Gastrointestinal polyps and cancer in Peutz-Jeghers syndrome: clinical aspects
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- Latchford, A.R. & Phillips, R.K.S. Familial Cancer (2011) 10: 455. doi:10.1007/s10689-011-9442-1
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The two main problems in the management of the gastrointestinal tract in patients with Peutz-Jeghers syndrome (PJS) are the long term cancer risk and managing polyp related complications, such as intussusception and bleeding. In this article we will focus mainly on the clinical management of these problems. We will highlight some of the controversies regarding gastrointestinal PJS polyps, cancer development and cancer risk. We will review the available literature, particularly focusing on clinical data, to provide insights into these controversies. We describe guidelines for the surveillance and management of gastrointestinal polyps in PJS and review the data behind current recommendations.
Peutz-Jeghers Syndrome (PJS) is an inherited polyposis syndrome in which multiple characteristic polyps occur in the gastrointestinal tract, associated with mucocutaneous pigmentation. It is inherited in an autosomal dominant manner and is caused by a germline mutation in the LKB1 (STK11) gene. Although PJS was initially documented by an English physician in 1895 , the eponym Peutz-Jeghers Syndrome was originally put forward in 1954  based on the work of Peutz , who described a family with autosomal dominant inheritance of gastrointestinal polyposis and pigmented skin and mucous membranes, and Jeghers  who defined the coexistence of mucocutaneous pigmentation and gastrointestinal polyposis as a distinct clinical entity.
The incidence of this condition is estimated to be between 1 in 50,000  to 1 in 200,000 live births . Even though this syndrome was first described over half a century ago, our understanding of the syndrome is still incomplete, largely because of its rarity.
Gastrointestinal polyps in PJS
Small bowel polyps may display the phenomenon of “pseudoinvasion”, which may be mistaken for invasive carcinoma . “Pseudo-invasion”, is the invagination of the epithelium occuring as smooth muscle extends up towards the epithelium, resulting in islands of epithelial cells trapped in the smooth muscle layer. The lack of cytological atypia among other features can distinguish between true and pseudo invasion.
Although the cancer risk in PJS has been debated historically, it is now widely accepted that there is an increased risk of many cancers in PJS. Unfortunately the majority of the literature reporting cancer in PJS are small single cohort studies [5, 12–19]. It is difficult to draw any conclusions from these papers as they are likely to overestimate cancer risk due to both ascertainment and publication bias.
Cumulative cancer risk by site and age in Peutz-Jeghers syndrome patients (from Hearle et al. )
Type of cancer
Cancer risk by age % (95% CI)
Risk analysis of PJS cancers by site (from Giardiello et al. )
No. of cases
Risk ratio (95% confidence intervals)
Cumulative risk 15–64 years (%)
From the studies by Hearle and Giardiello however it can be concluded that there is an increased risk of luminal gastrointestinal cancers, which along with breast cancer are the most common cancers to develop in PJS. It is striking in the Hearle study how risk increases rapidly after the age of 50 years for all cancers.
How cancer arises in PJS and the role of the PJS polyp in cancer development remain controversial. An hamartoma—adenoma—carcinoma pathway  has been proposed and the finding of adenomatous foci within PJS polyps and the description of cancer arising within PJS polyps  appear to support this hypothesis. Others suggest that PJS polyps have no malignant potential. Malignant transformation within a PJS polyp is only seen as a rare event  and in a recent single center study, 2641 polypectomies were performed at surveillance investigations or subsequent procedures and in over 1,000 polyps where histology was available only six polyps contained atypia (n = 2, both from the same patient) or dysplasia (n = 4, mild—moderate dysplasia, no severe dysplasia). There was no correlation between size and presence of dysplasia; dysplastic polyps ranged from <1 to 2.5 cm in size . Further evidence to support a lack of malignant potential is the demonstration that PJS polyps are polyclonal. The hypothesis proposed is that dysregulation of cell polarization leads concurrently to a cancer predisposition while also creating a predisposition for mucosal prolapse .
If PJS polyps have no malignant potential does cancer arise through conventional neoplastic pathways? There are some data to support the role of somatic mutation or loss of heterozygosity (LOH) of the unaffected LKB1 allele, and additional mutations of the beta-catenin and p53, however neither APC mutations nor 5q LOH have been identified [28, 29]. These differences in molecular genetic alterations noted between the adenoma–carcinoma sequence and PJS related tumours suggest the presence of a distinct pathway of carcinogenesis. Whether this pathway is accelerated is an intriguing question which has yet to be answered. Only one of the 17 colorectal cancers seen in the largest series  was detected at surveillance raises the possibility of an accelerated pathway leading to interval cancers (provided that patients were under surveillance and compliance was adequate). Further research in this area is required to clarify these issues.
Colonoscopic and upper GI tract surveillance is reported to be safe . During 786 surveillance examinations and over 1,500 polypectomies, there were only two cases of perforation (both following resection of polyps larger than 2 cm) and no post polypectomy bleeding was observed. The age at which surveillance should be started has been debated. One study has shown that significant polyps may develop at a young age . Of 28 patients who had undergone one or more surveillance endoscopies by the age of 18 years, 17 were found to have developed significant gastroduodenal or colonic polyps; 39 colonic polyps and 20 gastroduodenal polyps larger than 1 cm were detected in these patients, the largest lesions were a 6 cm colonic polyp and an 8 cm gastric polyp . This data supports the initiation of surveillance before the age of 18 years , which had been previously recommended .
