Digestion
Review
Digestion
DOI: 10.1159/000529799
Received: December 7, 2022
Accepted: February 14, 2023
Published online: April 13, 2023
Clinical Guidelines for Diagnosis and
Management of Peutz-Jeghers
Syndrome in Children and Adults
Hironori Yamamoto
a
Hirotsugu Sakamoto
a
Hideki Kumagai
b
Takashi Abe
c
Shingo Ishiguro
d
Keiichi Uchida
e
Yuko Kawasaki
f
Yoshihisa Saida
g
Yasushi Sano
h
Yoji Takeuchi
i
Masahiro Tajika
j
Takeshi Nakajima
k
Kouji Banno
l
Yoko Funasaka
m
Shinichiro Hori
n
Tatsuro Yamaguchi
o
Teruhiko Yoshida
p
Hideki Ishikawa
q,r
Takeo Iwama
s
Yasushi Okazaki
t
Yutaka Saito
u
Nariaki Matsuura
v
Michihiro Mutoh
q
Naohiro Tomita
w
Takashi Akiyama
x
Toshiki Yamamoto
y
Hideyuki Ishida
s
Yoshiko Nakayama
z
a
Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan;
b
Department of Pediatrics, Jichi Medical University, Shimotsuke, Tochigi, Japan;
c
Department of Gastroenterology,
Hanwa Sumiyoshi General Hospital, Osaka, Japan;
d
PCL JAPAN, INC, Kawagoe, Saitama, Japan;
e
Department of
Pediatric Surgery, Mie University Hospital, Tsu, Japan;
f
University of Hyogo, College of Nursing, Akashi, Japan;
g
Department of Surgery, Toho University Ohashi Medical Center, Tokyo, Japan;
h
Gastrointestinal Center &
Institute of Minimally-invasive Endoscopic Care, Sano Hospital, Kobe, Japan;
i
Division of Hereditary Tumors,
Department of Gastrointestinal Oncology, And Department of Genetic Oncology, Osaka International Cancer
Institute, Osaka, Japan;
j
Department of Endoscopy, Aichi Cancer Center, Nagoya, Japan;
k
Department of Clinical
Genetic Oncology, Cancer Institute Hospital of JFCR, Tokyo, Japan;
l
Department of Obstetrics and Gynecology,
Keio University School of Medicine, Tokyo, Japan;
m
Department of Dermatology, Nippon Medical School, Tokyo,
Japan;
n
Department of Cancer Genomic Medicine, NHO Shikoku Cancer Center, Matsuyama, Japan;
o
Department
of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan;
p
Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan;
q
Department of
Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan;
r
Ishikawa
Gastroenterology Clinic, Osaka, Japan;
s
Department of Digestive Tract and General Surgery, Saitama Medical
Center, Saitama Medical University, Kawagoe, Japan;
t
Intractable Disease Research Center, Graduate School of
Medicine, Juntendo University, Tokyo, Japan;
u
Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan;
v
Osaka International Cancer Institute, Osaka, Japan;
w
Cancer Treatment Center, Toyonaka Municipal Hospital,
Toyonaka, Osaka, Japan;
x
Department of Pediatric Surgery, Chuden Hospital, Hiroshima, Hiroshima, Japan;
y
Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine,
Tokyo, Japan;
z
Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
Keywords
Peutz-Jeghers syndrome · Child · Adult · STK11 ·
Hamartomatous polyps
Abstract
Background: Peutz-Jeghers syndrome (PJS) is a rare dis-
ease characterized by the presence of hamartomatous
karger@karger.com
www.karger.com/dig
? 2023 S. Karger AG, Basel
Correspondence to:
Hirotsugu Sakamoto, 94036hs @ jichi.ac.jp
polyposis throughout the gastrointestinal tract, except for
the esophagus, along with characteristic mucocutaneous
pigmentation. It is caused by germline pathogenic variants
of the STK11 gene, which exhibit an autosomal dominant
mode of inheritance. Some patients with PJS develop
gastrointestinal lesions in childhood and require continu-
ous medical care until adulthood and sometimes have
serious complications that signi?cantly reduce their quality
of life. Hamartomatous polyps in the small bowel may
causebleeding,intestinalobstruction,andintussusception.
Novel diagnostic and therapeutic endoscopic procedures
such as small-bowel capsule endoscopy and balloon-
assisted enteroscopy have been developed in
recent years. Summary: Under these circumstances, there
is growing concern about the management of PJS in Japan,
and there are no practice guidelines available. To address
this situation, the guideline committee was organized by
the Research Group on Rare and Intractable Diseases
granted by the Ministry of Health, Labour and Welfare with
specialists from multiple academic societies. The present
clinical guidelines explain the principles in the diagnosis
and management of PJS together with four clinical ques-
tions and corresponding recommendations based on a
careful review of the evidence and involved incorporating
the concept of the Grading of Recommendations Assess-
ment, Development and Evaluation system. KeyMessages:
Herein, we present the English version of the clinical
practice guidelines of PJS to promote seamless imple-
mentation of accurate diagnosis and appropriate man-
agement of pediatric, adolescent, and adult patients
with PJS. ? 2023 S. Karger AG, Basel
Introduction
Peutz-Jeghers syndrome (PJS) is a rare disease
characterized by the presence of hamartomatous poly-
posisthroughoutthegastrointestinaltract,exceptforthe
esophagus, along with characteristic mucocutaneous
pigmentation. Some patients with PJS develop gastro-
intestinal lesions in childhood and require continuous
medical care until adulthood and sometimes have se-
rious complications that signi?cantly reduce their
quality of life. The germline variants of the causative
genes of PJS may be identi?ed by cancer gene panel tests
to identify effective drugs. Novel diagnostic and ther-
apeutic endoscopic procedures, such as small-bowel
capsule endoscopy (SBCE) and balloon-assisted
enteroscopy (BAE), have been developed in recent
years. However, because of the diversity of clinical
features and low incidence of this disease, there have
been no Japanese guidelines for diagnosis, treatment,
and surveillance. Medical management of patients and
their relatives with this disease may be required as a
result of cancer genome medicine or as a part of the
characteristics of the disease, and it is dif?cult to apply
overseasguidelinesdirectlyto Japanese patientsin terms
of cost, clinical applicability, and the medical health
insurance system. Therefore, there is a need to develop
seamless clinical practice guidelines for children and
adults in Japan.
