three of these, APC, KRAS and p53, are mutated in greater than 11% of all CRCs. The initial genetic alteration in the classic pathway is inactivation of the WNT signaling pathway, which is a key concept for understanding familial adenomatous polyposis (FAP). This usually occurs by biallelic inactivation of the APC gene, removing the protein that regulates the intracellular concentration of β-catenin, which is a transcription factor that helps turn on the growth program, and it is also involved in the intercellular adhesion complex that holds colonic epithelial cells together. However, the same

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Inherited Colorectal Cancer and the Genetics of Colorectal Cancer  CHAPTER 165 1959.e1

ABSTRACT Colorectal cancer (CRC) results from a series of complex, multistep genetic and molecular events causing uncontrolled cell growth. The underlying changes within the cells define distinct but somewhat overlapping tumor phenotypes. There are at least three well-defined pathways leading to CRC: chromosomal instability, microsatellite instability, and DNA hypermethylation. These pathways are present in cancers that develop via somatic mutations or within hereditary syndromes. The changes are manifest in both sporadic cancers and in hereditary syndromes. A relatively small proportion of CRCs develop as a consequence of a highly penetrant germline mutation in one gene, resulting in a familial cancer syndrome. The tumors that develop in these syndromes then follow the same evolutionary paths as sporadic tumors, but the risk for cancer is greatly elevated, forms at an early age, and is associated with multiple and metachronous colorectal and extracolonic cancers. The hereditary CRC syndromes are broadly classified as polyposis (adenomatous, hamartomatous, or mixed) or nonpolyposis syndromes (including hereditary nonpolyposis CRC, Lynch syndrome, and familial CRC type X). Each of these syndromes is associated with specific gene mutations that determine the clinical phenotype and define the cancer risk. This chapter provides an overview of the underlying changes in colorectal carcinogenesis and the hereditary CRC syndromes.

KEYWORDS Colorectal cancer, genetics, polyposis, Lynch syndrome, hereditary syndromes, desmoids, familial adenomatous polyposis

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SECTION IV  Colon, Rectum, and Anus

APC/ β -catenin

PIK3CA/ TP53 Smad4/ PTEN BAX TGF-β Rll

CDC4/ KRAS/ CIN BRAF

? Normal

Small adenoma

Large adenoma

Carcinoma

Metastasis

FIGURE 165.1  Classic chromosomal instability (CIN) and multistep carcinogenesis. The classic multistep carcinogenesis model proposed in 1990 has been repeatedly confirmed over the decades. The initial step is the disruption of WNT signaling, either by loss of adenomatous polyposis coli (APC) or a “downstream” event that achieves the same result. The adenoma can remain small indefinitely, but if it acquires additional mutations that activate proto-oncogenes, they become larger and more dysplastic. The loss of p53 is the most common event at the adenoma-to-carcinoma transition. Initially, colorectal cancers (CRCs) may have minimal ability to metastasize, but the accumulation of additional mutations or other alterations eventually permits tumor cells to escape the primary tumor mass and grow at a distant site. TGF-β, Transforming growth factor beta. (From Jones S, Chen WD, Parmigiani G, et al. Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A. 2008;105:4283–4288.)

NEW WNT SIGNALING MODEL Wnt OFF

Wnt ON

P

Dvl

Dvl

Axin CK1GSK3 βcat APC βTrCP P P P P

Ub Ub Ub

P

Axin P CK1GSK3 P P βcat APC P βcat

βcat

βTrCP

βcat

FIGURE 165.2  Wnt signaling. On the left, when there is no Wnt ligand interacting with the 7-transmembrane spanning receptor (unnamed here but termed “frizzled” in lower organisms), Wnt signaling is off, APC interacts with β-catenin leading to its phosphorylation and degradation, and the proliferative program is inactive. (Wnt derived its name from a conflation of the wingless gene in flies–wt—and the Int-1 proto-oncogene; there are 19 human Wnt genes.) On the right, the yellow Wnt ligand is secreted by an adjacent cell, binds to the receptor complex, which prevents APC from interacting with β-catenin, permitting its intracellular concentration to rise, triggering a growth program and inhibiting the differentiation program.4 Dysregulation of Wnt signaling is seen in almost all colorectal neoplasms, and germline mutations in APC cause FAP. β-cat, β-catenin; βTrCP, β-transducin repeats-containing proteins (a ubiquitin ligase subunit involved in the degradation of β-catenin in the proteasome); APC, adenomatous polyposis coli gene; Axin, part of the APC-containing complex; CK1, casein kinase-1 (together with GSK3, phosphorylates β-cat at multiple sites, which leads to its destruction); Dvl, disheveled; GSK3, glycogen synthase kinase-3. (From Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149:1192–1205.)

effect can be achieved through a stabilizing mutation in the β-catenin gene that renders the protein incapable of being degraded by the adenomatous polyposis coli (APC) protein. Indeed, additional downstream events involving T-cell factor/lymphoid enhancer-binding factor (TCF or LEF) proteins can do this as well.4 The WNT signaling pathway is depicted in Fig. 165.2. Once WNT signaling is dysregulated, the colonic epithelial cell can undergo uncontrolled divisions and fails to differentiate. The colorectal adenoma is a collection of epithelial cells that continue to grow outside of the colonic crypt, do not fully differentiate, and form a mass

lesion. The actual “drivers” of the process are the β-catenin gene (now upregulated), and eventually, other activated oncogenes. CIN begins in benign adenomas, which can remain stable for decades, or grow slowly. But once the p53 gene is lost (typically by one inactivating mutation and loss of the other allele), there is an increase in the accumulation of abnormal chromosomal rearrangements, which results in large numbers of deleted, duplicated, and rearranged genes. These changes synergize to drive the neoplastic process forward. Because of the very large number of specific genetic alterations that can contribute to the process, CRCs that evolve through the classic pathway

Inherited Colorectal Cancer and the Genetics of Colorectal Cancer  CHAPTER 165 

can be quite heterogeneous in appearance and clinical behavior. Most families with FAP have a germline mutation in the APC gene. Occasional families with FAP have no detectable mutation in APC; however, there are no convincing examples of germline mutations in any other gene that cause typical FAP. Even a mutation that results in the deletion of a long-range promoter sequence in APC (literally over 46,000 bases upstream of the start codon) can cause full-blown FAP. Since biallelic mutations in APC are required for neoplastic colonic epithelial cell growth to occur, the phenotype in a person with a germline mutation in APC is normal at birth, but over time, losses of the other “wild type” allele occurs in individual epithelial cells, which results in adenomas. Over time, unregulated growth predisposes the adenoma to the accumulation of more mutations in the multistep pathway. Illustrating the long time frame in which this occurs, the median age for the first adenoma in FAP is 16, but the median age for cancer is 39. There are no instances of inheriting biallelic APC germline mutations as that phenotype is embryonically lethal.

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Normal colon epithelium

Exon 1

Exon 2

Exon 3

Open chromatin structure

Colorectal cancer

Exon 1

Exon 2

Exon 3

CPG ISLAND METHYLATOR PHENOTYPE The second CRC pathway involves the inactivation of tumor suppressor genes through hypermethylation of gene promoters, a normal physiologic process for silencing genes that becomes accelerated through a process that is not completely understood.5 The sequences in the promoters that are hypermethylated are C-G dinucleotide pairs (called CpG sequences, in which the p stands for the phosphodiester bond between the C and G). These sequences are infrequent in the genome except in gene promoters (the on–off switch or rheostat for gene expression), and they occur in clusters called CpG islands. When there is an excess of promoter methylation in the cancer genome, this is the CpG island methylator phenotype, or CIMP. This occurs as a predominant epigenetic “lesion” in about 32% of CRCs, but increased CpG methylation is also seen in many other CRCs, so the methylation must be quantitated at selected promoters for the CRC to be categorized as CIMP. CIMP often (but not always) occurs in association with a mutation in the BRAF gene (V600E), and this is associated with more aggressive, lethal CRCs compared with tumors arising from the other pathways. Tumors in the CIMP pathway are thought to begin as sessile serrated adenomas (SSAs) rather than as typical adenomatous polyps; consequently, this has been called the serrated carcinoma pathway. Both SSAs and CIMP CRCs occur predominantly in the proximal colon. The genetic or epigenetic events that drive the SSA from a benign, nonneoplastic-appearing lesion to CRC are not specifically known, although the genes that commonly undergo promoter methylation in CIMP include p16, CDKN2A, THBS1, HPP1, and MLH1. The underlying “instability” involves excessive promoter methylation, whereas it is the silencing of tumor suppressor genes that acts as the “driver” of carcinogenesis in CIMP-related tumors. Additionally, a number of microRNAs, which are key regulators of gene expression, are silenced by methylation in cancer, and are an increasingly important part of the driving force in

Closed chromatin structure

FIGURE 165.3  CIMP and methylation-induced silencing of genes. A gene is depicted as a line with three (blue) exons and multiple CpG sites indicated by circles on sticks; white circles are unmethylated cytosines and blue circles are methylated. The CpG sites are clustered just to the left of the start site of the gene and in the first exon. At the top, the unmethylated CpG sites leave the chromatin “open” and available to transcription factors for gene expression. After the methylation of the cytosines in a CIMP-CRC (lower panel), the closed chromatin structure silences gene expression. Only the CpG clusters in the promoter and first exon are important for gene silencing as shown here.6 β-cat, β-catenin; βTrCP, β-transducin repeats-containing proteins; APC, adenomatous polyposis coli gene; Axin, part of the APC-containing complex; CK1, casein kinase-1; Dvl, disheveled; GSK3, glycogen synthase kinase-3. (Image source: Lao VV, Grady WM. Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol. 2011;8:686–700.)

CIMP-mediated carcinogenesis. Fig. 165.3 illustrates the CIMP and methylation-mediated gene silencing.

MICROSATELLITE INSTABILITY The third pathway for colorectal carcinogenesis is a secondary consequence of either CIN (in the setting of Lynch syndrome) or CIMP, and is called “microsatellite instability” or MSI. The nucleus has multiple enzyme systems that monitor DNA for damage, and either repair the mutation or prevent the cell from replicating. One of these is mainly an S-phase monitor for errors introduced by DNA polymerase (also playing a role outside of DNA synthesis), called the DNA mismatch repair (MMR) system. During DNA replication, DNA polymerases are prone to errors while copying the correct number of nucleotides at simple

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SECTION IV  Colon, Rectum, and Anus Single mismatch

MutSα ADP MSH2

MSH6 ADP ATP

ADP 5' Daughter strand 3' Template strand

3' 5'

G T

MutLα

ATP MSH2

MLH1

5' 3'

3' 5'

G T

5' 3'

PMS2 3' 5'

MSH6

A

ATP Exonuclease complex and resynthesis ExoDNA nuclease polymerase 5' 3'

B

Excised nucleotides 5'

T

PCNA

PCNA

5' 3'

A T

DNA polymerase 3' 5'

Insertion/deletion loop and variations in MutL complexes MutSβ ADP MSH3

MSH2

ATP

ADP 5' 3'

MLH1

MLH3 3' 5'

5' 3'

3' 5'

MutLγ

? MLH1

ATP

3' 5'

5' 3' ?

