Hereditary Hamartomatous Polyposis Syndromes

Abstract

Hamartomatous polyposis syndromes are a rare group of hereditary autosomal dominant disorders that comprise less than 1% of all hereditary colorectal cancers. Hamartomatous polyps, in and of themselves, are benign entities; however, these hamartomatous polyposis syndromes have a malignant potential for the development of colorectal cancer as well as extracolonic cancers. Early detection and proper surveillance are vital to minimizing the risk of carcinoma. This article provides a critical review of the clinical presentation, pathology, genetics, and screening and surveillance guidelines of juvenile polyposis syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome.

Hamartomatous polyposis syndromes are a rare group of hereditary autosomal dominant disorders that comprise less than 1% of all hereditary colorectal cancers.^1-3 Hamartomatous polyps, in and of themselves, are benign entities comprised of cells that are indigenous to the area in which they are found (ie, all cell layers with a mesenchymal predominance). However, these hamartomatous polyposis syndromes have a malignant potential for the development of colorectal cancer as well as extracolonic cancers. The progression of hamartomatous polyps to carcinoma is still being elucidated. Unlike adenomatous polyps, in which malignant transformation progresses through the adenomacarcinoma sequence via a gatekeeper or caretaker defect, in hamartomatous polyps, a proposed hamartoma-carcinoma sequence hypothesis involves a landscaper defect in which stromal elements create a local environment that promotes epithelial dysplasia and ultimately leads to carcinoma.⁴

The hamartomatous polyposis syndromes include juvenile polyposis syndrome (JPS); PTEN hamartoma tumor syndrome, which includes Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS); and Peutz-Jeghers syndrome (PJS). Due to the rarity of these conditions, a thorough understanding of their clinical presentation, including extraintestinal manifestations (gross and histopathologic), and genetics is important. For pediatric gastroenterologists, understanding how to recognize and establish the appropriate diagnosis and cancer risk and following appropriate screening and surveillance guidelines is crucial for early detection to minimize the risk of carcinoma as children reach adulthood.

Juvenile Polyposis Syndrome

Clinical Presentation

Juvenile polyps are the most common type of pediatric gastrointestinal polyps. Solitary juvenile polyps can develop at any age, though they appear most frequently in preschool children and have an incidence of 2% in children under 10 years of age. Solitary polyps are generally located in the rectosigmoid area and are usually considered to be a separate entity from JPS, which has an incidence of 1 in 100,000–160,000 individuals.^5,6 A family history of juvenile polyps is found in 20–50% of patients with JPS, with an autosomal dominant inheritance pattern of variable penetrance.^1,7-10

In JPS, affected individuals develop multiple gastrointestinal juvenile polyps, predominantly in the colon, though the condition may also affect the rest of the gastrointestinal tract.^11-13 JPS has been phenotypically classified into 3 categories¹⁴: juvenile polyposis coli, in which polyp growth affects only the colon; the rare and often fatal form of JPS called juvenile polyposis of infancy, which is characterized by diarrhea, protein-losing enteropathy, bleeding, and rectal prolapse¹⁵; and generalized juvenile polyposis, in which polyp growth can affect the colon, stomach, and small bowel. As opposed to solitary juvenile polyps, which occur in children most commonly at 4–5 years of age, JPS presents in the first or second decade of life, with an average age of 18.5 years at the time of diagnosis.^12,16 Typical presenting symptoms include rectal bleeding, anemia, abdominal pain, diarrhea, intussusception, obstruction, and polyp prolapse, though many JPS patients may be asymptomatic.^8,17,18

Extraintestinal Manifestations

Multiple extraintestinal manifestations have been reported with JPS, including heart defects, polydactyl, clubbing, intestinal malrotation, Meckel diverticulum, hydrocephalus, macrocephaly, hypertelorism, cleft lip, cleft palate, double renal pelvis and ureter, bifid uterus and vagina, undescended testes, and supernumery teeth.^13,16,19 These abnormalities have been reported in approximately 11–20% of cases,^8,19,20 mainly in case reports. However, due to the overlap of JPS, CS, and BRRS, the true incidence of extraintestinal manifestations based upon these case reports is difficult to interpret. JPS and hereditary hemorrhagic telangiectasia (HHT) have also been reported together.²¹ Further credence to this association has been made with the recent report of 2 JPS patients having a germline mutation in the ENG gene, which is the causative gene in HHT.²²