In 2017, as a project of “Research group to improve
the medical standard and equalize the treatment of
benign multiple tumors of the gastrointestinal tract”
(representer: Ishikawa H.), which was the research on
rare and intractable diseases granted by the Ministry of
Health, Labour and Welfare, a working group was
establishedtodevelop “ClinicalGuidelinesforDiagnosis
and Managements of Peutz-Jeghers Syndrome in
Children and Adults.” Thecommitteemembersin-
cludedspecialistsininternalmedicine,gastroenterology,
surgery, pediatric gastroenterology, pediatric surgery,
dermatology, gynecology, pathology, genetics, genetic
counseling, and nursing. From 2019, the Japanese So-
ciety for Hereditary Tumors, the Gastrointestinal Pol-
yposis Study Group of the Japanese Gastroenterological
Association, and Japanese Society for Pediatric Gas-
troenterology, Hepatology and Nutrition continued to
work on the preparation of the guidelines with the
cooperation of other organizations. In 2020, the “Re-
search group for establishing a seamless medical care
system from children to adults in the gastrointestinal
hamartoma predisposition diseases” (representer:
Nakayama Y.), granted by the Ministry of Health, La-
bour and Welfare as a research on rare and intractable
diseases, published the clinical guidelines in Journal of
Hereditary Tumors in Japanese [1]. Herein, we present
an English version of the clinical practice guidelines
for PJS.
Developing the Guidelines
Indevelopingtheguidelines,theconceptofevidence-
based medicine was emphasized, and a project to
promote the distribution of the evidence-based medi-
cine guideline development guide [2] and the Grading
of Recommendations Assessment, Development, and
Evaluation (GRADE) [3] system were used. The
guidelines included detailed explanations of the PJS and
clinical questions (CQs) and recommendations.
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Collecting the Evidence
Basedontheidenti?edkeyclinicalissuesandeachCQ,
evidence was extracted using P (Patients), I (Interven-
tion), C (Control) or (Comparison), and O (Outcome) as
search keywords. We searched PubMed from January
1998 to December 2018, and the Internet version of the
Central Journal of Medicine was searched from inception
until December 2018.
Evaluating the Articles and De?ning the Quality
of Evidence
Articles selected for use in the guidelines were clas-
si?ed based on the study design (clinical practice
guidelines, systematic reviews, meta-analyses, random-
ized controlled trials, controlled clinical trials, cohort
studies, case-control studies, cross-sectional studies, case
series, case reports, and reviews). As PJS is a rare disease,
case reports and case series were included in the sys-
tematic review. A structured abstract was developed for
each article to evaluate the risk of bias. The overall evi-
dence was determined using the systematic review
method (Table 1); the overall level of evidence for each
CQ is listed from A to D.
De?ning the Strength of Recommendation
The strengths of these recommendations are listed in
Table 2. Decisions were made upon agreement among
committee members after careful consideration of the (i)
quality of evidence and (ii) balance of bene?ts and harms
(balance between disadvantages such as patient burden,
cost, and bene?ts acquired by implementing the
recommended practice). The consensus was formed by
voting according to the GRADE grid method [4], and a
decisionwasmadewhenmorethan70%ofthevoteswere
in favor.
Public Comments
A draft of the guidelines was published on the website,
and public comments were solicitedfrom the members of
the Japanese Society for Hereditary Tumors; the Japanese
Gastroenterological Association; the Japanese Society of
Gastroenterology; the Japan Gastroenterological Endos-
copy Society (JGES); the Japanese Society for Pediatric
Gastroenterology, Hepatology and Nutrition; and the
Japanese Society of Pediatric Surgery. Further revisions
were made based on public comments, and the Japanese
version was published in 2020 [1].
Detailed Explanations of PJS
Overview
The PJS was ?rst described in a family by Peutz in
1921, and the concept of the disease was proposed by
Jeghers et al. in 1949 [5]. It is characterized by hamar-
tomatous polyposis of the gastrointestinal tract, except
the esophagus, and pigmentations on the skin, mucous
membranes,mainlyonthelips,oralcavity,and?ngertips.
PJS is an autosomal dominant inherited disease with a
germline pathogenic variant in the STK11 gene as the
only currently known cause. Approximately 17–50% of
cases are solitary cases with no family history of the
Table 1. Quality of evidence
Quality of evidence at the start of the
evaluation
Systematic review, meta-analysis, randomized controlled trial = “high”
Cross-sectional study, cohort study, case-control study = “low”
Case series, case report = “very low”
When to lower the grade
p
There are very serious limitations to the quality of the research
There are signi?cant inconsistencies in the results
The directness of the evidence is somewhat or considerably uncertain
Data are inaccurate or inconsistent
Publication bias is highly likely
When to raise the grade
p
The degree of effect is large
There is a dose-response gradient
Possible confounding factors weaken the true effect
De?ning the quality of evidence about research on outcomes in general
A: “High” It is certain that the estimated of effect is virtually identical to the actual effect
B: “Moderate” Con?dence in the estimate of effect is moderate
C: “Low” Con?dence in the estimate of effect is limited
D: “Very low” The estimate of effect is quite uncertain
p
Ifthedegreeofeffectislargeorifitisconsidereddif?culttoconductarandomizedcontrolledtrialbecausePJSisararedisease,
the grade can be increased.