C

MLH1 5' 3'

PMS1

PMS2 3' 5'

MutLβ

MutLα

FIGURE 165.4  DNA mismatch repair (MMR). The DNA MMR system involves a series of cooperating enzymes. (A) The heterodimer of MSH2 and MSH6 proteins make up the MutSα mismatch recognition complex as shown. MutSα binds to DNA at random locations (with an exchange of ADP for ATP) and slides along the nascent DNA strand until it encounters a DNA mismatch, at which time the MutLα complex (made up of MLH1 and PMS2 proteins) is recruited. MutSα preferentially recognizes single base-pair mismatches and single base insertion-deletion lesions. (B) Exonuclease is recruited to the mismatch by MutSα and nucleotides are serially excised specifically from the daughter strand and the mismatch is excised. Then DNA polymerase resynthesizes the daughter strand. (C) The human MMR system broadens its specificity for mismatch recognition when MSH2 heterodimerizes with the MSH3 protein, forming MutSβ, which has additional specificity to recognize larger insertion-deletion loops containing 2 to 6 nucleotides. Also, MLH1 can heterodimerize with PMS1 (forming MutLβ) or MLH3 (forming MutLγ), but the precise roles of these complexes is incompletely understood. ADP, Adenosine diphosphate; ATP, adenosine triphosphate. (From Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010;138:2073–2087, e2073.)

repetitive sequences (mono-, di-, tri-, and tetra-nucleotide repeats) called microsatellites. The DNA MMR system identifies these small DNA copying errors and removes the faulty sequences, which permits the cell to resynthesize the sequence correctly. In the absence of DNA MMR activity, there is greater than 100-fold increase in synthetic errors in microsatellite sequences, which is where the term MSI was derived.7 The DNA MMR system is shown in Fig. 165.4. CRCs with MSI can occur in three circumstances. First, approximately 12% of all CRCs begin as CIMP tumors, but when methylation occurs at both alleles of one of the

DNA MMR genes (MLH1), MSI ensues and overwhelms the CIMP background, as the accumulation of mutations occurs rapidly. These tumors have a background of CIMP, but are recognized as MSI tumors because of this overwhelming phenotype, and often have an activating mutation in BRAF. If they do not have a mutation in BRAF, the prognosis is better than for CIN or pure CIMP CRCs. Second, about 3% of CRCs occur in the setting of Lynch syndrome (previously referred to as hereditary nonpolyposis CRC [HNPCC]), of which most have MSI. There is evidence that neoplasms in Lynch syndrome

Inherited Colorectal Cancer and the Genetics of Colorectal Cancer  CHAPTER 165 

arise initially as otherwise ordinary adenomatous polyps, and then develop MSI when there is loss of the wild-type allele of the DNA MMR gene responsible for the Lynch syndrome.8 However, it is possible that some neoplasms may arise directly from a nonneoplastic colonic crypt with defective DNA MMR activity, which is present in large numbers in the nonneoplastic epithelium of the colon.9 Once there is a DNA MMR-deficient cell, the progeny accumulate mutations at DNA sequences that encode mononucleotide repeat nucleotides (i.e., C n, Tn, Gn, or An where n = 6 to 10). There are about 30 genes in the human genome that have microsatellites in coding sequences, and these include a number of critical tumor suppressor genes (such as TGF-β receptor 2, BAX, Caspase-5, and others) that are frequently mutated at the microsatellite by deletion or insertion of one base pair in the sequence, which inactivates the gene. As such, these microsatellite-encoding genes are the actual “drivers” of carcinogenesis once mutated. Third, a very small proportion of CRCs begin in the CIN pathway, and develop biallelic mutations at one of the DNA MMR genes, after which MSI ensues, which rapidly overtakes the prior phenotype. This is called “Lynch-like syndrome.”6 Curiously, it can be familial, which is not understood. MSI can occur in the context of CIMP, in which approximately 90% of the tumors are in the proximal colon, and the patients are on average about 5 years older than those with sporadic CRCs. It can also occur in the context of Lynch syndrome, in which case about two-thirds of the tumors are in the proximal colon and the patients are 15 to 20 years younger than others with CRC. It can also occur due to biallelic somatic mutations in DNA MMR genes, and will masquerade as Lynch syndrome.

WHY COLORECTAL CANCERS ARE SO HETEROGENEOUS Because the “driver” mutations are different for each of these pathways, the clinical behavior of the tumors is different for each group. Importantly, however, the CIN or classic pathway is the sequence seen in the disease FAP, which is always associated with a germline mutation in the APC gene. The MSI pathway is present in essentially all CRCs that occur in Lynch syndrome, which is caused by germline mutations in one of the four DNA MMR genes ( MLH1 , MSH2, MSH6, and PMS2). However, most CRCs with MSI are not Lynch syndrome, but are a consequence of methylation-induced silencing of MLH1, or less commonly, Lynch-like syndrome. There has been no identifiable form of a familial CIMP syndrome. The hamartomatous polyposis syndromes are quite distinct from either FAP or Lynch syndrome. In these instances, the germline mutations cause benign lesions to develop in the small and/or large intestine, usually in the context of a unique, identifiable phenotype. However, all of the hamartoma syndromes are associated with a variety of cancers in the gut and elsewhere because of the dysregulation of growth they cause. These are discussed later in this chapter.

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INHERITED COLORECTAL CANCER SYNDROMES POLYPOSIS SYNDROMES There are several hereditary syndromes of CRC predisposition that are associated with a strong tendency toward multiple colorectal polyps. Polyposis simply means “lots of polyps,” but in practical terms it is defined as more than 100 polyps at one examination. Fewer numbers of polyps, from 10 to 100, are often referred to as attenuated polyposis or “oligopolyposis.” Polyposis syndromes also can be classified according to polyp histology (the phenotype) and according to the gene that is mutated in the patients’ germline (genotype). The various syndromes, along with their clinical and genetic criteria, are listed in Table 165.1. Management of the polyposis syndromes involves diagnosis, evaluation, and management with the goals to (1) prevent death from cancer and (2) maintain adequate quality of life. Familial Adenomatous Polyposis Epidemiology and Genetics.  FAP is rare, with an incidence of approximately 1 in 10,000 live births. Prevalence is estimated at 1 in 24,000 to 1 in 60,00010 and depends on the average size of families in a country or region, and the completeness of registration of the disease. FAP affects all races and both genders equally. The expression of the disease may vary according to genotype and vary even within patients who share the same mutation, due to modifying factors, such as gender.11 FAP is caused by a germline APC mutation, which results in a generalized growth disorder expressed as benign and malignant tumors in a variety of tissues.12 Manifestations associated with the mutation are summarized in Table 165.2. The severity of the growth disorder and the risks and age at onset of cancer vary between and within families. Diagnosis.  Most patients with FAP are diagnosed based on family history. For a dominantly inherited syndrome with close to 100% penetrance, the family history of CRC and other manifestations of the APC mutation is compelling. Children of an affected parent usually undergo genetic testing at puberty and, if affected, start colonoscopy at that time.13 Testing in infancy is generally discouraged because of the possible effect of a positive result on the parent’s attitude to their affected children, but this fear may not be borne out in practice. However, the possibility of hepatoblastoma, a rare manifestation of the germline APC mutation, is a reason to perform genetic testing of newborns and then hepatoblastoma screening (6-monthly liver ultrasound and alpha fetoprotein) until the age of 7. Approximately 25% of patients with FAP have no knowledge of a family history of the disease. Reasons for this include adoption, deliberate withholding of information by affected family members, nonpaternity, germline mosaicism, and a de novo mutation at conception. These patients are unaware of the risk posed by the unsuspected germline mutation and usually present with symptoms of their polyposis or cancer, such as rectal bleeding, abdominal pain, and diarrhea. They have a high chance of having CRC at diagnosis.14

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SECTION IV  Colon, Rectum, and Anus

TABLE 165.1  The Hereditary Colorectal Polyposes Syndrome

Polyp Histology

Gene(s)

Familial adenomatous polyposis

Adenoma

APC

MutYH-associated polyposis NTHL1-associated polyposis Polymerase proofreadingassociated polyposis Lynch syndrome

Adenoma Adenoma Adenoma

MutYH NTHL1 POLD, POLE

Adenoma

Serrated polyposis

Serrated polyp

MLH1, MSH2, MSH6, PMS2 EPCAM ?

Hereditary mixed polyposis syndrome PTEN hamartoma tumor syndrome

GREM1

Juvenile polyposis

Adenoma, serrated polyp, hamartoma Juvenile polyp, hamartoma, lipoma, fibroma, neurofibroma, serrated polyp Juvenile polyp

Peutz-Jeghers polyposis

Peutz-Jeghers polyp

STK11

TABLE 165.2  Manifestations of the Germline APC Mutation in Patients With Familial Adenomatous Polyposis Organ

Benign

Malignant

Colon and rectum Stomach

Adenoma Adenoma Fundic gland polyp Adenoma — Adenoma Osteoma Epidermoid cyst Extra teeth Desmoid disease — —

Carcinoma Carcinoma

Small intestine Thyroid Adrenal gland Bone Skin Teeth Fibroblasts Brain Liver

Carcinoma Papillary carcinoma Carcinoma — — — — Medulloblastoma Hepatoblastoma

Clinical diagnosis of FAP is usually made on colonoscopy followed by efforts to establish a genetic diagnosis so that the family can be triaged. The odds of identifying an APC mutation are greater than 80% in patients with greater than 100 adenomas. If a germline APC mutation is found, then all at-risk relatives can be offered screening. Other genetic mechanisms may cause FAP and include deletion of the APC promoter 1B,15 chromosomal loss (often associated with reduced mental capacity),16 and APC haploinsufficiency.17 If genetic testing is negative,

PTEN

SMAD4 BMPR1A

Number of Polyps for Diagnosis

Inheritance Pattern

Severe/profuse: >1000 Mild: 100–1000 Attenuated: <100 Any Any Any

Recessive Recessive Dominant

>10

Dominant

>20 of any size and location >5 proximal to the sigmoid, 2 >10-mm diameter >5, at least 1 juvenile polyp —

?

>5 >1 plus a family history of juvenile polyposis >1 plus a family history of Peutz-Jegher polyposis

Dominant

Dominant

Dominant (Ashkenazi Jews) Dominant

Dominant

sometimes extracolonic manifestations can be used to predict an affected relative. Initial Evaluation and Management.  Care of patients with FAP and their families is best given by centers of experience and excellence.18 Such centers are scattered around the world, and are often linked by organizations such as the Collaborative Group of the Americas for Inherited CRC (cgaicc.com) and the International Society for Gastrointestinal Hereditary Tumors (InSiGHT). Patients and their families who enroll in a registry benefit at least from enhanced survival due to organized surveillance. CRC is the main risk in patients with FAP and is the most common cause of death.19 In classic FAP (>100 synchronous adenomas), the average age at cancer diagnosis is 39 years, with much younger onset in patients with profuse polyposis. The most effective way of preventing cancer is to remove the colon, and thus thought should be given regarding the timing of prophylactic surgery once a diagnosis is established. Symptomatic patients should undergo colectomy using an oncologic technique as occult cancer risk is elevated in these patients. For patients who do not require a colectomy around the time of diagnosis, annual colonoscopy should be performed with removal of larger polyps and continued thoughtfulness of the timing of surgery. Almost all patients with FAP develop fundic gland polyps in the stomach, and adenomas in the duodenum.20 Duodenal cancers are the third most common cause of death in FAP (after CRC and desmoid disease) and

Inherited Colorectal Cancer and the Genetics of Colorectal Cancer  CHAPTER 165 

upper GI surveillance begins at 20 to 25 years old. An esophagoduodenoscopy should be done with a side-viewing duodenoscope so that the duodenal ampulla can be examined. Timing of Prophylactic Colectomy.  CRC is rare in FAP patients younger than 20 years old.21 For patients diagnosed in their teenage years, the timing of surgery depends primarily on the severity of the polyposis. Factors governing the timing of colectomy are shown in Table 165.3. While the top priority is to avoid cancer or to remove it as early as possible, lifestyle concerns are real and need to be considered. Many FAP patients are in their teens or twenties when faced with the prospect of surgery, and are often asymptomatic. They have academic, financial, social, and developmental concerns, and the idea of a stoma or the chance of a complication is scary. This is especially the case where other members of the family have had unfortunate outcomes. Therefore, appropriate surgery selection is key to decrease the cancer risk, maintain the quality of life, and minimize the complications. Note that increased risk of desmoid disease is listed as an indication to defer surgery as long as possible in Table 165.3. This is because approximately 80% of desmoid disease in FAP develops after abdominal surgery, presumably secondary to the intervention.22 Choice of Surgery.  There are three main options for prophylactic surgery in patients with FAP: colectomy with ileorectal anastomosis (IRA), total proctocolectomy with ileal pouch–anal anastomosis (IPAA), and total proctocolectomy with end ileostomy (TPC-EI). These surgeries

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can be done by open or minimally invasive techniques, and the IPAA can be done with a stapled anastomosis or with a mucosectomy and handsewn anastomosis. Tables 165.4 and 165.5 show the factors that favor or disfavor the different surgeries. An oncologic technique with high ligation of the feeding vessels and removal of the mesentery and the omentum should always be used because unsuspected cancer may be found in the specimen.23

TABLE 165.3  Timing of Prophylactic Colectomy Urgency

Timing

Indication

Immediate

Next available list

Soon

Within 3 months

Sometime

On a year-byyear basis

Defer

Put off as long as possible

Cancer Symptoms Complications of colonoscopy Profuse polyposis (>1000 adenomas) Multiple large (>1 cm) adenomas High-grade dysplasia in an adenoma Mild polyposis (100–1000 adenomas) Asymptomatic Social, intellectual, academic, financial, family factors High risk of desmoid disease High comorbidity

TABLE 165.4  Analysis of the Advantages and Disadvantages, Indications and Contraindications of the Three Main Colorectal Surgical Options of Patients With Familial Adenomatous Polyposis Ileorectal anastomosis

Ileal pouch–anal anastomosis

Advantages

Disadvantages

Indications

Contraindications

Quick, safe, uncomplicated Good quality of life Bowel function acceptable Controls colonic polyposis Avoids any ileostomy Surveillance easy Controls most colorectal polyposis Avoids permanent ileostomy Reasonable quality of life

Risk of rectal cancer Surveillance required

<20 rectal adenomas <1000 colonic adenomas

Rectal cancer

High complications Bowel function unpredictable Ileostomy needed Risk of pouch polyposis Risk of ATZ cancer Quality of life unpredictable Surveillance can be difficult Permanent ileostomy

>20 rectal adenomas Rectal cancer

High desmoid risk Lack of surgical expertise <20 rectal adenomas

Low rectal cancer IPAA impossible Poor anal sphincter function Slim, young patients Expertise available

Good sphincters No rectal cancer

Best for IPAA patients with high desmoid risk

Patients where cosmesis is an issue, high morbidity

Proctocolectomy and ileostomy

Least risk of complications Complete removal of cancer risk in lower GI tract

Minimally invasive

Less trauma, less pain, reduced length of stay, quicker recovery, minimal scars Less operative time

Open

Expertise required, slower, may cause issues with IPAA More pain, longer recovery, scar

ATZ, Anal transition zone; GI, gastrointestinal tract; IPAA, ileal pouch–anal anastomosis.