Diagnosis

The diagnosis of JPS is clinically established based upon the presence of at least 1 of the following criteria^18,23,24: at least 3–10 polyps detected on colonoscopy; polyps located outside of the colon; and any number of polyps in a patient with a family history of juvenile polyps. The number of polyps needed to establish the diagnosis of JPS varies in the literature. Sachatello and associates proposed 10 polyps as the benchmark; however, this number was reduced to 5 polyps by Jass and colleagues and then to 3 polyps by Giardiello and coworkers.^18,23,24 There is currently no clear consensus on the number of polyps to use for diagnosis,hence the range of 3–10 listed above.

Gastrointestinal Pathology

The gross appearance of a juvenile polyp is spherical to slightly lobular in shape, and most are pedunculated with long stalks.²⁵ In patients with JPS, polyps may have a multilobulated appearance of a villiform or papillary shape.⁸ Jass and colleagues reported that approximately 20% of polyps have the latter appearance.¹⁸ Polyp size can range from several millimeters to 3 cm (Figure 1A). These polyps are typically very vascular, with a smooth and glistening appearance on the surface; however, they may also have an ulcerated surface from auto-infarction.

Figure 1.

Resection of a colon from a patient with juvenile polyposis syndrome containing multiple juvenile polyps (A).

Reproduced from Demetris AJ, Finkelstein SD, Nalensnik MA, et al. Slide carousel of GI pathology course for medical students. Available at: http://itchforum.net/content/index_eng.html. © Department of Pathology, University of Pittsburgh School of Medicine.

Histologic image of a juvenile polyp showing its characteristic large cystic spaces and a lamina propria with an inflammatory cell component (B).

Reproduced from Mulholland M, Lillemoe K, Doherty G, Maier R, Upchurch G. Greenfield's Surgery: Scientific Principles and Practice. 4th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2006.

The histologic appearance of juvenile polyps shows multiple large mucus-filled glands lined with columnar epithelium (Figure 1B). The lamina propria usually has an inflammatory cell component.¹⁸ Smooth muscle components are not present in juvenile polyps, which distinguishes them from PJS polyps, but not from polyps of the other hamartomatous polyposis syndromes.^26,27

Genetics

A family history of JPS is found in 20–50% of patients with JPS, with an autosomal dominant inheritance pattern of variable penetrance.^17,18 Three genes have been associated with JPS: SMAD4, BMPR1A, and ENG, all of which are part of the transforming growth factor-b(TGF-b) superfamily of proteins.²⁷ The PTEN gene mutation in patients with juvenile polyposis is a controversial topic. It is generally thought that patients with the PTEN gene mutation likely represent CS or BRRS patients who have not yet expressed the extraintestinal clinical features of these conditions.^27-29

The SMAD4 gene, located on chromosome 18q21.1, was first identified by Howe using gene linkage analysis on affected families with JPS.^30,31 Germline mutations in the SMAD4 gene have a prevalence of 20% in JPS patients.³² Patients with the SMAD4 mutation are more likely to have upper gastrointestinal polyps. A subset of JPS patients also has HHT, which has been linked to patients with SMAD4 mutations. Multiple types of mutations have been reported in the SMAD4 gene, including missense, nonsense, deletions, and insertions; however, the most common mutation is the one originally discovered by Howe (the 4-base pair deletion in exon 9).³³ SMAD4 is an intracellular mediator in the TGF-βsignal-ing pathway. It binds to other members of the SMAD family and is involved in transcriptional activation and nuclear localization.^26,34,35 In JPS, SMAD4 is thought to act as a tumor suppressor gene, and the inactivation of SMAD4 in the unaffected allele is an important step in polyp development.³⁶ These data are supported by the SMAD4 knockout mouse model.^37-39