Clinical Guidelines for Peutz-Jeghers
Syndrome
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DOI: 10.1159/000529799
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disease [6]. The polyps are characterized by hamar-
tomatous hyperplasia of the mucosal epithelium and
dendriticgrowthofsmoothmuscle?berbundlesfromthe
muscularis mucosae and are called Peutz-Jeghers polyps.
Theincidence of various tumors (including malignant) in
the entire gastrointestinal tract, including the esophagus,
breast, pancreas, uterus, ovary, lung, and testis, is fre-
quently observed, and appropriate surveillance is
necessary [7].
Clinical Features
Pigmentations are inconspicuous at birth but occur
before the age of 5 years and increase until puberty [6].
Theymaybecomeinconspicuousinadulthood,butthey
often remain on the buccal mucosa. Peutz-Jeghers
polyps cause symptoms such as black stool, anemia,
abdominal pain, and vomiting. Enlarged polyps cause
intussusception, and surgical treatment is often
necessary [8].
Disease Frequency
The prevalence of PJS in Japan is currently uncertain.
The prevalence is estimated to be approximately 1 in
50,000–200,000livebirths[9],andthenumberofpatients
in Japan with PJS is estimated to be approximately
600–2,400.
Causative Genes
The serine/threonine kinase 11 (STK11)geneislo-
cated on the short arm of chromosome 19 (19p13.3) and
was previously named liver kinase B1 (LKB1) gene [10].
It has been reported that pathogenic variants in the
STK11 gene can be detected in 94% of PJS patients by
sequencing or copy number analysis within the gene
region [11, 12]. STK11 is a serine/threonine kinase that
phosphorylates and activates AMP-activated protein
kinase (AMPK) [13] and is widely expressed in human
tissues. Activated AMPK plays a variety of roles, in-
cluding regulation of intracellular energy metabolism,
inhibition of cell cycle progression, inhibition of cell
differentiation, regulation of cell polarity, induction of
apoptosis, and repair of DNA damage [13, 14]. Because
of these various intracellular functions, STK11 is
considered a tumor suppressor gene, and its variants
have been identi?ed in a variety of carcinomas, not just
PJS [6].
Mechanism of Peutz-Jeghers Polyp Formation
In Peutz-Jeghers polyps that develop in STK11
knockout mice, the expression of factors involved in
protein synthesis and cell proliferation, such as the
mammalian target of rapamycin complex1 (mTORC1)
and hypoxia-inducible factor-1α (HIF-1α), which are
inactivated by activated AMPK, is upregulated. These
factors are thought to play a key role in the development
of Peutz-Jeghers polyps in humans, but the detailed
mechanism has not been elucidated [15].
Diagnosis
Diagnostic Criteria
Clinical diagnostic criteria have been proposed by the
Research Group for Improving the Medical Standard of
gastrointestinal polyposis syndromes in the Japanese
Ministry of Health, Labour and Welfare and are used as
diagnostic criteria for speci?c pediatric chronic diseases
in Japan (https://www.shouman.jp/disease/instructions/
12_02_011/). In this guideline, we have modi?ed these
criteria to clarify the position of diagnosis based on ge-
netic testing (Table 3).
Clinical Characteristics
Hamartomatous polyposis (Fig. 1): Peutz-Jeghers
polyps are pathologically characterized by hamartom-
atous hyperplasia of the mucosal epithelium and den-
dritic growth of smooth muscle ?ber bundles from the
muscularis mucosae (Fig. 2). They are found in the
entiregastrointestinaltractexcepttheesophagusandare
especially common in the duodenum and upper jeju-
num. Endoscopic ?ndings reveal polyps that are pe-
dunculated or semi-pedunculated and slightly
erythematous. Some lesions are branched, bi?d, or
multinodular, re?ecting dendritic growth of the mus-
cularis mucosae. The surface structure displays a mix-
ture of tubular and dendritic structures. Small intestinal
polyps may present with pseudo-invasion, in which they
invade the muscular layer without cellular atypia and
Table 2. Strength of recommendations
1. Strong recommendation Implementation is recommended as “do it”
Implementation is recommended as “do not do it”
2. Weak recommendation Implementation is proposed as “probably do it”
Implementation is proposed as “probably do not do it”
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Table 3. Diagnostic criteria of PJS
A. Symptoms
1. Mucocutaneus pigmentations of 1–5 mm on the lips, mouth, and ?ngertips
B. Examination ?ndings
1. Endoscopic ?ndings: Upper gastrointestinal endoscopy, colonoscopy, and small-bowel endoscopy (capsule endoscopy or
balloon-assisted endoscopy) show hamartomatous polyps in any gastrointestinal tract except the esophagus
2. Pathological ?ndings: Hamartomatous polyps have hamartomatous hyperplasia of the mucosal epithelium and dendritic
growth of smooth muscle ?ber bundles from the muscularis mucosae, which can be diagnosed as Peutz-Jeghers polyps
C. Differential diagnosis
Differentiate from the following diseases
Familial adenomatous polyposis, juvenile polyposis syndrome, Cowden syndrome/PTEN hamartomatous syndrome, tuberous
sclerosis, in?ammatory polyposis, serrated polyposis syndrome, Cronkhite-Canada syndrome, hereditary mixed polyposis
syndrome, and Laugier-Hunziker-Baran syndrome
D. Genetic testing
Germline pathogenic variants in STK11 gene
1. A is ful?lled, two of B are ful?lled, and the differential diagnoses in C are excluded
2. A is ful?lled in an individual who has a family history of PJS in close relation, and the differential diagnoses in C are excluded
3. Two of B are ful?lled in an individual who has a family history of PJS in close relation, and the differential diagnoses in C are
excluded
4. B-1 is ful?lled, B-2 is met for multiple lesions, and the differential diagnoses in C are excluded
5. D is ful?lled
For patients who meet some of the diagnostic criteria but do not meet the above diagnostic categories (1–4) based on
symptoms and laboratory ?ndings, a search for germline pathogenic variants in STK11 should be considered for diagnosis by
genetic testing. If a germline pathogenic variant in STK11 is identi?ed, PJS can be diagnosed.
