Best Practice & Research Clinical Gastroenterology 58-59 (2022) 101789

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Best Practice & Research Clinical Gastroenterology

journal homepage: www.elsevier.com/locate/bpg

Gastrointestinal aspects of Peutz-Jeghers syndrome

A.R. Latchford a, b, *, S.K. Clark a, b
a
Polyposis Registry, St Mark’s Hospital, Harrow, UK
b
Department of Surgery and Cancer, Imperial College, London, UK

A R T I C L E I N F O A B S T R A C T

Keywords: There are two main problems in the clinical management of the gastrointestinal (GI) tract in patients with Peutz-
Peutz-Jeghers Jeghers syndrome (PJS), namely long-term cancer risk and managing polyp related complications (of which the
Polyp most important clinically is intussusception). Given the rarity of this condition, the evidence base upon which to
Intussusception
make recommendations is small. Furthermore, controversies persist regarding the relationship between PJ
Surveillance
Endoscopy
polyps, cancer development and cancer risk.
In this article we will explore some of these controversies, to put into context the recommendations for clinical
management of these patients. We will provide an overview, particularly focusing on clinical data, and on the
recommendations for clinical management and surveillance of the GI tract in PJS. We highlight knowledge gaps
which need to be addressed by further research.

1. Introduction
In 1895, an English physician provided the first description of PJS,
illustrated the following year by Hutchinson [1,2]. These twin girls with
oral pigmentation died at age 20 and 52 years, from intussusception and
breast cancer respectively. In the 1920’s Peutz {Peutz, 1921 #90},
described a family with autosomal dominant inheritance of gastroin­
testinal polyposis and pigmented mucous membranes [3], and two de­
cades later Jeghers {Jeghers, 1949 #9; Jeghers, 1949 #10} defined the
key clinical features of mucocutaneous pigmentation and gastrointes­
tinal polyposis as a distinct clinical entity [4]. The eponym
Peutz-Jeghers syndrome was proposed in 1954 [5].
PJS is rare; the incidence is estimated to be between 1 in 50,000 to 1
in 200,000 live births [6,7]. It can be diagnosed either clinically or
genetically. A clinical diagnosis can be made on the basis of [8]:
1. Two or more histologically confirmed PJ polyps
2. Any number of PJ polyps detected in one individual who has a family
history of PJS in close relative(s)
3. Characteristic mucocutaneous pigmentation in an individual who
has a family history of PJS in close relative(s)
4. Any number of PJ polyps in an individual who also has characteristic
mucocutaneous pigmentation.
These clinical criteria have been used widely and are the criteria
upon which much of the literature are based. However, they have sub­
sequently been amended by the WHO [9], with the first criterion
amended to three or more histologically confirmed PJ polyps. Which of
these is superior remains unclear; certainly, changing the diagnostic
criteria may lead to difficulties in data interpretation in the future.
A genetic diagnosis is made by identifying a constitutional patho­
genic variant in the tumour suppressor gene LKB1 (also called STK11)
gene. Of those with a clinical diagnosis, an underlying constitutional
pathogenic variant can be identified in around 95% of cases [10]. The
function of LKB1 is complex and still being clarified, but it has roles in
the regulation of cellular proliferation and p53 mediated apoptosis, as
well as regulation of Wnt signalling. Furthermore, it has a role in cell
polarity, cell metabolism and energy homeostasis. It is an upstream
regulator of AMP activated protein kinase (AMPK), thereby acting as a
negative regulator of the mTOR (mammalian target of rapamycin)
pathway; this is an important final common pathway that is also dys­
regulated by other hamartomatous polyposis syndromes, caused by
constitutional variants in PTEN, BMPR1A and SMAD4.
2. Gastrointestinal polyps in PJS
2.1. Histology
PJ polyps have very distinct histological features (see Fig. 1). The
epithelial component is elongated and frond-like. Cystic gland dilatation

* Corresponding author. Department of Surgery and Cancer, Imperial College, London, UK.
E-mail address: andrew.latchford@nhs.net (A.R. Latchford).

