Gastrointestinal Polyposis Syndromes

Clinical Features

Numerous conventional adenomas occur in the colon and in the upper GI tract in three major familial settings: the classic and attenuated FAP syndrome and the MUTYH -associated polyposis (MAP) syndrome.

Classic FAP is an autosomal dominant syndrome caused by pathogenic germline mutations in the adenomatous polyposis coli (APC) gene, affecting approximately 1 in 8000 to 10,000 individuals. Males and females are equally affected, and fewer than 1% of all colorectal cancers occur in patients with FAP. The disorder is characterized by the development of adenomas at an early age along with characteristic extracolonic manifestations. Patients with classic FAP have more than 100 adenomas at presentation, and the colon may be completely carpeted with hundreds to thousands of adenomas in severe cases. The polyp burden can be lower in children because adenomas usually appear in the second decade of life. Colorectal cancers occur at an average of 39 years, and nearly all patients develop cancer by the time they are 45 to 50 years of age. However, cancer is exceedingly rare before 15 years of age, and prophylactic colectomy is typically performed around this age in most patients.

Duodenal adenomas occur in almost all patients with FAP and typically involve the periampullary region and the distal duodenum. Duodenal adenocarcinomas occur in 5% to 10% patients and are a common cause of death in patients who have undergone a prophylactic colectomy. Gastric involvement occurs in more than half of patients with FAP and typically manifests as numerous fundic gland polyps, some of which may show cytologic dysplasia. However, gastric cancer in the setting of FAP occurs in association with conventional or pyloric gland adenomas and not fundic gland polyps. A distinct FAP variant called GAPPS has been recently described and is discussed in greater detail in the chapter on gastric neoplasms ( Chapter 4 ).

Extraintestinal manifestations in FAP are common and include osteomas, epidermoid cysts, fibromas, supernumerary teeth, odontomas, and congenital hypertrophy of the retinal pigment 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. The small intestinal mesentery and the abdominal wall or the extremities are common sites of involvement with this tumor. FAP is also associated with an increased risk of extracolonic tumors, such as papillary thyroid carcinoma, childhood hepatoblastoma, benign and malignant adrenocortical tumors, and brain tumors, particularly medulloblastoma.

Gardner’s and Turcot syndromes were terms used in the past to describe a subset of patients with FAP, but their use is no longer recommended; the former because nearly all patients with FAP have this constellation of findings and the latter because many of these patients ended up being eventually diagnosed as having Lynch syndrome rather than FAP.

An attenuated form of FAP (AFAP) is also recognized that shows autosomal dominant inheritance and is distinguished from classic FAP by the presence of fewer adenomas (<100), later onset of adenomas (35–45 years of age), later onset of colorectal cancer (mean age, 55 years), and a lower lifetime risk of colorectal cancer (80%). However, it must be recognized that colonoscopic methods using enhanced visualization may show more than 100 adenomas, which is an arbitrary threshold for distinguishing the classic and attenuated forms of the disease. Adenomas show preferential right colon involvement in AFAP, and the rectum may be relatively spared. Upper GI adenomas and fundic gland polyps occur similar to classic FAP but extracolonic manifestations may be limited. The diagnosis of AFAP can be excluded if any family member shows more than 100 adenomas before 30 years of age.

MUTYH - (formerly known as MYH -) associated polyposis (MAP) syndrome is an autosomal recessive syndrome caused by biallelic germline mutations in the MUTYH gene. Patients typically present in the fifth or sixth decade of life and show between 10 and 100 adenomas, but more than 100 adenomas may be seen in one-third of all patients. Germline MUTYH mutations are identified in roughly 30% of APC -negative patients with 10 to 100 adenomas and 14% of APC -negative patients with 100 to 1000 adenomas. Duodenal polyposis occurs in about 25% of patients and duodenal cancer in 4%. Sebaceous gland tumors and congenital hypertrophy of retinal pigmentary epithelium is uncommon, and the lifetime risks of extraintestinal manifestations, similar to FAP, is about 38%. Serrated polyps also occur in almost 50% of patients with MAP and are caused by KRAS gene mutations that are typically G:C to T:A transversions that are a consequence of defective DNA repair.

According to current screening guidelines for adenomatous polyposis syndromes, patients with a personal history of more than 10 cumulative colorectal adenomas or those with fewer than 10 adenomas but a positive family history or adenomas with FAP-type extracolonic manifestations (duodenal or ampullary adenoma, desmoids; papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium [CHRPE]), epidermal cysts, and osteomas should be tested. Genetic testing should include APC and MUTYH gene mutation analysis.