Color
version
avai
lable
online
a b
Fig. 1. Endoscopic ?ndings of Peutz-
Jeghers polyp. a Hamartomatous polyps
of approximately 10 mm in diameter are
congregated. b Pedunculated hamartom-
atous polyp 10 mm in diameter.
Color
version
available
onl
ine
a b
Fig. 2. Pathological ?ndings of Peutz-
Jeghers polyp (HE staining). a Loupe
image. b Low magni?cation. Hamar-
tomatous hyperplasia of the mucosal ep-
ithelium and dendritic growth of smooth
muscle ?ber bundles from the muscularis
mucosae are observed.
Clinical Guidelines for Peutz-Jeghers
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DOI: 10.1159/000529799
5
may be mistaken for malignant tumors [16]. Enlarge-
ment of polyps causes gastrointestinal bleeding and
anemia. Polyps larger than 15 mm may cause intus-
susception, and endoscopic or surgical treatment is
required [8]. The number of PJS patients who do not
require surgery is approximately 30%at the age of 18–20
years. However, in many cases, surgical treatment has
been performed when PJS is initially diagnosed in
childhood [17, 18].
Pigmentations(Fig. 3) (see CQ4):Pigmentationisoften
found on the lips but may also be found on the buccal
mucosa, ?ngertips, phalanges, and heels. The lesions are
blackish brown or brown, 1–5 mm in diameter, and
usually longitudinal in shape. Pathologically, there is an
increaseinmelaninpigmentandmelanocytesinthebasal
layeroftheepidermis,anditisspeculatedthatthismaybe
due to in?ammation inhibiting the migration of melanin
from melanocytes to keratinocytes [19]. Pigmentations
occur at birth, in early childhood, and increases until
puberty. They may become inconspicuous in adulthood,
but they often remain on the buccal mucosa. Although
there are no reports of malignant transformation, laser
treatment has been used from a cosmetic point of
view [20].
Malignant tumor (see CQ3): PJS is associated with a
highincidenceofvariousmalignancies,includingthoseof
the entire gastrointestinal tract; including the esophagus,
breast, pancreas, uterus, ovary, lung, and testis. For early
detection of malignancy, the American College of Gas-
troenterology (ACG) guidelines recommend surveillance
for PJS [7].
Treatment (See CQ2)
Peutz-Jeghers polyps can be resected endoscopically
to avoid symptoms associated with their growth.
Surgical resection is required for polyps that cannot be
treated endoscopically. Resection of Peutz-Jeghers
polyps in the small intestine using balloon-assisted
endoscopy may avoid the need for subsequent
surgical treatment [21, 22]. Surgery is the most
commontreatmentforintussusceptionduetoenlarged
polyps, but in some cases, endoscopic resection after
reduction of intussusception with balloon-assisted
endoscopy may be possible [23].
Risk Assessment of Patient’s Relatives of the Proband
If a germline pathogenic variant of the proband is
known, it is appropriate to offer genetic testing to de-
termine whethercloserelativeshave thesamevariant, but
adequate genetic counseling and privacy considerations
areimportant.Morbidityandmortalitycanbereducedby
early diagnosis, treatment, and surveillance in individuals
identi?ed as having pathogenic variant [6]. If a germline
pathogenic variant has not been identi?ed, the presence
or absence of characteristic pigmentation or Peutz-
Jeghers polyps should be evaluated to determine
whether the diagnostic criteria for PJS are met in order to
identify close relatives who would bene?t from early
diagnosis and treatment [6].
Parents of the Proband
Itisnecessarytocon?rmthatthediagnosticcriteriafor
PJS are met. If a germline pathogenic variant of the
proband has been identi?ed, it is also useful to con?rm if
the parents have the same variant [6].
Sibling of the Proband
The likelihoodthatsiblingsofthe probandwillhave
the same pathogenic variant as the proband is es-
sentially50%in bothsexes.Iftheproband’sparentsdo
not have PJS, it is more likely that only the proband
will have the de novo variant and less likely that his or
hersiblingswillhavethesamevariant.However,
because of the possibility of gonadal mosaicism (so-
matic mutations in the germline), it should be con-
?rmed that the affected siblings meet the diagnostic
criteria for PJS, regardless of whether the parents have
symptoms [24].
Color
version
a
vai
lable
online
a b
Fig. 3. Pigmentations in PJS. a Lips. b
Fingertips. Pigmentations are blackish-
brown or brown, 1–5 mm in diameter,
and usually longitudinal in shape.