The bone morphogenetic protein receptor type IA (BMPR1A) gene is located on chromosome 10q22-23 and was reported by Howe and associates in 2001.^40-42 Germline mutations in the BMPR1A gene have a prevalence of 20% in JPS patients.³² BMPR1A is a type 1 serine/threonine kinase receptor protein that is bound to a type II serine/threonine kinase receptor protein.³⁴ This receptor complex is also involved in the TGF-βsignaling pathway upstream of SMAD4. It phosphorylates SMAD proteins that then bind to SMAD4.^43,44 BMPR1A knockout mice are homozygous lethal, whereas heterozygous mice appear normal with no polyp development.⁴⁵

ENG has recently been shown to be present in 2 patients with JPS; however, its role as a predisposition gene still requires additional confirmation.^22,46 The ENG gene is located on chromosome 9q34.1.⁴⁷ ENG encodes the protein endoglin, which is an accessory protein of the TGF-bsignaling pathway.⁴⁸ Endoglin signaling is initiated by the binding of TGF-bin combination with TBR-II and results in a series of activation steps leading to transcriptional activity. Endoglin inhibition appears to have an inhibitory effect on TGF-bin endothelial cells.^48,49 ENG knockout mice are homozygous lethal, and heterozygous mice exhibit large numbers of irregular, dilated, and thinner-walled vessels and serve as a model for HHT. There is no reported polyp growth in this mouse model.⁵⁰

Cancer Risk

Individuals with JPS are at risk for the development of colorectal, gastric, small intestinal, and pancreatic cancers. The risk of developing colorectal cancer from solitary juvenile polyps is thought to be negligible or nonexistent. However, individuals with JPS are at risk for developing adenomatous change and carcinoma. The incidence of colorectal cancer has been reported by Jass and associates to be 20.7%, with a mean age of 34 years (age range, 15–59 years) and an estimated cumulative colorectal cancer risk of 68% by 60 years of age.¹⁸ Coburn and colleagues reported a colorectal cancer risk of 17%, with a mean age of 35 years (age range, 15–59 years) at diagnosis.¹⁷ Howe and coworkers reported a colorectal cancer risk of 38% and a cumulative risk of gastrointestinal cancer of 55%, with a mean age of 43 years (age range, 17–68 years).⁵¹ There have been multiple case reports documenting gastric adenocarcinomas and pancreatic adenocarcinomas.^52-54 In an Iowa kindred, Howe and colleagues reported 4 gastric carcinomas, 1 duodenal carcinoma, and 1 pancreatic carcinoma, with an overall risk of upper gastrointestinal cancer of 21% in patients with JPS.⁵¹ In a review of JPS patients, Coburn and associates reported 1 gastric carcinoma and 1 duodenal carcinoma.¹⁷

Screening and Management

There are no standardized screening and surveillance guidelines for the management of JPS. Two proposed guidelines have been published, one by Howe and coworkers and another by Dunlop.^55,56 Howe and coworkers suggested that genetic testing be performed in patients at risk for JPS. According to their guidelines, a complete blood count (CBC), upper endoscopy, and colonoscopy should be performed for JPS in all at-risk patients when symptoms present or in asymptomatic patients by 15 years of age. If no polyps are found, a repeat colonoscopy should be performed every 3 years. If a genetic mutation is present, screening with upper endoscopy, colonoscopy, and CBC should also be performed every 3 years; however, if no genetic mutation is present and no polyps are found at the initial endoscopy, a repeat endoscopy should be performed every 10 years until 45 years of age. If no polyps are found by 45 years of age, standard colorectal cancer screening should be used (Figure 2).⁵⁵ Wirtzfeld and colleagues critiqued the every-10-year screening intervals for at-risk JPS patients without genetic mutations by claiming that, due to the genetic heterogeneity of JPS, a 10-year interval may be too long of a period of time to go without screening.³

Figure 2.

