Clinical Overview

Peutz-Jeghers syndrome (PJS) is a rare, highly penetrant, autosomal dominant disorder characterized by hamartomatous polyposis and mucocutaneous pigmentation. Polyps may occur anywhere along the gastrointestinal tract but occur most consistently in the jejunum. Extraintestinal sites of PJS polyps include kidney, ureter, gallbladder, bronchus, and nasal passages. About one-third of patients will develop polyp-related symptoms by age 10 years and close to two-thirds by age 20 years.

The incidence of PJS is estimated to be 1 in 8300 to 1 in 200,000 live births ; 25% of cases appear to be nonfamilial. PJS has been reported worldwide and occurs in males and females equally. There is variability in both the severity of disease as well as age of onset of symptoms.

The hyperpigmented macules of PJS develop in 95% of affected individuals and arise most commonly in the perioral region, around the eyes and nostrils, on the buccal mucosa, the perianal area, and on the digits of hands and feet. They usually appear by the end of the first year of life and are almost always present by age 5 years. The macules may be dark blue to dark brown, vary in size from 1 to 5 mm, and may fade in puberty and adulthood, and are not precancerous.

Classical PJS intestinal polyps are hamartomatous and experienced pathologists are capable of distinguishing PJS polyps from juvenile polyps. PJS polyps manifest characteristic hypertrophy or hyperplasia of the smooth-muscle layer branching in tree-like fashion (arborizes) into the superficial epithelial layer. Multiple adenomas may also occur, especially in the colon.

Cancer Risk

PJS carries an increased risk for multiple benign and malignant tumors (see Table 1 ). The cumulative risk of any cancer is 67% to 85% by age 70 and the cumulative risk for CRC is 3% (40 years), 5% (50 years), 15% (60 years), 39% (70 years). The risk to age 70 for cancers of the pancreas, uterus/ovary/cervix, breast, and lung were 11%, 18%, 45%, and 17%, in the same series, respectively. An increased risk of primitive biliary cancer was reported in PJS. No correlation has been found between risk of cancer and severity of polyposis or presence of pigmentation.

Molecular Basis of Disease

Germline mutations in STK11 (also known as LKB1 ) encoding a tyrosine kinase on chromosome 19p13.3 have been identified in nearly all PJS families and 94% of patients with PJS overall. Families without an identified mutation do not differ clinically or ethnically from those with a mutation. Only one transcript is known, a 433– amino acid protein that is ubiquitously expressed and present primarily in the cytoplasm and to a lesser extent in the nucleus. STK11 is a highly conserved gene with approximately 88% and 84% homology, respectively, with mouse and Xenopus homologs. STK11 is the only tyrosine kinase known to function as a tumor suppressor by physically associating with TP53 to regulate TP53 -dependent apoptosis pathways. STK11 also interacts with PTEN , which is responsible for other hereditary hamartoma syndromes and also plays a role in the vascular endothelial growth factor (VEGF) pathway and cellular polarity.

Inactivation of STK11 is a critical early event in the development of hamartomas and adenocarcinomas. Adenocarcinomas in Peutz-Jeghers syndrome demonstrate altered TP53 expression and loss of heterozygosity (LOH) in 17p and 18q. Microsatellite instability, LOH near the APC gene, or KRAS mutations have been identified in some tumors, with indications that tumorigenic potential of STK11 mutations is mediated through alternative mechanisms in different tissues, especially those in which hamartoma development is not a feature.

Hamartomatous polyps have generally been considered to have a very low malignant potential and it was uncertain that PJS-associated hamartomas were the premalignant lesions in PJS. However, molecular and histologic studies have confirmed that hamartomatous polyps can undergo malignant transformation in PJS. It is not known whether inactivation of both STK11 alleles is necessary for carcinogenesis or if a 50% decrease in protein expression is sufficient (haploinsufficiency). Data from studies in lkb1 −/+ and lkb1 −/− mice support both possibilities.

