The intestinal polyposis syndromes are responsible for less than 1% of all lower gastrointestinal (GI) tract malignancies but have provided vast insight into the genetic alterations that underlie GI neoplasia. Polyposis syndromes may be categorized into those that cause intestinal adenomatous polyps and those that cause nonadenomatous, or hamartomatous, polyps ( Table 12-1 ). Syndromes that cause adenomatous polyps most commonly include familial adenomatous polyposis and its phenotypic variants, whereas syndromes that cause hamartomatous polyps include Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, or Cowden’s disease. Polyposis syndromes may also be classified as those that are hereditary and those that occur in a sporadic manner. Important information necessary to make a diagnosis of an intestinal polyposis syndrome includes the number and location of intestinal polyps, the patient’s age, the patient’s family history, and other clinical features of the patient that may identify him or her as having a polyposis syndrome.
| Hereditary Polyposis Syndromes |
| Adenomas Familial adenomatous polyposis coli Attenuated familial adenomatous polyposis coli Gardner’s syndrome Turcot’s syndrome MYH adenomatous polyposis coli Hamartomatous Peutz-Jeghers syndrome Juvenile polyposis syndrome Cowden’s disease Bannayan-Riley-Ruvalcaba syndrome Devon family syndrome |
| Other |
| Hereditary mixed polyposis syndrome Neurofibromatosis type 1 Multiple endocrine neoplasia type 2 Nonhereditary polyposis syndromes Hyperplastic polyposis syndrome Cronkhite-Canada syndrome Lymphomatosis polyposis Nodular lymphoid hyperplasia Pneumatosis cystoides intestinalis Colitis cystica profunda |
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Familial adenomatous polyposis
Clinical features
Familial adenomatous polyposis (FAP) is the most common intestinal polyposis syndrome, affecting approximately 1 in 10,000 individuals. It is characterized by the development of adenomatous polyps at an early age in association with numerous extracolonic manifestations. FAP is the prototype of any hereditary cancer syndrome because the risk for affected patients developing colon cancer approaches 100%.
In the fully developed form, hundreds to thousands of adenomatous polyps are present throughout the colorectum. Adenomas emerge at an average age of 16 years, and colon cancers occur at an average age of 39 years. Colonic adenomas develop in more than 95% of patients with FAP by the age of 35 years and, without treatment, 93% of all patients with FAP will develop colon cancer before age 50 years.
Upper GI polyps are also found in up to 100% of patients with FAP. Most are fundic gland polyps, although adenomatous polyps of the gastric mucosa may also occur. Duodenal adenomatous polyps also develop in more than 90% of patients with FAP, with up to a 10% lifetime risk for duodenal or periampullary cancer. Adenomas occurring within the small bowel have been reported, but symptoms or malignancy from adenomas in this region is unusual.
Extraintestinal manifestations in FAP are common and include osteomas, epidermoid cysts, fibromas, supernumerary teeth, odontomas, and congenital hypertrophy of the retinal pigmented epithelium. These lesions are usually asymptomatic and are not associated with malignant potential. One exception, however, is desmoid tumor, occurring in 10% of patients with FAP. Desmoid tumors are considered benign lesions but result in significant morbidity (and sometimes mortality) in half of patients who have them.
When the extraintestinal manifestations of FAP are particularly prominent, the condition may be referred to as Gardner’s syndrome. An attenuated form of FAP (AFAP) is also well accepted, in which the average number of adenomatous polyps is approximately 30. Adenomas are typically present in a right colonic distribution, and adenomas and colon cancers arise an average of 10 years later than in the classic form of FAP. Turcot’s syndrome refers to those patients with brain cancer (particularly medulloblastomas) and intestinal polyposis.
Definition
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An autosomal dominantly inherited syndrome characterized by hundreds to thousands of adenomatous polyps throughout the colorectum and a variety of extracolonic manifestations
Incidence and location
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Most common polyposis syndrome (1 in 10,000)
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80% to 100% gene penetrance in affected families
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30% of patients with FAP have spontaneous new mutations of the APC gene
Morbidity and mortality
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Average age of colorectal cancer diagnosis is 39 years
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More than 90% of patients develop colorectal cancer by age 50 years
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100% of patients have upper GI polyps, typically fundic gland polyps
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Age of adenoma and cancer onset is 10 years later for AFAP than for classic FAP
Gender, race, and age distribution
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Males and females equally affected
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No racial or ethnic predominance
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Average age of onset in teens
Clinical features
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Most patients asymptomatic until puberty
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Adenomas often present years before symptoms occur
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Most common symptoms are rectal bleeding (75% of patients) or diarrhea (63% of patients)
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Carcinomas develop on average 6 years after symptom onset
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Synchronous cancers (40% of patients) and metachronous cancers (70% of patients) common
Prognosis and therapy
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100% risk of colon cancer without intervention
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Only treatment is prophylactic total colectomy
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Following colectomy, most common cause of mortality is periampullary cancer (22% of patients)
Pathologic features
Gross findings
Adenomas develop throughout the entire colorectum and appendix. While they tend to be evenly dispersed, adenomas are relatively larger in the rectosigmoid, giving the appearance of a greater density of polyps in this region. In the classic and most dramatic form, the entire mucosa becomes carpeted with adenomatous polyps so that no intervening normal mucosa is recognizable ( Fig. 12-1 A and B). In these cases, the total number of adenomas present is greater than 100, often exceeding 1000. Colorectal carcinomas may be multifocal and show a relative predilection for the left colon. The adenomatous polyps in FAP typically demonstrate a range of sizes and shapes. Adenomas may vary from large, pedunculated tubulovillous adenomas greater than 1 cm in diameter, to flat, broad-based nodular adenomatous polyps, to microscopic foci less than 1 mm in diameter.