Endoscopic surveillance for gastrointestinal cancer
One role for surveillance endoscopy is the detection of cancer. Colorectal cancer is the most common luminal gastrointestinal cancer in PJS and the risk of colorectal cancer has been reported as 3, 5, 15 and 39% at ages 40, 50, 60 and 70 years respectively  . In the meta-analysis by Giardiello et al. the age range for colorectal cancer was 27–71 years and an overall risk of 39%, the majority of which are in males. Upper gastrointestinal cancers are less common and gastric cancer is far more common than oesophageal . Although gastric cancer has been reported in the first and second decades of life, the average age of stomach cancer diagnosis is 30 years .
Because of this GI cancer risk endoscopic surveillance is recommended. There are however limited data as to whether such an approach is effective. In the large series reported by Hearle et al.  only one case of sigmoid cancer was detected during surveillance, although surveillance protocol and compliance are not detailed.
Endoscopic surveillance for polyp related complications
The other indication for endoscopic surveillance is the detection of large polyps allowing early therapy and the prevention of polyp related complications. If an hamartoma-carcinoma pathway exists, surveillance and polypectomy may also prevent cancer.
There are no data regarding polyp related symptoms. However a report of outcomes of GI tract surveillance from a single institution has raised the intriguing possibility that endoscopic tract surveillance and polypectomies may prevent cancer . In this cohort of 51 patients with 683 patient years follow up, no patients developed luminal GI cancer. Patients did however develop breast and pancreatic cancer, the most common other cancers seen in PJS, although neither of these were part of the surveillance programme. From current literature [20, 21] the risk of GI cancers is roughly equal to breast cancer (cumulative risk 9% age 40, 15% age 50) and three times greater than the risk of pancreatic cancer. We would therefore have expected to observe 2–3 cases of GI cancers to develop in this study. If gastrointestinal cancers do arise through an hamartoma-carcinoma pathway, then polypectomy would prevent cancer formation, in a manner analogous to sporadic colorectal adenomatous polyps. It is more likely however that the lack of GI cancers seen in this cohort reflects either the relatively small cohort size or an overestimation of GI cancers in the literature.
It has been recommended that a baseline colonoscopy and upper GI endoscopy is indicated at age 8 years . In those in whom significant polyps are detected these should be repeated every three years. In those in whom there are no significant polyps at baseline endoscopy, routine surveillance is repeated at age 18, or sooner should symptoms arise, and then three yearly. It has also been recommended that after the age of 50 years the frequency is increased to every 1–2 years due to the rapid increase in cancer risk at this age. Currently there are no firm data to provide evidence of benefit.
Small bowel surveillance
Small bowel surveillance is performed to allow the detection of significant polyps and polypectomy before symptoms develop and to prevent intussusception and the need for emergency laparotomy. There are limited data to guide when to start small bowel surveillance. A survey of adults with PJS , found that by the age of 18 years, 23/34 (68%) of adults had undergone laparotomy, 70% of which were performed as an emergency. By the age of 10 years, 30% had required a laparotomy. In order to reduce the likelihood of developing intestinal obstruction, the study recommended that asymptomatic children start small bowel screening at the age of 8 years.
A recent study provides evidence that small bowel surveillance and removal of significant polyps is of benefit; no patients enrolled on the programme required emergency surgery for obstruction or intussusception during 683 patient years follow up .
Mode of surveillance
A variety of investigations can be used to assess the small bowel in PJS. Barium follow through (BaFT) and video capsule endoscopy (VCE) have been compared. Two studies in adult patients found that video capsule endoscopy (VCE) has a greater sensitivity in detecting small bowel polyps [33, 34], although the study size was small in both studies. A prospective study has been performed comparing BaFT and VCE in paediatric patients with PJS . No significant difference was found in detection rates of polyps >1 cm but VCE detected more polyps <1 cm and also was much better tolerated. Many centres now use VCE, since it appears at least as accurate as barium follow through, is preferred by patients and reduces radiation exposure.
A number studies have assessed the use of magnetic resonance enterography (MRE) to image the small bowel in patients with PJS. The results have been somewhat mixed. Kurugoglu et al.  compared barium follow through with ultrasound and MRE and found that polyps were detected equally with contrast studies and MRE. Caspari et al.  compared VCE with MRE and observed that VCE was superior at detecting small polyps. Polyps of 15 mm and above were detected equally with both modalities and location of polyps and determination of their exact sizes was more accurate with MRE. More recently it has been reported that MRE was less likely to miss large polyps and was more accurate at polyp sizing than VCE, although VCE was more comfortable for patients .
There are no data to support the use of double balloon enteroscopy (DBE) as a method of small bowel surveillance in PJS. It is a prolonged, very invasive procedure and does not guarantee visualisation of the entire small bowel, especially in those who have undergone previous abdominal surgery.