Clinical Risk Management

The cancer risk with PJS supports efforts at directed surveillance strategies for early detection of tumors. Multiple guidelines based solely on expert opinion exist; none have been validated in controlled trials. Table 2 shows one set of screening recommendations for PJS. A guiding principle in management is prevention of bowel intussusceptions or obstructions. In one series, laparotomy for bowel obstruction was performed in 30% of individuals by age 10 years and in 68% by age 18 years. Substantial morbidity arises from short-gut syndrome, as a consequence of multiple small-bowel resections for intussusception; therefore, prophylactic removal of small bowel polyps is advised. For small bowel polyps not accessible endoscopically, surgery has been recommended if symptomatic or when larger than 1.5 cm. Intraoperative small bowel endoscopy can allow removal of all identifiable polyps and may decrease the overall frequency of laparotomy.

Clinical genetic testing for PJS is available. If a disease-causing mutation has been identified, it is appropriate to offer genetic testing to at-risk relatives and, if positive, surveillance is indicated. If no disease-causing mutation is found in an individual with PJS, then first-degree relatives must be advised that they may still be at risk for PJS and that PJS cancer surveillance is advisable.

Clinical Overview

Juvenile polyposis (JP) is an autosomal dominant disorder characterized by multiple (5–200) hamartomatous polyps of the gastrointestinal tract. It is the most common of the hamartomatous polyp syndromes. Population prevalence is estimated to be between 1 in 16,000 and 1 in 100,000. Twenty percent to 50% of cases are inherited.

Solitary juvenile polyps may be seen in approximately 2% of healthy children but these are seldom dysplastic and are not associated with increased malignancy or extracolonic manifestations. In JP, “juvenile” refers to the type of polyp (resembling sporadic inflammatory hamartomatous polyps of childhood) rather than the age of onset, although most affected individuals have some polyps by age 20 years. The hamartomas of JP have a frondlike growth pattern and fewer stroma and dilated glands with more proliferative smaller glands compared with solitary, sporadic juvenile polyps.

Clinical criteria for defining JP have been proposed ( Box 1 ). Although only 5 polyps have been proposed as the minimum number for diagnosis, some individuals will have more than 100 polyps. In a review of 272 individuals with JP of undefined genetic subtype, 98% had involvement of the colorectum, 14% of the stomach, 7% of the jejunum and ileum, and 2% of the duodenum. Polyps usually range from 5 to 50 mm in size, can be single or multilobulated, are spherical in shape, and commonly show surface erosion. Clinical symptoms of JP may include bleeding, diarrhea, abdominal pain, intussusceptions, and rectal prolapse and even protein-losing enteropathy. Digital clubbing has been noted, perhaps owing to the overlap with hereditary hemorrhagic telangiectasia and arteriovenous shunting in those patients.

JP may be misdiagnosed, as it shares clinical features with several other colonic hamartomatous polyp syndromes (Cowden, Bannayan-Riley-Ruvalcaba, Peutz-Jeghers, Basal Cell Nevus/Gorlin) so is therefore a diagnosis of exclusion. Physical examination, family history, and molecular testing may help differentiate between these possibilities.

Cancer Risk

Most juvenile polyps are benign but malignant transformation may occur resulting in increased lifetime risk for cancers of the colon (10%–40%), stomach (21%), and less commonly involving the small bowel and pancreas. The lifetime risk of cancers has been hard to define and may vary with underlying genetic cause and is likely reduced by screening polypectomies.

Malignant transformation is suspected to follow a juvenile polyp → adenomatous change → dysplasia → carcinoma sequence. However, additional work is required to determine if individuals with JP are also predisposed to malignancy separately from the predisposition to polyps.

Molecular Basis of Disease

JP is clinically and genetically heterogeneous. Three genes, SMAD4 , BMPR1A, and ENG, have been implicated so far. Each encodes proteins of either transforming growth factor (TGF)-β or bone morphogenetic protein (BMP)-signaling pathways. The low combined mutation detection rate has prompted a search for other candidate genes/proteins within these pathways.

