Polyposis and Hereditary Cancer Syndromes

Amy E. Noffsinger

▪ POLYPOSIS SYNDROMES

Introduction

Polyps may develop anywhere throughout the gastrointestinal (GI) system and arise either as sporadic lesions or as part of a polyposis or hereditary cancer syndrome. The most common syndromes are those that involve neoplastic intestinal adenomas. These include familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer, or Lynch syndrome. Other syndromes, such as MYH polyposis, serrated polyposis, and hereditary mixed polyposis, include both adenomatous and nonadenomatous polyps. Less common polyposis syndromes are associated with development of hamartomas and include Peutz-Jeghers, juvenile polyposis, Bannayan-Riley-Ruvalcaba, neurofibromatosis 1 (NF1), and Cowden syndromes. Another hamartomatous polyposis syndrome, Cronkhite-Canada syndrome (CCS), is nonfamilial. Some rare forms of polyposis involve proliferation of lymphoid or mesenchymal tissues and are discussed elsewhere in this text.

Less than 1% of all GI malignancies result from intestinal polyposis syndromes. One classification scheme of polyposis syndromes is shown in Table 12.1. In order to diagnose a specific polyposis syndrome, one must be aware of (a) the number of polyps a patient has and their location, (b) the patient’s age, (c) the family history, and (d) other clinical information that identifies a patient as having a specific syndrome. Overlap exists between several syndromes.

Familial Adenomatous Polyposis and Its Variants

General Comments

FAP is a generalized growth disorder that includes intestinal polyposis as well as numerous extracolonic manifestations. Overlap exists among the different adenomatous polyposis syndromes, and the varied extraintestinal manifestations of FAP have led to confusion in their nomenclature. Gardner syndrome was the term applied to patients with colonic polyposis, epidermoid cysts, osteomas, and desmoid tumors. Turcot syndrome was diagnosed if the patient had colonic polyps with brain tumors. However, our current understanding of these disorders indicates that FAP and Gardner syndrome represent variations of the same disease rather than distinct entities and result from defects in a single pleiotropic gene with variable expressivity. Turcot syndrome may be seen in patients with either FAP or Lynch syndrome.

Genetic Features

The FAP-associated gene is located on chromosome 5q22 and is called APC for adenomatous polyposis coli (1,2,3). APC has 15 exons (Fig. 12.1) and encodes a protein of 2,843 amino acids (2,3). The large size of the gene may account for the high frequency of new mutations that occur in it. Germ-line mutations in APC account for most cases of classical FAP (2,4). Attenuated FAP (AFAP), in which smaller numbers of polyps are found, is less frequently associated with detectable APC alterations (5,6). Every cell in an FAP patient contains one inactive APC allele; an alteration in the other allele gives rise to intestinal tumors. Inactivation of the second allele occurs in the earliest recognizable phase of the tumors, including some lesions containing as few as two adenomatous crypts, confirming that inactivation of the second APC allele occurs early in neoplastic development.

APC germ-line mutations are most commonly single base pair (bp) changes leading to termination codons or small (1 to 4 bp) deletions, insertions, or splice-altering mutations causing translational frameshifts and subsequent downstream stop codons (2,7). Less commonly, large gene deletions or duplications occur (8). Mutations are located throughout the length of the APC gene.

The first clue to the function of the APC protein came when immunoprecipitation experiments showed that anti-APC antibodies precipitated &bgr;-catenin (9). APC and &bgr;-catenin are part of a complex signaling pathway, the Wnt pathway, which
controls many cellular processes including proliferation, differentiation, apoptosis, and body patterning during development. Under normal circumstances, APC acts a negative regulator of &bgr;-catenin. APC forms a complex with GSK3B, CSNK1A1, and AXIN, which binds to &bgr;-catenin, phosphorylates it, and induces its degradation (10). When normal APC function is lost, &bgr;-catenin accumulates in the cytoplasm, translocates into the nucleus, and binds to the transcription factor T-cell factor (TCF)/lymphoid enhancing factor (LEF). TCF/LEF, in turn, regulates a number of downstream target genes including c-MYC, cyclin D1, CD44, and BMP4 (10,11,12,13,14). APC also stabilizes microtubules and plays a role in cellular migration and cytoskeletal organization (15,16,17). The absence of APC results in abnormal mitosis and development of chromosomal instability (18).

TABLE 12.1 CLASSIFICATION OF INTESTINAL POLYPOSES

	Familial Disorders		Nonfamilial Disorders
Adenomatous	Nonadenomatous		Nonadenomatous
	Serrated	Hamartomatous	Other
Familial adenomatous polyposis and its variants	MYH-associated polyposis	Peutz-Jeghers syndrome	Basal cell nevus syndrome	Cronkhite-Canada syndrome
MYH-associated polyposis	Hereditary mixed polyposis	Juvenile polyposis	NF type 1	Lymphoid polyposis
Lynch syndrome	Serrated polyposis	Bannayan-Riley-Ruvalcaba syndrome	MEN IIB
Muir-Torre syndrome		Cowden syndrome
Familial colorectal cancer type X syndrome
Hereditary mixed polyposis
NF, neurofibromatosis; MEN, multiple endocrine neoplasia.