https://doi.org/10.1016/j.bpg.2022.101789
Received 28 February 2022; Accepted 8 March 2022
Available online 6 April 2022
1521-6918/© 2022 Elsevier Ltd. All rights reserved.
A.R. Latchford and S.K. Clark
extending into the sub-mucosa or muscularis propria may be observed.
Perhaps the most characteristic feature is the branching muscular core,
which extends into the superficial epithelial layer. This resembles the
trunk and branches of a tree and is therefore termed arborisation.
Although PJ polyps are usually classified as hamartomas, this is
contentious. It has been proposed that rather than being true hamarto­
mas, there is a mechanical process underlying the development of PJ
polyps. Polypoid lesions associated with mucosal prolapse histologically
are very similar to a PJ polyp. LKB1 has an important role in cell polarity
[11]; it may well be that disruption of cell polarity pathways causes
mucosal prolapse and PJ polyps are an epiphenomenon reflecting this
process [12].
Another important histological observation in PJ polyps is the phe­
nomenon of “pseudoinvasion”, particularly seen in small bowel polyps.
This phenomenon may be mistaken for invasive carcinoma [13].
“Pseudo-invasion”, is the invagination of the epithelium occurring as
smooth muscle extends up towards the epithelium. As a result, the
smooth muscle layer may contain trapped islands of epithelial cells. True
and pseudo invasion can be distinguished by the lack of cytological
atypia.
2.2. Clinical
PJ polyps may be found at extra-intestinal sites, but seen are most
often in the GI tract. Within the GI tract, they are observed most
commonly in the small bowel (60–90%; in particular the jejunum) and
frequently in the large bowel and stomach(50–64% and 15–30%
respectively) [6,14].
PJ polyps are symptomatic in one third of patients by 10 years of age,
and in one half of patients by 20 years of age [15]. They usually present
with intussusception, obstruction or bleeding. A survey of adults with
PJS [16], 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. A two centre
Dutch study confirmed a high rate of intussusception, being experienced
by 50% at the age of 20 years, with a median age of 16 years (range 3–50
years) [17]. The vast majority (95%) of intussusceptions occurred in the
small intestine and 80% of all intussusceptions presented as an acute
abdomen. Intussusceptions were caused by polyps with a median size of
35 mm (range 15–60 mm).
Further prospective data about the age of polyp development are
Fig. 1. 1a. Macroscopic appearances of a solitary PJ polyp and severe gastric polyposis. 1b Microscopic features of a PJ polyp.
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Best Practice & Research Clinical Gastroenterology 58-59 (2022) 101789
available from a single centre UK study, addressing outcomes of sur­
veillance in PJS [18]. Significant polyps were observed to 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.
3. Gastrointestinal cancer
Understanding the cancer risk in PJS is difficult. Although it is widely
accepted that there is an increased risk of many cancers in PJS, the
majority of the literature reporting cancer in PJS consists of small single
cohort studies, which are likely to overestimate cancer risk due to both
ascertainment and publication bias.
The most comprehensive data available are a meta-analysis assessing
210 patients from six studies [19] and a study by Hearle et al. [20] of a
cohort of 419 patients with PJS. These data however remain imperfect.
In the meta-analysis, relative risk of cancer incidence rates were based
on US figures, whereas the study population were all European (UK and
Dutch). The meta-analysis was on a small cohort and within this, two of
the six studies reported on single pedigrees, which may bias the data due
in the presence of inter-familial phenotypic variation.
Both studies reported an increased risk of luminal gastrointestinal
cancers. Reported cumulative incidence of GI cancers were 1, 9, 15, 33
and 57% by age 30, 40, 50, 60 and 70 years respectively [20]. The
relative risk of site-specific cancers reported in the meta-analysis [19]
are shown in Table 1.
There have been two more recent publications addressing cancer risk
in PJS. The first is a multi-centre, international study reporting on a
cohort of 149 patients [21] They reported a cumulative risk of gastro­
intestinal cancer of 4, 12, 24, 34 and 63% at 30, 40, 50, 60 and 70 years
Table 1
Risk ratios, frequencies of PJS GI cancers reported by Giardiello et al.19
Site Risk Ratio (95% confidence intervals) Frequency
Oesophagus 57 (2.5–557) 0.5%
Stomach 213 (96–368) 29.0%
Small bowel 520 (220–1306) 13%
Colon 84 (47–137) 39%
A.R. Latchford and S.K. Clark
respectively. Of these 11 were large bowel, five gastric, four small bowel
and one oesophageal. However, as before this is likely to be a biased
cohort. In addition, it includes countries with high background popu­
lation rates of upper GI cancers in particular, which may artificially
inflate perceived risk.
The second paper is a multi-centre Dutch study [22]. Eighteen
luminal GI cancers were diagnosed in this cohort of 133 patients. As with
other studies, colorectal cancer was the predominant cancer reported