Severe desmoid risk IPAA

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SECTION IV  Colon, Rectum, and Anus

TABLE 165.5  A Staging System for Intraabdominal Desmoid Disease Stage

Size

Symptoms

Growth

I II III IV

<10 cm <10 cm 11–20 cm >20 cm

None Mild Moderate Severe

None <25% in 6 months 25% to 50% in 6 months >50% in 6 months

Note: Many patients have multiple desmoids. The worst stage is taken for treatment planning.

In practical terms, the decision for IRA or IPAA is driven by the severity of the polyposis: the more severe the polyposis the higher the risk of metachronous rectal polyposis and/or rectal cancer. Church et al. showed that when there were 5 or fewer rectal adenomas and 1000 or fewer colonic polyps, no patient needed a subsequent proctectomy. When there were 6 to 20 rectal adenomas, 15% of patients needed later proctectomy; however, with 20 or more rectal adenomas, the incidence of later proctectomy was more than 50%.24 Recently this “rule” has been stretched in favor of a conservative approach.25 Teenagers who might otherwise need proctectomy and a pouch have been treated with a laparoscopic IRA, for the benefits of a quicker, safe surgery, better bowel function, lower risk of desmoid disease, no stoma, and quicker recovery.26 These are considerable benefits for young, active patients; however, annually, careful proctoscopy is needed to keep the rectal polyposis in check. Colectomy and Ileorectal Anastomosis.  The need for postoperative surveillance should be considered when planning the surgery. The ideal length of the rectum is 15 cm, which provides reasonable bowel function while still allowing easy endoscopic evaluation. With an IRA at 15 cm from the anal verge, patients on average have between 4 and 5 semiformed bowel movements without urgency or incontinence. A diverting stoma is not routine and recovery is quick, particularly after a laparoscopic approach. Preoperatively, all large rectal polyps must be removed to assure there is not cancer. Small (<5 mm) polyps may be left for future surveillance and removal as needed. Postoperatively, the rectal polyp burden may spontaneously reduce, likely because of the different types of stool the mucosa encounters.27 The IRA itself can be tricky to construct because of the disparity in luminal diameter between the ileum and the rectum. A technical point to limit this disparity is to resect the terminal ileum flush with the ileocecal valve to preserve the “trumpet-like” flare of the bowel just before it reaches the cecum. The ileal mesentery can also be a source of trouble as the mesenteric defect can allow an internal hernia, which could cause small bowel obstruction. Small mesenteric defects should be closed. Proctocolectomy With Ileal Pouch–Anal Anastomosis.  The main differences between IRA and IPAA are

(1) the loss of the rectum; (2) the extent of surgery that requires deep pelvic dissection; and (3) the different physiology of an ileal pouch. If the low rectum is relatively free of adenomas, a stapled IPAA can be performed with an ileal J pouch. This gives decent function with the

expectation of an average of 5 to 6 daily bowel movements and good control with the ability to defer the movement for 1 to 2 hours.28 If the anal transition zone (ATZ) and the low rectum are carpeted by adenoma, then mucosectomy and handsewn IPAA should be performed. An S pouch is the preferred configuration under these circumstances.29 A handsewn IPAA is prone to stricture and leak, and has a higher rate of seepage and a need for the patients to wear pads.30 Surgeons performing IPAA should be familiar with either anastomotic technique, and be able to perform the operation open as well as laparoscopically. Taking the pouch down to the anus without twists is critical to good function, as even a twist of 90 degrees can cause shelves in the pouch that hinder defecation. A diverting loop ileostomy is routine. However, if the IPAA procedure is stapled, the operation goes well, the stapler donuts are intact, and the leak test on the anastomosis is negative, then omitting the temporary loop ileostomy may be considered. Total Proctocolectomy With End Ileostomy.  For patients who prefer an operation that completely removes the chance of large bowel cancer, and who do not mind an EI, this is the best choice. It is critical that the ileostomy be well positioned and well constructed, with a 2-cm spout, so that pouching is easy and the skin-protective appliance lasts 3 to 4 days. Postoperative Surveillance.  Patients with an IRA and an IPAA need surveillance of their rectum or pouch, as adenomas and cancers can occur. Adenomas and cancers can also occur on an EI, although cancer takes at least 15 years to develop. Surveillance of the rectum and ileal pouch is performed yearly, usually as an office procedure without sedation, after two fleet enemas. The terminal ileum above the IRA or pouch is examined for at least 15 cm. The anastomosis itself is checked and the body of the pouch or rectum is examined for adenomas. 31 Polyps may be hyperplastic or lymphoid follicles, and pouch adenomas can be quite subtle. Because the ileal mucosa has villi, the adenomas tend to blend into the surrounding epithelium. Ulcers may be seen at the IRA and at the entry of the ileum into the pouch. They should be biopsied, but they are common and do not have any clinical significance in asymptomatic patients. The ATZ is a “hot spot” for adenomas. Whereas pouch adenomas usually take several years to form (42% of pouches have adenomas by 7 years follow-up),32 ATZ adenomas may be there at the time of surgery and can sprout quite quickly. They are twice as common after a stapled IPAA as after a handsewn IPAA and, if not dealt with, can turn to cancer.33 They can often be simply snared, but carpeting with villous adenoma requires stripping of the ATZ and a handsewn reanastomosis if possible. Sometimes this needs a formal redo of the IPAA with transabdominal pouch mobilization; the preferred technique is to do this transanally, with half the circumference done initially and the other half after the ATZ has healed from the first procedure. Pouch cancer is rare.33 EIs should be checked once a year and the patient educated in the appearance of adenomas on the stoma. Chemoprevention.  Chemoprevention in FAP means treating colorectal, ileal, and duodenal adenoma risk with medications to suppress the neoplasia, as an alternative to surgery and polypectomy, or at least to postpone it. Many

Inherited Colorectal Cancer and the Genetics of Colorectal Cancer  CHAPTER 165 

studies have tested a variety of agents in patients with FAP, mostly because the accelerated adenoma to carcinoma sequence in FAP allows the effects of putative chemotherapeutic agents to become obvious relatively quickly. The most tested drug is sulindac (Clinoril), a nonsteroidal antiinflammatory agent with cyclooxygenase (COX)-1 and COX-2 inhibiting activity.34 However, sulindac can cause GI distress, bleeding, intestinal ulceration, and renal effects, and is not tolerated in 20% of patients.35 That being said, a dose of 150 to 200 mg twice daily suppresses colorectal adenomas and desmoid disease,36,37 but its effectiveness depends on strict compliance with taking the drug. There is a concern that cancers can still develop in patients whose adenomas have been suppressed for years.38 For this reason, and because no chemotherapeutic agent has been shown to be completely effective in FAP, we do not favor chemoprevention as a routine option for colorectal adenomas in FAP. However, chemoprevention with sulindac is reasonable in FAP patients with pouch polyposis as the surgical alternative is pouch removal and likely an EI. Other agents that have shown some effect include difluorometylornithine (DFMO) and celecoxib (Celebrex), although neither is used in standard practice. For duodenal adenomas in FAP, the epidermal growth factor receptor inhibitor erlotinib (Tarceva), in combination with sulindac, has recently shown great promise in the treatment of duodenal adenomas in FAP.39 Combination chemotherapy, whereby multiple pathways to cancer are targeted at once, holds great promise for the future. Desmoid Disease in Familial Adenomatous Polyposis.  Desmoid disease is a manifestation of the APC mutation that is found in 30% of FAP patients, mostly in the abdominal wall, in the small bowel mesentery, and in the retroperitoneum. It is an abnormal proliferation of fibroblasts that can produce tumors, or hard white sheets. Desmoid tumors can grow rapidly and be fatal, while even desmoid sheets can pucker adjacent organs, causing bowel or ureteric obstruction, and enterocutaneous fistulas.40–43 The clinical behavior of desmoid disease varies from patient to patient and even within a patient, becoming less aggressive over time. Overall, about 12% regress, 7% are lethal, and the remainder never disappear, but rather grow and shrink to a small extent while remaining relatively asymptomatic.44 There is no predictably effective treatment for desmoid disease and thus, for patients at high risk (see later), deferring its onset by avoiding abdominal surgery needs consideration. Desmoid disease can interfere with plans for an IPAA by restricting the length of the small intestinal mesentery so that the pouch will not reach the anus. A recent Cleveland Clinic study of patients undergoing proctectomy after an initial IRA showed that desmoid disease was present in 26 of 67 patients. Although proctectomy can still be completed in nearly all patients, desmoid disease prevented a planned IPAA in 8 of 62 patients.45 This possibility should be discussed with patients preoperatively. Desmoid Disease Risk Factors.  The risk factors predicting the possibility of desmoid disease include sex (females twice as likely as males), family history of desmoids, extracolonic manifestations of Gardner syndrome (epidermoid cysts, osteomas, extra teeth), and genotype. Traditionally, the location of the APC mutation was believed to determine

1967

TABLE 165.6  Treatment of Intraabdominal Desmoid Disease in Familial Adenomatous Polyposis, According to Stage Stage

Treatment

Surveillance

I

Repeat scan in 1 year Repeat scan in 6 months

III

Nothing, or sulindac 150–200 mg by mouth twice a day Sulindac 150–200 mg twice a day with raloxifene 60 mg by mouth twice a day Methotrexate/vinorelbine or sorafenib

IV

Doxil, Adriamycin

II

Repeat scan in 3 months Repeat scan in 3 months

the likelihood of an FAP patient to develop desmoid disease, but a recent Cleveland Clinic study showed that the location of the mutation does not predict the occurrence of desmoids, but rather predicts their severity; tumors in patients with mutations at the 3 prime end of codon 1400 tend to have more severe disease.46 Church et al. have proposed a staging system for desmoid tumors based on size, symptoms, and pattern of growth, as summarized in Table 165.5.47,48 Treatment of Desmoids.  While there is no predictably successful treatment for desmoid disease, a staging system can be used to triage patients for the various options (Table 165.6). Since complete eradication of desmoid disease is unlikely, the achievable therapy goal is to stabilize the disease and render the patient asymptomatic. For early-stage desmoid disease, sulindac is effective, but the response may take up to 2 years to be clinically evident.37 Sulindac is usually given in combination with systemic estrogen-modifying agents such as tamoxifen or raloxifene.49 For higher stage, more symptomatic patients, a quicker response is sought and chemotherapy may be used. Methotrexate and vinorelbine is effective in about 30% of cases,50 while doxorubicin (Doxil) is perhaps even more effective.51 Doxorubicin and dacarbazine are the most toxic options, but they do have the highest rate of regression or disappearance.52 Surgery is usually reserved to treat symptoms or to treat or preempt complications. Studies reporting the results of surgery for desmoid tumors rarely separate FAPrelated tumors from sporadic tumors. Results for mixed populations of patients need to be reviewed carefully as the presence of a germline mutation may well influence recurrence rates, and FAP-related desmoids are often multiple. Abdominal wall desmoids can be resected with success, often requiring abdominal wall repair with mesh. Local recurrence occurs in about one-third of cases. Intraabdominal desmoids are less often resectable because of their predilection to occur in the retroperitoneum and the small bowel mesentery. However, desmoids in the distal mesentery away from the root vessels are often resectable, but have a local recurrence rate ranging from 50% to 80%.53,54 These are challenging cases and can be technically difficult, resulting in large volume blood loss.55 In some cases, when there are no other options, a complete enterectomy can be considered with small bowel

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SECTION IV  Colon, Rectum, and Anus

transplant. Although desmoid tumors may be sensitive to radiation, this is not an option for intraabdominal desmoids due to the proximity of the small bowel. Upper Gastrointestinal Tract in Familial Adenomatous Polyposis.  Almost all patients with FAP have fundic gland polyps in the stomach, and adenomas in the duodenum.20 Duodenal cancers are the third most common (10%) cause of death in FAP after CRC and desmoid disease.56 Surveillance with esophagogastroduodenoscopy (EGD) using a side-viewing duodenoscope begins for patients at 20 to 25 years old. The duodenal ampulla must be examined. The density of duodenal adenomas tends to be centered on the duodenal ampulla, establishing a relationship between bile exposure and duodenal neoplasia risk where every epithelial cell carries a mutation in APC. Fifty percent of normal-appearing ampullas have epithelial dysplasia, although the significance of this is questionable.20 Fundic gland polyps are nonneoplastic, hyperplastic polyps of gastric mucosa. However, they can be numerous, and when proliferative can hide an underlying carcinoma. Low-grade dysplasia has been found in up to 40% of random biopsies and a low threshold for concern is appropriate.57 Gastric adenomas occur in approximately 10% of FAP patients. They are frequently located in the antrum and may develop as a result of bile reflux into the stomach. As they may be precursors to gastric cancer, removal is recommended.58 Duodenal adenomas are more common with a near 100% incidence, and they have a tendency to progress to cancer. The severity of duodenal adenomatosis predicts the chances of duodenal cancer, and can be described using the Spigelman staging system that is based on adenoma number, size, and histology (Table 165.7).59 Patients with stage 0 disease (no adenomas) can be surveyed again in 5 years. Stage I patients can be surveyed in 3 years; stage II in 1 year; stage III in 6 months; and stage IV is an indication to consider surgery. Groves et al. from St. Mark’s Hospital showed that 36% of patients with stage IV duodenal adenomas developed cancer.60 In such patients, a pancreas-preserving duodenectomy is effective in preventing cancer without the full range of morbidity and lifestyle change incurred after a pancreaticoduodenectomy (Whipple procedure). A Whipple is indicated for a duodenal cancer that is definitively operable. Duodenal adenomas can be treated by snare polypectomy or by transduodenal polypectomy. Ampullary adenomas can be treated by endoscopic mucosal resection or surgical ampullectomy. All of these lesser procedures have lower