Disease Expression

Patients with FAP exhibit considerable phenotypic variability of their colonic and extracolonic lesions. Mutations in specific regions of APC produce different clinical phenotypes, and the length of the truncated gene product influences the severity of the colonic disease and the presence of eye lesions or desmoid tumors (Fig. 12.1). Three FAP phenotypes have been suggested. Mild or AFAP is characterized by lower polyp numbers (<100) and later age of disease onset. These patients have an elevated risk for colorectal cancer development, although it is less than that of individuals with classical or severe FAP phenotypes. The AFAP phenotype has been associated with germ-line APC mutations before codon 157, after codon 1595, or in the alternatively spliced fragment of exon 9 (6,19). Classical FAP is characterized by greater than 100 adenomatous polyps and onset at or slightly after puberty. This phenotype is associated with mutations at the 5′ end of the gene between codon 168 and 1550/1580 and excluding codon 1309 (20,21). Severe FAP is characterized by polyps numbering in excess of 2000, and an earlier age of onset, and is associated with mutations between codons 1250 and 1464, and especially codon 1309 (21,22,23,24). Survival in this group of patients is lower than that for other FAP phenotypes (25).

FIG. 12.1 The APC gene with its 15 exons shown as blue boxes. Mutations occurring within the part of the gene designated by the red line result in a CHRPE-negative phenotype. Those occurring in the area designated by the yellow line are associated with CHRPE lesions. The yellow arrow indicates the region of the gene in which mutations begin to result in the appearance of CHRPE lesions. The orange area of the gene is associated with formation of desmoid tumors. Mutations in the green and purple areas result in the attenuated APC and full-blown APC phenotypes, respectively.

Some extraintestinal manifestations of FAP are also associated with specific APC alterations (20). The presence of congenital hypertrophy of the retinal pigment epithelium
(CHRPE) appears to be limited to individuals with germ-line mutations between codons 311 and 1465. Desmoid tumors occur in patients with mutations downstream of codon 1400.

Differences in phenotypic expression of FAP also exist within individual families (26,27). This suggests that the nature of the inherited genetic defect is only one parameter determining patient phenotype. These differences may be due to modifier genes or epigenetic factors. Additionally, inactivation of APC may provide affected cells with a proliferative growth advantage allowing the colon to then acquire additional genetic abnormalities, thereby facilitating disease progression. Environmental factors may also be important. Bile from FAP patients appears to be more mutagenic than that from non-FAP patients (28), perhaps inducing secondary changes both in APC and other genes in the adenoma-carcinoma sequence (see Chapter 14). Many manifestations of FAP may be partially controlled by hormonal status and other genetic factors. Data supporting such a postulate include (a) stimulation of polyp growth during puberty, (b) adenoma inhibition by sulindac, (c) the preponderant development of thyroid carcinomas in women (29), and (d) the association of repeated trauma with development of desmoid tumors (see Chapter 19).

Attenuated Adenomatous Polyposis

A less severe form of FAP, known as AFAP, is characterized by a relatively low number of adenomas. AFAP is associated with a germ-line APC mutation in approximately 10% of affected patients (30). It is important to note that as many as 25% of patients with an AFAP phenotype do not carry mutations in APC but in a gene termed MYH. MYH-associated polyposis (MAP) is discussed in another section in this chapter. AFAP differs significantly from classical FAP in that affected individuals have fewer adenomas that tend to cluster on the right side of the colon where they appear flat rather than polypoid. The number of adenomas varies among family members, ranging from 1 or 2 to 100. Upper GI lesions, particularly fundic gland polyps, are almost invariably present. In addition, affected patients exhibit a reduced risk for colorectal cancer compared with those with classical FAP.

The lifetime penetrance of colon cancer is high in AFAP families, however, even among members with relatively few adenomas. When colorectal cancers do develop, they arise later than in classical FAP. The average age of colon cancer onset in AFAP patients is approximately 15 years later than that of patients with classical FAP and approximately 10 years earlier than individuals with sporadic colorectal cancer. Table 12.2 compares classical FAP and AFAP.

Clinical Features

FAP is the most frequent genetic polyposis syndrome, affecting approximately 2 to 3 per 100,000 individuals in the general population (31,32,33). It is transmitted as an autosomal dominant disorder with up to 90% penetrance. Fifty percent of the children of an affected individual and a normal individual will inherit the polyposis gene and will develop the disease. Fifteen to twenty percent of patients with FAP have no familial history and represent spontaneous new mutations (34). FAP occurs in all ethnic groups, and males and females are equally affected.

TABLE 12.2 COMPARISON OF FAP AND AFAP COLORECTAL CANCER SYNDROMES

Classical FAP		AFAP
*Number of colonic adenomas*
	Sometimes thousands; usually more than 100	Usually 1-50; seldom more than 100
*Gross features*
	Invisible to polypoid adenomas	Flat or slightly elevated plaques
*Histology*
	Polypoid or sessile	Flat adenomas
*Location of colonic adenomas*
	Throughout the colon	Predominantly located proximal to splenic flexure
Location of colon cancer
	Throughout the colon	Predominantly located proximal to splenic flexure
*Average age of cancer onset*
	39	55
Fundic gland polyps
	Present	Almost invariably present
*Extracolonic cancers*
	Periampullary carcinoma, papillary thyroid carcinoma, sarcomas, brain tumors, and small bowel cancer	Periampullary carcinoma
FAP, familial adenomatous polyposis; AFAP, attenuated FAP.

Adenomas are not present at birth in FAP patients. Most affected individuals remain asymptomatic until puberty, at which time the polyps begin to appear. In untreated, unscreened patients, the mean age of polyp development is 24.5 years, symptom onset is 33 years, polyp diagnosis is 35.8 years, cancer diagnosis is at 39.2 years, and death from cancer averages a mean of 42 years (35). Young patients present with a small number of polyps, the number of which progressively increases with time. Eventually, the entire length of the colon becomes carpeted with adenomas. By the time a patient comes to colectomy, he or she may have hundreds to tens of thousands of polyps. Progression to cancer is inevitable; by age 30, approximately 75% of FAP patients will have developed colon carcinoma unless a prophylactic colectomy is performed. Most untreated patients die of cancer by the fifth decade of life.