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Child of the Proband
The likelihood that children of the proband will have
the same pathogenic variant as the proband is 50% for
both sexes. Because of the risk of developing intussus-
ception in childhood and requiring surgical treatment, it
is strongly recommended that endoscopic surveillance be
performed at least once before the age of 8 years if the
child has the germline pathogenic variant in STK11 gene
[6]. Even if the pathogenic variant in STK11 has not been
con?rmed, endoscopic surveillance is recommended at
least once by the age of 8 years if the child has charac-
teristic pigmentations [6].
Medical Expense Subsidy System
PJS is certi?ed as one of the Speci?c Pediatric Chronic
Diseases in Japan. Pediatric patients can receive ?nancial
support for medical costs from a government-funded and
medical aid project for children with chronic diseases.
CQs and Recommendations
CQ1: Is It Recommended to Perform Genetic Testing on
Patients Who Meet the Diagnostic Criteria for
Peutz-Jeghers Syndrome?
It is strongly recommended that patients who meet the
diagnosticcriteriaforPeutz-Jegherssyndromeshouldnot
be genetically tested for the purpose of their own diag-
nosis or medical management.
Evidence level: B
Recommendation level 1: strong
Genetic testing for diagnostic purposes is weakly
recommended for patients who meet some of the
diagnostic criteria for PJS.
Evidence level: B
Recommendation level 2: weak
Explanation
In patients who meet the diagnostic criteria for PJS,
germline pathogenic variants in the STK11 gene are
identi?ed in 80–94% of cases, and approximately one-third
of these cases are associated with large deletions [12, 25, 26].
Therefore, it is necessary to combine both direct sequencing
and multiplex ligation-dependent probe ampli?cation to
detectlargedeletionsandduplications[26].Insolitarycases,
the detection rate of pathogenic variants is 25–57% [7, 27],
suggesting the possibility of somatic mosaicism [24].
There are no reproducible reports on the genotype-
phenotype relationship, and the genotype-phenotype
relationship is unclear in clinical guidelines [6, 8, 19,
28]. There are no reports on genotype-phenotype
relationships in Japanese patients with PJS, and it is
hoped that a nationwide registry system will be estab-
lished and genotype-phenotype relationships will be
examined in Japanese patients with PJS. It has been re-
ported that the risk of cholangiocarcinoma is higher in
patients withPJS with noidenti?ed STK11 mutation[29],
but reproducibility has not been reported, and there is no
clear difference in the clinical features between patients
with a pathogenic variant and those in with no detected
pathogenicvariant [19].Agermlinepathogenicvariantof
the STK11 gene can be identi?ed even in atypical PJS
cases [30–32], whereas genetic testing of patients with a
single Peutz-Jeghers polyp does not completely rule out
PJS, even if the result is negative [33].
Therefore, we do not recommend genetic testing be-
cause there is no evidence that identi?cation of patho-
genic variants in STK11 is useful in the medical
management of clinically diagnosed PJS patients. Genetic
testing for STK11 is recommended for patients who do
not meet the diagnostic criteria based on symptoms and
gastrointestinal ?ndings alone because the results of the
test can bene?t the patient in terms of appropriate
medical management.
CQ2: Is Surveillance and Treatment of Gastrointestinal
Lesions Recommended in Peutz-Jeghers Syndrome?
Surveillance of the stomach, small intestine, and large
intestine is strongly recommended.
Evidence level: B
Recommendation level 1: strong
It is weakly recommended that the ?rst surveillance
should be performed around the age of 8 years, even if
there are no symptoms.
Evidence level: C
Recommendation level 2: weak
Resection of polyps larger than 15 mm (10 mm, if
possible) is strongly recommended.
Evidence level: B
Recommendation level 1: strong
Explanation
The purpose of surveillance in PJS is to identify polyps
that are large enough to cause symptoms such as intes-
tinal obstruction or bleeding and to detect malignancy at
an early stage. With regard to malignant tumors that
develop in PJS patients, a number of articles and reviews
have shown a high risk of occurrence in all parts of the
gastrointestinal tracts, and the lifetime risk of cancer has
been reported to be 0.5% in the esophagus, 29% in the
stomach, 13% in the small intestine, and 39% in the large
intestine, which is a high risk compared to the general
Clinical Guidelines for Peutz-Jeghers
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DOI: 10.1159/000529799
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population [7, 34]. A review of papers on malignant
tumors in Japanese patients with PJS also reported a high
lifetime risk of developing malignant tumors 24.0% in the
stomach, 10.3% in the duodenum, 13.8% in the small
intestine (jejunum/ileum), and 36.4% in the large in-
testine [35]. These results are similar to those reported in
Europe and the USA. The youngest age of onset is 7 years
in the stomach and 12 years in the colon, and therefore,
the risk of carcinogenesis should be considered even in
children.
In PJS, polyps are found in the stomach (24%), small
intestine (96%), colon (27%), and rectum (24%) [7].
Polyps occur by the age of 10 years, but bleeding, in-
farction, intestinal obstruction, and intussusception
usually occur by the age of 20–30 years. The median age
of the ?rst onset of intussusception is 16 years (3–50
years),and50%ofthesecasesarereportedtooccurbefore
the age of 20 years [8]. Ninety-?ve percent of intussus-
ceptions occur in the small intestine, and 80% of these
present as an acute abdomen. Although PJS is a rare
disease and there have been no controlled trials on the
effectiveness of surveillance, we strongly recommend
surveillance of the entire gastrointestinal tract in con-
sideration of the risk of carcinogenesis and prevention of
polyp-associated symptoms.