Proposed algorithm for endoscopic surveillance of juvenile polyposis syndrome.

Dunlop's proposed guidelines for JPS screening starts at 15–18 years of age for colonoscopy in asymptomatic atrisk patients and at 25 years of age for upper endoscopy. If a genetic mutation is found and no polyps are detected at the time of the initial endoscopy, screening should continue until 70 years of age; however, if no genetic mutation is found and no polyps are detected at the initial endoscopy, repeat endoscopy should be performed every 1–2 years until 35 years of age.⁵⁶

Both sets of authors agree that any found polyps should be removed endoscopically. Endoscopy should then be repeated yearly until no polyps are detected, at which point screening should return to every 3 years, according to Howe and coworkers, or every 1–2 years, according to Dunlop.

The indications for surgery include a large polyp burden that cannot be managed endoscopically, polyps with adenomatous change, severe diarrhea with hypoprotenemia, or gastrointestinal bleeding with anemia. There are no standards for the type of surgery. Surgical options include subtotal colectomy with ileorectal anastomosis and total colectomy with J-pouch ileoanal anastomo-^57,58 Regardless of the surgery performed, endoscopic surveillance is recommended after surgery for polyp recurrence in the pouch.^57,58

Gastric polyps should be removed endoscopically; however, this guideline may be challenging due to the number of polyps found. Indications for total or subtotal gastrectomy include severe anemia due to chronic bleeding,adenomatous change,or adenocarcinoma.²⁶

PTEN Hamartoma Tumor Syndrome

PTEN hamartoma tumor syndrome is the term that has been used recently to describe both CS and BRRS.⁵⁹ These disorders are both caused by mutations in the PTEN gene and are both characterized by extraintestinal manifestations more than intestinal polyposis. The clinical presentations for the diseases will be discussed separately in this paper, though it should be noted that the differences between them are likely due to the variable phenotypic expression seen in PTEN gene mutations.^59-62

Cowden Syndrome

Clinical Presentation CS is a rare autosomal dominant syndrome, with a reported incidence of 1 in 200,000 individuals.⁶³ This syndrome is characterized by macrocephaly, mucocutaneous lesions (such as facial trichilemmoma), acral keratosis, and papillomatous papules (Figure 3). It is also associated with thyroid, breast, and endometrial manifestations, including cancer in all of these areas.^26,27,64 CS has been linked to Lhermitte-Duclos disease, which is characterized by hamartomas of the cerebellum.⁶⁵ Hamartomatous polyps throughout the gastrointestinal tract are associated with this syndrome but are not as common as the extraintestinal findings associated with the syndrome. The incidence of gastrointestinal polyps in CS varies in the literature, ranging anywhere from 30% ^64,66,67 It is generally thought that the incidence of gastrointestinal polyps in CS is less than that of BRRS, though this belief is debated in the literature.⁶⁶ Another gastrointestinal manifestation of CS is glycogenic acanthosis of the esophagus (Figure 4), which involves large benign glycogen-filled epithelial cells that are gray to white in color.⁶⁸

Figure 4.

Glycogenic acanthosis Table 1. Extraintestinal Manifestations of Cowden Syndrome of the esophagus in a patient With Their Diagnostic Criteria with Cowden syndrome.

Figure 3.

Multiple skin-colored facial warty papules representing tricholemmonas (A). Multiple reddish confluent papules on the oral mucosa revealing a cobblestone appearance (B).

Both figures are reproduced from Wolff K, Johnson RA, Fitzpatrick TB. Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology. 6th ed. New York, New York: McGraw-Hill Medical; 2009.

Extraintestinal Manifestations As stated above, extraintestinal manifestations are the hallmark of the syndrome and summarized in Table 1.

Table 1.