Current consensus recommendations are that small bowel surveillance using VCE should be initiated at 8 years of age or earlier if the patient is symptomatic . Thereafter VCE should be performed every 3 years if polyps are found at the initial examination; if few or no polyps are found at the initial examination, screening should commence again at the age of 18. MRE and BaFT are reasonable alternatives in adult patients but BaFT is not favoured in children due to radiation exposure.
It is important to note that the rate of growth and development of new PJS polyps is highly variable and so there should be a low threshold for investigation of symptoms and anaemia if they arise between scheduled surveillance investigations.
Surgical and endoscopic treatment of small bowel polyps in PJS
When significant small bowel polyps are detected, the two treatment options are laparotomy and intra-operative enteroscopy (IOE) or DBE and polypectomy. The “clean sweep” approach, whereby at laparotomy, on table enteroscopy to assess and remove polyps from the entire small bowel, has been demonstrated to reduce the need for surgical intervention [39, 40].
Although currently data are sparse, one series has shown DBE polypectomy to be safe and none of the cohort 13 patients developed small-intestine-polyp-related complications occurred during a follow-up period of 356 person-months . Another series retrospectively assessed DBE and IOE polypectomy in patients with PJS and observed that the two were comparable in terms of number of polypectomies per session, size of polyps removed and complications . They concluded that polypectomy using DBE may obviate the need for repeated urgent operations and small-bowel resections leading to short-bowel syndrome.
Both DBE and IOE facilitate exploration and treatment of the small intestine. DBE is less invasive and more convenient for the patient. Both procedures are generally safe and useful. This safety profile is not found universally however. Despott and colleagues observed one post-polypectomy haemorrhage and one perforation in a cohort of nine patients who underwent 13 DBEs .
No firm recommendations can be made but it would seem logical that if there are numerous large polyps laparotomy and OTE would be the preferred mode of treatment and DBE preferred for patients in whom there are fewer significant small bowel polyps.
Medical treatment of GI polyps in PJS
Historically, focus has been on surgical and endoscopic management of polyps in the GI tract. More recently potential medical therapies in PJS are being sought and assessed. Polyp prevention or reduction of polyp burden, may prevent polyp related complications and therefore reduce the need for invasive intervention by endoscopic and surgical methods. Medical therapy is therefore a very attractive proposition.
LKB1 mutations cause dysregulation of the mTOR (mammalian target of rapamycin) pathway . The mTOR pathway is particularly important as it is a final common pathway that is also dysregulated by other hamartomatous polyposis syndromes caused by germline PTEN, BMPR1A and SMAD4 mutations. The mTOR pathway inhibitor rapamycin has been studied in LKB1 ± mice . It was found that tumour burden decreased significantly in the treatment group, suggesting that rapamycin may have potential as a therapeutic agent in patients with PJS. There is a clinical trial (NCT00811590) underway to assess the mTOR inhibitor Everolimus (RAD001) in PJS patients. Although these agents are promising they are not currently used in clinical practice.
Overexpression of COX-2 has been noted in PJS polyps and cancers , and may present a therapeutic target for modulation of polyp development. The role of the pro-inflammatory cyclo-oxygenase pathway in the pathogenesis of PJS polyps has been studied in a mouse model . Mice treated with celecoxib, a selective COX2 inhibitor, were found to have a 54% reduction in polyp burden. A very small clinical trial within this study was carried out in six patients with documented LKB1 mutations, who were treated with 400 mg of celecoxib daily for 6 months. In two patients gastric polyp burden was reduced after treatment with celecoxib. For those patients with PJS in whom small bowel polyps rapidly develop requiring multiple surgical interventions or very frequent DBE and polypectomy, some experts may consider using celecoxib to try and reduce polyp development, although as demonstrated the evidence base for this is poor.
Huang et al.  demonstrated that activation of the LKB1-AMPK pathway by metformin significantly slowed tumour onset and identified the potential of metformin in polyposis syndromes associated with the dysregulation of LKB1 and PTEN. Metfromin is not currently in clinical use in patients with PJS.
No firm recommendations can be made on the basis of current evidence but in specialist centers celecoxib may be considered for those with recurrent, significant small bowel polyps.
Gastrointestinal polyps are one of the hallmarks of PJS. Although historically thought to be hamartomas, their true origin is not yet defined. Although there is an undoubted increased risk of luminal GI cancers in PJS, it is not clear whether such cancers arise from the PJS polyp or arise on a background of mucosal instability. Even though PJS polyps may have no role in gastrointestinal cancer they can be responsible for significant morbidity due to polyp related complications such as obstruction/intussusception, bleeding and anaemia.
Summary of GI tract surveillance recommendations in patients with PJS (from Beggs et al. )
1. Baseline upper GI endoscopy/colonoscopy age 8
Polyps detected, continue 3 yearly until 50 years
No polyps detected, repeat age 18 years, then 3 yearly until 50 years
2. Colonoscopy 1–2 yearly after age 50 years
3. VCE every 3 years from age 8 years
Some promising medical therapies for PJS polyps are on the horizon but are still being evaluated. None currently have the clinical data to support routine clinical use.