Regarding the timing and interval of gastric and co-
lorectal surveillance, European and American guidelines
recommend initial upper gastrointestinal endoscopy and
full colonoscopy at age 8 years and surveillance every
1–3 years if polyps are found [7, 36, 37]. If no polyps are
found at the initial examination, the second surveillance
should be performed at the age of 18 years and then every
3 years thereafter. If symptoms appear before the age of
18 years, the second surveillance should be performed
earlier.Theriskofcancerincreasesrapidlyaftertheageof
50 years, and surveillance every 1–2 years is recom-
mended. However, there is no evidence of the bene?ts of
this surveillance method.
Surveillance methods for the small intestine include
SBCE, BAE, small-bowel series, magnetic resonance
enterography (MRE), and computed tomography
enterography. SBCE and MRE are often used to reduce
invasiveness and radiation exposure. The sensitivity of
SBCE is higher than that of small-bowel series [38–40]
and MRE, for smaller polyps; the sensitivity of these
respective imaging modalities for larger polyps (>1 cm) is
similar [41–43]. It is recommended that the ?rst SBCE
should be performed at the age of 8 years and earlier if
symptoms are present, and surveillance should be per-
formedevery1–3yearsifpolypsarefound[7,36,37].The
interval between examinations should be determined
based on the rate of polyp growth. SBCE can be inserted
into the duodenum with an insertion aid attached to the
tipoftheendoscope,eveninpatientswhocannotswallow
capsules, and it can be performed even in infants [44]. It
has been reported that SBCE was able to observe the
entire small intestine in a 10-month-old infant weighing
7.9 kg [45]. A case of a 3-year-old girl with intussus-
ception in the context of a 2-year history of recurrent
abdominalpainandvomitinghasalsobeenreported[46].
SBCE should be considered for patients of any age when
the presence of polyps is suspected. Computed tomog-
raphy enterography and small-bowel series are also op-
tions, but they are not preferred in children because of
radiation exposure. For small intestinal polyps, if post-
operative adhesions occur due to surgical treatment, it
would become dif?cult to insert BAE into the deep small
intestine; therefore, endoscopic treatment should be
attempted whenever possible, and efforts should be made
to avoid surgical treatment as much as possible. For this
reason, it is necessary to diagnose and start endoscopic
treatment before intussusception occurs, and surveillance
for small intestinal polyps should be performed once
around the age of 8 years for patients diagnosed with PJS
or suspected of having PJS. If there are few polyps or no
polyps at the initial examination, a second surveillance is
recommended at the age of 18 years.
In terms of treatment, guidelines published by the JGES
and the European Society of Gastrointestinal Endoscopy
(ESGE) strongly recommend polypectomy using BAE for
small intestinal polyps larger than 10–15 mm con?rmed
by SBCE or other imaging studies [36, 37, 47]. It is well
knownthat polypsizeisthe most signi?cantrisk factorfor
intussusception, which is generally causedbypolypslarger
than 15 mm [8, 21, 22, 48–51]. Endoscopic resection of
small-bowel polyps with BAE has been reported to reduce
the need for surgical treatment in both the short and long
term [21, 22]. Polyps larger than 10–15 mm, symptomatic
polyps,andrapidlygrowingpolypsshouldberesected,and
polyps smaller than 10–15 mm may be considered for
resection, while the procedure is easy as they are expected
to grow in the future. Endoscopic resection using BAE is a
relatively safe procedure for adults and children [8, 21, 22,
48–51]. BAE has been reported to be performed in infants
asyoungas1yearoldandweighing8kg[51],andBAEcan
generally be performed in patients 3 years old and
weighing 14 kg or more [52]. Acute pancreatitis and post-
polypectomy syndrome have been reported as complica-
tions [21, 22, 48, 50]. Deep within the small intestine, it is
inevitablydif?culttomaneuverBAEtoapplyasnaretothe
stalk of the polyp, and ischemic polypectomy using a
detachable snare or clip has been described [53, 54]. It has
8
Digestion
DOI: 10.1159/000529799
Yamamoto et al.
been reported that ischemic polypectomy can treat many
polypsinashorterperiodthanendoscopicresection,andit
is less likely to cause complications [18]. Therefore, it is
desirable to verify the ef?cacy and safety of ischemic
polypectomy in larger cohorts. When polyps are excep-
tionallylargeand dif?culttoresectorcannotbereachedby
BAE, intraoperative endoscopic polypectomy or removal
through an intestinal incision should be considered.
Regarding the usefulness of endoscopic resection of
gastric and colorectal polyps, there is an expert opinion
that polyps larger than 10 mm should be resected endo-
scopically [9]. Therefore, it is dif?cult to make a clear
recommendation, but endoscopic resection should be
actively considered for polyps that are large enough to
cause intussusceptions, polyps that are thought to cause
symptoms such as anemia or abdominal pain, and polyps
that have structural irregularities and are suspected to
contain malignancy. At present, there are no studies on
whether resection of gastrointestinal polyps reduces the
riskof carcinogenesis,andthis is a subject for future study.
CQ3: Is Surveillance for Extragastrointestinal Lesions
Recommended in Peutz-Jeghers Syndrome?
It is weakly recommended that surveillance be con-
ducted for each organ with a high incidence of
malignancy.