In patients with AFAP, the number of polyps present is typically less than 100 and preferentially involves the right colon (see Fig. 12-1 C). Sparing of the rectum by adenomatous polyps may also indicate AFAP, as well as the presence of numerous flat adenomas in that patient.
Microscopic findings
The adenomas and carcinomas that arise in FAP are indistinguishable from their sporadic counterparts ( Fig. 12-2 A). Similar to sporadic adenomas and colorectal carcinomas, the incidence of malignancy is related to adenoma size and frequency. Single, double, or tricryptal adenomas are common in grossly normal mucosa (see Fig. 12-2 B). The adenomas of AFAP show similar cytologic changes characteristic of adenomatous epithelium. However, in contrast to the adenomas of classic FAP, the adenomas of AFAP are more commonly flat, depressed, or polypoid adenomas. Specifically, in flat adenomas, the adenoma lacks a concave surface and may be seen as a plaque on the mucosal surface, whereas in depressed adenomas, the adenoma surface lies below the level of the adjacent normal mucosa.
Upper GI polyps are found in virtually 100% of patients with FAP, most commonly fundic gland polyps and adenomatous polyps of the small bowel ( Fig. 12-3 ). The histologic features of fundic gland polyps in this condition are similar to their sporadic counterparts. Epithelial dysplasia is not an uncommon finding, characterized by nuclear enlargement, hyperchromasia, and loss of polarity within dilated oxyntic glands that extend to the polyp surface. However, high-grade dysplasia or frank carcinoma arising in a fundic gland polyp in FAP is rare. Adenomatous polyps within the small bowel are grossly and histologically similar to those that are sporadic in nature.
Gross findings
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Hundreds to thousands of adenomas evenly distributed throughout colorectum and appendix
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Adenomas tend to be larger in the rectosigmoid
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Adenomas range in size from microscopic (crypt adenomas) to pedunculated lesions greater than 1 cm in diameter
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The rectum is occasionally spared, particularly in AFAP
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Colorectal carcinomas may be multifocal
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No differences in the distribution or pathology of colorectal adenomas or carcinomas among sporadic or inherited forms
Microscopic findings
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Grossly and histologically identical to sporadic adenomas
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Early adenomas consist of small tubules lined by adenomatous epithelium that may be unicryptal, bicryptal, or tricryptal lesions in grossly normal appearing mucosa
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When multiple crypts become involved by adenomatous epithelium, more typical polypoid configuration is seen grossly
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Continued proliferation results in pedunculated tubulovillous gross appearance
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AFAP more commonly associated with flat, depressed, or polypoid adenomas
Genetics
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As a result of homozygous inactivation of the APC gene on chromosome 5q
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Mutations within the mutation cluster region in exon 15 associated with classic FAP
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Mutations in the 5′ region of the APC gene associated with AFAP
Differential diagnosis
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Chronic IBD with pseudopolyposis
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Peutz-Jeghers syndrome
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Juvenile polyposis coli syndrome (JPS)
Ancillary studies
Genetic testing for germline mutations in the adenomatous polyposis coli ( APC ) gene identifies 95% of patients with FAP. Germline mutations in the MYH gene have been reported in a subset of patients with polyposis coli, no germline APC mutation, and a family history compatible with recessive inheritance.
Differential diagnosis
Few entities enter into the differential diagnosis of the classic form of FAP because polyposis syndromes are generally rare and the histopathologic features of this disease are diagnostic. Differentiation from other polyposis syndromes may become problematic in the absence of an appropriate clinical history.
Prognosis and therapy
The key to the management of FAP is to identify presymptomatic individuals, predominantly through screening of relatives of affected patients. The diagnosis can easily be made or excluded by sigmoidoscopy or barium enema examinations performed annually beginning at 10 to 12 years of age with histologic confirmation of adenoma. Further workup of the colon is not required other than to rule out the presence of an infiltrating carcinoma. The development of an infiltrating carcinoma is inevitable by the age of 50 years in the absence of a total or subtotal proctocolectomy. Thus surgical management is recommended even in asymptomatic individuals who have not completed puberty.
Preservation of the rectum may be considered for those patients with few rectal polyps. However, this segment must be continuously monitored for the development of adenomas and carcinomas, in that some reports suggest more than 50% of patients will develop carcinomas in this region despite semiannual surveillance. A recent approach to the surveillance of the rectal stump is to treat these patients with nonsteroidal anti-inflammatory drugs such as sulindac. Patients who undergo prophylactic colectomy may still die of carcinomas arising in other sites, most commonly periampullary carcinomas. Thus evaluation of the upper GI tract is also necessary at the time of diagnosis of colonic disease and afterward every 1 to 3 years at least.