(six cases, age 30–76 years). Of the other cases, there is concern as to the
validity of the diagnoses for some. Two of the three small bowel cancers
were diagnosed in teenagers, and it is far more likely that these historic
cases were not cancer at all, but were polyps with pseudoinvasion. There
were also three cases of cancer of the “digestive tract”, without further
detail.
Interestingly, in a recent smaller cohort, followed prospectively, no
luminal cancers were diagnosed during 683 patient years follow up
(median 10 years) in 68 patients [18]. It is difficult to know whether this
reflects the cohort size, overestimation of risk in past studies or sur­
veillance preventing cancer.
The value of surveillance in cancer prevention is not established.
Fundamentally, this is because carcinogenesis in PJS and the role of the
PJ polyp in cancer development remain controversial and poorly un­
derstood. A hamartoma - adenoma - carcinoma pathway [23] has been
proposed and the finding of adenomatous foci within PJ polyps and the
description of cancer arising within PJ polyps [24] could be interpreted
as supporting this hypothesis. However, there are perhaps more
convincing data which support a lack of malignant potential in PJ
polyps. Although malignant transformation within a PJ polyp has been
described, it is really only seen as a rare event [25]. Perhaps more
compelling are data from a single centre study, where 2641 poly­
pectomies were performed at surveillance investigations or subsequent
procedures and in over 1000 polyps where histology was available, only
four polyps contained dysplasia (all mild – moderate dysplasia, no se­
vere dysplasia). The presence of dysplasia was not observed to correlate
with polyp size (which ranged from <1 cm–2.5 cm in size) [18]. Further
evidence to support a lack of malignant potential is the demonstration
that PJ polyps are polyclonal. It has been postulated that cell polarity
dysregulation leads both to a predisposition to cancer and also to
mucosal prolapse [12].
If PJ 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 unaf­
fected LKB1 allele, and additional mutations of beta-catenin (CTNNB1)
and p53 but neither APC mutation nor 5q LOH have been identified [26,
27]. Although these data suggest the presence of a distinct pathway of
carcinogenesis, this is an area which needs to be studied further.
4. Surveillance/treatment
4.1. Surveillance
Gastrointestinal tract surveillance is recommended both for cancer
prevention/early detection as well as to prevent polyp related compli­
cations. However, prospective studies evaluating the effect of surveil­
lance strategies for gastric, duodenal or colorectal cancer are largely
lacking. The prospective data previously described are of interest as no
luminal cancers were diagnosed during follow-up, however the cohort
really is not of sufficient size to draw any meaningful conclusions [18].
This study did however demonstrate a benefit for polyp complication
prevention; no patients on surveillance and undergoing elective small
bowel polyp intervention suffered an intussusception and none required
emergency surgery.
Although the use of endoscopic surveillance of the upper GI tract and
large bowel are established is the appropriate modality, more options
are available for small bowel surveillance. Currently MRI enteroclysis/
enterography (MRI-E) and video capsule endoscopy (VCE) are the most
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Best Practice & Research Clinical Gastroenterology 58-59 (2022) 101789
used imaging modalities [28–31]. A number of studies comparing MRI-E
and VCE have been performed, including a total of 47 patients with PJS
[30–32]. Gupta et al. [30] did not find a significant difference between
the two modalities for the detection of clinically relevant polyps (>10
mm), as opposed to Urquhart et al. [31] who showed superiority of VCE
over MRI-E. While patients tend to prefer VCE to MRI-E, data show that
both modalities do miss clinical relevant polyps (>15–20 mm or smaller
polyps that are associated with symptoms.). VCE may does miss large
lesions, especially in the proximal small bowel [30,32]. Based on the
current literature, both VCE and small bowel MRI are reasonable options
for surveillance. Although patients prefer VCE, it is less accurate in polyp
sizing and localisation compared with MRI-E.
There are no robust 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, requiring a general anaesthetic and
does not guarantee visualisation of the entire small bowel, especially in
those who have undergone previous abdominal surgery. In addition, the
vast majority of patients do not have polyps of sufficient size to warrant
intervention, therefore such an invasive procedure seems unjustified.
Current adult and paediatric guideline recommendations are sum­
marised in Table 2. It is important to highlight that there is huge vari­
ation in the rate of growth and development of new PJ polyps.
Therefore, there should be a low threshold for investigation of symptoms
and/or anaemia if they arise between scheduled surveillance
investigations.
4.2. Endoscopic polypectomy
There are no data to suggest when polypectomy should be performed
