Gastrointestinal Inherited Polyposis Syndromes

INTRODUCTION

Many polyposis syndromes involve the gastrointestinal (GI) tract (Tables 1 and 2; 1, 2, 3). These include both nonhereditary (Table 1; 3) and hereditary types (Table 2; 1, 2). Tremendous advances have accrued in recent years regarding the underlying genetics of the known hereditary GI polyposis syndromes. The causative genes are now known in all seven of the major hereditary GI polyposis syndromes (Table 2; 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18). The genetic advances will be reviewed, along with the clinicopathologic features of these syndromes. Cancer predisposition will be emphasized.

TABLE 1 Non-Hereditary GI Polyposes

TABLE 2 Classification of Hereditary GI Polyposis Syndromes (Gene)

Genetic testing is now available for all of the GI polyposis syndromes and can be readily accessed through GeneTests-GeneClinics on the Internet at www.genetests.org. The Website is a U.S. government–funded public medical genetics resource for healthcare providers and researchers and is available at no cost. The site’s mission statement is as follows: “providing current, authoritative information on genetic testing and its use in diagnosis, management, and genetic counseling.”

Familial Adenomatous Polyposis

Clinical Aspects

Familial adenomatous polyposis (FAP) and its variant phenotypic syndromes, attenuated FAP (AFAP), Gardner’s syndrome, and Turcot’s syndrome, are different manifestations of a single autosomal-dominant disorder caused by germline mutation of the adenomatous polyposis coli (APC) gene (17). The disease frequency is 1 in 8300 to 1 in 14,025 live births, and there is an equal gender and worldwide distribution. FAP patients express a variety of extraintestinal manifestations (see below), but all have adenomatous (dysplastic) polyps of the gastrointestinal tract that predispose to a high rate of adenocarcinoma (Table 3). The age of polyposis diagnosis is variable, but colonic adenomas generally begin to emerge in the 2nd decade, and by the 4th decade, the majority of affected individuals have developed polyps. The average age at diagnosis for new probands is in the mid-30s (17, 19). Colonic adenocarcinoma is inevitable if the patient is left untreated (19). Upper gastrointestinal adenomas and adenocarcinomas may also develop in FAP, including those of the small intestine and, less commonly, the stomach (Table 4; 2, 20). In particular, the periampullary region is commonly involved and, unfortunately, is the most difficult to clinically manage (Tables 4 and 5; 2, 20).

TABLE 3 FAP Syndrome

TABLE 4 Relative Risk of Upper GI Cancer in FAP

TABLE 5 Extracolonic Manifestations of FAP

FAP Variant Phenotypes

The classic form of FAP has innumerable colonic adenomas that by definition number >100 but usually range into the thousands (Fig. 1). Variant syndromes include attenuated familial adenomatous polyposis (AFAP) and Gardner’s and Turcot’s syndromes (17).

FIGURE 1

Colectomy resection specimen demonstrating classic familial adenomatous polyposis (FAP) with thousands of adenomatous polyps.

Attenuated FAP

The attenuated form derives its name from the diminished number of polyps in these patients, averaging around 30 adenomas within the colon, but with prominent variation within families. Colonic cancer in AFAP patients develops an average of 12 years later than in patients with classic FAP. Upper tract lesions and extraintestinal manifestations develop in AFAP as in classic FAP (17, 21).

Gardner’s Syndrome

The numerous extracolonic manifestations that may develop in FAP are noted in Table 5. These additional manifestations were termed Gardner’s syndrome in the older literature, especially in regards to the development of desmoid tumors, which are seen in approximately 10% of FAP patients (22). These tumors may be aggressive, difficult to cure, and can result in significant morbidity and mortality in FAP patients. Desmoid tumors in FAP patients also develop outside the abdomen, including in such unusual places as the breast (23).

Turcot’s Syndrome

Turcot’s syndrome results from distinct germ-line defects in either the APC gene (FAP) or the DNA mismatch repair genes (HNPCC). FAP/Turcot patients make up approximately 75% of these patients, who develop CNS cerebellar medulloblastomas in addition to their adenomatous polyposis (24). HNPCC/Turcot patients make up the remaining 25%, and they manifest CNS glioblastoma multiforme (24).

