Review

Diagnosis and clinical features

PJS, which has an incidence of 1 in 150,000 in North America and Western Europe,³ is characterized by the presence of hamartomatous polyps in the gastrointestinal tract, and is associated with a distinctive mucocutaneous pigmentation. Polyps occur most commonly in the small intestine (64%), although involvement of the colon (53%), stomach (49%), and rectum (32%) is also seen.⁴ Polyps have also been found in the upper and lower respiratory tract and bladder.⁵ There are usually fewer than 20 polyps present in each case, and the polyps vary in size from several millimeters to more than 5 cm in diameter.⁶ Patients usually present with PJS in the second or third decade of life, and the presenting symptoms include abdominal pain, rectal bleeding, anemia, small intestinal intussusception, bowel obstruction, and rectal prolapse of polyps.⁵

The characteristic pigmentation, which is usually dark blue to dark brown in color, is present in 95% of patients with PJS and is most commonly seen on the vermillion border of the lips, the buccal mucosa, and the hands and feet.⁴ Perinasal, perianal, genital, and periorbital pigmentation can also be observed, but this pigmentation often fades after puberty. In contrast to the lentigines seen in individuals with PJS, common freckles spare the buccal mucosa, and are usually rare around the lips and nose.

The diagnostic criteria for PJS include the presence of characteristic mucocutaneous pigmentation, the presence of small-bowel hamartomatous polyps and a family history of PJS. Patients need to fulfill two of these three criteria for a clinical diagnosis of PJS to be made.⁷

On endoscopy, the polyps seen in patients with PJS have no defining features, although they can develop long stalks that predispose the intestine to intussusception.⁵ Microscopically, extensive smooth-muscle proliferation, with an elongated, arborized pattern of polyp formation, can be seen (Figure 1).⁸ This characteristic microscopic appearance of PJS polyps enables experienced gastrointestinal pathologists to confirm the clinical diagnosis.

Figure 1 A typical Peutz–Jeghers syndrome polyp demonstrating the arborizing pattern of smooth-muscle proliferation.

Abbreviation: mm, muscularis mucosa. Permission obtained from Macmillan Publishers Ltd © Bronner (2003)⁷⁹ Modern Pathology 16: 359–365.

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Cancer risk

PJS is associated with a markedly increased risk of malignancy that is not confined to the gastrointestinal tract. A meta-analysis found that, compared with the general population, patients with PJS have a relative risk (RR) of greater than 15 for developing any type of cancer.⁹ According to this meta-analysis, the cumulative risk of developing any type of cancer was 93% by the time a PJS patient was 65 years old. Very high RRs for the development of cancer were observed for the small intestine (520), stomach (213), pancreas (132), colon (84), and esophagus (57), with RRs of greater than 10 for the development of breast, lung and ovarian cancer.

A follow-up study restricted to patients with PJS who had a germline mutation in the tumor suppressor gene STK11 (also known as LKB1) confirmed that these patients have a very high risk of developing cancer.¹⁰ The cumulative risk of developing any type of cancer was 81% by the time these patients were 70 years of age, the cumulative risk of developing any gastrointestinal cancer (including small intestine, colorectal, esophageal and pancreatic cancer) was 66% by the time they were 70 years of age, and for female patients the cumulative risk of developing breast cancer was 32% by the time they were 60 years of age.¹⁰

PJS also predisposes females to development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.¹¹ In addition, females with PJS commonly develop benign ovarian sex-cord tumors with annular tubules, whereas males with PJS are predisposed to development of Sertoli-cell testicular tumors;¹² although neither of these two tumor types is malignant, they can cause symptoms related to increased estrogen production.

Surveillance recommendations

Surveillance recommendations for the hamartomatous polyposis syndromes are based on expert opinion, but no randomized trials have evaluated the efficacy of surveillance for the management of these disorders. The surveillance recommendations for patients with PJS are complex, and focus on the increased risk of gastrointestinal, gynecologic, breast, and testicular neoplasms. A strategy proposed in 2006 by Giardiello and Trimbath is illustrated in Figure 2.⁸

Figure 2 The suggested age-range-specific surveillance recommendations for patients with Peutz–Jeghers syndrome.