About 20% of individuals with JP have a mutation of SMAD (also known as MADH4 or DPC ). SMAD4 is part of the TGF-β signal transduction pathway. The SMAD gene family is on chromosome 18q21.1, adjacent to DCC (deleted in colon cancer). SMAD4 complexes combine with other members of the SMAD family of proteins to transmit the TGF-β growth-suppressing signal from the cell surface receptor to nuclear downstream targets, mediating apoptosis and growth inhibition. It has been postulated that the abundant stroma in JP may create an abnormal microenvironment, disrupting TGF-β signaling. This theory is supported by the fact that as hamartomatous polyps enlarge and mesenchymal component expands, they take on a serrated or villous-type configuration associated with epithelial dysplasia.

Mutations in BMPR1A ( ALK3 ) at 10q22.3, are found in about 20% to 25% of individuals with JP. BMPR1A is a serine-threonine kinase type I receptor of the TGF-β superfamily, which when activated leads to phosphorylation of SMAD4 . A reduced number of gastric polyps have been observed in BMPR1A mutation–positive patients compared with SMAD4 mutation–positive patients.

Mutations in ENG on chromosome 9q34.1 have been reported in very early onset JP. ENG encodes endoglin, an accessory receptor protein that binds to specific TGF-β proteins. Mutations in ENG are more often found in individuals with hereditary hemorrhagic telangiectasia (HHT). The combined syndrome of JPS and HHT (termed JPS/HHT) may be present in 15% to 22% of individuals with a SMAD4 mutation and has also been associated with ENG ( Table 3 ). The prevalence of ENG mutations in patients with JP without HHT has yet to be adequately described.

Clinical Risk Management

No evidence-based guidelines exist to determine optimal screening modalities or intervals in JP. Because of the perceived high risk for malignancies, guidelines based on expert opinion have advised that those affected with or who are at risk for JP receive a complete blood count, upper gastrointestinal endoscopy, and colonoscopy beginning from the onset of symptoms or the age of 15. If no polyps are found, screening should be repeated every 1 to 3 years. Any polyps found should be removed and screening should be annual or based on polyp burden until no polyps are found. For those with extremely numerous polyps, colectomy and/or gastrectomy may be indicated. Colorectal adenocarcinoma should be treated with definitive surgery, and consideration of total colectomy with or without ileorectal anastomosis based on clinical findings.

Clinical Overview

Juvenile polyposis (JP) is an autosomal dominant disorder characterized by multiple (5–200) hamartomatous polyps of the gastrointestinal tract. It is the most common of the hamartomatous polyp syndromes. Population prevalence is estimated to be between 1 in 16,000 and 1 in 100,000. Twenty percent to 50% of cases are inherited.

Solitary juvenile polyps may be seen in approximately 2% of healthy children but these are seldom dysplastic and are not associated with increased malignancy or extracolonic manifestations. In JP, “juvenile” refers to the type of polyp (resembling sporadic inflammatory hamartomatous polyps of childhood) rather than the age of onset, although most affected individuals have some polyps by age 20 years. The hamartomas of JP have a frondlike growth pattern and fewer stroma and dilated glands with more proliferative smaller glands compared with solitary, sporadic juvenile polyps.

Clinical criteria for defining JP have been proposed ( Box 1 ). Although only 5 polyps have been proposed as the minimum number for diagnosis, some individuals will have more than 100 polyps. In a review of 272 individuals with JP of undefined genetic subtype, 98% had involvement of the colorectum, 14% of the stomach, 7% of the jejunum and ileum, and 2% of the duodenum. Polyps usually range from 5 to 50 mm in size, can be single or multilobulated, are spherical in shape, and commonly show surface erosion. Clinical symptoms of JP may include bleeding, diarrhea, abdominal pain, intussusceptions, and rectal prolapse and even protein-losing enteropathy. Digital clubbing has been noted, perhaps owing to the overlap with hereditary hemorrhagic telangiectasia and arteriovenous shunting in those patients.