Pathologic Features

Gross Findings

Adenomas develop throughout the entire colorectum and appendix and macroscopically resemble their sporadic counterparts in classic FAP. The number, size, and shape of the adenomas can vary greatly between patients. Although 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 ( Figs. 11.1A–D ). The size can vary from diminutive to large, and lesions may be sessile, pedunculated, or flat lateral spreading type. Colorectal carcinoma, when present, may be multifocal and shows a relative predilection for the left colon.

In AFAP, the polyp burden is much lower and typically less than 100, preferentially involving the right colon ( Fig. 11.1E ). Sparing of the rectum by adenomatous polyps may also be suggestive of a diagnosis of AFAP, as can the presence of numerous flat adenomas. The latter is not a specific feature and may be seen in patients with Lynch syndrome as well.

In addition to conventional adenomas, patients with MAP can also harbor a variable number of serrated polyps. The polyp burden is much lower than classic FAP in most patients, but a subset may present with severe polyposis similar to FAP.

Microscopic Findings

The adenomas and carcinomas that arise in FAP, AFAP, and MAP are morphologically indistinguishable from their sporadic counterparts ( Fig. 11.2A ). Similar to sporadic lesions, the incidence of malignancy is related to adenoma number, size, and histology. Single, double, or tricryptal adenomas are common in sections taken from grossly normal mucosa ( Figs. 11.2B and C ) in classic FAP and can be seen in AFAP as well. A variable number of serrated polyps can be seen in MAP, and they may resemble sporadic hyperplastic polyps or sessile serrated polyps. The predominance of adenomas is indicative of the correct diagnosis in such cases, but in patients with a low polyp burden and a combination of adenomas and serrated polyps, it may be virtually impossible to distinguish MAP from serrated polyposis syndrome (SPS; see later), and genetic testing is key to establishing the diagnosis. Carcinomas in MAP often show a high number of intratumoral lymphocytes and a mucinous adenocarcinoma phenotype, mimicking microsatellite instability high (MSI-H) colorectal carcinomas, but DNA mismatch repair immunohistochemistry (IHC) shows intact staining in the tumor cells.

Upper GI polyps are found in virtually 100% of patients with FAP, most commonly fundic gland polyps and small bowel adenomas involving the ampulla and distal duodenum ( Fig. 11.3 ). The histologic features of fundic gland polyps in FAP are similar to their sporadic counterparts, but dysplasia is more common in the syndromic setting and manifests as nuclear enlargement, hyperchromasia, and loss of polarity within dilated oxyntic glands that extends to the polyp surface. However, high-grade dysplasia or carcinoma arising in a fundic gland polyp in FAP is extremely rare. In additional to conventional adenomas, pyloric gland adenomas ( Fig. 11.4 ), traditional serrated adenomas, and adenomas with hybrid features have also been described in FAP. The spectrum of upper GI findings in AFAP and MAP is similar to classic FAP, but the polyp burden is much lower than in FAP. Mesenchymal tumors, such as desmoid and Gardner fibroma, that occur in association with adenomatous polyposis syndromes are discussed in Chapter 7 .

Genetic testing for germline mutations in the APC gene identifies most patients with FAP and AFAP. As mentioned earlier, germline mutations in the MUTYH gene are detected in a subset of patients resembling FAP or AFAP who are negative for germline APC mutation. MUTYH gene is now universally included in the panels used for germline testing of patients with suspected hereditary polyposis syndromes.

Adenomatous Polyposis Syndromes—Pathologic Features

Gross Findings

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  Hundreds to thousands of adenomas evenly distributed throughout colorectum and appendix in classic familial adenomatous polyposis (FAP); lower polyp burden in attenuated form of FAP (AFAP) and MUTYH -associated polyposis (MAP)

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  Adenomas tend to be larger in the rectosigmoid in FAP; right-sided dominance, relative rectal sparing, and flat adenomas more common in AFAP; serrated polyps more common in MAP

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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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  Colorectal carcinomas may be multifocal

Microscopic Findings

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  Adenomas in FAP, AFAP, and MAP are identical to sporadic adenomas

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  Random sections of grossly normal mucosa may show early adenomas consisting of small tubules lined by adenomatous epithelium involving one or just a few crypts

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  Adenomas may be tubular, tubulovillous, or villous

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  Pyloric gland adenomas and traditional serrated adenomas can also occur

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  Fundic gland polyps can be numerous and show dysplasia

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  Carcinomas in MAP have high number of intratumoral lymphocytes and may be of a mucinous phenotype

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  Gastric adenocarcinomas in FAP arise in adenomas and not in fundic gland polyps