Abbreviations: EUS, endoscopic ultrasound; Hx, history; Pap smear, Papanicolaou smear; Px, physical examination; TVUS, transvaginal ultrasound; UGI, upper gastrointestinal; US, ultrasound. Adapted from data presented in Reference 8.

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Surveillance and management of polyposis of the small intestine has been markedly improved by advances in capsule and double-balloon endoscopy. Although the precise role of these techniques in the management of patients with PJS has not yet been established, they will undoubtedly prove useful in the nonsurgical treatment of patients with polyps of the small intestine,¹³ and might replace surveillance performed by small-bowel barium follow-through.

Genetics

Germline mutations of STK11 are documented in up to 70–80% of patients with PJS; up to 15% of cases have germline deletions of all or part of STK11.¹⁴ Although the classic clinical and histopathologic features of PJS might sometimes obviate the need for genetic testing, analysis of germline STK11 mutations can be helpful when the clinical features are subtle or when the histological diagnosis is in question.¹⁵ STK11 encodes a serine–threonine kinase that modulates cellular proliferation, controls cell polarity, and seems to have an important role in responding to low cellular energy levels.¹⁶ In the performance of this last role, the STK11 protein is involved in the inhibition of AMP-activated protein kinase (AMPK), and signals downstream to inhibit the mTOR (mammalian target of rapamycin; also known as FRAP; FKBP12-rapamycin complex-associated protein) pathway;¹⁷ the mTOR pathway is dysregulated in patients with PJS and in patients with PHTS (Figure 3). Genotype–phenotype correlation suggests that patients with PJS who have mutations in STK11 that result in truncation of the encoded STK11 protein have a significantly earlier age of onset than those who have a missense mutation or no detectable mutation of STK11.¹⁸ Interestingly, heterozygous Stk11 knockout mice develop hamartomatous polyps in the stomach and small intestine, but the predominant malignancy they develop is hepatocellular carcinoma, which is not a malignancy characteristic of human PJS.¹⁹

Figure 3 Signaling pathways dysregulated in patients with Peutz–Jeghers syndrome or PTEN hamartoma tumor syndrome.

PTEN and STK11 both downregulate the mTOR pathway, a growth promoting pathway, which when dysregulated contributes to the pathogenesis of PJS and PHTS. Both PTEN and STK11 act indirectly on mTOR through modulation of the TSC1–TSC2 complex upstream of mTOR. By contrast, the mTOR inhibitors, which include rapamycin and CCI-779, inhibit mTOR directly, downstream of both PTEN and STK11, making them potentially useful agents for the treatment of both PJS and PHTS. Abbreviations: AKT, protein kinase B; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin (also known as FRAP; FKBP12-rapamycin complex-associated protein); PI3K, phosphoinositide-3 kinase; PIP2, phosphoinositol 4,5-bisphosphate; PIP3, phosphoinositol 3,4,5-trisphosphate; PHTS, PTEN hamartoma tumor syndrome; PJS, Peutz–Jegher syndrome; PTEN, phosphatase and tensin homolog, deleted on chromosome TEN; STK11, serine–threonine protein kinase 11 (also known as LKB1); TSC1, tuberous sclerosis 1 protein; TSC2, tuberous sclerosis 2 protein.

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Diagnosis and clinical features

The term PHTS was developed to unify the heterogeneous group of disorders that are all caused by germline mutations of the tumor suppressor gene PTEN.²⁰ PHTS encompasses the disorders Cowden syndrome, BRRS, and Proteus syndrome. Several other disorders have also been associated with germline PTEN mutations, but a detailed discussion of this group of disorders is beyond the scope of this Review, and the prevalence of polyposis in many of these disorders is unknown.

Cowden syndrome is an uncommon, under-recognized disorder with an estimated incidence of 1 per 200,000 of the population, at least in Europe and North America;²¹ the syndrome confers an increased risk of breast, thyroid, and endometrial cancer. Other features of the disorder include the following: macrocephaly; gastrointestinal polyps; benign breast, thyroid, and endometrial manifestations; and characteristic mucocutaneous lesions (Table 1). Many of the benign manifestations are hamartomatous in nature, and Cowden syndrome has previously been referred to as the multiple hamartoma syndrome. Operational diagnostic criteria for Cowden syndrome are updated annually by the National Comprehensive Cancer Network.²²

Table 1 Common manifestations of Cowden syndrome²⁹.