TABLE 165.7  Spigelman Staging System for Duodenal Adenomas Polyp number Polyp size Polyp histology Degree of dysplasia

1 Point

2 Points

3 Points

1–4 1–4 Tubular Low

5–20 5–10 Tubulovillous Moderate*

>20 >10 Villous High

*Now combined with low-grade dysplasia. Stage 0 = 0 points; stage I = 1–4 points; stage II = 5–6 points; stage III = 7–8 points; stage IV = 9–12 points.

morbidity than duodenectomy but have much higher recurrence rates.61–63 Other Extracolonic Manifestations of Familial Adenomatous Polyposis.  Several other organs are affected by FAP and can develop a range of benign and malignant tumors. The cluster of manifestations referred to as Gardner syndrome includes osteomas (usually in the head and face), epidermoid cysts, extra teeth, and desmoids. The osteomas and cysts should be removed if they become symptomatic. Papillary thyroid cancer is approximately 7 times more common in FAP than in the general population, and is twice as common in women as in men with FAP.64 Annual thyroid ultrasound is recommended for surveillance. It is quick, noninvasive, and effective as a screening test. Cleveland Clinic has shown that thyroid cancers detected on screening are smaller than incident cancer and have a better outcome.64 Adrenal adenomas are often seen incidentally on computed tomography (CT) scans obtained to investigate desmoid disease. They are rarely symptomatic and even more rarely functional, and can be observed as long as they are less than 5 cm in diameter.65 Turcot syndrome refers to the association of brain tumors with hereditary CRC and medulloblastoma is most common. The risk is relatively low but is higher than that in the general population. Hepatoblastoma is a potentially lethal liver tumor that is rare but is associated with FAP in infants. If found early, it is curable with surgery, making the case for screening infants to age 7 with ultrasound and α-fetoprotein.66 Attenuated Familial Adenomatous Polyposis.  Attenuated FAP (aFAP) describes a subset of patients with a germline APC mutation in whom the colorectal phenotype is weak, or “attenuated.” These patients are clinically defined as having less than 100 synchronous colorectal adenomas. They present at a later age than patients with classical FAP and develop CRC 10 to 20 years older.67 APC mutations associated with attenuated polyposis tend to be at either extremity of the gene. With extreme 3 prime mutations there is a predilection for severe desmoid disease, and sometimes there are no colorectal adenomas at all (hereditary desmoid disease). Patients with aFAP are at the same, if not greater, risk of upper GI polyposis as those with classical FAP. Desmoid disease is common in those with 3 prime mutations but can also happen with 5 prime mutations. Colorectal surgery tends to occur later and is almost always colectomy and IRA. Patients with very mild colorectal polyposis may be treated with colonoscopy every year rather than colectomy. There is an overlap in phenotype between aFAP and MutYH-associated polyposis (MAP), and with otherwise undefined oligopolyposis. MutYH-Associated Polyposis and NTHL1-Associated Polyposis MutYH and NTHL1 are genes involved in DNA base excision repair, a pathway that repairs oxidative damage to DNA. Oxidation causes guanine to mispair with thymine during replication, creating CG:TA transversions that produce mutations in a range of genes.68 MutYH and NTHL1 are two of a series of genes that corrects this problem and prevents the mutations from occurring. Recessive inheritance of mutations in both copies of these genes causes CRC predisposition and usually an

Inherited Colorectal Cancer and the Genetics of Colorectal Cancer  CHAPTER 165 

attenuated form of adenomatous polyposis resembling aFAP.68,69 This is likely because APC is frequently affected by unrepaired oxidation. The incidence of MAP is very rare (<1% of all CRCs), while only an NTHL1-associated polyposis (NAP) is even more rare with only a few families described to date. Since these diseases are recessively inherited, a mutated copy from each parent must be passed on for the offspring to develop the syndrome. In that situation, both parents must be at least carriers (i.e., one mutated allele and one normal allele) and the odds of a child inheriting both copies is 1 in 4. If one parent has the disease and the other parent is a carrier, the odds of the children developing the disease are 1 in 2. The population frequency of the carrier state (monoallelic mutation) is about 2%. There has been some debate about the risk to carriers for developing CRC. There is an approximately twofold CRC risk compared with the general population in MutYH mutation carriers, and thus some recommend colorectal surveillance commensurate with guidelines for people with similar risk, such as people with one affected first-degree relative. Lefevre et al. describe a similar risk of cancer for both monoallelic and biallelic mutation carriers who both have polyposis, suggesting that even in these monoallelic carriers gene expression is significantly reduced, leading to the phenotype.70 Clinical Features.  MAP can present in many different ways, mimicking almost all other syndromes of hereditary CRC.71 Classic MAP phenotypically resembles aFAP, with less than 100 synchronous adenomas and a young age of onset of microsatellite stable (MSS) CRC. However, various reports in the literature show that cancers in patients with biallelic MutYH mutations can be solitary (no polyposis), and can occur in either very young or older patients and in patients with no family history. The polyps may develop early or late, and can include adenomas and serrated polyps. Cancers can be microsatellite unstable. Church and Kravochuck recently reported rectal “studding” as a possible pathognomonic sign of MAP.72 Although the family history is classically recessive, with unaffected parents and affected second-degree relatives, sometimes a dominant inheritance pattern or even no family history of CRC is seen. Patients with suspicion for MAP, or patients thought to have FAP but who do not have an APC mutation, should be tested for MutYH mutations. The advent of panel testing allows more screening for MutYH mutations and the identification of atypical cases. Testing of patients for NTHL1 mutations is not yet commercially available. Extracolonic Manifestations.  MAP seems to have a spectrum of extracolonic manifestations similar to that found with classical FAP. There are reports of gastric and duodenal adenomas, small bowel carcinomas, desmoid tumors, and thyroid cancer. The phenotypic spectrum of patients with NTHL1 mutations has yet to be defined. Clinical Management.  Management depends on the severity of colorectal polyposis and the age of the patient at presentation. If the colorectal neoplasia is controllable by colonoscopy, this is a reasonable option, especially when expert colonoscopy is available and the patient is compliant. Rules for endoscopic management of patients with MAP include a high quality, uncompromising colonoscopy with excellent bowel preparation. If no polyps are seen,

1969

the exam can be repeated in 3 to 5 years. If neoplasia is found, all adenomas greater than 5 mm diameter should be removed. The exam is repeated at an interval appropriate for the polyp number, size, and degree of dysplasia, but no longer than 1 to 2 years. Colectomy is reserved for patients with an uncontrolled polyp burden or for CRC. The risk of developing CRC in biallelic carriers is approximately 75%. If a colon cancer is present, and there is a known MAP diagnosis, an extended colectomy and IRA is recommended. If an MAP patient presents more like classical FAP, with greater than 1000 adenomas, they are treated as if they had FAP. Extracolonic surveillance includes thyroid screening with ultrasound, and EGD, starting at presentation and continuing at intervals appropriate for the findings. Without findings, the exam is repeated every 3 to 5 years. There are no recommendations for the treatment of NAP, and, indeed, the syndrome is so new and the number of families so small that the phenotype of the syndrome has not yet been established. Polymerase Proofreading-Associated Polyposis DNA replication is a key event occurring during cell division, and multiple biologic systems are designed to maximize the fidelity of replication. One key system is the DNA proofreading domains of DNA polymerase. Failure of these proofreading domains can lead to a dominantly inherited syndrome of colorectal and endometrial cancer predisposition.73 Such a failure of proofreading creates a mutator phenotype where mistakes in DNA replication persist in daughter cells and lead to secondary mutations in other genes. When these genes are drivers of colorectal carcinogenesis, tumors occur. The polymerases shown to be involved are POLD1 and POLE. The syndrome is characterized by oligoadenomatous polyposis and early age of onset CRC, and endometrial cancer in patients with a POLE mutation. Recent studies show that POLE mutations can be associated with both MSS and unstable CRCs, and so polymerase proofreading-associated polyposis is among the differential diagnoses of Lynch syndrome. There are few families reported with this syndrome, so the full picture of the phenotype is lacking. However, a young age of onset CRC, and multiple, advanced adenomas are suggestive. Patients must be treated according to their presentation, although in those already diagnosed who present with a cancer, extended surgery seems reasonable. In patients with an early age of onset CRC and oligoadenomatous polyposis, germline mutations in POLD1/POLE can be sought via panels offered by various commercial laboratories.

HAMARTOMATOUS POLYPOSIS SYNDROMES Hamartomatous polyps are benign, localized overgrowths of mature epithelial cells. The hamartomatous polyp syndromes are rare entities that include juvenile polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS), and PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). Less than 1% of all CRC is associated with hamartomatous polyposis syndromes. Knowledge of these syndromes allows the appropriate genetic counseling and testing, the assessment of cancer risk, and the screening recommendations.

1970

SECTION IV  Colon, Rectum, and Anus

Juvenile Polyposis Syndrome Solitary juvenile polyps are the most frequent colorectal polyps in children. They are bright red, usually pedunculated, and histologically are hamartomas that feature an inflammatory infiltrate with large mucus-filled spaces distributed in an expanded lamina propria and a prominent inflammatory infiltrate. Isolated juvenile polyps are not inherited and are not premalignant. However, multiple juvenile polyps raise the possibility of JPS. Diagnosis and Genetics.  Diagnostic criteria for diagnosis of JPS include any juvenile polyp in a patient with a family history of juvenile polyposis, or greater than 4 synchronous juvenile polyps in the large intestine. The polyps are usually found in the colon and rectum, but they may also be found in the stomach, duodenum or small bowel, and occasionally diffusely throughout the GI tract. The estimated incidence of JPS ranges from 1 in 50,000 to 1 in 100,000. JPS is genetically heterogeneous, and is associated with germline mutations in SMAD4 and BMPR1A genes, two members of the TGF-β superfamily. Germline mutations in the SMAD4 suppressor gene, located on chromosome 18q21.1, account for 18% to 50% of JPS cases. This gene encodes a cytoplasmic mediator involved in the TGF-β signal transduction pathway. The finding of JPS kindred with BMPR1A mutations further supports the importance of TGF-β superfamily mutations in this syndrome. It is inherited in an autosomal dominant manner with variable penetrance. Approximately 20% to 50% of cases have a family history of JPS. In sporadic cases, the condition may represent a new mutation or incomplete penetrance of the gene, but it also may result from environmental factors. Clinical Features.  Polyp growth begins in the first decade of life and there are variable numbers, usually between 50 and 200.74 Macroscopically, the polyps are 5 to 50 mm in size, red to brown in color, spherical or lobulated, and pedunculated, often with superficial ulceration. The cut surface shows cystic spaces, and microscopically, the characteristic feature is dilated cystic glands lined by tall columnar epithelium. The lamina propria is expanded and consists of an inflammatory infiltrate consisting of neutrophils, eosinophils, and a few lymphocytes. 74 Polyps are distributed throughout the GI tract, but most commonly are in the colon. Hofting et al. described the following distribution of polyps in 262 cases of juvenile polyposis: colorectum 98%, stomach 13.6%, duodenum 2.3%, and jejunum and ileum 6.5%.75 As the upper GI tract has not often been screened adequately, the rate of upper GI tract involvement may be higher. The colorectal polyps appear to be evenly distributed throughout the large bowel. Isolated polyposis involving only the stomach has been described. Sachatello et al. subdivided JPS into three categories based upon clinical presentation and disease course76: (1) juvenile polyposis of infancy; (2) juvenile polyposis coli; and (3) generalized juvenile polyposis. Juvenile polyposis of infancy is an extremely rare syndrome in which the entire GI tract is usually affected. Patients present with bloody diarrhea, protein-losing enteropathy, intussusception, and rectal prolapse. The prognosis is unfavorable and is related to the severity and extent of GI involvement. The