Adenomas also develop in extracolonic sites, most commonly in the duodenum around the ampulla of Vater. Duodenal adenocarcinomas represent the second most common cancer arising in FAP patients. The lifetime risk for duodenal cancer development in individuals affected by FAP is 3% to 5% (36,37,38,39). Patients less frequently develop adenomas in the stomach or in other portions of the small intestine. Gastric cancers are more common in FAP patients living in
parts of the world where gastric cancer rates are high. Fifty percent of Japanese FAP patients develop gastric adenomas, and gastric carcinoma is more common in these patients than ampullary cancers. In contrast, Western gene carriers exhibit a higher rate of ampullary than gastric neoplasms (40).

Colonic adenomas are often present for years before giving rise to symptoms including rectal bleeding, colicky abdominal pain, diarrhea, and mucous discharge (35). Seventy-five percent of polyposis patients without cancer have rectal bleeding, and 63% have diarrhea (35). When symptoms are severe enough to cause concern, two thirds of the patients have already developed a carcinoma. Very rarely, patients develop severe electrolyte depletion as a result of diffuse polyposis (41). Acute pancreatitis develops secondary to obstruction of the pancreatic duct at the ampulla of Vater by adenomas. Intussusception due to the adenomas may also occur.

Diagnosis of FAP

The diagnosis of symptomatic patients is usually not difficult because they present with bleeding, diarrhea, or abdominal pain. Surveillance of children in affected kindreds results in earlier adenoma detection and in a lower cancer incidence. Today, the tendency is to diagnose the presymptomatic individual by genetic testing and then confirm the diagnosis by sigmoidoscopy. The child of an FAP patient has a 50% likelihood of inheriting the genetic mutation. Prescreening strategies can be designed to detect mutations at the 12 most commonly mutated loci, which account for nearly 40% of germ-line mutations in FAP patients (42). The association of the DNA markers and the presence of CHRPE make it possible to identify gene carriers even in the absence of rectal polyps. CHRPEs affect up to 90% of classical FAP patients, especially those with both upper GI and extraintestinal manifestations (43). They may be single or multiple, bilateral or unilateral, and are easily identified on funduscopic examination. These congenital lesions are observed in very young or even preterm infants and represent the earliest diagnostic stigma of FAP. If one family member has CHRPE, all family members with the disease will have CHRPE. Similarly, other kindreds exist in which no family members have the retinal lesions.

Cancer Development

Carcinoma invariably develops in FAP patients if the colon is not resected by age 40 or 50. Indeed, FAP is the “experiment of nature” that provides support for the colonic adenoma-carcinoma sequence. Adenomas also represent the precursor for small intestinal cancer, but small intestinal adenomas are less likely to become malignant than are colonic lesions. Adenomas and carcinomas also develop in the retained rectum following colectomy.

Carcinomas develop approximately 6 years after symptom onset. The incidence of carcinoma is approximately 10% in patients observed for 5 years and 50% in those observed for 20 years. Each 10-year age group has a 2.4-fold increase in cancer risk (44). Multiple cancers are frequent, with synchronous lesions affecting 41% of patients and metachronous lesions affecting 70%. Polyp count and patient age, but not sex, predict cancer risk. Patients with greater than 1,000 polyps have a 2.3 times greater risk of cancer than those with less than 1,000 polyps.

TABLE 12.3 SPIGELMAN CLASSIFICATION FOR DUODENAL POLYPOSIS IN FAP

Criterion	1 Point	2 Points	3 Points
Polyp number	1-4	5-20	>20
Polyp size (mm)	1-4	5-10	>10
Histology	Tubular	Tubulovillous	Villous
Dysplasia	Mild (low grade)	Moderate (low grade)	Severe (high grade)
Stage 0, 0 points
Stage I, 1-4 points
Stage II, 5-6 points
Stage III, 7-8 points
Stage IV, 9-12 points

Patients who undergo prophylactic colectomy may still die of other tumors, including ampullary cancers, brain tumors, hepatoblastomas, and desmoid and other tumors.

Surveillance

The general recommendations are to begin annual flexible sigmoidoscopy or colonoscopy between 10 and 12 years of age in asymptomatic patients with a family history or confirmed mutation compatible with classical or severe FAP (45). Symptomatic individuals should be evaluated as symptoms develop. Annual colonoscopic surveillance should be started at age 18 to 20 for those with AFAP (45). If no adenomas are detected, the surveillance interval is 2 years and then annually once adenomas are found.

Upper GI surveillance should also be undertaken for patients with FAP since the duodenum is involved by the disease in 50% to 90% of cases (36,37). The extent of duodenal polyposis is currently staged by means of the Spigelman classification (Table 12.3). The surveillance interval for the duodenum is dependent on the Spigelman stage as outlined in Table 12.4.

Chemoprevention

Many drugs and dietary supplements have been studied as potential chemopreventive agents for adenomas in the setting
of FAP. The nonsteroidal anti-inflammatory drug, sulindac, was the first drug shown to be effective in decreasing polyp numbers in FAP patients (46). Both sulindac and the COX-2 inhibitor, celecoxib, have now both been studied extensively and show efficacy in reducing polyp burden in FAP patients. Chemoprevention is generally considered in FAP patients who are postcolectomy, especially those with a retained rectum (45,47). The role of chemopreventive agents in managing duodenal polyposis is less clear. Sulindac is generally not considered effective in reducing upper GI polyp burden (48,49), and results of studies using celecoxib have shown unclear benefits (50). The use of either of these agents must be weighed against the risk of GI and cardiovascular complications known to occur with the use of these drugs.