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BRRS is characterized by the presence of multiple lipomas, gastrointestinal hamartomatous polyps, macrocephaly, hemangiomas, developmental delay and, in males, pigmented macules on the glans penis.²³ Formal diagnostic criteria have not been established.

Proteus syndrome is a complex multisystem disorder that is characterized by congenital malformations, hemihypertrophy, hamartomatous overgrowths, epidermal nevi and hyperostosis.²⁴

Historically, it was felt that gastrointestinal polyps were more commonly seen in patients with BRRS than in patients with Cowden syndrome, as these polyps are present in approximately 50% of patients with BRRS.²³ It is possible, however, that asymptomatic polyps are at least as common in patients with Cowden syndrome. Series have suggested that diminutive colonic polyps, mostly present distal to the hepatic flexure, occur in 60–90% of patients with Cowden syndrome.^{25, 26, 27} One small study of patients with this syndrome, which has been presented in abstract form only, reported that such polyps have a markedly varied histology, with adenomatous, juvenile, hyperplastic, lipomatous, and ganglioneuromatous polyps all being described.²⁶ Whether such varied polyp pathology is common in patients with Cowden syndrome is, however, questioned by some in he field.

Another manifestation of Cowden syndrome is glycogenic acanthosis. This manifestation is recognized as elevated gray-white plaques in the distal mucosa of the esophagus that, on histological examination, demonstrate epithelial thickening associated with the proliferation of large glycogen-filled squamous cells.²⁸ One study sought to classify patients with gastrointestinal polyposis syndromes on the basis of the germline mutation status of several genes known to confer predisposition to gastrointestinal polyps.¹⁵ All the patients studied had more than five colorectal polyps in their lifetime, one of which was either hamartomatous or hyperplastic. Germline PTEN mutations were identified in 2 of the 23 patients (9%) who had a combination of hyperplastic and adenomatous polyps. These two patients had features reminiscent of Cowden syndrome, but did not meet diagnostic criteria.

Cancer risk

Among the different PHTS disorders, cancer risk has been clearly documented only in patients with Cowden syndrome. In female patients the syndrome is associated with up to a 50% lifetime risk of developing breast cancer²⁵ and a 5–10% risk of developing endometrial cancer.²⁹ The risk of developing breast cancer might also be increased for male patients with the syndrome,³⁰ and all patients with the syndrome have a 10% lifetime risk of developing follicular thyroid cancer.²⁵ The risk of colon cancer associated with Cowden syndrome is not well characterized. One case report described a patient with Cowden syndrome who had a PTEN mutation and metachronous colon carcinomas, both of which appeared to arise from within hamartomatous polyps.³¹ In addition, the authors reported the presence of a somatic mutation (i.e. the 'second hit' according to the two-hit hypothesis of cancer development) in PTEN within the carcinoma. In a large cohort of patients with PTEN mutations, a modestly increased RR for the development of colon cancer has been noted (Pilarski R and Eng C, unpublished data); however, further research is necessary to confirm this association.

Surveillance recommendations

Current clinical opinion is that, irrespective of their phenotype, all patients who have germline PTEN mutations should be monitored by use of the surveillance recommendations established for Cowden syndrome.²⁹ At present, the National Comprehensive Cancer Network guidelines for Cowden syndrome make no specific recommendations for gastrointestinal system screening (Table 2), but rather focus largely on the increased risk of breast, thyroid and endometrial cancer.²² Nevertheless, these guidelines are updated annually, and will incorporate screening for colorectal cancer if ongoing research confirms that patients with Cowden syndrome are at an increased risk of colon cancer.

Table 2 Surveillance recommendations for Cowden syndrome.