common manifestations lead to anemia, hypoproteinemia, anasarca, failure to thrive, and finally death within 2 years of life in 90% of infants. In juvenile polyposis coli, as the name implies, the juvenile polyps are limited to the colon and rectum, while in generalized JPS, the polyps occur anywhere from the stomach to the rectum. Presentation of both these subtypes usually occurs in the first and second decades of life, and almost always by 30 years of age. In a review examining 218 patients with JPS, Coburn et al. found that juvenile polyposis coli patients usually presented between the ages of 5 to 15 years, while patients with generalized JPS presented at age 12. The most common manifestations are rectal bleeding and anemia, which may occur in as many as 75% of patients. Other frequent symptoms are prolapse of either a polyp or the rectum itself, abdominal cramps or pain, and diarrhea. Some patients may present with clubbing of the fingers. Besides anemia, laboratory findings may include hypoproteinemia, hypokalemia, and a skin test anergy. Different clinical subtypes of JPS can exist in the same kindred, suggesting variable penetrance, and making the distinction between subtypes somewhat arbitrary. Patients with juvenile polyposis may have extraintestinal morphologic abnormalities. Congenital anomalies were described in up to 20% of cases and have included macrocephaly, mental retardation, atrial and ventricular septal defects, pulmonary arteriovenous malformations, pulmonary stenosis, Meckel diverticulum, malrotation, cryptorchidism, hypertelorism, and telangiectasia. Genotype/phenotype correlations in JPS patients have emerged. The results are consistent with the suggestions that some carriers of SMAD4 mutations may have higher cancer risk than patients without SMAD4 mutations.77 SMAD4 families were found to have more upper GI juvenile polyps when compared with BMPR1A-mutation positive or no-mutation families, and so it seems that SMAD4 mutations predispose to generalized JPS, while SMAD4-mutation negative cases are more likely to have a juvenile polyposis coli phenotype. In addition, SMAD4 mutation carriers seem to be the patients prone to hereditary hemorrhagic telangiectasia (HHT).78 The association is strong enough to suggest that patients with JPS and an SMAD4 mutation should undergo HHT screening before surgery. Malignant Potential in Juvenile Polyposis Syndrome.  While CRC was the first to be described, and is the most frequent malignancy seen in JPS patients, carcinoma of the stomach, pancreas, duodenum, and small intestine occurs. CRC cases have been reported in patients with both colorectal and generalized juvenile polyposis, as well as in sporadic forms and in familial ones. Howe et al. reported that 55% of affected members of a large Iowa JPS kindred developed GI cancer; 38% had CRC and 21% had gastric cancer.79 A similar risk for CRC was reported by Brosens et al.80 The mean age for diagnosing GI cancer in JPS is around 35 years in different series, but the range is wide (4 to 60 years). Carcinomas can develop 1 to 25 years (average 15 years) after the onset of symptoms or the diagnosis. Jass et al. suggested a more aggressive behavior of CRCs in JPS patients. In 18 of 80 (22%) patients who developed CRC, 5 patients were not resectable for cure, and tumors from 9 of these patients showed mucinous features

Inherited Colorectal Cancer and the Genetics of Colorectal Cancer  CHAPTER 165 

and/or poor differentiation.81 A hamartoma-adenomadysplasia-carcinoma sequence in JPS patients is proposed by several authors. There are not enough data to support a transition of juvenile polyps into adenocarcinoma, although juvenile polyps with adenomatous areas, mixed juvenile adenomatous polyps, and purely adenomatous polyps can be found in affected colons. Kinzler and Vogelstein have postulated that the overgrowth of the stromal/mesenchymal elements leads to the production of a microenvironment, which influences or “landscapes” the epithelial element of the hamartomatous polyps.82 Jass and colleagues retrospectively studied the pathologic findings of 1032 polyps from 80 JPS patients.81 A total of 840 polyps were typical juvenile polyps, whereas 169 differed in being multilobulated or showed villous configuration. Of the latter, 47% contained foci of epithelial dysplasia (with a tendency toward a higher degree of moderate to marked epithelial dysplasia), whereas only 9% of typical polyps were dysplastic (typically mild dysplasia). Clinical Management: Screening and Surveillance.  For kindred in which a gene mutation is known, other potentially affected individuals can be diagnosed by genetic testing. Screening by colonoscopy should begin at age 12 to 15, or earlier if symptoms are present. If no neoplasia is seen, colonoscopy should be repeated in 2 to 3 years. If polyps are present, they should be removed at colonoscopy and examined histologically, with repeat colonoscopy annually until the exam is clear. If that is achieved, the interval can be pushed back to every 2 to 3 years. Upper GI screening should be done by EGD and begin between the ages of 15 and 25 or earlier if symptoms develop. If a mutation is not identified in the proband, first-degree relatives should be screened as mentioned earlier. Diffuse or symptomatic polyposis may need colectomy or gastrectomy. Clinical Management: Surgery.  In a symptomatic JPS patient, initial management includes correction of anemia, electrolyte imbalance, and nutritional deficits. After complete evaluation of the extent of the disease, surgery is considered. Indications for surgery in JPS patients are controversial. For children with generalized juvenile polyposis and hypoproteinemia, failure to thrive, or instances of intussusception, surgery is recommended. Other troublesome symptoms, such as bleeding and diarrhea may also be an indication for surgery. Surgery is indicated for patients with any suspicion of dysplasia or cancer. Because of the high risk of CRC, most authors believe that all polyps, symptomatic or not, should be removed endoscopically or surgically. Currently, there are insufficient data from JPS patients to justify performing a routine prophylactic colectomy in asymptomatic patients, solely for the risk of colorectal carcinoma. Colonoscopic polypectomy followed by colonoscopic surveillance is a reasonable alternative, as long as polyp clearance is possible and patient compliance is good. Factors in favor of prophylactic colectomy due to presumably increased potential for CRC include multiple polyps that cannot be controlled by snaring, adenomatous elements in polyps that have been snared, and those cases where CRC is a feature of the family history. Unlike FAP, a patient’s age at prophylactic colectomy is variable, reflecting both the heterogeneous phenotype of the disease and the varying recommendations for prophylactic colectomy. The

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percentage of JPS patients who will eventually have surgery is difficult to estimate as most reported series are small. Coburn et al. reviewed 218 cases published in the English literature and found that 99 (45%) patients underwent 138 surgical procedures.83 Of these, 121 were colorectal operations, including 41 partial colectomies, 56 subtotal or total colectomies, 7 restorative proctocolectomies, 3 total proctocolectomies with ileostomy, 2 abdominoperineal resections (APRs), and 12 operative polypectomies. The remaining 17 operations involved the stomach in 12 cases, and the small bowel in 5 cases. Almost all patients who did not have surgery were treated with endoscopic polypectomy. The surgical choices for managing large bowel disease in JPS are similar to those for FAP: colectomy and IRA or proctocolectomy with ileal pouch–anal anastomosis. When choosing the surgical procedure, the balance between the morbidity of the procedure and the need for lifetime surveillance of any remaining colon and rectum should be considered. Partial colectomy does not seem to be an appropriate procedure due to the high probability for recurrent polyps and cancer in the remaining colon. In general, colectomy and IRA might be recommended in those cases in which surgery is necessary, and the rectum can be cleared endoscopically. A TPC is required for significant involvement of both the colon and rectum. However, as opposed to FAP, the number of preoperative rectal polyps may not be a good indicator of the need for proctectomy. Oncel and associates reported that 5 of 10 patients whose rectums were spared at the initial procedure subsequently underwent proctectomy for rectal polyposis. Four of the remaining five patients required multiple endoscopic polypectomies. No correlation between the initial number of rectal polyps and the need for subsequent proctectomy was noted.84 Two of eight patients who underwent ileal pouch procedures required endoscopic or surgical excision of polyps in the pouch. Hence, follow-up after both procedures is necessary due to the high recurrence rates of juvenile polyps in either the remnant rectum or the pouch. The role of mucosectomy while performing a pouch procedure for JPS patients is not well discussed in the literature. Prior to colon surgery for JPS, an EGD and small bowel evaluation should be performed. Alternatively, upper endoscopy including small bowel visualization can be performed at the time of surgical exploration. In the future, capsule endoscopy may have a place in preoperative evaluation and surveillance of the small bowel in JPS patients. Managing polyps of the stomach is more challenging than those of the colon, for these are usually diffuse and cannot be removed endoscopically. These patients often have severe anemia and will eventually require subtotal or total gastrectomy. Gastric resection is also the treatment of choice for dysplasia or carcinoma. In patients with duodenal or small bowel polyps, enterotomy should be performed at the time of surgery and the polyps excised because these polyps may harbor a carcinoma. More extensive resection may be necessary in case of diffuse polyposis or malignancy. Surveillance after surgery for involvement of either part of the GI tract should be resumed and include periodic upper and lower GI tract examinations. Anecdotally, in two patients who had removal of recurrent polyps from

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ileal pouches after a pouch procedure, sulindac therapy was associated with further long-term polyp-free pouches,84 but future studies are needed to determine the role of sulindac in the management of JPS patients. Peutz-Jeghers Syndrome Diagnosis and Genetics.  PJS is diagnosed using clinical criteria, which includes the presence of ≥2 Peutz-Jeghers polyps anywhere in the GI tract, or at least one intestinal Peutz-Jeghers polyp in a patient that has a family history of PJS or the classic finding of mucocutaneous pigmentation. In the absence of Peutz-Jeghers polyps, a diagnosis can still be made when there is a family history of the disease and typical pigmentations. As many as 50% of affected individuals are new cases and have no family history of the disease. When inherited, it is with a dominant inheritance pattern, with a reported incidence of 1 in 120,000 live births.85 It is caused by genetic alterations in a serine threonine kinase gene (STK11, also known as LKB1), located on chromosome 19. Mutations in STK11 are found in up to 69% of carefully selected individuals. Clinical Features.  PJS is characterized by diffuse hamartomatous polyposis. The polyps can arise anywhere in the GI tract, but the small intestine is the most common site, being involved in greater than 75% of individuals.85 Polyps affect the colon in 42% of cases, the stomach in 38%, and the rectum in 28%. Less common locations for tumors include the upper respiratory, biliary, and urinary tracts. Peutz-Jeghers polyps are typically different from juvenile polyps in that they have smooth muscle bundles within the lamina propria of the stalk and head of the polyp, and do not have dilated cystic-filled spaces pathognomonic for juvenile polyps. The other characteristic finding in PJS is the characteristic pigmented melanin macules on the skin or mucous membranes, which can be identified in over 95% of patients. The lips and perioral region (94%), hands (74%), and feet (62%) are most commonly affected. The macules increase in intensity from infancy and early childhood but often fade in adult life with complete disappearance in some cases. Pigmented spots on the buccal mucosa are present in over two-thirds of individuals, but unlike the skin macules, the buccal lesions usually persist throughout life. Abdominal discomfort and distention are the most common presenting symptoms, and small bowel obstruction due to intussusception is the presenting feature in nearly half of individuals. One-third of PJS patients become symptomatic during the first decade of life and nearly half experience symptoms that require an operation for bowel obstruction by the age of 20 years. Recurrent obstruction requiring relaparotomy is common and is performed between 1 and 4 times per patient.86 Polyps may also cause GI bleeding which, depending on its severity and chronicity, may be occult, overt, or associated with an iron deficiency anemia. Risk of Cancer.  PJS is a cancer predisposition syndrome. This risk of cancer was first appreciated in the original family described by Peutz. The age of death in affected family members was substantially younger (38 years) when compared with that in unaffected members (69 years) and was usually due to intestinal obstruction and cancer. Spigelman et al. reported that 48% of PJS patients

died of malignancy by the age of 57 years.87 There is a substantial risk of both GI and non-GI cancers with a combined occurrence of any sort of cancer up to 93% by age 65 years.88,89 The intestinal cancer risks included colon (39%), pancreas (36%), stomach (29%), small bowel (13%), and esophagus (0.5%). Nondigestive organs at risk for cancer include breast (54%), ovary (21%), lung (15%), and uterus (9%). Cancers of the biliary tree and gallbladder have also been reported. Unusual genital tract tumors including adenoma malignum of the cervix, ovarian sex cord tumors with annular tubules (SCTAT), or testicular tumors resembling SCTAT (also referred to as large cell calcifying Sertoli cell tumors) also occur. Clinical Management.  As multiple organ systems are affected in PJS, screening and surveillance protocols are complex and aim to reduce cancer risk and symptomatic disease. For the GI tract, this equates to minimizing the risk of bowel obstruction, GI bleeding, or cancer, but the efficacy of surveillance in reducing cancer incidence or mortality is unknown.90 Although recommendations on the age to begin surveillance and frequency of exams vary, most guidelines advocate upper endoscopy and complete small bowel evaluation every second year starting at age 10 years, and colonoscopy every 2 to 3 years from the age of 25. Upper endoscopy, small bowel enteroscopy, and polypectomy are the cornerstone of management of proximal small bowel polyposis in PJS. An aggressive approach to the diagnosis and resection of small bowel polyps is mandatory to minimize the need for emergency surgery. Small bowel radiography has been the traditional method for the detection of small bowel polyps, but capsule endoscopy is more accurate and should supplant small bowel radiograph.91 Polyps detected on capsule endoscopy lead to surgery in at least 50% of patients.92 The imaging capsule is safe to use in individuals who have had previous bowel resection and in those with mild symptoms due to small bowel polyposis. Patients with symptoms suggesting complications of small bowel polyposis or asymptomatic patients who have polyps greater than 1 to 1.5 cm in size detected on capsule endoscopy should undergo laparotomy or laparoscopy with intraoperative endoscopy. The goal of the combined endoscopic and surgical approach is to clear all small bowel polyps, not just those causing symptoms. There are several reports suggesting that that the combined approach with clearance of all polyps may delay the time between operations.86 Intraoperative enteroscopy is required because external palpation of the small bowel and small bowel transillumination may not detect all polyps that require polypectomy. Asymptomatic gastric or colonic polyps greater than 1 cm should be removed endoscopically. For extraintestinal screening in PJS, the National Comprehensive Cancer Network (NCCN) recommends males should undergo annual testicular physical examination starting at the age of 10 years, and females should undergo annual pelvic examination and Papanicolaou stain starting at the age of 18 to 20 years. Women should have breast physical examinations every 6 months and yearly mammogram and breast magnetic resonance imaging starting at the age of 25 years. Pancreatic cancer screening involves endoscopic ultrasound or magnetic resonance cholangiopancreatography along with serum CA19-9 every 1 to 2 years starting

