Polyposis Syndromes

Introduction

Hereditary colorectal cancer syndromes account for approximately 5% of all colorectal cancers. Traditionally they have been categorized according to the number and histologic features of colorectal polyps in affected patients, although there is significant blurring of the distinction between “polyposis” and “nonpolyposis” syndromes. The most common hereditary syndrome of colorectal cancer (Lynch syndrome) is not usually associated with polyposis and is the subject of a separate chapter. In this chapter, polyposis syndromes will be discussed.

Registries

Polyposis syndromes are rare, with the most common, familial adenomatous polyposis (FAP), found in 1:8000 live births. The syndromes are complex, with variable and sometimes confusing genotypes and a spectrum of overlapping phenotypes. The aims of management of affected patients are prevention of death from cancer with maintenance of optimal quality of life. Achieving these aims depends on aggressive investigation of the family, lifelong surveillance of all affected members, and the choice of appropriate investigations and procedures. Lapses in surveillance allow cancers to occur, and inappropriate management risks destruction of quality of life. Caring for families affected by hereditary polyposis syndromes takes a team of experienced experts, such as those found at registries and cancer centers throughout the United States. Patients with hereditary polyposis can be referred to such centers for a second opinion or for definitive care. Patients then return to local caregivers for continued care. Even in the absence of a registry or cancer center, genetic counseling is important as a prelude to testing and as part of the interpretation of the results.

Definitions

“Polyposis” simply means “a lot” of polyps. In practical terms, a patient has adenomatous polyposis if more than 100 synchronous adenomas are present, and he or she has serrated polyposis (SPS) if more than 20 synchronous serrated polyps are present. Fewer adenomas (10 to 100) can be classified as oligopolyposis or attenuated polyposis, and in these cases, cumulative polyp counts are relevant. A description of the polyposis syndromes, their genotypes, and a summary of their phenotypes is provided in Table 57-1 .

TABLE 57-1

Syndromes of Hereditary Polyposis

Syndrome	Colorectal Polyp Count	Genotype	Phenotype
Profuse FAP	>1000 adenomas	APC (codon 1309)	Colorectal, gastric, small intestinal neoplasia; desmoid disease; benign and malignant tumors of thyroid, skin, bone, brain, liver, and pancreas
Classical FAP	100-1000 adenomas	APC	Same
Attenuated FAP	10-100 adenomas	APC (5′ and 3′ mutations)	Same
MAP	Any adenomas	MYH	Same
PPAP	>5 adenomas	POLD1 POLE	Young age of onset, microsatellite stable colorectal cancer; endometrial cancer ( POLE )
Juvenile polyposis	>5 juvenile polyps	SMAD4 BMPR1A ENG	Gastric and colorectal hamartomas and cancer
Peutz-Jeghers	Peutz-Jegher polyps/small bowel > colorectum	STK11	Oral/cutaneous pigmentation, cancers of the breast, pancreas, stomach, ovary, testis, and small intestine
Hereditary mixed polyposis	>5 adenomas, serrated polyps, and hamartomas (the hamartoma is important)	GREM1 expression
SPS	>20 serrated polyps of any size anywhere; any serrated polyps and a family history of SPS >5 serrated polyps proximal to the sigmoid, 2 of which are >10 mm	Unknown

FAP, Familial adenomatous polyposis; MAP, MYH -associated polyposis; PPAP, polymerase proofreading-associated polyposis; SPS, serrated polyposis.

Familial Adenomatous Polyposis

FAP was the first syndrome of hereditary colorectal cancer to be described. FAP is due to dominant inheritance of a mutation in the tumor suppressor gene APC , a key part of the wnt/wingless signal transduction pathway. APC forms a complex with AXIN and GSK, degrades cytoplasmic β catenin and stops it from entering the nucleus, where it would stimulate downstream growth-enhancing pathways. Dysfunctional APC means that β catenin–induced stimulation of cell growth happens inappropriately. APC has other important functions, including roles in chromosomal segregation and microtubule formation. Mutations in APC promote chromosomal instability, and sporadic APC mutations are an initiating event in sporadic colorectal neoplasia.