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Genetics

Germline PTEN mutations are found in 85% of patients with Cowden syndrome and in more than 60% of patients with BRRS.^{20, 32, 33} Mutations have been detected in the promoter region of PTEN in patients with Cowden syndrome, whereas deletions of all or part of PTEN (not normally detectable by conventional polymerase chain reaction) have been documented in patients with BRRS.³⁴ The PTEN protein is a ubiquitously expressed, dual-specificity phosphatase that has both lipid and protein phosphatase activity. The lipid phosphatase activity of PTEN is best characterized; its major substrate is phosphoinositol triphosphate. By regulating the levels of phosphoinositol triphosphate, PTEN acts as a negative regulator of the AKT pathway.³⁵ As a tumor suppressor, PTEN has a crucial role in the control of cell growth, proliferation and angiogenesis (reviewed by Waite and Eng³⁶), and somatic PTEN mutations are prevalent in various malignancies.³⁷

Mouse models often provide helpful complementary insights into the human disease; however, although mouse models of Pten deficiency are available their usefulness in helping to dissect the pathogenesis of human PHTS and/or Cowden syndrome is limited. Heterozygous Pten^+/- mice develop hamartomatous polyps of the gastrointestinal tract, but the spectrum of neoplasia and malignancies observed bears little resemblance to that seen with Cowden syndrome; mice often develop thymic and peripheral lymphomas and prostate cancer at a young age.^{35, 38}

Diagnosis and clinical features

JPS is characterized by the presence of multiple juvenile polyps. These polyps are named for their histological appearance and can occur at any age. The presence of isolated juvenile polyps in the colorectum is relatively common; up to 2% of children who are under 10 years of age have an isolated juvenile polyp.^{39, 40} The diagnosis of JPS, therefore, requires the presence of more than three to five juvenile polyps in the colorectum, or the presence of juvenile polyps throughout the gastrointestinal tract, or the presence of any number of juvenile polyps in an individual who has a family history of juvenile polyposis syndrome.^{41, 42} The appearance of the polyps associated with JPS can be indistinguishable from that of those seen in other hamartomatous polyposis syndromes (especially those in Cowden syndrome), and the features of these syndromes should, therefore, be carefully sought when evaluating a patient with suspected JPS.

On endoscopy, the characteristic juvenile polyp is spherical in shape, often pedunculated, and has a smooth and often shiny appearance.¹ Juvenile polyps can reach several centimeters in diameter. At the microscopic level, these polyps appear as mucous-filled, dilated glands that are often associated with inflammatory cell infiltration (Figure 4).⁴¹ Unlike the PJS polyp there is no smooth-muscle proliferation. Most juvenile polyps occur in the colon and rectum; the frequency of polyps in the stomach and small intestine is less than 20%,⁴³ although individuals who have SMAD4 mutations (see below) have a much higher frequency of upper gastrointestinal polyps than this.^{44, 45} Tens to hundreds of polyps are often present in affected individuals, and a diagnosis of JPS is usually made before a patient reaches 20 years of age.⁴⁶ Common presenting symptoms include rectal bleeding, anemia, abdominal pain, obstruction, and less commonly rectal prolapse of polyps.⁴⁷

Figure 4 A typical juvenile polyp demonstrating gland dilatation, inflammatory cell infiltrate and absence of smooth-muscle proliferation.

Permission obtained from Macmillan Publishers Ltd © Bronner (2003)⁷⁹ Modern Pathology 16: 359–365.

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Cancer risk

The predisposition to the development of malignancy conferred by JPS seems to be confined to malignancies of the gastrointestinal system. Colorectal cancer is by far the most common malignancy that develops, and the lifetime risk of an individual with JPS developing this form of cancer might be as high as 40–50%;⁴³ a study by Brosens et al. demonstrated that, compared with the general population, patients with JPS have a RR for colon cancer of 34, with a mean age at diagnosis of 43 years.⁴⁸ There are probably also increased risks of gastric cancer, carcinoma of the small intestine and possibly pancreatic cancer associated with JPS, although there were no upper gastrointestinal malignancies detected in the cohort described by Brosens et al.^{43, 48}

Surveillance recommendations

There are several surveillance recommendations for individuals affected with JPS.^{43, 49} First, affected individuals should be monitored for rectal bleeding, anemia, abdominal pain, constipation, diarrhea, or change in stool size, shape, and/or color; these symptoms might warrant additional investigation including endoscopy. Second, CBC, colonoscopy, and upper endoscopy should begin by the time the affected individual is 15 years of age. Third, if screening results are negative, screening should be repeated in 3 years' time. Fourth, if only a few polyps are identified, they should be removed; screening should then be performed annually until no additional polyps are found, at which time screening every 3 years can resume. Fifth, if the polyp burden or dysplastic changes necessitate colectomy, or gastrectomy/small-bowel resection, subsequent screening should be performed annually until no additional polyps are found, at which time screening every 3 years can resume.