Evidence level: C
Recommendation level 2: weak
Explanation
The cumulative risk of overall cancer, including cancer
ofthegastrointestinaltract,increasessharplyaftertheage
of40yearsandoccursinmorethanhalfofthepatients by
the age of 60 years [7, 35, 55]. In a systematic review of
Japanese patients with PJS, the cumulative risk of ma-
lignancy was 2.8% at age 20 years, 16.3% at age 30 years,
35.2% at age 40 years, 64.1% at age 50 years, 76.5% at age
60 years, and 83.0% at age 70 years [35]. The frequency of
malignancy at the following locations has been reported
[28]: breast cancer (24–54%), ovarian cancer (21%),
cervical cancer (10–23%), uterine cancer (9%), testicular
cancer (9%), lung cancer (7–17%), and pancreatic cancer
(11–36%). The mean (or median) age of onset is
37–59 years for breast cancer, 28 years for ovarian cancer,
34–40 years for cervical cancer, 43 years for uterine
cancer, 6–9 years for testicular tumors, 47 years for lung
cancer, and 41–52 years for pancreatic cancer [7].
Surveillance without invasion or radiation exposure
can be recommended at a young age because of the high
incidence of extragastrointestinal cancers. However, it is
necessary to consider the burden on the patient and the
usefulness of each examination when deciding on inva-
sive and radiation exposure-associated examinations.
Table 4 lists the surveillance organs (including gastro-
intestinal organs included in CQ2), methods, intervals,
andstartingpointsforeachorganthathasbeendescribed
in overseas guidelines (ACG [7], National Comprehen-
sive Cancer Network [NCCN] [56], and European expert
groups) [19] and are considered appropriate. There is no
evidence that these surveillance methods improve the
prognosis, and further validation is needed.
The tumor characteristics of female patients with PJS
include ovarian sex cord tumors with annular tubules
(SCTAT), ovarian mucinous tumors, and minimal de-
viation adenocarcinoma, while those of male patients
include large cell calcifying Sertoli cell tumors. SCTAT
accounts for the majority of ovarian tumors in patients
with PJS and is thought to occur in almost all female
patients with PJS [7]. It occurs from childhood but is
more common in individuals in their 40s and 50s. Ma-
lignant transformation is estimated to occur in approx-
imately 20% of the cases. Internal examinations and
transvaginal (transabdominal) ultrasound examinations
are recommended at 1-year intervals from the age of
18–25 years to monitor the ovary and uterus, but CA125
is not recommended. However, the effectiveness of pe-
riodic surveillance is unclear, and there is concern that
screening and surveillance at a young age may increase
unnecessary surgical treatment of benign tumors. There
are some case reports of ovarian mucinous tumors as-
sociated with PJS, but the exact incidence and rate of
carcinogenesis are unknown, and the appropriate sur-
veillance interval is unclear. Minimal deviation adeno-
carcinoma is a subtype of hyperdifferentiated gastric-type
mucinous adenocarcinoma that is often dif?cult to dif-
ferentiate from benign lesions and has been reported in a
number of cases associated with PJS [57]. However, it is a
malignant tumor that invades the deep cervix and par-
acervical connective tissue from an early stage, resulting
in lymph node metastasis and poor prognosis. SCTAT-
induced hyperestrogenism is thought to induce lobular
endocervical glandular hyperplasia, which is a precursor
lesion of, at least, some malignant adenomas and cervical
adenocarcinomas [58]. In a systematic review of Japanese
patients with PJS, case reports have been accumulated
from patients aged 20 years, and surveillance from a
young age is important [35]. Experts recommended that
cervical smears using liquid-based cytology be performed
every2–3yearsstartingattheageof21years[35].Lackof
cytological atypia means that cytology is not sensitive,
and cervical histology, transvaginal (transabdominal)
ultrasound, and pelvic MRI should be considered, as
Clinical Guidelines for Peutz-Jeghers
Syndrome
Digestion
DOI: 10.1159/000529799
9
necessary.LargecellcalcifyingSertolicelltumorsoccurin
9% of male patients with PJS before puberty and produce
gynecomastia [7, 19]. The malignancy rate has been
reported to be 10–20%. Testicular palpation should be
performed every year from birth, and ultrasonography
should be performed if palpation is abnormal or if gy-
necomastia is observed.
CQ4: Is Treatment of Pigmentations in Peutz-Jeghers
Syndrome with the Expectation of a Cosmetic
Bene?t Recommended?
Laser treatment of pigmentations is weakly recom-
mended if the patient requests treatment for cosmetic
reasons.
Evidence level: C
Recommendation level 2: weak
Explanation
Laser therapy for pigmentations in patients with PJS has
been performed using a Q-switched ruby laser [59, 60],
Q-switched alexandrite laser [20, 61–63], Q-switched Nd
(YAG) laser [64], pulsed ruby laser [65], argon laser [66],
potassiumtitanylphosphate(KTP)laser[67],erbium(YAG)
laser [67], carbon dioxide laser [68], and intense pulsed light
[69], all of which are effective. There were several reports
indicating thatQ-switchedlaserirradiationwaseffective,and
among them, the Q-switched alexandrite laser was effective
in a total of 60 cases [20, 61–63], including 14 cases in which
non-recurrence was con?rmed during a median observation
period of 2 years [61]. Although treatment with carbon
dioxide laser evaporation was reported to be useful, patients
refused treatment for all pigmentations, suggesting that the
burden of pain and postirradiation care seemed to be a
deterrent [68]. Therefore, there was no literature that could
recommend robust evidence because there was no literature
with a suf?cientnumberofpatientswhometthepowerof
detection, and there was no randomized clinical trial.
However, all these articles recommend laser treatment for
pigmentations for cosmetic effects, and a certain recom-
mendation can be made.
