GIE GUIDELINE

Diagnosis and management of cancer risk in the

gastrointestinal hamartomatous polyposis syndromes:
recommendations from the U.S. Multi-Society Task Force on
Colorectal Cancer
C. Richard Boland,1,* Gregory E. Idos,2,* Carol Durno,3,4 Francis M. Giardiello,5 Joseph C. Anderson,6,7,8
Carol A. Burke,9 Jason A. Dominitz,10,11 Seth Gross,12 Samir Gupta,13,14,15 Brian C. Jacobson,16
Swati G. Patel,17 Aasma Shaukat,18,19 Sapna Syngal,20,21,22 Douglas J. Robertson6,7

San Diego, California, USA; Duarte, California, USA; Toronto, Ontario, Canada; Baltimore, Maryland, USA; White River
Junction, Vermont, USA; Hanover, New Hampshire, USA; Farmington, Connecticut, USA; Cleveland, Ohio, USA; Seattle,
Washington, USA; New York, New York, USA; San Diego, California, USA; La Jolla, California, USA; San Diego, California,
USA; Boston, Massachusetts, USA; Aurora, Colorado, USA; Minneapolis, Minnesota, USA; Boston, Massachusetts, USA

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated
with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-
Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden’s
syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses
are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline path-
ogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by
germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and
mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer.
Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes,
with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis,
which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations
usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis
syndrome–hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal
bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants
in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes),
including Cowden’s syndrome and related disorders that are associated with an increased risk of gastrointes-
tinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the rela-
tive rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few
studies. This U.S. Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical
features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of
patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management. (Gastrointest
Endosc 2022;95:1025-47.)

(footnotes appear on last page of article)

The gastrointestinal hamartomatous polyposis syn-
dromes are rare, autosomal dominant disorders associ-
ated with an increased risk of benign and malignant
intestinal and extraintestinal tumors. Nevertheless, there
has been tremendous progress in recent years, both in
understanding the underlying genetics that underpin
these disorders and in elucidating the biology of associ-
ated premalignant and malignant conditions. Emerging
data in affected populations focus increasingly on those
with defined cancer susceptibility germline pathogenic
variants leading to less heterogeneity in terms of quanti-
fying cancer risk.
The U.S. Multi-Society Task Force on Colorectal
Cancer (USMSTF) is a group of colorectal cancer (CRC)
content experts appointed by the American College
of Gastroenterology, American Gastroenterological

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Gastrointestinal hamartomatous polyposis syndromes
Association, and American Society for Gastrointestinal
Endoscopy, supplemented at times by other experts to
complement existing expertise. In this USMSTF
Consensus Statement, the gastrointestinal hamartoma-
tous polyposis syndromes were chosen because of recent
progress in understanding these diseases. The following
entities reviewed are: Peutz-Jeghers syndrome (PJS), ju-
venile polyposis syndrome (JPS), PTEN hamartoma tumor
syndrome (PHTS, including Cowden’s syndrome [CS]
and Bannayan-Riley-Ruvalcaba syndrome [BRRS]), and
hereditary mixed polyposis syndrome (HMPS). Germline
alterations are known to cause each of these disorders,
but the diagnosis can also be made on the basis of clinical
criteria.
Although there are essentially no long-term prospec-
tive controlled studies of comparative effectiveness of
management strategies for these syndromes, there have
been consensus statements by expert panels that made
management recommendations for these disorders. The
goal of this USMSTF Statement was to review the litera-
ture focusing on the most recent data, synthesize both
the data and the suggested approaches to diagnosis and
management by other expert groups, and present the
consensus recommendations of the USMSTF (Table 1).
Review of summary tables, conference calls, and
revisions of iterative drafts, including recommendation
statements, were used to reach consensus, at which
time documents were forwarded to Governing Boards
for approval. As our USMSTF is a group of individuals
with expertise in gastroenterology and gastrointestinal
malignancies, we have reserved our management
recommendations to these areas and defer to other
expert groups’ recommendations for other cancers
(which are reviewed here). This document therefore
recommends clinical approaches to diagnosing and
managing these conditions that affect children and
adults, focuses on cancer risk, and provides insights into
future research opportunities.
METHODS
A computer-aided PubMed search was performed
from 2000 to 2018, with additional back searches as
required, and consisted of the following search terms:
hamartoma, hamartomatous polyp, hamartoma syn-
drome, Peutz-Jeghers syndrome, juvenile polyp, juve-
nile polyposis, Cowden’s syndrome, Cowden’s disease,
PTEN-hamartoma, Bannayan-Riley-Ruvalcaba syn-
drome, hyperplastic polyposis, serrated polyposis, and
hereditary mixed polyposis syndrome. Only English-
language articles were reviewed. Published articles
were selected on the basis of relevance to the diagnosis
or clinical management of these diseases. Emphasis was
1026 GASTROINTESTINAL ENDOSCOPY Volume 95, No. 6 : 2022
placed on the risk for gastrointestinal cancer in these
disorders to gain consensus on rational and reasonable
strategies for management once these diseases are diag-
nosed in a family. The document was approved by the
governing boards of each of the sponsoring gastroenter-
ology societies.
The USMSTF approach to an adapted use of Grading
of Recommendations Assessment, Development and
Evaluation (GRADE) has been described previously.1 In
brief, the GRADE process categorizes the quality of the
evidence as high, moderate, low, or very low on the
basis of the strength of underlying studies, and that
categorization can be adjusted on the basis of study
limitations. For example, randomized trials begin as
high-quality evidence and observational studies as low-
quality evidence, but their quality may be adjusted up
or down on the basis of specific study factors. Although
the GRADE process entails a formal meta-analysis to
assess the quality of evidence for each recommendation,
the USMSTF employs a modified, qualitative approach
for this assessment. The GRADE process separates eval-
uation of the quality of the evidence to support a recom-
mendation from the strength of that recommendation.
This is done in recognition of the fact that, although
the quality of the evidence can influence the strength
of the recommendation, other factors can influence a
recommendation, such as adverse effects, patient prefer-
ences, values, and cost. Generally, strong recommenda-
tions mean that most informed patients would choose
the recommended management. Weak recommenda-
tions mean that patients’ choices will vary according to
their values and preferences, and clinicians should
ensure that patient care is in keeping with their values
and preferences. When the quality of the evidence to
support a recommendation is low or very low, or if
there is a close balance between desirable and undesir-
able consequences, then usually only a weak recommen-
dation would be warranted. Weaker recommendations
are indicated by phrases such as “we suggest,” and
stronger recommendations are typically stated as “we
recommend.”
However, the relative infrequency of, and absence of
controlled prospective trials of the interventions (eg, to
prevent cancer) in, these syndromes leave all of the rec-
ommendations without a robust basis of underlying evi-
dence. Thus, all of the interventional recommendations
fall (at best) into the “low quality of evidence” GRADE
category, indicating that the true effect of the interven-
tions may be markedly different than estimated at this
time, and that further research is likely to impact or
change our confidence in the effects. As such, this review
is intended to establish a starting point for future research
into the care of patients with the hamartomatous polypo-
sis syndromes.
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 Gastrointestinal hamartomatous polyposis syndromes