Importantly, there have been families with SMAD4 mutations described (see below) that have family members with both JPS and hereditary hemorrhagic telangectasia.⁵⁰ This situation indicates the need to screen patients with SMAD4 mutations for occult vascular malformations; however, a discussion of the details of this is beyond the scope of this Review.

Genetics

Germline mutations of SMAD4, BMPR1A, and ENG have all been described in patients with JPS, and all three genes encode proteins that are involved in the transforming growth factor (TGF-) signaling pathway.¹⁵ The TGF- signaling pathway is an important modulator of many cellular processes, including proliferation, differentiation and adhesion (reviewed by Waite and Eng⁵¹), and TGF- itself has a major role in the control of colonic epithelial growth.⁵²

The importance of the TGF- pathway in colon cancer development is illustrated by the finding that somatic mutations of the TGF- receptor II are present in most colorectal cancers from patients with Lynch syndrome, and are also common in sporadic colorectal cancers that exhibit microsatellite instability. In addition, somatic mutations in the part of the gene that encodes the kinase domain of TGF- receptor II are seen in approximately 15% of sporadic microsatellite stable colorectal cancers.⁵³ Somatic mutations of other members of the TGF- signaling pathway, including SMAD2 and SMAD4, are found in sporadic colon cancers; SMAD4 mutations are more commonly found in advanced malignancy or metastasis. Although such mutations occur only in approximately 15% of sporadic colorectal cancers, loss of heterozygosity at 18q, the region containing both of the SMAD2 and SMAD4 loci, is found in up to 70% of adenocarcinomas and in at least 10% of early adenomas.⁵⁴ It is possible, but yet to be confirmed, that such mutations occur at increased frequency in patients with JPS, representing a somatic 'second hit' within the TGF- pathway.

The prevalences of germline mutations of BMPR1A and SMAD4 are 20% each in patients with JPS.⁵⁵ The prevalence of germline ENG mutations is currently unknown, but germline ENG mutations seem to predispose to the development of JPS in early childhood.¹⁵ One additional study has documented missense variation in ENG in patients with JPS who are younger than 10 years of age, but it is not clear whether these variants are pathogenic.⁵⁶

In addition, several cases of JPS of infancy, characterized by generalized polyposis and often diagnosed in the first 2 years of life, have been associated with germline deletions that encompass both PTEN and BMPR1A.^{15, 57, 58, 59} These patients' clinical features often overlap with those seen in patients with Cowden syndrome and BRRS. These patients usually present with a fulminant disease course characterized by intussusception, rectal bleeding, and protein-losing enteropathy, which is often fatal early in life. The similarity of the polyps associated with JPS and Cowden syndrome initially led to speculation that PTEN mutations might cause some cases of JPS. It is now realized however, that these cases were in fact Cowden syndrome cases that were not recognized as such.^{60, 61}

Genotype–phenotype correlation analyses have demonstrated that patients who have SMAD4 mutations are more likely to develop massive upper gastrointestinal polyps and have a family history of upper gastrointestinal polyposis than are those patients who have BMPR1A mutations.^{44, 45} The Smad4^+/- mouse exhibits a phenotype that is similar to that of human JPS; this mouse develops multiple gastric and small intestinal polyps that are very similar histologically to juvenile polyps, although no polyps are seen in the colon.⁶² Moreover, areas of adenocarcinoma are also seen in the stomach and small intestine. Heterozygous Bmpr1a knockout mice appear grossly normal,⁶³ while the Eng^+/- heterozygous knockout mouse exhibits features of hereditary hemorrhagic telangiectasia, but does not develop overt gastrointestinal polyps.⁶⁴ It is not clear from the literature, however, how carefully either of these mice models was examined for evidence of polyposis, as their generation preceded by several years the recognition of ENG and BMPR1A mutations as causes of JPS.