TABLE 12.4 RECOMMENDED SURVEILLANCE INTERVALS FOR UPPER ENDOSCOPY IN FAP

Spigelman Classification	Surveillance Interval
0/I	5 y
II	3 y
III	1-2 y
IV	Consider surgery

Treatment

Because of the high cancer risk, FAP patients undergo prophylactic total colectomy once the diagnosis is established. There are no guidelines with regard to the timing of the surgery. Proctocolectomy is indicated in patients with large numbers of adenomas greater than 5 mm in size or in patients with adenomas showing high-grade dysplasia (45). In general, the procedure is performed between the ages of 15 and 25. There are basically two surgical options available to FAP patients, ileorectal anastomosis (IRA) and ileal pouch-anal anastomosis (IPAA). IRA is a relatively simple procedure with a low complication rate and good postoperative bowel function. IPAA is more complicated, requiring more extensive surgery and pelvic dissection. Following IRA, a portion of the rectum is retained and remains at risk for adenoma and carcinoma development. As a result, IPAA is the procedure of choice for patients with large numbers of rectal adenomas (45). In those with few or no rectal polyps, IRA or IPAA are options. Some authors suggest that the type of operation performed be guided by results of genetic testing, with those patients with genotypes associated with the severe form of polyposis undergoing IPAA (51,52,53,54,55).

FIG. 12.2 Gross features of familial polyposis. (A) through (D) demonstrates the different forms this disorder may take. A: Numerous sessile, small rounded polypoid lesions are present, often on the mucosal folds. Large intervening areas of apparently normal colon are present. B: Clusters of pedunculated adenomatous polyps, larger than those seen in (A), are present. They tend to pull up the mucosal folds into stalks. C: Numerous sessile and pedunculated polyps are scattered over the mucosal surface. D: The bowel is carpeted by numerous larger raspberrylike pedunculated polyps.

Adenoma and Carcinoma Distribution

Adenomas develop throughout the entire colon (Fig. 12.2) and appendix. They are fairly evenly distributed throughout the large intestine, with a tendency for them to be larger in the sigmoid and the rectum, thereby making the density appear greater in this region (35). Rarely, the rectum is spared,
especially in AFAP. When extensive, the entire large bowel becomes carpeted with adenomas (Fig. 12.2). Adenomas show gradations in size and shape from pedunculated tumors 1 cm or more in diameter to smaller, broader-based nodules to tiny lesions 1 mm or less in size. Adenomas tend to be larger in propositi (Figs. 12.2 and 12.3) than in patients undergoing surveillance (Fig. 12.4). In classical FAP, the number of polyps ranges from less than 100 (Fig. 12.2) to greater than 5,000 with an average of 1,000, depending on when one sees the patient (35). Colorectal carcinomas may be multifocal and more frequently develop on the left side of the colon (56). Patients with AFAP develop flatter, nonpolypoid adenomas than are seen in classical FAP. They arise throughout the colon, with preferential involvement of the right colon. They also originate in the retained rectum following colectomy.

FIG. 12.3 Resection specimen in a familial adenomatous polyposis (FAP) patient.There is a large fungating tumor present that represented an invasive carcinoma. Numerous pedunculated adenomas are seen in the surrounding mucosa.

FIG. 12.4 Resection specimen from a patient who was part of a surveillance program. The patient has numerous small nodular lesions only mildly elevated over the mucosal surface. The lesions are smaller in patients undergoing surveillance than those who are not part of surveillance programs.

Pathologic Features of Adenomas

Adenomas and carcinomas in FAP patients grossly resemble their sporadic counterparts. Endoscopically, very small adenomas resemble hyperplastic polyps (Figs. 12.2 and 12.4). It is only when they become larger that the typical raspberrylike configuration of an adenoma becomes evident. As in sporadic colon cancer, the incidence of malignancy relates to adenoma size.

In the early stages, adenomas consist of small groups of adenomatous tubules. They range from unicryptal, bicryptal, or tricryptal lesions in grossly normal-appearing mucosa (Figs. 12.5 and 12.6) to the more typical multicryptal grossly visible polyps seen in patients without FAP (Fig. 12.7). Even in unicryptal adenomas, the entire tubule is completely lined by neoplastic epithelium (Fig. 12.6). Proliferation throughout the entire length of the adenomatous crypt leads to branching, budding, infolding, and mucosal elevation.

FAP patients develop depressed, flat, or polypoid adenomas (57) with AFAP patients showing a tendency to develop flat lesions. In contrast to pedunculated adenomas, the whole surface of flat or depressed adenomas lies at or below the level of the normal mucosa (Fig. 12.8). Polypoid adenomas are those with convex surfaces. Flat adenomas differ endoscopically and histologically from the usual adenoma. They present as slightly elevated plaques of adenomatous mucosa, not more than twice as thick as the adjacent normal mucosa. Further growth is by radial extension of adenomatous epithelium so that the lesions remain flat. When cancer develops, then one sees a reddish depression surrounded by marginal elevations (58).

Upper Gastrointestinal Lesions

Nearly all FAP patients have polyps in the upper GI tract, with as many as 90% of patients developing gastric or duodenal adenomas by age 70 (36). Adenomas develop in the gastric antrum, duodenum, periampullary region, and ileum. However, it is the periampullary region that is most commonly involved, and adenomas tend to cluster at this site. More than 50% of FAP patients who undergo upper endoscopy have a grossly polypoid lesion, 90% of which arise in the periampullary region (59), suggesting that bile plays a role in their growth (60). The bile of FAP patients has a greater proportion of chenodeoxycholic and a lower proportion of deoxycholic acid than does the bile of patients without polyposis (60) and is more mutagenic. Patients also exhibit fecal flora abnormalities resulting in the possible production of carcinogenic compounds.