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at the age of 25 to 30 years.64 Other screening regimens have been proposed by other authors.93–95 PTEN Hamartoma Tumor Syndromes PHTS represents a spectrum of rare hereditary syndromes characterized by hamartomatous polyps in the GI tract and abnormalities of the skull, skeleton, and skin. This extremely rare group of syndromes includes CS, BRRS, Gorlin syndrome, and Proteus syndrome. CS and BRRS are the more common syndromes and are associated with an increased risk of CRC. The phenotypes are often overlapping. Genetics.  PTEN is a tumor suppressor gene that encodes a phosphatase in the PI3K/AKT signaling pathway. It plays a key role in apoptosis and acts as a tumor suppressor gene. PTEN mutations are found in association with a variety of sporadic and hereditary tumors affecting multiple organs, including the colon and rectum, uterus, brain, thyroid, breast, skin, and prostate. CS and BRRS are both autosomally dominant inherited disorders associated with a PTEN mutation. Approximately 80% of patients who meet the diagnostic criteria for CS, and 60% of patients with BRRS, have PTEN mutations.96,97 Now that PTEN is included in most gene panels offered by commercial laboratories, the diagnosis of PHTS may be made more often. Cowden Syndrome.  Patients with CS develop multiple hamartomas and are at risk of multiple benign and malignant tumors. The International Cowden Consortium developed clinical CS diagnostic criteria and include major and minor criteria.94,98 Major criteria include breast cancer, thyroid cancer (especially follicular), macrocephaly, endometrial cancer, and Lhermitte-Duclos disease. Minor features include benign thyroid changes (e.g., goiter), mental retardation, hamartomatous intestinal polyps, fibrocystic changes in the breast, lipomas, fibromas, genitourinary tumors (such as kidney cancer or uterine fibroids), or malformations. If a patient has either macrocephaly or Lhermitte-Duclos disease and one other major feature, a CS diagnosis is made. CS diagnosis is also present if one major feature and three minor features, or at least four minor features are met. Common skin manifestations associated with CS include trichilemmomas and papillomatous papules, and macrocephaly is common. Colorectal features include hamartomas, but also serrated or hyperplastic polyps, inflammatory polyps, adenomas, and ganglioneuromas. A germline PTEN mutation supports the clinical diagnosis. Malignancy risk in CS is significant outside the GI tract. Women have a 50% lifetime risk of developing breast cancer and a 5% to 10% lifetime risk of developing endometrial cancer. Men and women with CS have a 10% lifetime risk of developing epithelial thyroid cancer. Other malignancies described in association with CS include transitional carcinoma of the bladder, melanoma, and renal cell carcinoma. The main colorectal feature of CS is colorectal polyps with a variety of histology. Most of these are of subepithelial origin and include fibromas, lipomas, neuromas, ganglioneuromas, and neurofibromas. There are also adenomas, serrated polyps, and juvenile-like hamartomas.99 The polyps can be numerous but rarely carpet the colon. Until recently there was not thought to be an increased risk of CRC in

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CS. However, Heald et al. reported on 69 PTEN mutation carriers who met relaxed criteria for CS; 64 had colorectal polyps,99 24 had both upper GI and colorectal polyps, and 9 (13%) had CRC. The standardized incidence ratio for CRC was 224.1 (95% confidence interval, 109.3 to 411.3; P < .0001). Other groups have supported a 9% to 16% lifetime risk for CRC.100–102 It is uncertain if the cancers develop from the hamartomatous or adenomatous polyps. In the upper GI tract, gastric and duodenal polyps are common and can include hyperplastic polyps, hamartomas, and adenomas. As the cancer risk spans many organs, the CS screening regimen is complex and includes the following: (1) physical exam starting at 18 years of age, or 5 years before the earliest cancer was diagnosed in the family; (2) breast screening with monthly self-examinations and an annual clinical examination starting at age 18 years; mammography starting at 30 years of age, or 5 years younger than the earliest family breast cancer; (3) thyroid ultrasound starting at age 18, every 1 to 2 years; (4) colonoscopy starting at age 20 and repeated every 1 to 3 years depending on the findings at the examination; (5) EGD starting at age 30, repeated every 3 to 5 years depending on the findings; (6) endometrial cancer screening by pelvic ultrasound at the age of 35 to 40 years, or five years prior to the earliest family case of endometrial cancer; and (7) dermatologic exam to screen for melanoma.103 Bannayan-Riley-Ruvalcaba Syndrome.  BRRS, like CS, is an autosomal dominant disorder characterized by multiple phenotypic abnormalities and hamartomas in the intestine and other tissues. Specific diagnostic criteria for BRRS are not established, but patients with macrocephaly, hamartomatous colonic polyposis, lipomas, and pigmented macules of the glans penis should be considered for genetic testing.104 Less common manifestations include Hashimoto thyroiditis, vascular malformations, and mental retardation. The series of case reports in the literature suggest that patients with BRRS have a similar colorectal phenotype to those with CS. The intestinal polyps are most commonly juvenile polyps, which develop early in life and may contain adenomatous dysplasia. BRRS is not often associated with an increased cancer risk, although the multiple colorectal polyps may be symptomatic (intussusception and obstruction). While surgery for CRC is rare in patients with BRRS, patients may need a colectomy or at least a polypectomy for the symptoms caused by the polyps. The possibility of adenomatous dysplasia in the juvenile polyps suggests that regular surveillance is indicated. Other Clinical Syndromes Associated With PTEN Mutations.  Proteus syndrome (“Elephant Man” syndrome) and Gorlin syndrome (nevoid basal cell carcinoma syndrome) are rare syndromes without any obvious colorectal involvement. However, it seems reasonable to follow such patients with colonoscopy after a baseline exam of upper and lower GI tracts, as the germline PTEN mutation may produce epithelial and subepithelial polyps. There are a paucity of data on these syndromes, and much of the available information is from small series or case reports. Hereditary Mixed Polyposis Syndrome Hereditary mixed polyposis syndrome (HMPS) is an autosomal dominantly inherited syndrome, which was

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originally reported in an Ashkenazi Jewish family and is characterized by the finding of colorectal polyps of multiple histologies.105 In particular, adenomas, serrated polyps, and juvenile hamartomas are found in the same colon, and there is an increased risk for CRC. In the original family, 42 family members developed either colorectal polyps or CRC.105 No patient in this family had more than 15 polyps, and 13 patients developed CRC. There did not seem to be a risk for extracolonic cancers. The mutation in this family was identified as a deletion in GREM1.106 A similar syndrome has been found in other Jewish families, and in one non-Jewish family; however, not all of these families have had GREM1 sequencing analysis. The management goal of HMPS is to control the CRC risk in the least invasive way possible. Colonoscopy with polypectomy may suffice, but if cancer is diagnosed then an extended resection should be considered.

NONPOLYPOSIS COLORECTAL CANCER Overview The term nonpolyposis CRC syndromes was introduced to distinguish from the previously better characterized polyposis syndromes. As more is learned about the underlying genetics that cause these syndromes, a more precise definition is being formed. As such, it is important to distinguish these syndromes to assign more precise risk stratification. Historically, nonpolyposis syndromes were generically called HNPCC. Current understanding defines HNPCC as a clinical diagnosis based on cancer patterns within a family defined by the Amsterdam II criteria, which include the following107: (1) within a family, there should be at least three relatives with an HNPCC-associated cancer (cancer of the colorectum, endometrium, ovaries, small bowel, stomach, ureter or renal pelvis, pancreas, brain, skin); (2) one should be a first-degree relative to the other two; (3) at least two successive generations should be affected; (4) at least one cancer should be diagnosed before age 50; and (5) FAP is excluded. Patients with a heritable deleterious or pathogenic genetic variant in one of the MMR genes are defined as having Lynch syndrome, regardless of the clinical context or family history. As described earlier, approximately 93% of patients with Lynch syndrome have microsatellite unstable tumors. Patients who meet Amsterdam criteria, but have MSS tumors are given a diagnosis of familial CRC type X (FCC X).108,109 As expected, in addition to having MSS tumors, patients with FCC X do not have a causative MMR gene mutation. Approximately 50% of patients with Lynch syndrome do not meet Amsterdam criteria.110 This is an important distinction as the colorectal and extracolonic risks are different for Lynch syndrome and FCC X. Lastly, there is a subset of patients who have microsatellite unstable tumors and with loss of MMR protein expression, but do not have an identifiable MMR gene germline defect. These patients have more recently been defined as Lynch-like, or TumorLynch. Each of these classifications has unique risk profiles and thus has different management recommendations. Lynch Syndrome Lynch syndrome is defined as the inherited cancerpredisposing disease caused by a germline mutation in

one of the DNA MMR genes: MLH1, MSH2, MSH6, and PMS2. Additionally, there are cases of Lynch syndrome caused by germline deletions of EPCAM. Lynch syndrome patients develop colorectal and extracolonic cancers at a young age. It accounts for approximately 3% of all CRCs, and 10% to 19% of CRCs diagnosed before age 50.110–112 Lynch syndrome is an autosomal dominant condition, and thus all first-degree relatives of an affected patient have a 50% chance of also carrying the mutation. Therefore, identification of individuals who potentially have Lynch syndrome has implications for both the patient and their families. Screening and Diagnosis.  Clinical characteristics such as Amsterdam criteria and Bethesda criteria113 are used to identify patients who should undergo further testing for Lynch syndrome. Several histologic features such as poor differentiation, signet cell histology, abundance of extracellular mucin, tumor-infiltrating lymphocytes, and a lymphoid host response to tumor are associated with microsatellite instability, which is a molecular hallmark of Lynch syndrome. These factors should trigger testing for microsatellite instability or evaluation of MMR protein expression by immunohistochemistry. In Lynch syndrome-associated CRC, up to 91% exhibit MSI-H,114 and approximately 83% have loss of expression for one of the four MMR proteins.114 These test results guide genetic counseling and testing for germline mutations in a specific gene. To combat the lack of adequate sensitivity in targeted screening programs, several groups have recently endorsed universal screening for Lynch syndrome on all CRCs.115 The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommended that all newly diagnosed CRCs undergo MSI and/or immunohistochemistry (IHC) as screening for Lynch syndrome.114,116 The NCCN recommends universal screening of all CRCs under age 70 and those older than 70 that meet Bethesda guidelines.117 Ideally, preoperative testing is done on the cancer biopsy before surgery in which Lynch syndrome is suspected, which would provide an opportunity for definitive diagnosis and would guide surgical management. However, this is not always practical as some patients do not want to delay surgery to wait for genetic testing results. MSI-H or loss of MMR protein expression do not confirm a Lynch syndrome diagnosis. The majority of MSI-H CRCs arise via acquired methylation of the MLH1 promoter.118,119 Therefore, if MMR screening reveals loss of MLH1 protein expression, further analysis is required to determine the cause. As the majority of non-Lynch MLH1-deficient tumors harbor BRAF mutations and are methylated at the MLH1 promoter, BRAF mutation and/or MLH1 methylation testing should be done.108 A wild-type BRAF or methylated MLH1 promoter suggest a sporadic MSI-H cancer. If IHC reveals MSH2, MSH6, or PMS2 are lost, Lynch syndrome is suspected and germline confirmation is pursued for those specific genes. Several predictive models have been developed to help identify patients to be screened for Lynch syndrome. For patients without a personal history of CRC, but with a family history suggestive of Lynch syndrome, the use of readily available prediction models such as PREMM1,2,6 (http://premm.dfci.harvard.edu/) or MMRpro (http://