Gastric Fundic Gland Polyposis and Foveolar Dysplasia

Fundic gland polyps commonly develop in FAP. They are similar to sporadic-type fundic gland polyps, with the exception that in FAP they may also have dysplasia of the surface foveolar epithelium (Fig. 2). In fact, foveolar dysplasia in a gastric fundic gland polyp appears to be an excellent marker of FAP, as it is rare in sporadic-type fundic gland polyps (25).

FIGURE 2

Gastric fundic gland polyp in FAP (A) showing cystically dilated fundic glands lined by parietal and chief cells (black asterisk), admixed with mucinous glands (white asterisk). Foveolar dysplasia (B) at the surface of a fundic gland polyp (arrowheads) strongly suggests FAP.

FAP Genetics

It is now known that the classic and variant FAP forms derive from mutation in the APC gene on chromosome 5q21–22 (Table 6; 26, 27). Approximately 75% of FAP patients inherit their genetic mutation and, therefore, have a parent and possibly other relatives with the mutation. The remaining 25% have a new mutation, rather than an inherited one (27). The gene itself is very large, and the reported mutations now number >300 (26). Mutation screening is difficult because of their distribution throughout the gene and the gene’s large size (see below). The attenuated FAP variant tends to develop from mutations in the 3′ and 5′ regions of the gene, whereas the classic form with thousands of polyps, tends to develop from more central mutations. Other genotype–phenotype correlations have also been reported, but even patients within the same family with identical mutations may manifest pronounced phenotypic heterogeneity (17).

TABLE 6 APC Gene

FAP Molecular Diagnosis

Molecular diagnosis is now available for FAP (Table 7; 17) and currently includes standard linkage analysis, direct sequencing, protein truncation testing (PTT), and the more recently developed refinement of conversion PTT. Fortunately, most of the known mutations in APC result in a shortened or truncated protein. The PTT test combines transcription and translation tests to take advantage of this phenomenon. The truncated protein is ultimately identified as the endpoint of the assay. The sensitivity of this test is imperfect, although it is between 80 and 90%. A recent improvement in the sensitivity to 96% uses a conversion technique to test individual alleles and holds much promise for FAP genetic testing (28).

TABLE 7 Molecular Diagnosis in FAP (Sensitivity)

FAP Screening and Treatment Guidelines

FAP screening guidelines (Table 8; 17) and treatment recommendations (Table 9; 17, 29, 30) have been endorsed by the American Gastroenterological Association (AGA) Clinical Practice Committee.

TABLE 8 FAP Screening Guidelines

TABLE 9 FAP Treatment Guidelines

PEUTZ-JEGHERS SYNDROME

Clinical Aspects

Peutz-Jeghers syndrome (PJS) is an autosomal-dominant condition with an estimated incidence of 1 in 120,000 births (2, 18). Approximately 50% of cases are familial, and 50% have new mutations. The syndrome is defined by a gastrointestinal hamartomatous polyposis, mucocutaneous melanin spots, and an elevated risk for a wide array of malignancies (Table 10). The melanin spots of PJS are present in >95% of patients and occur most commonly on the lips (95%) and buccal mucosa (66–83%) but are found also on circumoral and facial skin around the eyes and nose, on the palms and soles, and on the digits (1, 2, 18, 31). The lip and circumoral spots tend to fade with age, whereas the buccal spots generally remain visible (1, 2, 31, 32, 33, 34).

TABLE 10 Peutz-Jeghers Syndrome (PJS)

The hamartomatous polyps of PJS are most frequent in the small bowel (64–96% of cases) but are only slightly less frequent in the stomach and colon in many reported series (1, 2, 32, 33). Because rectal polyps have been reported in only 24–32% of cases, sigmoidoscopy is diagnostically less useful in PJS than it is in familial adenomatous polyposis (FAP; 2). The polyps of PJS are composed of normal elements indigenous to the site in which they arise, but the polyps have markedly abnormal architecture. Histologically, the lesions characteristically possess a frondlike growth pattern with normal epithelium. Smooth muscle forms an important component of these polyps, and it extends in an arborizing pattern from the muscularis mucosae into the polyp head (Fig. 3; 2).