Periampullary carcinoma is a major cause of death in FAP patients (61), affecting from 2.9% to 12% of all FAP patients (35,61,62) and causing death in 22.2% of patients following colectomy (62).

FIG. 12.5 Cross-sections of the grossly apparently normal mucosa in patients with familial polyposis. Low-power picture showing two foci containing adenomatous glands (A). A unicryptal adenoma is present above the star. A tricryptal adenoma is illustrated by the arrow. A tricryptal adenoma is illustrated in (B).

Duodenal Lesions

Duodenal adenomas develop in as many as 100% of patients in Japanese series (62,63) and in 50% in Western countries (35,64,65). Duodenal adenomas develop when patients are in their second to fifth decades of life. The average age of FAP patients with adenomas involving the ampulla of Vater is 31.7 years, compared with 59.6 years in those without FAP. Duodenal adenomas vary in size and appearance from microadenomas in a normal-appearing ampulla to sessile polyps measuring 3 cm in diameter (65). Duodenal adenomas are generally small in screened populations. Over 90% of duodenal adenomas are tubular lesions. Larger lesions may become tubulovillous. FAP-associated duodenal adenomas show a significant increase in the number of Paneth cells (Fig. 12.9) and endocrine cells per crypt compared to controls. This specialized cell hyperplasia affects the flat mucosa of FAP patients, regardless of the presence or absence of adenomas, and may represent a primary defect in the regulation of duodenal stem cell differentiation in FAP patients (66).

FIG. 12.6 Longitudinal section of the mucosa showing the presence of a unicryptal adenoma (arrow). Even the single adenomatous crypts are easily visible.

Lleal and Jejunal Lesions

Adenomas also develop in the ileum and jejunum but to a lesser extent than in the duodenum. As many as 82% of FAP patients develop ileal adenomas (67). Ileorectal anastomoses, ileostomies, and ileal pouches predispose
the ileal mucosa to become neoplastic (68,69,70). The ileal mucosa undergoes colonic metaplasia, which then gives rise to adenomas. Ileal adenomas resemble duodenal, gastric, and large intestinal adenomas. Ileal adenomas tend to be sessile, measuring 1 to 5 mm in size. Multiple lymphoid polyps also develop in the terminal ileum in FAP patients.

FIG. 12.7 Familial polyposis. Histologic section through the mucosa demonstrating the presence of multiple adenomatous polyps arising on the surface of the mucosa.

FIG. 12.8 Flat adenoma in a patient with attenuated adenomatous polyposis coli (AFAP). Note that the adenomatous glands (center) lie at or below the level of the normal mucosa.

FIG 12.9. Duodenal adenoma in a familial adenomatous polyposis patient showing the presence of adenomatous epithelium and a large number of Paneth cells, as evidenced by the eosinophilic granules within the cytoplasm.

Gastric Lesions

Gastric polyps develop in approximately two thirds of FAP patients (71). Two different types of polyps arise in the stomach. Antral polyps are usually adenomas, whereas the small polyps arising in the fundus and body are usually fundic gland polyps (see Chapter 4) (72). Fundic gland polyps affect 25% to 60% of FAP patients.

Fundic gland polyps occur earlier than gastric adenomas, presumably because they originate in the existing fundic mucosa without the requirement for intervening intestinal metaplasia. Most patients with fundic polyps are under age 20. Fundic gland polyps are often multiple and small in diameter, appearing sessile or semisessile. They are histologically identical to sporadic fundic gland polyps (see Chapter 4) (Fig. 12.10). The gastric mucosa may be studded with numerous small, sometimes eroded, polyps that may increase in number and size over a several year period. Alternately, they may decrease in size and number or even disappear. Lesions that decrease or disappear may be followed by the appearance of a new crop of polyps (72). The fundic gland lesions are generally considered to be benign with little or no malignant potential, yet dysplasias and carcinomas have been described in FAP-associated fundic gland polyps (73,74) (Fig. 12.10). Superimposed gastric adenomas may give the false impression of dysplasia arising in a fundic gland polyp.

In Western countries, FAP-associated gastric adenomas and carcinomas are rare, contrasting with the Japanese experience and supporting the role of environmental or other genetic factors in gastric cancer development. Gastric adenomas develop in the antrum in areas of intestinal metaplasia, a histologic requirement for the formation of gastric adenomas. When one compares gastric adenomas with colonic adenomas, the gastric lesions tend to be smaller and more sparsely distributed. In addition, gastric adenomas occur later in life than colonic adenomas. Gastric adenocarcinomas develop in the adenomas.

Adenomas and Carcinomas in the Rectal Remnant

Overall, the cumulative risk of developing cancer in the retained rectum ranges from 4% to 59% during a period of 10 to 30 years following surgery (75,76). The cancers may be small, depressed, and restricted to the mucosa. The age of the patient at the time of colectomy, the length of the retained colon, the tendency for spontaneous regression of polyps in the retained rectum, and the presence of carcinoma in the excised colon all influence the subsequent development of rectal cancer. Carcinomas and adenomas can develop, even in patients who are closely followed (68).

Extraintestinal Manifestations

FAP patients have a high incidence of extraintestinal manifestations, including dental and skin abnormalities and the development of various types of neoplasms (Fig. 12.11). The dental abnormalities include unerupted teeth, supernumerary

teeth, dentigerous cysts, and mandibular cysts. Subcutaneous lesions include epidermoid cysts, lipomas, fibromas, neurofibromas, and trichoepitheliomas. The latter appear at an early age, even before polyps appear. Those that occur in prepubertal years are strong indicators for the presence of a polyposis syndrome, and to some represent an indicator for regular sigmoidoscopy, even without a history of polyposis. Epidermal inclusion cysts are often multiple. The epidermoid cysts occur anywhere on the body but most are located on the arms, buttocks, legs, face, and occasionally in the testis.