in the colon, stomach or duodenum. Pragmatically, many use a 10 mm
threshold for resection to prevent polyp related complications but there
really is no evidence to support this.
The data are better regarding the small bowel; guidelines recom­
mend intervening for small bowel polyps at 15–20 mm in size (or earlier
if symptomatic). A number of studies have shown that polypectomy of
relevant small bowel polyps can prevent the need of for emergency
surgery [18,33,34].
The preferred method of intervening for small bowel polyps is
balloon assisted enteroscopy (BAE), which allows polypectomy of
almost all clinically relevant polyps [35]; indeed very large polyps, up to
100 mm have been effectively resected using single and double balloon
approaches [36,37]. Prior abdominal surgery may limit the ability to
achieve adequate small bowel intubation to achieve therapeutic intent;
however, it should not be considered a contraindication to balloon
enteroscopy. BAE is also feasible and effective in a paediatric patients
[34], although the very young may be technically more challenging.
Although concern about the safety of polypectomy in PJS has been
raised, large volume centres have reported very low rates of complica­
tion [18]. Standard hot snare polypectomy technique suffices for most
lesions. However, an ESD dissection approach may be used, for techni­
cally more challenging/worrying lesions due to size of the polyp head or
indeed stalk. A novel technique of “ischaemic polypectomy” has also
been described and appears to be safe and effective [38] (see Fig. 2).
Table 2
Summary of GI surveillance guidelines.
Gastrointestinal should commence no later than 8 years:
1 Baseline OGD and colonoscopy age 8years.
If polyps are detected at the baseline repeat 1–3 yearly based on phenotype
If no polyps identified at baseline, repeat age 18 years and 1–3 yearly thereafter, based
on phenotype
2 Small bowel surveillance from the age of 8years and continue 1–3 yearly interval
based on phenotype
Earlier investigation of the GI tract should be performed in symptomatic patients.
A.R. Latchford and S.K. Clark
Fig. 2. Ischaemic polypectomy.
4.3. Surgery
Although surgery may occasionally be required to manage polyps/
polyp related complications in the stomach and the large bowel, its main
role is in the management of significant small bowel polyps. Combined
laparoscopy and BAE may be utilised when adhesions prevent a standard
BAE approach or to enhance the safety of endoscopic removal of a sol­
itary large high risk polyp [39]. However, the number of larger polyps
may be such that a laparotomy and intra-operative enteroscopy (IOE) is
required. 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 [40,
41]. In the authors’ experience, we have cleared over 200 polyps (5 mm
or more) at laparotomy and IOE, a feat that would seem unrealistic using
other modalities.
Surgery is the mainstay of management of a patient presenting with
an intussusception, where urgent surgical reduction of the intussus­
ception is required to avoid necrosis and the need for resection of the
small bowel. If at dessusception ischemia is reversible, resection of the
bowel is not required. Intraoperative enteroscopy through an enter­
otomy is recommended to identify and treat other large polyps to reduce
the risk of future surgical intervention [42].
4.4. Medical treatment
Although endoscopy and surgery have been the mainstays of treat­
ment of the GI tract in PJS, potential medical therapies in PJS are being
sought and assessed as chemoprevention agents. Even if one discounts
the role of such treatments to prevent cancer development, were they to
prevent polyp formation or reduce of polyp burden, this may prevent
polyp related complications and reduce the need for invasive endoscopic
or surgical intervention. Medical therapy is therefore a very attractive
proposition.
Given the mTOR pathway is dysregulated by variants in LKB1,
rapamycin is an obvious candidate for a chemoprevention agent in PJS.
It has been studied in LKB1 ± mice and was found that tumour burden
decreased significantly in the treatment group, suggesting that rapa­
mycin may have potential as a therapeutic agent in patients with PJS
[43,44]. A prospective non-randomized open label single arm clinical
trial to examine the efficacy and safety of rapamycin (sirolimus) in pa­
tients with PJS is underway, with a primary endpoint of polyp burden
(ClinicalTrials.gov Identifier: NCT03781050).
A clinical trial (NCT00811590) undertaken to assess the mTOR in­
hibitor Everolimus (RAD001) in PJS patients was terminated as it failed
to recruit, as did a further study assessing the effect of Everolimus in the
treatment of PJS cancer, as well as high risk polyps [45].
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Best Practice & Research Clinical Gastroenterology 58-59 (2022) 101789
There are studies addressing its utility in the setting of advanced
malignancy but there are however no data regarding its potential as a
chemoprevention agent. Therefore, although promising, these agents
are not currently used in clinical practice.
PJ polyps and cancers have been observed to overexpress COX-2,
which may present an alternative therapeutic target for modulation of