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www4.utsouthwestern.edu/breasthealth/cagene/) may be useful. Colorectal Cancer and Extracolonic Cancer Risks.  CRC risk for Lynch syndrome patients varies according to the underlying genetic etiology. For MLH1, MSH2, and PMS2 mutation carriers, the lifetime risk is 30% to 74%, while MSH6 carriers have 10% to 22% risk.103,120–123 Lynch syndrome CRCs occur earlier in life than sporadic cancer with a mean age at diagnosis between 44 and 61 years.125,126 Endometrial cancer represents the highest extracolonic cancer risk with rates as high as 44% in women with MSH6 and MSH2 mutations.123,127 PMS2 mutation carriers have the lowest endometrial lifetime risk at 15% to 20%.122,124 Like CRC, endometrial cancers develop at a younger age than sporadic cancer with the mean age between 48 and 62 years. Synchronous endometrial and ovarian cancers have been reported in 7% to 21% of the women with Lynch syndrome.129 Multiple other organs are at increased risk of malignancy compared with the general population. The more common sites include the urinary tract, stomach, small bowel, brain, skin, pancreas, prostate, and breast.130 Prostate and breast cancer risk continue to be debated and studied. Compared with the general population, patients with Lynch syndrome have nearly twice as much risk to develop prostate cancer,131 and possibly elevated risks for breast cancer.130,132 Clinical Management: Surveillance.  The best evidence for surveillance and intervention as a risk-reducing strategy is for colonoscopy. The purpose of surveillance in patients with Lynch syndrome is to detect and remove premalignant polyps before they develop into cancer. Surveillance colonoscopy can reduce CRC incidence by 62% reduction and reduce the CRC-related mortality by 72% in Lynch syndrome patients.133 Due to early-age onset and a shortened adenoma to carcinoma interval,121,134 patients with Lynch syndrome should undergo colonoscopy every 1 to 2 years starting at age 20 to 25 years.108,121 The benefit of screening for extracolonic cancers in Lynch syndrome is less established in the literature, but is established based on clinical expert opinion weighing risks and benefits. As endometrial cancer represents the second highest lifetime risk for women with Lynch syndrome, most experts recommend annual screening, including pelvic examination and transvaginal ultrasound with endometrial biopsy.135 Clinicians and patients must be aware of warning symptoms of endometrial cancer, such as abnormal uterine bleeding or pelvic pain so that early evaluation is performed. Due to the high risk of endometrial and ovarian cancers, prophylactic hysterectomy and bilateral salpingo-oopherectomy should be considered in Lynch syndrome women who have completed childbearing. Urinalysis and cytology have been considered for screening for urothelial cancers.136 While this is noninvasive and relatively inexpensive, these tests are not particularly sensitive nor specific. Upper endoscopy may be used to screen for gastric and small bowel cancers, but there is no evidence regarding their cost effectiveness. Annual or biannual dermatologic exams for patients with Lynch syndrome can be considered for the detection of sebaceous skin neoplasms.108,121

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Clinical Management: Chemoprevention.  The Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2) trial was a 2 × 2 design, large multicenter, double-blind, randomized study comparing the effect of 600 mg aspirin daily versus placebo, or resistant starch versus placebo, on the development of CRC in Lynch syndrome patients.137 Lynch syndrome patients who took aspirin for at least 2 years had an almost 60% decrease in CRC incidence compared with those patients who took a placebo. It is important to note that a statistical benefit was not realized until 10 years after entry into the study, even after stopping the aspirin. At least 2 years of aspirin use was also associated with a 55% reduction in other cancers associated with Lynch syndrome. The tested dose of aspirin (600 mg) used in CAPP2 is not a standard formulation in the United States. Currently, the evidence is not sufficiently mature to recommend the routine use of high-dose aspirin in Lynch syndrome patients.108,121 There is an ongoing CAPP3 trial that aims to establish the best effective dose and duration of aspirin treatment in Lynch patients.138 Clinical Management: Surgery for Colorectal Cancer.  CRC management in Lynch syndrome patients requires thoughtful decision making that balances the risk of metachronous CRC against expected postoperative quality of life. Surgery is based on the oncologic principles of obtaining adequate margins, high vascular ligation, and appropriate regional lymphadenectomy. However, unlike patients with sporadic CRC, Lynch syndrome patients have a significant risk of developing metachronous CRC in any residual colorectal tissue. Thus, expert opinion recommends the extended resection of colon cancer to include a total colectomy with IRA.108,121,139 Multiple retrospective studies have demonstrated a higher rate of metachronous CRC following segmental colectomy compared with extended colectomy with risks after segmental colectomy between 11% and 45%, at a follow-up of 8 to 13 years.140–142 In a large international study from the Colon Cancer Family Registries, the cumulative risk of metachronous CRC after segmental colectomy was 16%, 41%, and 62% at 10, 20, and 30 years, respectively.143 Although colectomy and IRA removes most mucosa at risk for cancer, the risk of metachronous rectal cancer is between 3% and 12% at 10 to 12 years, which underscores the importance of continued surveillance of the remaining rectum. Annual surveillance by flexible proctoscopy, which can be performed in the office setting without sedation, is recommended. Reduction in metachronous cancer risk must be balanced against the bowel functional expectations after an extended colectomy. A study from the Netherlands compared outcomes of Lynch syndrome patients who underwent a total abdominal colectomy and IRA compared with a segmental colectomy.144 Patients who underwent subtotal or total colectomy had a higher stool frequency, and a worse score on stool-related aspects and social impact. However, this did not equate to any difference in perceived quality of life based on the Short Form-36 survey. The authors concluded that although functional outcomes are worse after subtotal colectomy than after partial colectomy, generic quality of life does not differ after the two different surgeries in Lynch syndrome. Surgical decision making should be done after an educational conversation with the patient considering the family

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history, the patient’s individual situation, the patient’s feelings on risk aversion, other medical comorbidities, and life expectancy. Despite the relative incidence of proximal colonic lesions in Lynch syndrome, rectal cancer is common. Approximately 20% to 30% of patients with Lynch syndrome will develop rectal cancer, including 15% to 24% with rectal cancer as their initial presentation.145–147 As with colon cancer, there are many factors to consider when planning surgical management of rectal cancer in a Lynch syndrome patient. Surgical options include a proctectomy in the form of a low anterior resection (LAR) or APR, depending on sphincter involvement; or an extended resection that removes all at-risk colorectum in the form of a TPC and EI or more commonly a restorative IPAA. When determining the extent of resection, the surgeon must consider the risk of metachronous colon cancer, bowel function, quality of life, and patient comorbidities. The risk of colon cancer after proctectomy alone in Lynch syndrome is between 15% and 54% at about 10 to 15 years’ follow-up.145,146,148,149 In a study from the Colon Cancer Family Registries, the cumulative risk of metachronous colon cancer after proctectomy was 19% at 10 years, 47% at 20 years, and 69% at 30 years.149 However, there are functional implications after a TPC compared with a proctectomy alone. As there are no prospective trials data evaluating bowel function after IPAA for rectal cancer in Lynch syndrome, data can be extrapolated from pouch function and quality of life studied in other diseases, and that information can be applied to Lynch syndrome patients. Proctectomy alone with colorectal anastomosis yields less frequent bowel movements and more normal function (less incontinence and seepage) than after an IPAA.150 The consistency of stool is looser, and function may be worse in patients with baseline weak anal sphincter tone.151 However, this does not discount that IPAA can result in good functional outcomes. In FAP patients, TPC and IPAA is often done to reduce CRC risk, while maintaining acceptable bowel function with comparable results in terms of bowel movements per day, urgency, seepage, and incontinence.152 TPC for rectal cancer in Lynch syndrome remains debated, and several factors, including the patient’s age, medical comorbidities, rectal cancer stage, sphincter function, and compliance with surveillance regimens, should be evaluated with the patient in the larger clinical picture. Given the high risk of metachronous neoplasia after a segmental proctectomy, many experts recommend TPC with an IPAA. Variations of Lynch Syndrome Muir-Torre Syndrome.  Muir-Torre syndrome is a clinical variant of Lynch syndrome characterized by skin sebaceous gland neoplasms (sebaceous adenomas and carcinomas) and/or hair follicle neoplasms (keratoacanthomas) in addition to other Lynch-associated tumors. Sebaceous adenomas on the trunk or extremities are the most common presentation.153,154 It is most commonly associated with an MSH2 mutation.155 The clinical presentation of sebaceous adenomas should raise suspicion for Muir-Torre syndrome and prompt the obtaining of a detailed family history and referral to genetic counseling.

Turcot Syndrome.  Turcot syndrome is characterized by the presence of CRC and a brain tumor. It is associated with an MMR gene mutation in Lynch syndrome, or it also can be associated with an APC mutation. Turcot syndrome with an MMR gene mutation is commonly associated with glioblastoma,156 while cases associated with an APC mutation more commonly are associated with anaplastic astrocytoma, ependymoma or medulloblastoma. Constitutional Mismatch Repair Deficiency.  Constitutional mismatch repair deficiency (CMMRD) is a rare variant of Lynch syndrome caused by biallelic inheritance of MMR genetic variations. Patients exhibit a distinct phenotype with the development of CRC at very young ages (before age 20), multiple adenomatous polyps numbering between 10 and 100, café-au-lait skin lesions, hematologic malignancies, and brain tumors.157 The mean age of first cancer diagnosis is 16 years.157 The reader is referred to a recently published Multisociety Taskforce comprehensive review on CRC in CMMRD.157

FAMILIAL COLORECTAL CANCER TYPE X FCC X is a clinical diagnosis given to patients from families who satisfy Amsterdam criteria, but whose CRC is an MSS tumor.109,158,159 Approximately 40% of patients meeting Amsterdam I criteria have MSS tumors. The genetic causes of FCC X are not delineated, and it is likely that this group represents a heterogeneous population genetically. Although these patients do not have the same cancer risk as Lynch syndrome patients, they do have an approximately twofold increased CRC risk compared with the general population.109,159 The mean age of CRC diagnosis is 61 years, which is between that of Lynch syndrome patients and sporadic cancer patients. Screening by colonoscopy is recommended at age 45, or 10 years younger than the youngest CRC in that family. If no pathology is found on that exam, the colonoscopy should be repeated every 5 years. For FCC X patients who develop CRC, a segmental rather than total colectomy is recommended as the metachronous CRC risk is not completely defined, and there is no evidence that extended colectomy significantly decreases subsequent CRCs. Another important distinction between FCC X and Lynch syndrome is the lack of increased extracolonic cancer risk in FCC X patients. Thus, extracolonic screening is not recommended.109,159,160

LYNCH-LIKE OR TUMOR LYNCH There is a more recently defined subset of patients distinct from Lynch syndrome and FCC X. The practice of universal screening of CRCs for MSI-H and MMR protein deficiency has increasingly identified patients with tumor characteristics suggestive of Lynch syndrome. However, when germline testing for the causative mutation is explored, some patients have no identified genetic variant. This group of patients with a tumor profile suggesting Lynch syndrome, but without an explained germline variant in any of the major MMR genes, has been called Tumor Lynch, Lynch-like syndrome,6,161,162 suspected Lynch syndrome,163 or mutation-negative Lynch syndrome. 164 There are multiple reasons why a germline mutation is not found in these situations.6,165,166 Recently, studies have reported that up to 69% of these patients can be explained by biallelic somatic mutations within the tumor.161,165,166

Inherited Colorectal Cancer and the Genetics of Colorectal Cancer  CHAPTER 165 

These patients do not have Lynch syndrome, and thus, neither the individual nor their family have an increased risk of colorectal or extracolonic cancers based on genetics. These patients and families should be managed according to their family history and other risk factors. Importantly, 50% of these cases of Tumor Lynch are still not defined. In this situation, a family history is even more critical to help assess likely risk. If Lynch syndrome cannot be eliminated from the diagnosis, these patients should be managed as if they have Lynch syndrome, especially if they have a suspicious family history. This clinical situation is being actively researched, and nomenclature and risk assessments are evolving.