FIG. 12.10 A: Fundic gland polyp in a patient with attenuated FAP. The lesion is similar in appearance to a sporadic fundic gland polyp. B: Low-grade foveolar-type dysplasia is a fundic gland polyp from another patient with FAP.

FIG. 12.11 Diagram of the various manifestations of familial adenomatous polyposis, which is essentially a systemic disorder.

Not surprisingly, patients who carry germ-line mutations in a tumor suppressor gene such as APC exhibit tumors at sites other than the GI tract. These are summarized in Figure 12.11. Osteomas commonly occur in the skull or jaw, although they can affect any bone. These benign tumors rarely become malignant. FAP associates with nasopharyngeal angiofibromas (77). The lesion occurs 25 times more commonly in FAP patients when compared with the general population.

FAP patients also develop a number of endocrine and other neoplasms. Thyroid carcinomas, which occur with increased frequency in FAP patients, are all follicular neoplasms, sometimes containing papillary, cribriform, solid, and spindle cell components. FAP-associated thyroid cancers are commonly multifocal and predominantly affect young women. Since multicentricity is unusual for follicular thyroid tumors, it should alert the pathologist to the possibility of FAP (78). Soft tissue lesions include fibromas, lipomas, and desmoid tumors.

FIG. 12.12 Desmoid tumor in a patient who died of complications from the desmoid. A: Autopsy en bloc resection of the liver, spleen, intestines, and desmoid tumor. One can see that the tumor diffusely infiltrates the abdominal contents and extends up to the liver. Numerous organs were entrapped within this neoplasm, including the biliary tree, large numbers of vessels, and loops of bowel. B: Higher magnification of the neoplasm showing the presence of a fleshy mass with areas of ischemic necrosis.

Desmoid tumors are a locally invasive form of fibromatosis (see Chapter 19) that affects 9% to 32% of FAP patients (79,80), particularly women (81). Affected patients are often young, with a mean age of 29.8 years (82). The overall prevalence of these lesions in FAP is 15%, a risk approximately 850 times greater than that of the general population (82,83).

Desmoid tumors tend to involve members of the same family and associate with mutations in exon 15 of APC (Fig. 12.1). Most patients have undergone a previous colectomy (81). Hormonal factors such as pregnancy and estrogen use may also play etiologic roles in desmoid development. Although the desmoids can develop on the shoulder girdle, buttocks, and groin, most of the desmoid tumors associated with FAP arise in the abdominal wall or within the abdominal cavity (45).

Desmoid tumors represent an adverse prognostic factor in FAP patients because they associate with a high frequency of complications and tumor recurrence. These nonencapsulated, irregular, and infiltrative (Fig. 12.12), locally aggressive lesions do not metastasize, but they can cause significant intestinal obstruction, ureteral or vascular compression, or other local problems. Extensive mesenteric or retroperitoneal involvement leads to recurrent small bowel obstruction. A staging system
for these lesions was developed in 2005 (84) (Table 12.5). Five-year survival for patients with stage I, II, III, and IV intraabdominal desmoid tumors is 95%, 100%, 89%, and 76%, respectively (85). Death results from vascular compromise, small bowel gangrene, perforation, or intra-abdominal sepsis.

TABLE 12.5 DESMOID TUMOR STAGING SYSTEM

Stage I	Asymptomatic, <10 cm maximum diameter, not growing
Stage II	Mildly symptomatic, <10 cm maximum diameter, not growing
Stage III	Moderately symptomatic or bowel/ureter obstruction, or 10 to 20 cm, or slowly growing
Stage IV	Severely symptomatic, septic complications such as fistula or abscess, or >20 cm, or rapidly growing
Mildly symptomatic = sensation of a mass and pain; no restriction Moderately symptomatic = sensation of a mass and pain; restrictive but not hospitalized
Severely symptomatic = sensation of a mass and pain; restrictive and hospitalized

Currently, first-line treatment for patients with large or growing intra-abdominal desmoid tumors is pharmacologic and includes the nonsteroidal anti-inflammatory drug sulindac, usually in combination with either tamoxifen or toremifene (86,87,88,89). Patients who do not respond to firstline therapy may be treated with chemotherapy (doxorubicin and dacarbazine or methotrexate and vinblastine) or radiotherapy (90,91,92). The treatment for abdominal wall desmoid tumors is controversial with some authors advocating surgical excision (88) and others advising against surgery because of the high risk of recurrence (93).

FIG. 12.13 Desmoid tumor. A: A highly vascular spindled cell mass is present, which extends up to a large sclerotic vessel but does not invade it. B: Higher magnification showing the haphazard arrangement of the spindled cells.

Histologically, desmoids consist of uniform, mature fibroblasts arranged in intertwining bundles. Mitoses are infrequent and never atypical. The extent of vascularization varies and may be prominent (Fig. 12.13). This prominent vascular ectasia, which sometimes occurs in FAP patients, is not a feature in non-FAP individuals and may account for intraoperative hemorrhagic complications. The tumor infiltrates the intestinal loops and peritoneum. The arteries and veins become surrounded by tumor, but it does not infiltrate them (Fig. 12.13). The tumor cells actively produce collagen fibers.

Desmoids in FAP patients contain both germ-line and somatic APC mutations, suggesting that inactivation of this gene plays a role in the development of the lesions (94). Desmoid tumors also demonstrate deletion of 5q (95). Desmoid tumors from patients with FAP demonstrate more chromosomal copy number alterations than sporadic desmoid tumors (96), a finding that supports the hypothesis that loss of APC function results in chromosomal instability (97).