polyp development [46]. In a mouse model of PJS, mice treated with
celecoxib (a selective COX2 inhibitor), were found to have a 54%
reduction in polyp burden [47]. Within this study there was a very small
clinical trial, carried out in six patients with documented LKB1 muta­
tions, who were treated with 400 mg of celecoxib daily for 6 months. In
two patients, gastric polyp burden was reduced after treatment with
celecoxib. However more meaningful, powered studies with appropriate
endpoints have not been performed.
The “Biguanide” class of drugs have been identified as a potential
agent that could slow the development of neoplasia in PJS. Huang et al.
demonstrated that activation of the LKB1-AMPK pathway by metformin,
phenformin or A-769662 significantly slowed tumour onset and there­
fore may have a potential role in the management of polyposis syn­
dromes associated with the dysregulation of LKB1 and PTEN [48].
Clinical trials however have not been performed and these drugs are not
currently in clinical use in patients with PJS.
5. Areas for future research
Gastrointestinal polyps are one of the hallmarks of PJS. 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. A better un­
derstanding of the malignant potential of PJS polyps will be invaluable
to facilitate rationalising endoscopic intervention and its’ benefits.
Indeed, a better understanding of GI tract cancer risk from less biased,
prospective data is also an area of need.
Even if PJ polyps 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. Small
bowel complications are a particular problem in childhood. Interest­
ingly, current guidelines do not distinguish between children and adults
when it comes to recommendations for small bowel polyp intervention
to reduce the risk of intussusception. It seems illogical that the threshold
would be the same for a young child as it would for a fully grown adult.
However, data are lacking currently to inform an approach personalised
to a patient’s age and or height/weight. However these data should be
available but are likely to require multicentre collaborative studies, to
enable a sufficiently large cohort to be formed to produce data from
which meaningful conclusions can be drawn.
Medical therapies for PJ polyps lack the clinical data to support
routine clinical use. However, for those PJS patients who are rapid polyp
formers, a chemoprevention approach to reduce polyp related morbidity
and need for intervention would be worthy of further study. The diffi­
culties with such studies however include appropriate end points and
also difficulty recruiting to such studies given the rarity of the condition,
as well as the involvement of paediatric patients.
RESEARCH AGENDA:
- A better understanding of the malignant potential of PJ polyps is
required
- Defining GI cancer risk, as assessed in prospective, less bias cohorts
would be invaluable
- Defining polyp size in relation to risk of complications in different
age groups will allow for more personalised management
- Exploring chemoprevention to minimise polyp related complications
will be of value for this patient cohort
6. Summary
Peutz-Jeghers syndrome is a rare, with an increased (although poorly
A.R. Latchford and S.K. Clark
quantified) risk of cancer and with significant polyp related morbidity
associated, particularly intussusception in childhood. Surveillance of the
gastrointestinal tract is widely recommended to prevent polyp related
complications, for which there are data to support its effectiveness.
Whether surveillance has a role in cancer prevention or early detection
is not established. Initial pan-enteric examination is recommended at
the age of eight years (earlier if symptomatic). Thereafter the surveil­
lance is personalised according to an individual’s phenotype.
Surgery may be required, in particular for the management of small
bowel polyps, either electively or as an emergency in the setting of acute
obstruction related to intussusception. Intra-operative endoscopy is
recommended to detect and treat small bowel polyps, to reduce future
surgical need.
Although the concept of chemoprevention to reduce polyp devel­
opment is attractive, despite some agents showing promise, appropriate
clinical trials are lacking and these agents are not routinely used in
clinical practise.
We have highlighted areas where research is required, including a
better understanding of gastrointestinal cancer risk and indeed whether
or not they arise from the PJ polyp. A clearer idea of the size of polyp
which is associated with intussusception is required and this needs to be
stratified for age, particularly to better inform clinical management, in
the paediatric setting.
PRACTICE POINTS:
- GI tract surveillance is recommended, starting at age 8 years
- Earlier investigation is indicated if a child is symptomatic
- Treatment of polyps in the small bowel when 15–20 mm is recom­
mended to reduce risk of intussusception
- For elective or emergency surgical management of small bowel
polyps, an intra-operative enteroscopy and “clean sweep” of the
small bowel is recommended and reduces the need for future surgery
Declaration of competing interest
None to declare.
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