FIGURE 3

Peutz-Jeghers hamartomatous small bowel polyp (A), with its characteristic frond-like growth pattern and arborizing muscularis mucosae (mm). Ten percent of these polyps have benign misplaced epithelium (B) that can extend deeply into the bowel wall or even through the muscularis propria (MP). This should not be mistaken for adenocarcinoma and is differentiated by virtue of the benign lamina propria that envelops the typically rounded groups of misplaced glands.

PJS and Benign Misplaced Epithelium

Benign glands in PJ polyps may be surrounded by smooth muscle and extend into the submucosa, the muscularis propria, or even completely through the intestinal wall as benign misplaced epithelium (Fig. 3B; 2, 35, 36). Misplaced epithelium occurs in approximately 10% of small bowel PJ polyps and appears to be a phenomenon confined to the small bowel lesions (36). A rare example with misplaced dysplastic epithelium has been reported (35). The benign nature of misplaced epithelium is recognized by the accompanying lamina propria investing the glands, regardless of the dysplastic or normal nature of the epithelium. As a rule, dysplasia within PJ polyps is rare, and most examples of benign misplaced epithelium in these polyps contain normal, nondysplastic epithelium (2, 35, 36).

PJS: A Premalignant Condition

Carcinoma of the gastrointestinal tract is a frequent complication of PJS (Table 11; 37, 38). Thus, PJS is now one of the several hereditary GI cancer syndromes (18, 37, 38). Well-documented reports of GI carcinoma in PJS have appeared (esophageal, gastric, small bowel, and colonic), and in some cases, associated dysplasia has been observed within the hamartoma itself (2, 34). Most of the reported carcinomas of the gastrointestinal tract in PJS patients have not had evidence of origin from a hamartoma but rather derive from co-existing adenomas (2). The risk of nongastrointestinal carcinomas in PJS patients is 15 times greater than the expected rate in the general population (Table 11) and includes pancreatobiliary, lung, and breast (bilateral) adenocarcinomas (32, 37, 38). In fact, a 100-fold excess of pancreatic cancers has been noted in PJS patients in one large kindred (32).

TABLE 11 Cancer in PJS: Meta-Analysis of 210 Patients

The unusual benign ovarian tumor, termed sex cord tumor with annular tubules (SCTAT) can be identified in almost all female patients with PJS (39, 40). These tumors are usually asymptomatic, small, multifocal, and bilateral. Testicular tumors of the Sertoli cell type also occur in PJS (41). Well-differentiated adenocarcinoma of the uterine cervix (adenoma malignum; 42) has also been described with increased frequency in PJS patients.

PJS Genetics (Table 12)

TABLE 12 Peutz-Jeghers Syndrome Genetics

In 1997, the PJS gene was mapped to chromosome 19p13.3 using an ingenious approach combining morphological and genetic techniques (7) and was confirmed by another group using linkage analysis (4). Soon thereafter, in 1998, the PJS gene itself was cloned and characterized as the novel human serine threonine kinase STK11 (12, 43). Mouse knockout models also substantiate that STK11 heterozygotes develop a GI hamartomatous polyposis syndrome of the stomach and small bowel (44). This combined body of work unequivocally identifies STK11 (also termed Lkb1) as the PJS gene. This has opened genetic screening to affected families. Approximately 70% of familial PJS patients have STK11 mutations, and 30–70% of new onset cases also have mutations (43). Diagnostic testing currently involves full gene sequencing of this 23-kb gene with nine exons.

PJS Management Guidelines

Several position papers have been published on the clinical management of PJS patients and their at risk family members (Table 13; 18, 34).