Extraintestinal Manifestations of Cowden Syndrome With Their Diagnostic Criteria

Manifestation	Type of criteria
Facial tirchilemmomas	Pathognomonic
Acral keratoses	Pathognomonic
Papillomatous papules	Pathognomonic
Lhermitte-Duclos disease	Pathognomonic
Breast adenocarcinoma	Major
Fibrocystic breast disease	Minor
Thyroid multinodular goiter	Minor
Thyroid adenoma	Minor
Thyroid carcinoma	Major
Uterine leiomyomas	Minor
Endometrial carcinoma	Major
Bicornutae uterus	Minor
Macrocephaly	Major
Developmental delay	Minor
Lipomas	Minor
Fibromas	Minor
Melanoma	Minor

Diagnosis The diagnosis of CS is based upon pathognomonic, major, and minor criteria. These criteria are updated by the National Comprehensive Cancer Network (NCCN) and can be accessed via the Web site www.nccn.org.²⁷ A working diagnosis can be established by fulfilling 1 pathognomonic criterion; 2 major criteria; 1 major and 3 or more minor criteria; or 4 or more minor criteria. These criteria are listed in Table 1.

Bannayan-Riley-Ruvalcaba Syndrome

Clinical Presentation The term BRRS was first used by Gorlin and coworkers to describe 3 clinically similar autosomal dominant syndromes: Riley-Smith syndrome, Ban-nayan-Zonana syndrome, and Ruvalcaba-Myhre-Smith syndrome.⁶⁹ BRRS is characterized by macrocephaly; developmental delays; pigmented speckling of the penis; lipomas; and hamartomatous polyps of the intestine.^69,70 The incidence of gastrointestinal polyps in BRRS has been reported to be 45%.⁶⁹ Extraintestinal Manifestations As with CS, the extraintestinal manifestations of this syndrome are its hallmark and are summarized in Table 2.

Table 2.

Extraintestinal Manifestations of Bannayan-Riley-Ruvalcaba Syndrome

Macrocephaly Developmental delay Accelerated growth of first metacarpal and first proximal and middle phalanges Joint hyperflexibility Pectus excavatum Scoliosis Genital pigmentation Lipomas Hemangiomas Lipid storage myopathy

Diagnosis Due to the rarity of this syndrome, there are no formal diagnostic criteria for BRRS. The diagnosis of BRRS should be considered when a patient exhibits 1 or more extraintestinal manifestations with or without polyps, or has a family history of BRRS or CS.

Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome Gastrointestinal Pathology The appearance of polyps within the gastrointestinal tract in both CS and BRRS resembles the gross and histologic appearance of juvenile polyps.⁶⁹ Therefore, when juvenile polyps are detected, physicians should evaluate the patient for possible extraintestinal manifestations of CS and BRRS.

Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome Genetics CS and BRRS have an autosomal dominant inheritance pattern with variable penetrance. Both syndromes have been associated with the PTEN gene, which is located on chromosome 10q22-23. CS was linked to chromosome 10q22-23 by Nelen and associates, and the PTEN gene was later identified at this locus by Liaw and colleagues, and confirmed by Nelen and coworkers, as well as Lynch and associates.^63,71-73 Marsh and colleagues then found an association between PTEN and BRRS.⁷⁴ The PTEN gene is found in 80% of CS patients and 60% of BRRS patients.^62,75 CS and BRRS are allelic diseases in which a mutation of the PTEN gene is found in all exons except 1, 4, and 9 in CS. In BRRS, mutations occur preferentially in exons 6 and 7 and are also associated with balanced translocations and ^{62,63,71,72,74} It has been hypothesized that the differential expression of the PTEN gene correlates with the different phenotypes seen in CS and BRRS.⁷⁶

The PTEN gene is a tumor suppressor gene that is also a tyrosine phosphatase that dephosphorylates tyrosine, serine, and threonine.⁷⁷ PTEN is a negative regulator of the Akt/PKB signaling pathway,^77,78 which controls the levels of phosphoinositol triphosphate. PTEN is also involved in regulating cell cycle, apoptosis, and angiogenesis.^78,79