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Peutz-jeghers syndrome
Clinical features
PJS is the second most common form of intestinal polyposis, with an incidence approximately one tenth that of FAP. Similar to FAP, PJS is inherited in an autosomal dominant pattern. However, unlike FAP, the inherited dominant allele shows a variable and incomplete penetrance. PJS consists of two major and characteristic components: hamartomatous polyps involving the entire GI tract and pigmented macules involving the mucous membranes and skin.
The diagnosis of PJS can be made in infancy because most patients develop mucocutaneous pigmentation within 2 years, and small bowel hamartomatous polyps are frequently symptomatic. More than 95% of patients with PJS demonstrate pigmentation of the mucocutaneous membranes at birth, specifically around the nose, lips, buccal mucosa, hands and feet, genitalia, and perianal region ( Fig. 12-4 ). The pigmentation of PJS can easily be distinguished from freckles because freckles are not present at birth, are sparse near the lips, and never involve the mucous membranes. While the pigmentation of the skin may fade, the melanin deposits of the buccal mucosa persist throughout life.
Benign complications of PJS predominate in the pediatric population. Jejunal and ileal hamartomatous polyps often produce intussusception, leading to a partial or total bowel obstruction. When located within the rectum, hamartomatous polyps may prolapse, resulting in torsion, infarction, and GI bleeding. In adults with PJS, morbidity and mortality are related to the development of cancer. Tumors can develop in multiple organ sites in addition to the GI tract, including the breast, lung, pancreas, uterus, ovary, cervix, and Sertoli cells of the testis. Unique ovarian neoplasms may affect up to 12% of female patients with this syndrome, whereas hormonally active Sertoli cell testicular tumors may occur in males. Breast cancers, often bilateral, may be found in young women, with the breast cancer risk not unlike that found for the BRCA1 and BRCA2 genes.
Definition
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An autosomal dominantly inherited syndrome characterized by GI hamartomatous polyps and pigmented macules of mucous membranes and skin
Incidence and location
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1 in 200,000 live births
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Second most common polyposis syndrome
Morbidity and mortality
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Benign complications (intussusception and obstruction, torsion, infarction and bleeding) predominate in the pediatric population
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73% incidence of malignancies involving the reproductive organs, breast, or GI tract in adult population
Gender, race, and age distribution
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Males and females affected equally
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No racial or ethnic predilection
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Symptoms begin in infancy
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Average age of diagnosis of polyps is 25 years
Clinical features
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Pigmented lesions of the mucous membranes develop by 2 years of age
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Hamartomatous polyps present throughout the intestinal tract, most commonly the small bowel (jejunum)
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Polyps typically number in the tens
Prognosis and therapy
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93% lifetime risk of cancer in both intestinal and extraintestinal organs
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Screening and regular surveillance of high-risk organs (GI tract, breast, pancreas, reproductive organs)
Pathologic features
Gross findings
Hamartomatous polyps occur throughout the GI tract. In decreasing frequency, the most common sites of polyp formation are the jejunum, ileum, colon, stomach, duodenum, and appendix. Intestinal polyps are typically present in the dozens. They may be sessile or pedunculated, and often show a smooth, lobulated surface. The size of Peutz-Jeghers (PJ) polyps ranges from a few millimeters to several centimeters in diameter.
Microscopic findings
Although PJ polyps are not easily distinguished from adenomatous or inflammatory polyps based on their gross appearance, their histologic appearance is quite distinctive and characterized by a hyperplastic mature epithelium appropriate to the anatomic site and divided by broad bands of mature smooth muscle ( Figs. 12-5 and 12-6 ). Small intestinal PJ polyps consist of crypts and villi of varying lengths divided by arborizing bands of smooth muscle. The muscle fibers commonly fan out from the center of the polyp to form a treelike appearance. The lamina propria is normal. Cells normally present within small bowel mucosa, including absorptive enterocytes, Paneth cells, goblet cells, and argentaffin cells, are present within the hyperplastic epithelium of the PJ polyp ( Fig. 12-7 A and B). Erosion of the surface epithelium is common, particularly for larger polyps, and may be associated with reactive and regenerative epithelium containing prominent mitoses.
Colonic PJ polyps demonstrate similar histologic features, but less developed than those seen for their small bowel counterparts. Specifically, PJ polyps of the colon contain elongated, branched crypts that may simulate a villous architecture. Goblet cells are the predominant cell type lining the hyperplastic crypts, although absorptive cells may also be present (see Fig. 12-7 C). The replication zone at the crypt base is relatively short, with mature cells predominantly lining the crypts. However, in the presence of surface erosion, this replication zone may become expanded as the epithelial cells become regenerative. Arborizing bands of smooth muscle are less frequent in colonic PJ polyps than in the small bowel. Smooth muscle is not present in all polyps, particularly small lesions.
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