Turcot Syndrome

Turcot syndrome is the association of colonic polyps with malignant tumors of the central nervous system. Turcot syndrome may be associated with either FAP or Lynch syndrome. In FAP patients, central nervous system tumors
arise around the time of puberty, often before the diagnosis of the polyposis syndrome (Table 12.6). The brain tumors are often lethal (98).

FIG. 12.13 (Continued) C: A more hyalinized area of the tumor. D: A more vascular portion of the tumor.

Many cases of Turcot syndrome are linked to the APC locus. Hamilton et al. (99) detected genetic abnormalities in 13 of 14 registry families. Germ-line APC mutations were detected in 10. The glioblastomas and colorectal tumors in three of the families and in the original family studied by Turcot also had replication errors characteristic of hereditary nonpolyposis colorectal cancer (HNPCC). In addition, germline mutations in mismatch repair (MMR) genes MLH1 or PMS2 were found in two families. Homozygous MSH6 mutations were also identified in a family with childhood-onset glioblastoma, lymphoma, colorectal carcinoma, and a neurofibromatosis type 1 phenotype (100). Thus, the association between the brain tumors and multiple colorectal adenomas can result from two distinct types of germ-line defects, that is, mutation of APC or an MMR gene (99).

TABLE 12.6 CENTRAL NERVOUS SYSTEM LESIONS IN TURCOT SYNDROME

Medulloblastoma

Glioblastoma

Cavernous hemangioma

Astrocytoma

Arteriovenous malformation

Spongioblastoma

Lymphoma

Glioma

Ependymoma

Craniopharyngioma

Somatic p53 mutations are found in both the brain and colon tumors in Turcot syndrome, although the mutations are not the same in the two sites (101). Gliomas also exhibit allelic deletions of chromosome 17p (102). K-ras mutations are also found (102).

▪ NONHEREDITARY ADENOMATOUS POLYPOSIS

Multiple Colonic Adenomas

The presence of multiple adenomas (<100 in the colorectum) defines a group of patients without a clear genetic disorder but who exhibit an increased risk for developing colon carcinoma. Morson surveyed patients with intestinal neoplasia at St. Mark’s Hospital and found 1,846 individuals who had multiple adenomas (103). Of these, 27.9% had more than one adenoma; 4.5% had more than five adenomas. In this series, the patients with familial polyposis had a minimum of 200 polyps, whereas the nonfamilial group had a maximum of 48. The percentage of patients with associated carcinoma increased with increasing numbers of adenomas; 80% of patients with 6 to 48 polyps had a carcinoma (103). Some of these patients may in actuality have AFAP or MAP.

▪ POLYPOSIS SYNDROMES ASSOCIATED WITH ADENOMATOUS AND NONADENOMATOUS POLYPS

MYH-Associated Polyposis

In 2002, Al-Tassan et al. (104) reported a Welsh family in which three members had multiple colorectal adenomas and carcinoma with an autosomal recessive pattern of inheritance. Their tumors demonstrated an excess of somatic mutations in APC, all of which represented G:C to T:A substitutions in genes such as the APC and KRAS, both of which play major roles in colonic carcinogenesis. The authors observed that such mutations are frequently the result of oxidative injury to DNA and, therefore, tested oxidative repair genes for germline changes in these patients. They found that affected patients carried biallelic missense mutations (Y165C and G382D) in the human DNA glycosylase base excision repair gene MYH, located on chromosome 1. Besides the two originally described MYH mutations, other mutations have now been observed including truncating, missense, in-frame insertions, and putative splice site mutations (104,105,106,107). An immunostain for the gene product is now commercially available. Lack of nuclear staining for the protein may be a potential screening test for the disorder although preliminary studies need to be validated.

MAP is inherited as an autosomal recessive disorder. Germ-line biallelic MYH mutations result in a wide range of phenotypic presentations. Some individuals present clinically with multiple adenomatous polyps, early-onset colonic adenocarcinoma and upper GI neoplasms (105,108,109,110), and a phenotype resembling that seen in attenuated familial polyposis. In some patients, the number of adenomatous polyps can exceed 100 as seen in classical FAP (105). MYH mutations have been identified in approximately 30% of patients with between 10 and 100 polyps and no APC germ-line mutation (105,111). In addition, biallelic MYH mutations have recently been associated with a phenotype resembling serrated polyposis (see below) in which patients present with a combination of adenomas, serrated adenomas, sessile serrated adenomas, and hyperplastic polyps (112,113). Finally, biallelic MYH mutation carriers may present with early-onset colorectal cancer and no evidence of polyposis of any kind. In one report, 42% of patients with MYH-associated colorectal cancer had no more than one synchronous polyp (114). In another study, 35% of biallelic MYH carriers with colorectal cancer had no synchronous polyps at the time of diagnosis (115).

The MYH protein functions as a base excision repair DNA glycosylase that excises adenines incorrectly incorporated opposite 8-oxo-7,8-dihydro-2′-deoxyguanosine, one of the most stable products of oxidative DNA damage (116). Adenomas and carcinomas from patients with inherited defects in MYH demonstrate an excess of G:C → T:A transversions in both the APC and KRAS genes (104,117). These APC mutations are thought to account for the FAP-like presentation seen in many MAP patients. A recent report has additionally demonstrated somatic transversions in the MLH1 gene in the carcinomas of two MAP patients, resulting in microsatellite instability (MSI) and loss of MLH1 expression (118).