Cancer Risk Individuals with CS are at risk for developing breast, thyroid, and endometrial cancers. The risk of adenocarcinoma of the breast has been reported to range from 30% to 50% in women with CS.^27,64,66 In addition, there are reports of breast cancer in men with CS.⁸⁰ Individuals with CS are also subject to benign conditions of the breast such as fibrocystic disease.⁶⁴ Thyroid abnormalities such as multinodular goiter and thyroglossal duct cysts are associated with this syndrome, as well as a 10% risk of thyroid cancer. CS patients also have a risk of leiomyomas, as well as an up-to-10% risk of endometrial cancer.^64,81 Renal cell cancer has also been associated with CS.⁶⁴ The risk of developing gastrointestinal carcinoma in CS is unclear at this point. It has been reported by some studies that there is no increased risk of gastrointestinal cancer; however, there are multiple case reports of gastric and colorectal cancer.^64,82-84

In BRRS, the cancer risk is unclear. The limited number of patients with this disease makes it difficult to determine the risk; however, there have been case reports of breast and endometrial cancer.^62,85 With additional evidence supporting the idea that CS and BRRS are variable phenotypic expressions in the PTEN gene, it is therefore recommended that individuals with BRRS be considered at risk for malignancy, as with CS.

Screening and Management Individuals with CS and BRRS who have mutations in the PTEN gene should be screened according to the CS guidelines summarized in Table 3 ^1,5,59,68,86 These guidelines include breast cancer screening with self and clinical breast examinations, in addition to annual mammography and breast magnetic resonance imaging for breast cancer beginning at 25 years of age or 5–10 years earlier than the youngest case in the family. Thyroid cancer screening involves clinical examinations and yearly thyroid ultrasounds starting at 18 years of age. Endometrial cancer screening with endometrial biopsies should be performed at 35–40 years of age or 5 years earlier than the youngest case in the family. Renal cell cancer screening can be performed with yearly urinalysis and ultrasound.^1,5,68,86 Updated guidelines for CS screening can be found on the NCCN Web site.⁵⁹

Table 3.

Cowden and Bannayan-Riley-Ruvalcaba Syndrome Management

Thyroid – Annual thyroid ultrasound starting at age 18 Breast – Biannual breast examination at age 25 or 5–10 years from the earliest known family member with breast cancer – Annual mammography and breast magnetic resonance imaging screening at ages 30–35 or 5–10 years from the earliest known family member with breast cancer Endometrial cancer – Endometrial suction biopsies between the ages of 35–40 or 5 years before the earliest known family member, then followed by annual endometrial ultrasound Renal cell carcinoma – Annual urine analysis and renal ultrasound Melanoma – Annual dermatologic examination

Peutz-Jeghers Syndrome

Clinical Presentation

PJS, as with the other hamartomatous syndromes, is an autosomal dominant syndrome that is typified by its characteristic mucocutaneous pigmentation and intestinal hamartomatous polyps. The incidence of PJS is reported to be 1 in 150,000 to 200,000 individuals.^86,87 Pigmentation is seen around the vermilion border of the lips in over 95% of cases, with the buccal mucosa being the second most common site (80%; Figure 5).^88,89 Other areas of pigmentation include the hands, feet, genitals, and around the nose and eyes. Pigmentation typically presents in early childhood and starts to fade with age usually after the start of puberty.^90,91

Figure 5.

Multiple dark-brown lentigines on the vermillion border of the lip and buccal mucosa in a patient with Peutz-Jeghers syndrome.

Reproduced from Swartz MH. Textbook of Physical Diagnosis: History and Examination. 4th ed. Philadelphia, Pennsylvania: WB Saunders; 2002:295.

Hamartomatous polyps in PJS are commonly found in the small intestine; however, they are also found in the stomach and colon. The number of polyps in the intestine may range from 1 to a complete carpeting of the gastrointestinal tract (Figure 6).^89,92 The most common presentation of PJS is abdominal pain secondary to intussusception. Other clinical presentations include anemia, melena, hematochezia, hematemesis, and obstruction. Approximately one third of PJS patients present in the first decade of life, with up to 60% presenting by the second or third decade.^90,93,94

Figure 6.