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  Duodenal adenoma and adenocarcinomas and desmoid tumors also resemble their sporadic counterparts

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  Gardner fibroma is a distinctive mesenchymal tumor in children affected with FAP

Genetics

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  Germline APC gene mutations in FAP and AFAP

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  Mutations within the mutation cluster region in exon 15 is associated with classic FAP

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  Mutations in the 5′ or 3′ region or exon 9 of the APC gene associated with AFAP

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  Biallelic germline mutation involving the MUTYH gene in MAP

Differential Diagnosis

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  Adenomatous polyposis related to other germline mutations ( NTHL-1, POLE, MSH-3, AXIN2 )

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  Constitutional mismatch repair deficiency syndrome

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  Immune deficiency–associated polyposis

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  Serrated polyposis syndrome

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  Hereditary mixed polyposis syndrome

Differential Diagnosis

Classic FAP is easy to recognize when the adenoma burden is massive. AFAP and MAP may be hard to distinguish from each other, but the presence of a significant number of serrated polyps is in favor of MAP. A combination of adenomas and serrated polyps can also be seen in SPS, discussed later, but the predominant polyp types in the latter entity are hyperplastic polyps and sessile serrated polyps, whereas MAP shows a predominance of adenomas.

NHTL1 -associated polyposis (NAP) is an autosomal recessive base excision repair disorder that may resemble a Lynch-like syndrome or MAP because of the presence of sebaceous skin tumors and MSI-H phenotype of carcinomas. However, the tumors in the setting of NAP have a characteristic C→T somatic mutation spectrum. Polymerase proofreading–associated polyposis (PPAP) is an autosomal dominant disorder caused by mutations in POLD1 and POLE . Adenomas occur in the colon as well as the upper GI tract, similar to classic FAP, but at a later age of onset. The morphology of adenomas and carcinomas resembles sporadic lesions, but a characteristic hypermutant somatic mutation genotype is typically seen. MSH-3- and AXIN2- associated polyposis syndromes have also been described and can result in multiple adenomas involving the colon similar to FAP. Constitutional mismatch repair deficiency syndrome is an autosomal recessive disorder caused by biallelic inactivation in one of the four DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) . This contrasts with the autosomal dominant inheritance in Lynch syndrome caused by germline mutation in the same DNA mismatch repair genes. Brain tumors, particularly glioblastomas, are present in nearly 50% of patients, and tumors of the GI tract and hematologic malignancies are commonly seen. Similar to FAP, patients are susceptible to developing multiple adenomas and carcinoma of the colon in childhood or young adulthood. Immunohistochemistry shows loss of the involved DNA mismatch repair protein in both the normal epithelium and the tumor cells. Hereditary mixed polyposis syndrome (HMPS) is a rare condition caused by abnormalities in the GREM1 gene. Patients develop not just conventional adenomas but also inflammatory polyps, hyperplastic polyps, and mucosal prolapse-type polyps and have a high risk of colorectal cancer.

Prognosis and Therapy

The key to the management of FAP, AFAP, and MAP 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 an adenoma. Prophylactic colectomy is recommended in classic FAP even in asymptomatic individuals who may not have completed puberty. This may be delayed in AFAP given the later onset of adenomas and carcinomas. Apart from polyp burden in a patient, the youngest age for diagnosis of cancer in the family can also be a reasonable guide for timing a prophylactic colectomy. MAP shows an autosomal recessive inheritance, and no relevant family history of adenomas or cancer may be detected. In view of limited longitudinal data, the screening and surveillance recommendations for MAP are currently similar to those for AFAP. Patients with a prophylactic colectomy typically receive a small intestinal J-pouch reconstruction that serves as a neorectum. The remnant native rectum and the ileal J-pouch continue to be at risk, and periodic surveillance is recommended for early detection and removal of adenomas and cancer.

Patients who undergo prophylactic colectomy may still die of carcinomas arising in other sites, most commonly periampullary duodenal carcinomas or from desmoid tumors. Management of duodenal polyposis is often stratified using the Spiegelman classification that includes polyp number, size, histology, and degree of dysplasia. Surveillance may not be a viable option after adenomas develop or involve the ampulla, and a Whipple resection may be indicated for these patients. Gastrectomy is seldom indicated given the low risk of malignant transformation of gastric fundic gland polyps and adenomas. Endoscopic resections of any large lesions are the standard of care, and surgical resection is reserved for patients with deeply invasive adenocarcinomas.