JP may be misdiagnosed, as it shares clinical features with several other colonic hamartomatous polyp syndromes (Cowden, Bannayan-Riley-Ruvalcaba, Peutz-Jeghers, Basal Cell Nevus/Gorlin) so is therefore a diagnosis of exclusion. Physical examination, family history, and molecular testing may help differentiate between these possibilities.

Cancer Risk

Most juvenile polyps are benign but malignant transformation may occur resulting in increased lifetime risk for cancers of the colon (10%–40%), stomach (21%), and less commonly involving the small bowel and pancreas. The lifetime risk of cancers has been hard to define and may vary with underlying genetic cause and is likely reduced by screening polypectomies.

Malignant transformation is suspected to follow a juvenile polyp → adenomatous change → dysplasia → carcinoma sequence. However, additional work is required to determine if individuals with JP are also predisposed to malignancy separately from the predisposition to polyps.

Molecular Basis of Disease

JP is clinically and genetically heterogeneous. Three genes, SMAD4 , BMPR1A, and ENG, have been implicated so far. Each encodes proteins of either transforming growth factor (TGF)-β or bone morphogenetic protein (BMP)-signaling pathways. The low combined mutation detection rate has prompted a search for other candidate genes/proteins within these pathways.

About 20% of individuals with JP have a mutation of SMAD (also known as MADH4 or DPC ). SMAD4 is part of the TGF-β signal transduction pathway. The SMAD gene family is on chromosome 18q21.1, adjacent to DCC (deleted in colon cancer). SMAD4 complexes combine with other members of the SMAD family of proteins to transmit the TGF-β growth-suppressing signal from the cell surface receptor to nuclear downstream targets, mediating apoptosis and growth inhibition. It has been postulated that the abundant stroma in JP may create an abnormal microenvironment, disrupting TGF-β signaling. This theory is supported by the fact that as hamartomatous polyps enlarge and mesenchymal component expands, they take on a serrated or villous-type configuration associated with epithelial dysplasia.

Mutations in BMPR1A ( ALK3 ) at 10q22.3, are found in about 20% to 25% of individuals with JP. BMPR1A is a serine-threonine kinase type I receptor of the TGF-β superfamily, which when activated leads to phosphorylation of SMAD4 . A reduced number of gastric polyps have been observed in BMPR1A mutation–positive patients compared with SMAD4 mutation–positive patients.

Mutations in ENG on chromosome 9q34.1 have been reported in very early onset JP. ENG encodes endoglin, an accessory receptor protein that binds to specific TGF-β proteins. Mutations in ENG are more often found in individuals with hereditary hemorrhagic telangiectasia (HHT). The combined syndrome of JPS and HHT (termed JPS/HHT) may be present in 15% to 22% of individuals with a SMAD4 mutation and has also been associated with ENG ( Table 3 ). The prevalence of ENG mutations in patients with JP without HHT has yet to be adequately described.

Clinical Risk Management

No evidence-based guidelines exist to determine optimal screening modalities or intervals in JP. Because of the perceived high risk for malignancies, guidelines based on expert opinion have advised that those affected with or who are at risk for JP receive a complete blood count, upper gastrointestinal endoscopy, and colonoscopy beginning from the onset of symptoms or the age of 15. If no polyps are found, screening should be repeated every 1 to 3 years. Any polyps found should be removed and screening should be annual or based on polyp burden until no polyps are found. For those with extremely numerous polyps, colectomy and/or gastrectomy may be indicated. Colorectal adenocarcinoma should be treated with definitive surgery, and consideration of total colectomy with or without ileorectal anastomosis based on clinical findings.