Polyps from a patient with Peutz-Jeghers syndrome are pedunculated and tend to be large and multilobulated.

Reproduced from Mulholland M, Lillemoe K, Doherty G, Maier R, Upchurch G. Greenfield's Surgery: Scientific Principles and Practice. 4th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2006.

Extraintestinal Manifestations

In PJS, polyps have been reported outside of the gastrointestinal tract, including areas involving the nose, bronchi, renal pelvis, and bladder.⁹⁵ Polyps have also been reported in the gallbladder and bile ducts; however, polyps in the gallbladder have been histologically adenomatous and not hamartomatous.⁹⁶ Bile duct polyps have presented with jaundice secondary to obstructive symptoms.^97,98 PJS is also associated with various malignancies that will be described below.

Diagnosis

The diagnosis of PJS is clinically established on the presence of histologic tissue that is consistent with hamartomatous polyps and 2 of the following criteria⁹⁹: a family history of PJS; the presence of mucocutaneous pigmentation;and the presence of small-bowel polyps.

Pathology

The gross appearance of a polyp in PJS is typically pedunculated with long stalks. These polyps tend to be multilobulated and have a villiform or papillary shape. Polyp size can range from 0.5 cm to 5 cm in diameter. The polyp has a characteristic histologic appearance consisting of smooth muscle proliferation in a tree branch, a process that is called arborization (Figure 7).¹⁰⁰ The epithelium that covers the smooth muscle can become displaced into the submucosa and muscularis propria, giving a pseudocarcinoma appearance of a mucinousa denocarcinoma.¹⁰¹

Figure 7.

Histologic image of a Peutz-Jeghers po lyp showing its characteristic histologic appearance, which consists of smooth (a process that is called arborization) (A). Enlargement of a Peutz-Jeghers polyp showing smooth muscle proliferation (B).

Both images reproduced from Boland CR. The colon, rectum, and anus. In: Feldman M, ed. Gastroenterology and Hepatology: The Comprehensive Visual Reference. Philadelphia, Pennsylvania: Churchill Livingstone; 1996.

Genetics

PJS, as with the other hamartomatous syndromes, has an autosomal dominant pattern of inheritance with both familial and sporadic transmission.¹⁰² The gene associated with PJS is a serine-threonine kinase that is located on chromosome 19p13.3.^103,104 Hemminki and coworkers and Jenne and associates independently identified the gene in this region as LKB1/STK11.^105,106 This gene has been reported in 80% of patients with PJS.¹⁰⁷ Common mutations are frameshift and nonsense mutations in exons 1–6; however, large deletion mutations missed by direct sequencing have been recently described using multiple ligation probes.¹⁰⁷

LKB1/STK11 is a tumor suppressor gene that encodes a serine-threonine kinase that phosphorylates and activates members of the AMPK-related subfamily of protein kinases.¹⁰⁸ LKB1/STK11 has an essential role in G1 cell cycle arrest, cell polarity, p53-dependent apoptosis, and cellular energy levels.^109,110 LKB1 (+/-) mice develop gastrointestinal polyps with histologic characteristics resembling those of human PJS polyps.¹¹¹

Cancer Risk

Individuals with PJS are at risk for the development of colorectal, gastric, small intestinal, esophageal, and pancreatic cancers. PJS patients are also at risk for extraintestinal cancer such as lung, breast, ovarian, testicular, and endometrial cancers.^26,27,90 A meta-analysis showed that the risk of developing any type of cancer by 64 years of age was 93% (relative risk of 15).¹¹² Lim and colleagues evaluated the St. Mark's polyp registry and found that the relative risk of developing any type of cancer was 47% by 65 years of age in PJS patients with known genetic mutations in LKB1/STK11.¹¹³ More recently, a study looking at 419 PJS patients, 297 of whom had documented mutations, showed the risk of cancer to be 60% by 60 years of age and 85% by 70 years of age.¹¹⁴ This same study reported the risks of developing gastrointestinal cancer (31%), breast cancer (31%), gynecologic cancer (18%), pancreatic cancer (7%), and lung cancer (13%) by 60 years of age.¹¹⁴ Individuals with PJS are also at risk for developing rare sex cord tumors. Women are at risk for sex cord tumors with annular tubules that are benign, and men are at risk for developing Sertoli cell tumors, which result in feminization. Both of these tumors arise from the same embryonic tissue.^115,116