Clinical Features

Serrated polyposis syndrome is an underrecognized entity characterized by the presence of multiple serrated polyps throughout the colorectum. Concurrent carcinoma may be present at initial diagnosis in a subset of patients. There is no sex predominance. Prevalence in screening colonoscopy patients may be as high as 0.1%, and the majority of patients are diagnosed in the sixth decade of life. However, the age range at first diagnosis is quite broad. A diagnosis of SPS may be rendered when one of two criteria is met: (1) five or more serrated polyps (any histological subtype) proximal to the rectum, with all being at least 5 mm in size and at least two being 10 mm or more in greatest dimension or (2) more than 20 serrated polyps of any size distributed throughout the colon with at least five being proximal to the rectum. The criteria are applied in a cumulative manner over several examinations and do not require all polyps to be present concurrently at the same colonoscopy. No germline mutation has been identified, although RNF43 mutations have been reported in some families. Cigarette smoking and high body mass index are risk factors, and the risk of colorectal cancer is increased not just in the patient but also in first-degree relatives.

Pathologic Features

Gross Findings

The number of polyps is variable but usually reported to be within the 10 to 60 range. A more severe polyposis phenotype is rare which is why the disease often goes undiagnosed. The polyps show macroscopic appearance of a hyperplastic polyp or sessile serrated polyp. This is partly determined by the predominant location of the polyp burden. More proximal lesions are likely to be flat sessile polyps that blend into colonic mucosal folds and are easily missed. Distal lesions are more commonly sessile but elevated polyps that resemble sporadic hyperplastic polyps. Concurrent carcinoma may be present ( Fig. 11.5 ) as a polypoid, flat, or depressed mass with ulceration.

Microscopic Findings

Hyperplastic polyps, sessile serrated polyps with or without dysplasia, traditional serrated adenomas, or unclassified serrated polyps are included in the polyp count when rendering a diagnosis of SPS. The polyps in SPS resemble their sporadic counterparts. Hyperplastic polyps ( Fig. 11.6A ) show elongated colonic crypts with serrated architecture and a narrow base lined by cells with abundant microvesicular type mucin. Sessile serrated polyps are larger in size and show architectural distortion with dilated crypt bases and crypt disarray ( Figs. 11.6B and C ). Dysplastic change may be present and can resemble either traditional serrated adenoma or a conventional tubular adenoma ( Fig. 11.7 ). Traditional serrated adenomas also resemble their sporadic counterparts and show serrated crypts with abundant eosinophilic cytoplasm and nuclear stratification and hyperchromasia similar to an adenoma. Conventional adenomas may also be present in SPS and are an independent predictor of high risk for progression to carcinoma. The histologic type of polyp or largest polyp size or distribution of polyps within the colon are not predictive of cancer risk. Cancers in SPS may resemble MSI-H tumors, but nearly half of all cancers that occur in this setting are microsatellite stable with intact expression of DNA mismatch repair proteins.

Serrated Polyposis Syndrome—Pathologic Features

Gross Findings

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  Variable number and size of polyps, typically 10 to 60 in number

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  Flat, sessile lesions more common proximally

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  Distal small sessile elevated polyps resemble sporadic hyperplastic polyps

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  Concurrent mass lesions may be present in cases with carcinoma

Microscopic Findings

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  Serrated polyps in serrated polyposis syndrome (SPS) resemble sporadic hyperplastic polyps, sessile serrated polyps, and traditional serrated adenoma

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  Sessile serrated polyps may show cytologic dysplasia

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  Concurrent conventional adenomas can be seen and are predictive of a higher risk of cancer

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  Adenocarcinoma in SPS may show features of microsatellite instability high phenotype, but half of all cancers are microsatellite stable

Genetics

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  No high prevalence germline mutations identified so far

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  RNF43 germline mutations reported in some families

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  Increased risk of colorectal cancer in first- and second-degree relatives is indicative of a familial predisposition

Differential Diagnosis

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  MUTYH polyposis syndrome

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  Hereditary mixed polyposis syndrome

Differential Diagnosis

A combination of serrated polyps and adenomas can also be seen in MAP but the predominant histologic type in the latter is a conventional adenoma, whereas SPS is characterized by a preponderance of serrated polyps. HMPS is characterized by presence of serrated polyps and adenomas in addition to juvenile-type hamartomatous polyps, some of which may be dysplastic.

Prognosis and Therapy

Up to 35% of patients with SPS have a synchronous colon cancer, indicating the increased malignant potential associated with this condition. Annual colonoscopic surveillance is typically recommended after complete removal of all large polyps. Colectomy is reserved for those with a high polyp burden that precludes complete polyp removal and close surveillance.