Table 4. Recommended surveillance for patients with PJS [7, 19, 28, 34, 35, 56]
Organ Frequency (%) Risk ratio (95%
con?dence interval)
Surveillance
starting age
Surveillance
interval
Surveillance method
Stomach 29
Japan 24
213 (96–368) 8 years old 1–3 years
1
Upper gastrointestinal endoscopy
Colorectum 39
Japan 36.4
84 (47–137) 8 years old 1–3 years
1
Total colonoscopy
Small
intestine
13
Japan 13.8
(duodenum 10.3)
520 (220–1,306) 8 years old 1–3 years
1
SBCE
MRE
Mammary
gland
54
Japan 19.3
15.2 (7.6–27) 18 years old 1 year Self-checking
25 years old 1 year Breast MRI/US
After50 years old 1 year Mammography
Ovary 21
Japan 10.1
27 (7.3–68) 18–25 years old 1 year Internal examination/transvaginal
(transabdominal) US
Uterine
cervix
10
Japan 46.5 (as
uterine cancer)
1.5 (0.31–4.4) 18–25 years old 1–3 years Cervical smear
Uterine body 9 16 (1.9–56) 18–25 years old 1 year Internal examination/transvaginal
(transabdominal) US
Testicle 9 4.5 (0.12–25) From birth to
adulthood
1 year Palpation/US (if palpation is
abnormal or gynecomastia is
observed)
Lung 15
Japan 7.6
17 (5.4–39) None (consider starting earlier
than general medical checkups)
2
Pancreas 36
Japan 29.4
132 (44–261) 30 years old 1–2 years MRCP/EUS
SBCE, small-bowel capsule endoscopy; MRE, magnetic resonance enterography; MRI, magnetic resonance imaging; US, ul-
trasonography; MRCP, magnetic resonance cholangiopancreatography; EUS, endoscopic ultrasonography.
1
The second sur-
veillance should be performed at 18 years of age. If no polyps are found in the ?rst surveillance, the second surveillance should be
performed at the age of 18 years, and every 1–2 years after the age of 50 years.
2
Smoking cessation recommended.
10
Digestion
DOI: 10.1159/000529799
Yamamoto et al.
Acknowledgments
The authors thank the systematic review team identi?ed in the
inonlinesupplementarymaterial(forallonlinesuppl.material,see
www.karger.com/doi/10.1159/000527999) and Ms. Eri Okuda for
hersupportinpreparingtheseclinicalguidelines.Wewouldliketo
thank Editage (www.editage.com) for English language editing.
Finally, we also thank members of the Japanese Society for He-
reditaryTumors(JSHT),JapaneseGastroenterologicalAssociation
(JGA), Chairperson Kazuhide Higuchi, Japanese Society of Pe-
diatric Surgeons (JSPS), and Japanese Society for Pediatric Gas-
troenterology, Hepatology and Nutrition (JSPGHAN) for their
total support to these guidelines.
Statement of Ethics
The authors have no ethical con?icts to disclose.
Con?ict of Interest Statement
Priortothepreparationoftheseclinicalguidelines,allmembers
of the Guidelines Committee declared any con?ict of interest. H.Y.
has consultant relationship with S.R.J. Y.K.; honoraria for lectures
from Takeda Pharmaceutical Co., Ltd.; Fuji?lm Co.; Fuji?lm
Medical Co.; Eisai Co., Ltd.; and Daiichi Sankyo Co., Ltd. H.S. has
received grants from Fuji?lm Co. and Fuji?lm Medical Co. K.B.
has received payment for lectures from ASKA Pharmaceutical
Holdings Co., Ltd.; grants from Sano?, S.A.; Sysmex Co.; Taiho
Pharmaceutical Co., Ltd.; KISSEI Pharma, Co., Ltd.; Fuji Pharma,
Co., Ltd.; Astellas Pharma, Inc., and HEARZEST Co., Ltd. T.Y. has
received honoraria for lectures from Taiho Pharmaceutical Co.,
Ltd. N.T. has received grants from Taiho Pharmaceutical Co., Ltd.
H.I. has received grants from Taiho Pharmaceutical Co., Ltd., and
Yakult Honsha Co., Ltd. The other authors declare no con?ict of
interest.
Funding Sources
This article was supported by grants-in-aid from Health, La-
bour and Welfare Sciences Research on rare and intractable
diseases (Grant No. 201711053A and 20FC1007; to H.I. and Y.N.).
Author Contributions
Hironori Yamamoto and Yoshiko Nakayama: conception
and design, data analysis and interpretation, writing the
manuscript, and ?nalapprovalofmanuscript.Hirotsugu
Sakamoto: data collection, data analysis and interpretation,
drafting the manuscript, writing the manuscript, and ?nal
approval of manuscript. Hideki Kumagai, Takashi Abe, Shingo
Ishiguro, Keiichi Uchida, Yuko Kawasaki, Yoshihisa Saida,
Yasushi Sano, Yoji Takeuchi, Masahiro Tajika, Takeshi
Nakajima, Kouji Banno, Yoko Funasaka, Shinichiro Hori,
Tatsuro Yamaguchi, Teruhiko Yoshida, Takeo Iwama, Yasushi
Okazaki, Yutaka Saito, Nariaki Matsuura, Michihiro Mutoh,
Naohiro Tomita, and Takashi Akiyama: data analysis and in-
terpretation and ?nal approval of the manuscript. Hideki
Ishikawa and Hideyuki Ishida: data analysis and interpretation,
writing the manuscript, and ?nal approval of manuscript.
Toshiki Yamamoto: collecting data, data analysis and inter-
pretation, and ?nalapprovalofthemanuscript.
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Clinical Guidelines for Peutz-Jeghers
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