Screening and Management

Individuals at risk for PJS should be evaluated at birth for pigmented spots, precocious puberty, and testicular tumors. Asymptomatic at-risk individuals should undergo genetic testing for the affected member's mutation in the STK11/LKB1 gene at 8 years of age.⁹⁰ If the at-risk family member does not have a genetic mutation, they are not thought to have PJS. However, genetic testing is only useful if the family member with PJS has a known STK11/LKB1 mutation. If the family member with PJS has a mutation that is unidentifiable, endoscopic surveillance, as apposed to genetic testing, should be performed in at-risk family members. These asymptomatic at-risk individuals should, at the bare minimum, undergo small-bowel contrast studies every 2 years until 25 years of age. Alternatively, this group of at-risk patients should undergo upper endoscopy, colonoscopy, and small-bowel contrast study every 6 years starting at 12 years of age until 24 years of age. Any at-risk patients with pigmentation should undergo the PJS surveillance guidelines, as outlined below.

The PJS surveillance guidelines proposed by Giardiello and Trimbath⁹⁰ (Table 4) include upper endoscopy and small-bowel contrast study starting at 8 years of age every 2–3 years. Starting at 18 years of age, colonoscopy should be performed every 2–3 years in coordination with upper endoscopy and small-bowel contrast study. Pancreatic screening should begin at 25–30 years of age, with endoscopic ultrasound every 1–2 years, with possible computed tomography scan and CA 19-9 cancer marker. For women, breast cancer screening with self and clinical breast examinations should begin at 18 years of age. Annual mammography and/or breast magnetic resonance imaging should begin at 25 years of age or 5–10 years earlier than the youngest case in the family. Other genitourinary cancers should be evaluated starting at 21 years of age, with yearly transvaginal ultrasound and CA-125 cancer markers, as well as yearly pelvic examinations and pap smears. Men should undergo yearly testicular examinations starting at birth and testicular ultrasounds every 2 years up until 12 years of age.^27,93 Capsule endoscopy may replace small-bowel contrast studies in the future.

Table 4.

Peutz-Jeghers Syndrome Surveillance Recommendations

Cancer screening by organ	Disease	Diagnostic testing	Screening interval	Age interval to be screened
Testes	Sertoli tumor	History and physical examination History and physical examination	1 year 2 years	Birth to age 12
Ovary	Ovarian carcinoma	Transvaginal ultrasound CA-125	1 year 1 year	Start at age 25
Cervix and uterus	Cervical and uterine carcinoma	Pelvic examination and pap smear	1 year	Start at age 21
Breast	Breast carcinoma	Breast self-examination Clinical breast examination Mammography or magnetic resonance imaging	1 month 6 months 1 year	Start at age 18 Start at age 25 Start at age 25
Pancreas	Pancreatic carcinoma	Endoscopic ultrasound (computed tomography scan as an alternative) CA 19-9	1–2 years 1–2 years	Start at age 25 Start at age 25
Gastrointestinal tract	Gastric carcinoma, small-bowel polyps, and small-bowel carcinoma Colorectal carcinoma	Upper gastrointestinal endoscopy and upper gastrointestinal small bowel follow-through Colonoscopy	2–3 years 2–3 years	Start at age 8 Start at age 25

Polyps found in the stomach and colon should be removed at the time of surveillance endoscopy. Polyps detected in the small bowel that are 1–1.5 cm or larger in size should also be removed.^90,117,118 In the past, removal was performed by push enteroscopy or laparotomy by either polypectomy or, in the case of very large polyps, bowel resection. However, advances in enteroscopy with the use of double- and single-balloon technology, and now spiral enteroscopy, allow for more of the small bowel to be reached without requiring laparotomy.