TABLE 13 PJS Management Guidelines

FAMILIAL JUVENILE POLYPOSIS

Clinical Aspects

Juvenile polyposis syndrome (JPS; Table 14) is the most common of the hamartomatous polyposes and, like the rest, is inherited as an autosomal dominant trait with variable penetrance. Approximately 20–50% of affected individuals have a familial polyposis history. Patients may present in infancy with intussusception, rectal prolapse, GI bleeding, or a protein-losing enteropathy. In adults, the most common presentation is related to chronic or acute GI blood loss. Most of the polyps in JPS are in the rectosigmoid colon, in contrast to PJS, in which the polyps are mostly located in the small bowel. The polyps show an abundance of edematous, inflamed lamina propria stroma as their most characteristic feature (Fig. 4). In fact, the stromal elements have been shown to harbor the mutations in these hamartomatous polyps (11). The surface of the polyps is often eroded (Fig. 4). The epithelial elements are frequently cystic (Fig. 4) and may or may not be dysplastic (see below). The polyps of hereditary juvenile polyposis, in addition, are often larger and multilobated in their gross appearance and are more commonly dysplastic than their sporadic counterparts.

TABLE 14 Familial Juvenile Polyposis

FIGURE 4

Juvenile hamartomatous polyp of the colon with its characteristic inflamed, edematous stroma; eroded surface; and cystic epithelial elements. This example is negative for dysplasia, but all juvenile polyps and particularly large and multilobulated ones should be scrutinized for neoplastic change. Epithelial surface maturation, as seen in this example, differentiates reactive/reparative change from dysplastic change.

Juvenile Polyposis Genetics

Two different genes are known to cause JPS: the SMAD-4 gene and the BMPR1A gene, both of which are involved in the TGF-β signal transduction pathway (Table 15; 10, 18, 45). Genetic testing is clinically available for both genes.

TABLE 15 Juvenile Polyposis Genetics

Juvenile Polyposis Neoplastic Risk

It is now well established that JPS patients are at markedly elevated risk for GI adenocarcinoma, primarily colorectal cancer. The risk ranges from 20–70% and increases with age (Table 16; 46, 47, 48). All juvenile polyps should be carefully scrutinized for dysplasia, as cancer in JPS derives from neoplastic change within the juvenile polyps themselves. It is important, however, to avoid overdiagnosing reactive inflammatory atypia as true dysplasia. As in all GI inflammatory disorders, the most important differential criterion is whether the epithelium matures onto the surface of the polyp, which indicates a reactive, nondysplastic condition.

TABLE 16 Neoplastic Risk in Juvenile Polyposis

Juvenile Polyposis Management Guidelines

Because of the very high risk of colonic cancer, along with the characteristic acute and chronic blood loss, close colonoscopic surveillance is recommended. Some authorities recommend colectomy by the age of 20 years for all JPS patients (Table 17; 18).

TABLE 17 JPS Management Guidelines

PTEN HAMARTOMA TUMOR SYNDROME

At least two GI polyposis syndromes have now been linked to mutation in the PTEN gene on chromosome 10q23.3. These include Cowden’s syndrome and Ruvalcaba-Myhre-Smith syndrome, also known in the literature as Bannayan-Riley-Ruvalcaba syndrome. The features of both are summarized in Tables 18 and 19 (18). Histologically, the polyps are inflammatory-type polyps that are indistinguishable from juvenile polyps.

TABLE 18 Cowden’s Disease

TABLE 19 Ruvalcaba-Myhre-Smith Syndrome

INTESTINAL GANGLIONEUROMATOSIS

This disorder is heterogeneous in its genetic etiology and depends on the parent syndrome, as summarized in Table 20 (49). The polyps consist of neuromatous spindle cell proliferations with ganglion cells often involving the mucosa, where they do not normally reside in appreciable numbers. Genetic testing is available for the parent syndromes of MEN Type IIB, Von Recklinghausen disease, and Cowden’s disease caused by RET, NF-1, and PTEN mutations, respectively.

TABLE 20 Intestinal Ganglioneuromatosis (Genes)

TUBEROUS SCLEROSIS

Tuberous sclerosis patients may have benign hamartomatous polyps of the distal colon and rectum, but this is only a minor feature of the disorder. Morphologically, the polyps are inflammatory-type polyps identical in appearance to juvenile polyps. The characteristics of the syndrome are listed in Table 21 (16, 50). Genetic testing is currently available only on a research basis.

TABLE 21 Tuberous Sclerosis