FAP is dominantly inherited with 100% penetrance, which means that if a relative has inherited the mutation, the chance of them expressing the disease clinically is 100%. Although the mutation is dominantly inherited, 25% of patients do not have a family history, in some cases because of adoption, nonpaternity, or ignorance; biologic explanations include mosaicism or a new mutation occurring at conception. The lack of a family history is a significant problem for affected patients because it denies them awareness of risk. Such patients usually present serendipitously with symptoms or when typical extracolonic manifestations are recognized. Up to 60% of patients with a “new” mutation have cancer at the time of presentation.

Genetic Testing

A diagnosis of FAP can be confirmed by testing for a germline mutation in APC . The chances of detecting a mutation in patients with classic FAP are greater than 80%. Finding the mutation in a clinically affected patient means that at-risk relatives can be tested. If relatives do not carry the family mutation, they are excused from high-risk surveillance. If no APC mutation is found, large deletions and deletions in promoter 1B need to be excluded. Other genetic causes of polyposis can be sought (e.g., mutations in MYH , mismatch repair genes, and POLD1 and POLE ). If no genetic cause of the polyposis is identified, every at-risk relative must be screened with flexible sigmoidoscopy yearly.

Genetic testing is usually performed at puberty because this is the time that screening starts. Earlier testing can be performed if hepatoblastoma screening is contemplated.

Genotype/Phenotype

Apart from excusing unaffected patients from surveillance and confirming the disease in mutation carriers, knowing the genotype can help predict the phenotype of the syndrome. The 5′ and 3′ mutations are associated with attenuated polyposis, whereas mutations in the middle of the gene are associated with classic or profuse polyposis. Desmoid tumors are more severe with 3′ mutations, which are also associated with Gardner syndrome (polyposis, epidermoid cysts, osteoma, dental anomalies, and desmoids). Congenital hypertrophy of the retinal pigmented epithelium (CHRPE) is found with mutations in the middle of the gene. Some investigators have indicated that the genotype can be used to plan surgery, but surgery should always be determined by the colonic polyposis phenotype.

Colorectal Cancer in Familial Adenomatous Polyposis

In all patients with FAP who are untreated, a microsatellite stable, chromosomal unstable colorectal cancer will develop at an average age of 40 years. The age range is wide, although cancer in teenagers is rare. The cancer risk is proportional to the severity of the polyposis, with cancer in attenuated FAP occurring much later than with profuse FAP. Surveillance and prophylactic surgery aim to prevent cancer.

Surveillance begins at diagnosis or at puberty. Patients who are part of a family with established FAP undergo genetic testing, and yearly colonoscopic surveillance is targeted to mutation carriers. If no mutation is detectable, all at-risk relatives are screened with flexible sigmoidoscopy until adenomas are found (and colonoscopy starts) or until they reach their mid twenties, when surveillance schedules can be eased. Prophylactic surgery is performed if the colorectal polyps are symptomatic, profuse, or unstable (i.e., increase in size to >1 cm, display severe dysplasia, or increase in number). Children with mild polyposis can be followed up yearly, and elective surgery can be performed when physical and emotional maturity is reached and the time is right from a financial and psychological point of view.

It is critical to remember that FAP cannot be cured by surgery, many patients with FAP are asymptomatic and young, and the prophylactic operation should not worsen quality of life.

Surgical Options for the Large Bowel

The two main surgical options for the large bowel are colectomy and ileorectal anastomosis (IRA) and proctocolectomy and ileal pouch–anal anastomosis (IPAA). The respective indications, advantages, and disadvantages of each option are shown in Table 57-2 .

TABLE 57-2

Two Main Options for Prophylactic Treatment of the Large Bowel in Familial Adenomatous Polyposis

Option	Indications	Contraindications	Advantages	Disadvantages
Colectomy and ileorectal anastomosis	<20 rectal adenomas; <1000 colonic adenomas; high risk of desmoid disease	>20 rectal adenomas; rectal cancer	Relatively normal bowel function; no pelvic dissection (no impact on sexual function or fecundity); less complex and complicated surgery; no stoma	Rectal mucosa at risk for progressive neoplasia and cancer
Proctocolectomy and ileal pouch–anal anastomosis	>20 rectal polyps; >1000 colon polyps; curable rectal cancer; good anal function	Advanced rectal cancer; weak anal sphincters	Maintains per anal defecation; minimizes cancer risk	Range of function from good to bad; risk of pouch and anal transition zone neoplasia; temporary ileostomy; risk of complications (including pelvic nerve damage and reduced fecundity)