Clinical Overview

Familial adenomatour polyposis (FAP) is a highly penetrant, autosomal dominant syndrome caused by germline mutations of the APC (adenomatous polyposis coli) gene at 5q21. FAP has a frequency of 1 in 5000 to 10,000 live births and affects males and females equally. It accounts for 1% of all CRC. Ten percent to 30% of cases arise from de novo mutations. It was the first CRC syndrome to be recognized clinically and the first for which a gene was identified. It offers a model for the adenoma → carcinoma paradigm that is shared by sporadic as well as several familial colorectal cancers and, through this, offers a basis for the concept of all CRC being “genetic.”

FAP is the result of an inactivating mutation in APC and clinical presentation may be associated with the site of mutation, although it may also be clinically heterogeneous even within the same family. This suggests a role for modifier genes and/or environmental factors in modulating disease expression. Colorectal polyposis, numbering from hundreds to thousands, is nearly pathognomic of FAP. Polyps are generally less than 1 cm and occur throughout the colorectum with a predilection for sigmoid colon and rectum. They may be sessile or pedunculated with histology varying from tubular to villous adenoma.

FAP has multiple extracolonic manifestations involving all 3 embryologic layers. The term Gardner syndrome refers to FAP plus extracolonic features. Endodermal lesions include gastric and small bowel polyps and carcinomas. Mesodermal abnormalities include desmoid tumors, osteomas, and dental abnormalities. Ectodermal lesions can affect the eye, brain, and skin. The combination of CRC and brain tumors was referred to as Turcot syndrome. However, molecular studies have shown that although the combination of colonic polyposis and medulloblastoma is associated with APC mutations, the combination of CRC and glioblastoma is associated with defective mismatch repair genes and was also called Turcot syndrome. Hence, there seems to be little clinical value in perpetuating the use of this ambiguous term.

Desmoid tumors are histologically benign clonal neoplasms composed of fibrous tissue. They arise as mostly intra-abdominal soft tissue tumors and occur in approximately 10% to 25% of patients with FAP. Trauma has been suggested to be a factor, as 84% of FAP-associated desmoids developed within 5 years of abdominal surgery in one series. They do not usually metastasize but they can be highly locally invasive and can cause significant mass effect, obstruction, pain, and death. Desmoid tumor may also occur sporadically or in a hereditary manner without colon findings, but in cases of families with desmoid tumors or individuals with 2 or more desmoids, attempts should be made to exclude APC mutation.

Osteomas may occur in any bone but often localize to the face or skull. Dental abnormalities affect 70% of patients with FAP and include supernumerary teeth, congenitally absent teeth, fused roots, and osteomas of the jaw. Depending on the location, they can lead to symptoms and identification of FAP. Congenital hypertrophy of retinal pigment epithelium (CHRPE) is an asymptomatic hamartoma of the retinal epithelium occurring in 66% to 92% of patients with FAP.

“Attenuated FAP” (AFAP), defined as fewer than 100 synchronous colorectal adenomas, shows a right-sided colonic predilection with rectal sparing and a later presentation. Extracolonic manifestations may occur similar to classic FAP. It has been linked to mutations in exons 1 to 4, 3′ regions of APC distal to codon 1580, and the alternatively spliced site of exon 9. However, some patients with this phenotype and no identified APC mutation have been shown to have compound heterozygous mutations in the base excision repair gene MYH, leaving open the possibility that cases of AFAP may be hitherto unidentified MYH -associated polyposis (MAP). If germline APC mutation testing is negative in suspected AFAP, testing for MYH mutations may be indicated.

Cancer Risk

The age at onset of colorectal adenomas is variable, being present in only 15% of FAP gene carriers at age 10 years, 75% by age 20, and 90% by 30 years if untreated. In a review of more than 180 families and 922 affected individuals, the mean age at presentation was 27 and mean age at colectomy was 29.