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20. Church JM, McGannon E, Hull-Boiner S, et al. Gastroduodenal polyps in patients with familial adenomatous polyposis. Dis Colon Rectum. 1992;35(12):1170-1173. 21. Church JM, McGannon E, Burke C, Clark B. Teenagers with familial adenomatous polyposis: what is their risk for colorectal cancer? Dis Colon Rectum. 2002;45(7):887-889. 22. Hartley JE, Church JM, Gupta S, McGannon E, Fazio VW. Significance of incidental desmoids identified during surgery for familial adenomatous polyposis. Dis Colon Rectum. 2004;47(3):334-338, discussion 339–340. 23. Liang J, Church JM. Rectal cancers in patients with familial adenomatous polyposis. Fam Cancer. 2013;12(4):749-754. 24. Church J, Burke C, McGannon E, Pastean O, Clark B. Predicting polyposis severity by proctoscopy: how reliable is it? Dis Colon Rectum. 2001;44(9):1249-1254. 25. Church JM. Controversies in the surgery of patients with familial adenomatous polyposis and Lynch syndrome. Fam Cancer. 2016;15(3):447-451. 26. Ziv Y, Church JM, Oakley JR, McGannon E, Fazio VW. Surgery for the teenager with familial adenomatous polyposis: ileo-rectal anastomosis or restorative proctocolectomy? Int J Colorectal Dis. 1995;10(1):6-9. 27. Feinberg SM, Jagelman DG, Sarre RG, et al. Spontaneous resolution of rectal polyps in patients with familial polyposis following abdominal colectomy and ileorectal anastomosis. Dis Colon Rectum. 1988;31(3):169-175. 28. Hassan I, Chua HK, Wolff BG, et al. Quality of life after ileal pouchanal anastomosis and ileorectal anastomosis in patients with familial adenomatous polyposis. Dis Colon Rectum. 2005;48(11):2032-2037. 29. Wu XR, Kirat HT, Kalady MF, Church JM. Restorative proctocolectomy with a handsewn IPAA: S-pouch or J-pouch? Dis Colon Rectum. 2015;58(2):205-213. 30. Lovegrove RE, Constantinides VA, Heriot AG, et al. A comparison of hand-sewn versus stapled ileal pouch anal anastomosis (IPAA) following proctocolectomy: a meta-analysis of 4183 patients. Ann Surg. 2006;244(1):18-26. 31. Hurlstone DP, Saunders BP, Church JM. Endoscopic surveillance of the ileoanal pouch following restorative proctocolectomy for familial adenomatous polyposis. Endoscopy. 2008;40(5):437-442. 32. Parc YR, Olschwang S, Desaint B, Schmitt G, Parc RG, Tiret E. Familial adenomatous polyposis: prevalence of adenomas in the ileal pouch after restorative proctocolectomy. Ann Surg. 2001;233(3):360-364. 33. Church J. Ileoanal pouch neoplasia in familial adenomatous polyposis: an underestimated threat. Dis Colon Rectum. 2005;48(9):1708-1713. 34. Cruz-Correa M, Hylind LM, Romans KE, Booker SV, Giardiello FM. Long-term treatment with sulindac in familial adenomatous polyposis: a prospective cohort study. Gastroenterology. 2002;122(3):641-645. 35. Park GD, Spector R, Headstream T, Goldberg M. Serious adverse reactions associated with sulindac. Arch Intern Med. 1982;142(7):1292-1294. 36. Winde G, Schmid KW, Brandt B, Müller O, Osswald H. Clinical and genomic influence of sulindac on rectal mucosa in familial adenomatous polyposis. Dis Colon Rectum. 1997;40(10):1156-1168, discussion 1168–1159. 37. Tsukada K, Church JM, Jagelman DG, et al. Noncytotoxic drug therapy for intra-abdominal desmoid tumor in patients with familial adenomatous polyposis. Dis Colon Rectum. 1992;35(1):29-33. 38. Lynch HT, Thorson AG, Smyrk T. Rectal cancer after prolonged sulindac chemoprevention. A case report. Cancer. 1995;75(4):936-938. 39. Samadder NJ, Neklason DW, Boucher KM, et al. Effect of sulindac and erlotinib vs placebo on duodenal neoplasia in familial adenomatous polyposis: a randomized clinical trial. JAMA. 2016;315(12):1266-1275. 40. Quintini C, Ward G, Shatnawei A, et al. Mortality of intra-abdominal desmoid tumors in patients with familial adenomatous polyposis: a single center review of 154 patients. Ann Surg. 2012;255(3):511-516. 41. Xhaja X, Church J. Small bowel obstruction in patients with familial adenomatous polyposis related desmoid disease. Colorectal Dis. 2013;15(12):1489-1492. 42. Joyce M, Mignanelli E, Church J. Ureteric obstruction in familial adenomatous polyposis-associated desmoid disease. Dis Colon Rectum. 2010;53(3):327-332. 43. Xhaja X, Church J. Enterocutaneous fistulae in familial adenomatous polyposis patients with abdominal desmoid disease. Colorectal Dis. 2013;15(10):1238-1242.

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SECTION IV  Colon, Rectum, and Anus

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Inherited Colorectal Cancer and the Genetics of Colorectal Cancer  CHAPTER 165  96. Marsh DJ, Dahia PL, Caron S, et al. Germline PTEN mutations in Cowden syndrome-like families. J Med Genet. 1998;35(11):881-885. 97. Marsh DJ, Dahia PL, Coulon V, et al. Allelic imbalance, including deletion of PTEN/MMACI, at the Cowden disease locus on 10q22-23, in hamartomas from patients with Cowden syndrome and germline PTEN mutation. Genes Chromosomes Cancer. 1998;21(1):61-69. 98. Gustafson S, Zbuk KM, Scacheri C, Eng C. Cowden syndrome. Semin Oncol. 2007;34(5):428-434. 99. Heald B, Mester J, Rybicki L, Orloff MS, Burke CA, Eng C. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology. 2010;139(6):1927-1933. 100. Stanich PP, Owens VL, Sweetser S, et al. Colonic polyposis and neoplasia in Cowden syndrome. Mayo Clin Proc. 2011;86(6):489-492. 101. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400-407. 102. Riegert-Johnson DL, Gleeson FC, Roberts M, et al. Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pract. 2010;8(1):6. 103. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110(2):223-262, quiz 263. 104. Gorlin RJ, Cohen MM Jr, Condon LM, et al. Bannayan-RileyRuvalcaba syndrome. Am J Med Genet. 1992;44(3):307-314. 105. Whitelaw SC, Murday VA, Tomlinson IP, et al. Clinical and molecular features of the hereditary mixed polyposis syndrome. Gastroenterology. 1997;112(2):327-334. 106. Jaeger E, Leedham S, Lewis A, et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet. 2012;44(6):699-703. 107. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999;116(6):1453-1456. 108. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Coloretal Cancer. Am J Gastroenterol. 2014;109(8):1159-1179. 109. Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293(16):19791985. 110. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352(18):1851-1860. 111. Aaltonen LA, Sankila R, Mecklin JP, et al. A novel approach to estimate the proportion of hereditary nonpolyposis colorectal cancer of total colorectal cancer burden. Cancer Detect Prev. 1994;18(1):57-63. 112. de la Chapelle A. The incidence of Lynch syndrome. Fam Cancer. 2005;4(3):233-237. 113. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261-268. 114. Teutsch SM, Bradley LA, Palomaki GE, et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med. 2009;11(1):3-14. 115. Beamer LC, Grant ML, Espenschied CR, et al. Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results. J Clin Oncol. 2012;30(10):1058-1063. 116. Weissman SM, Burt R, Church J, et al. Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline. J Genet Couns. 2012;21(4):484-493. 117. Genetic/Familial High-Risk Assessment: Colorectal. NCCN Clinical Practice Guidelines in Oncology. 2014. 118. Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260(5109):812-816. 119. Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. 1994;145(1):148-156.

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120. Barrow E, Hill J, Evans DG. Cancer risk in Lynch syndrome. Fam Cancer. 2013;12(2):229-240. 121. Vasen HF, Blanco I, Aktan-Collan K, et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62(6):812823. 122. Goodenberger ML, Thomas BC, Riegert-Johnson D, et al. PMS2 monoallelic mutation carriers: the known unknown. Genet Med. 2016;18(1):13-19. 123. Baglietto LI, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102(3):193-201. 124. Senter LI, Clendenning M, Sotamaa K, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135(2):419-428. 125. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer. 1999;81(2): 214-218. 126. Hampel H, Stephens JA, Pukkala E, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005;129(2):415-421. 127. Stoffel E, Mukherjee B, Raymond VM, et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009;137(5):1621-1627. 128. Deleted in review. 129. Pal T, Permuth-Wey J, Sellers TA. A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer. Cancer. 2008;113(4):733-742. 130. Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30(9):958-964. 131. Raymond VM, Mukherjee B, Wang F, et al. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol. 2013;31(14):1713-1718. 132. Buerki N, Gautier L, Kovac M, et al. Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosomes Cancer. 2012;51(1):83-91. 133. Jarvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. 2000;118(5):829-834. 134. Vasen HF, Tomlinson I, Castells A. Clinical management of hereditary colorectal cancer syndromes. Nat Rev Gastroenterol Hepatol. 2015;12(2):88-97. 135. Reitamo JJ. The desmoid tumor. IV. Choice of treatment, results, and complications. Arch Surg. 1983;118(11):1318-1322. 136. Mork M, Hubosky SG, Roupret M, et al. Lynch syndrome: a primer for urologists and panel recommendations. J Urol. 2015;194(1):21-29. 137. Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378(9809):2081-2087. 138. Burn J, Mathers JC, Bishop DT. Chemoprevention in Lynch syndrome. Fam Cancer. 2013;12(4):707-718. 139. Kalady MF. Surgical management of hereditary nonpolyposis colorectal cancer. Adv Surg. 2011;45:265-274. 140. Fitzgibbons RJ Jr, Lynch HT, Stanislav GV, et al. Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and II). Ann Surg. 1987;206(3):289-295. 141. Kalady MF, McGannon E, Vogel JD, Manilich E, Fazio VW, Church JM. Risk of colorectal adenoma and carcinoma after colectomy for colorectal cancer in patients meeting Amsterdam criteria. Ann Surg. 2010;252(3):507-511, discussion 511–503. 142. Natarajan N, Watson P, Silva-Lopez E, Lynch HT. Comparison of extended colectomy and limited resection in patients with Lynch syndrome. Dis Colon Rectum. 2010;53(1):77-82. 143. Parry S, Win AK, Parry B, et al. Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery. Gut. 2011;60(7):950-957. 144. Haanstra JF, de Vos Tot Nederveen Cappel WH, Gopie JP, et al. Quality of life after surgery for colon cancer in patients with Lynch syndrome: partial versus subtotal colectomy. Dis Colon Rectum. 2012;55(6):653-659. 145. Kalady MF, Lipman J, McGannon E, Church JM. Risk of colonic neoplasia after proctectomy for rectal cancer in hereditary nonpolyposis colorectal cancer. Ann Surg. 2012;255(6):1121-1125.

1980

SECTION IV  Colon, Rectum, and Anus

146. Lee JS, Petrelli NJ, Rodriguez-Bigas MA. Rectal cancer in hereditary nonpolyposis colorectal cancer. Am J Surg. 2001;181(3):207-210. 147. Moslein G, Nelson H, Thibodeau S, Dozois RR. Rectal carcinomas in HNPCC. Langenbecks Arch Chir Suppl Kongressbd. 1998;115:1467-1469. 148. Cirillo L, Urso ED, Parrinello G, et al. High risk of rectal cancer and of metachronous colorectal cancer in probands of families fulfilling the Amsterdam criteria. Ann Surg. 2013;257(5):900-904. 149. Win AK, Parry S, Parry B, et al. Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers. Ann Surg Oncol. 2013;20(6):1829-1836. 150. Fazio VW, Kiran RP, Remzi FH, et al. Ileal pouch anal anastomosis: analysis of outcome and quality of life in 3707 patients. Ann Surg. 2013;257(4):679-685. 151. Fazio VW, O’Riordain MG, Lavery IC, et al. Long-term functional outcome and quality of life after stapled restorative proctocolectomy. Ann Surg. 1999;230(4):575-584, discussion 584–576. 152. Erkek AB, Church JM, Remzi FH. Age-related analysis of functional outcome and quality of life after restorative proctocolectomy and ileal pouch-anal anastomosis for familial adenomatous polyposis. J Gastroenterol Hepatol. 2007;22(5):710-714. 153. Roberts ME, Riegert-Johnson DL, Thomas BC, et al. Screening for Muir-Torre syndrome using mismatch repair protein immunohistochemistry of sebaceous neoplasms. J Genet Couns. 2013;22(3):393-405. 154. Cesinaro AM, Ubiali A, Sighinolfi P, et al. Mismatch repair proteins expression and microsatellite instability in skin lesions with sebaceous differentiation: a study in different clinical subgroups with and without extracutaneous cancer. Am J Dermatopathol. 2007;29(4):351-358. 155. Lazar AJ, Lyle S, Calonje E. Sebaceous neoplasia and Torre-Muir syndrome. Curr Diagn Pathol. 2007;13(4):301-319. 156. Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot’s syndrome. N Engl J Med. 1995;332(13):839-847. 157. Durno CA, Holter S, Sherman PM, Gallinger S. The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations. Am J Gastroenterol. 2010;105(11):2449-2456.

158. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2014;147(2):502-526. 159. Lindor NM, Petersen GM, Hadley DW, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA. 2006;296(12):1507-1517. 160. Shiovitz S, Copeland WK, Passarelli MN, et al. Characterisation of familial colorectal cancer Type X, Lynch syndrome, and non-familial colorectal cancer. Br J Cancer. 2014;111(3):598-602. 161. Carethers JM. Differentiating Lynch-like from Lynch syndrome. Gastroenterology. 2014;146(3):602-604. 162. Boland CR. The mystery of mismatch repair deficiency: Lynch or Lynch-like? Gastroenterology. 2013;144(5):868-870. 163. Buchanan DD, Rosty C, Clendenning M, Spurdle AB, Win AK. Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome). Appl Clin Genet. 2014;7: 183-193. 164. You YN, Vilar E. Classifying MMR variants: time for revised nomenclature in Lynch syndrome. Clin Cancer Res. 2013;19(9): 2280-2282. 165. Haraldsdottir S, Hampel H, Tomsic J, et al. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology. 2014;147(6):1308-1316, e1301. 166. Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA, et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatchrepair deficiency in Lynch syndrome-like tumors. Gastroenterology. 2014;146(3):643-646, e648.