Some data suggest that heterozygous (monoallelic) MYH mutations may also associate with an increased risk for carcinoma and may act in an autosomal dominant mode of inheritance with relatively low penetrance (114). In fact, 47% of colorectal carcinomas arising in patients with monoallelic MYH mutation show loss of heterozygosity at the MYH locus, a finding that suggests that MYH may be an important factor in cancer development in this group of patients. In addition, patients with monoallelic MYH mutation more commonly report a family history of colorectal cancer (114). Loss of heterozygosity at MYH has been observed in sporadic colon carcinomas (119).

The histological features of the tumors may differ depending on whether the tumors arise on a biallelic or monoallelic mutation background. Carcinomas in biallelics demonstrate tubular, papillary, or cribriform patterns as the predominant histological subtype. Furthermore, the biallelic tumors are low grade. Serrated carcinoma may be the predominant type in monoallelics although these patients do demonstrate a range of histologies (107).

Patients with MAP have an increased risk for extracolonic neoplasms as well. In one study, 28% of MAP patients had at least one extraintestinal tumor, of which 40% were malignant (120). Extracolonic sites of involvement included esophagus, stomach, duodenum, bladder, skin, lung, breast, ovary, and endometrium. The overall risk for extraintestinal malignancies in MAP patients was double that of the general population (120).

Serrated Polyposis Syndrome

Serrated polyposis syndrome (SPS) is a rare syndrome first described in 1980 as “metaplastic polyposis” (121) and then later renamed hyperplastic polyposis. Currently, the term “serrated polyposis” is favored because affected patients develop not only hyperplastic polyps but other forms of serrated polyp as well. The true incidence of SPS is unknown, in part because the syndrome is frequently unrecognized (122,123). Prevalence estimates range from 1:100,000 to 1:3,000 to 1:151 among patients being screened for colorectal cancer (124,125,126). The incidence is higher among patients with large (<2 cm) flat or sessile colonic polyps, reaching 4% in one study (123). Patients with SPS have an increased risk for development of colorectal, as well as extracolonic cancers (127,128,129). Colorectal cancers develop in 25% to 40% of SPS patients (127,128,130,131). In addition, both first- and second-degree relatives of SPS patients are at significantly heightened risk for development of colorectal cancers (127,132).

The phenotypic expression of SPS is variable. Patients with SPS develop not only hyperplastic polyps but also sessile serrated adenomas, traditional serrated adenomas, classical
adenomas, and mixed serrated and adenomatous polyps (Fig. 12.14). Polyps appear to be limited to the colon; in one study of 44 SPS patients, no gastric or duodenal polyps were found (129). The criteria for diagnosis of the syndrome are summarized in Table 12.7 (133). The mean age at diagnosis is 37 to 62 years (130), although the disease has also been reported in younger patients. Both sexes appear to be affected equally. Most patients have more than 30, but fewer than 100 polyps, although smaller numbers of polyps do occur in some patients. Some studies suggest that there may be several different, but overlapping, clinical phenotypes of SPS. The first group includes those patients with predominantly larger rightsided polyps, while the second group includes individuals with more numerous, smaller, left-sided polyps (127). Finally, a third group exists with features of both the first and second groups. Clinical differences also exist among patients with large versus small polyp numbers, with individuals with
numerous polyps exhibiting a higher risk for cancer development than those with fewer polyps (130). This phenotypic diversity suggests there may be multiple underlying genetic alterations that may contribute the SPS.

FIG. 12.14 Serrated polyposis. A: Low-power view showing areas of serrated-appearing glands in a patient with serrated polyposis. B: Some polyps resemble typical hyperplastic polyps, while others show features of sessile serrated adenomas/polyps (C). D: Occasional foci of cytologic dysplasia are present in some polyps.

TABLE 12.7 DIAGNOSTIC CRITERIA FOR SERRATED POLYPOSIS

At least five histologically diagnosed serrated polyps proximal to the sigmoid colon, of which two are >10 mm in diameter
Any number of serrated polyps occurring proximal to the sigmoid colon in an individual with a first-degree relative with serrated polyposis
Greater than 20 serrated polyps distributed throughout the colon

The genetic alterations underlying SPS are largely unknown. Alterations in components of the serrated neoplasia pathway as described for sporadic serrated polyps are commonly altered in both polyps and carcinomas in SPS (134), but no underlying germline alteration in any components of this pathway have yet been identified in SPS patients. Involvement of additional pathways, including MYH, further suggests that SPS likely represents a heterogeneous disorder (135).

Hereditary Mixed Polyposis Syndrome

As the name implies, hereditary mixed polyposis syndrome is characterized by a variety of colorectal tumor types including atypical juvenile polyps and serrated polyps including serrated adenomas, classical adenomas, and carcinomas (136). This disease appears to affect the colon only; no other GI or extraintestinal manifestations have been described. Two forms of hereditary mixed polyposis syndrome appear to exist. The first is linked to a genetic locus mapped to chromosome 15 (137,138) and the second to the BMPR1A locus on 10q23 (139,140).

▪ HEREDITARY HAMARTOMATOUS POLYPOSIS SYNDROMES

Peutz-Jeghers Syndrome

Clinical Features

The Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder with pleiotropic inheritance and variable penetrance. PJS has an estimated incidence of 1/120,000 to 1/200,000 births (141,142). Approximately 50% of cases are familial; the remaining 50% are new mutations. The incidence of PJS is roughly one tenth that of FAP (143). The syndrome consists of two major components: GI hamartomatous polyps and pigmented macules involving mucous membranes and skin (Fig. 12.15). The pigmentation affects 90% of patients, and polyps may occasionally be absent. Conversely, some family members have only the intestinal polyps. The disease affects males and females equally. The diagnostic criteria for PJS are listed in Table 12.8.

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