Extracolonic tumors ( Table 4 ) cause significant morbidity in FAP with desmoid tumors and duodenal cancers being the second and third commonest causes of death after CRC. In one series, 88% of patients with FAP developed duodenal polyps, often near the ampulla and papilla, with a lifetime risk of duodenal carcinoma of 4% to 12%. Duodenal polyps may be associated with different germline APC mutations than those with severe colonic polyposis. Gastric cystic fundic gland polyps may develop in up to 33% of FAP patients. Gastric carcinoma is rare in FAP but may be higher in Asian populations.

Hepatoblastoma occurs in an estimated 0.6% of children before 6 years but is rare thereafter. Thyroid carcinoma may affect 12% of patients with FAP but carries a good prognosis. They are predominantly well-differentiated papillary cancers affecting young women.

Molecular Basis of Disease

APC is a tumor suppressor gene consisting of 15 exons and encodes a protein of 2843 amino acids that is involved in cell adhesion, signal transduction, transcription regulation, cell cycle control, apoptosis, and maintenance of the fidelity of chromosomal segregation. As part of a scaffolding protein complex it negatively regulates Wnt signaling.

APC inactivation is the hallmark of the chromosomal instability pathway (CIN) phenotype that occurs in most of CRC. Increasing size, number, and worsening histology of polyps reflect the linear process of carcinogenesis along the CIN pathway.

More than 800 different APC germline mutations were reported through 2007 with the vast majority associated with FAP being frameshift or nonsense mutations. APC mutations are not distributed evenly, with “hotspots” at codons 1061 and 1309 accounting for approximately 11% and 17%, respectively, of germline mutations. Most lie in the “mutation cluster region” (MCR) between codons 1250 and 1464 in the 5′ region of exon 15.

Clinical Risk Management

Mutation analysis can identify sequence changes in up to 95% of classic FAP cases. However, the early development of adenomas raises special considerations relating to genetic testing of children. Genetic consultation is recommended for newly diagnosed FAP families as this can determine whether genetic testing would be informative for at-risk relatives. A negative test within a family with a known APC mutation allows colorectal screening to revert to that recommended to the population with background cancer risk, ie, colonoscopy or equivalent test starting at age 50.

Management can be affected by genotype, as severity of disease and extracolonic tumors may correlate with the location of APC mutations. Mutations between codons 1250 and 1464, especially codon 1309, often lead to profuse polyposis with earlier presentations.

For those with an FAP phenotype/confirmed mutation or from an affected family but where they have not yet been tested, the following surveillance is advised:

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  Birth to 6 years:

  
  
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  Annual hepatoblastoma screening by abdominal ultrasound and alpha-fetoprotein serum concentration.

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  10 years and up:

  
  
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  Annual palpation of the thyroid gland.

  
  
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  Sigmoidoscopy or colonoscopy every 1 to 2 years. Once polyps are detected by either procedure, full colonoscopy should be repeated annually. AFAP family members may begin in the late teens and repeat every 2 to 3 years.

  
  
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  Esophagogastroduodenoscopy (EGD) with side-viewing endoscope should be performed after the development of colonic polyposis or age 25, whichever is sooner. EGD should be repeated every 1 to 3 years depending on number, size, and degree of dysplasia of duodenal adenomas. Removal of duodenal adenomas is indicated if polyps (1) exhibit villous or severe dysplastic histology, (2) exceed 1 cm in size, or (3) cause symptoms.

  
  
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  Small bowel contrast studies or computerized tomography (CT) of abdomen and pelvis with oral contrast may also assist in monitoring duodenal and colorectal adenomas. Biopsy of an enlarged but otherwise normal ampullary papilla and endoscopic retrograde cholangiopancreatography (ERCP) to identify duodenal and common bile duct adenomas may also be indicated. Gastric cancer risk may be higher in Asian populations and specific screening may be indicated for these groups.

Prophylactic colectomy before malignant transformation is recommended for classic FAP once polyps have appeared, but timing will depend on adenoma size, number, and degree of dysplasia. Colectomy for AFAP is often deferred until polyps become too difficult to control. For desmoid tumors, as surgery may accelerate growth, a conservative approach may be reasonable.