TABLE 1. Questions and recommendations of best practice

Which individuals with hamartomatous polyps should be referred for genetic evaluation?
We recommend patients with any of the following undergo a genetic evaluation: 2 or more lifetime hamartomatous polyps, a family history of
hamartomatous polyps, or a cancer associated with a hamartomatous polyposis syndrome in first or second-degree relatives. Genetic testing (if
indicated) should be performed using a multigene panel test. (Strong recommendation, low quality of evidence)
Peutz-Jeghers syndrome
Who should undergo a genetic evaluation for Peutz-Jeghers syndrome?
We recommend genetic evaluation for any individual with the following: 1) 2 or more histologically confirmed Peutz-Jeghers polyps, 2) any
number of Peutz-Jeghers polyps in an individual who has a family history of Peutz-Jeghers syndrome in a first-degree relative, 3)
characteristic mucocutaneous pigmentation in a person with a family history of Peutz-Jeghers syndrome, 4) any number of Peutz-Jeghers
polyps in a person with the characteristic mucocutaneous pigmentation of Peutz-Jeghers syndrome. (Strong recommendation, low quality of
evidence)
Which organs should undergo surveillance when caring for a patient with Peutz-Jeghers syndrome?
Patients with Peutz-Jeghers syndrome are at increased risk for cancer in multiple organs including cancer of the breast, small bowel, colon,
stomach, pancreas, ovaries, testes, and lungs.
Given this risk, we recommend a multidisciplinary approach to cancer surveillance in these organs (Strong recommendation, low quality of
evidence)
How and when should small bowel surveillance be performed in Peutz-Jeghers syndrome?
We recommend that baseline small bowel surveillance using video capsule endoscopy or magnetic resonance enterography be performed
between ages 8-10 years or earlier if the patient is symptomatic. If no polyps are found at the initial examination, surveillance should resume
at age 18. Because of the risk of small bowel intussusception, small bowel surveillance in adulthood is recommended to continue throughout
life every 2-3 years. (Strong recommendation, low quality of evidence)
What is the recommended approach to endoscopic surveillance of the colon, stomach, and duodenum in Peutz-Jeghers syndrome?
We suggest a baseline upper gastrointestinal endoscopy between the ages of 8 and 10 years, which could be performed at the time of capsule
placement for small bowel surveillance or if polyps are identified on magnetic resonance enterography. Although the initiation age for
colonoscopy remains uncertain, we also suggest initiation of colonoscopy at same time as esophagogastroduodenoscopy. In those in whom
characteristic polyps are detected, both colonoscopy and esophagogastroduodenoscopy should be repeated every 2–3 years. In those in
whom there are no Peutz-Jeghers polyps at baseline, surveillance is repeated at age 18 years, or sooner should symptoms arise, and then
every 3 years. (Weak recommendation, very low quality of evidence)
What size polyps found on small bowel imaging in Peutz-Jeghers syndrome should be removed?
We recommend polypectomy of small bowel polyps that are symptomatic or
10 mm to prevent intussusception and other complications, such
as bleeding. (Strong recommendation, low quality of evidence)
What is the recommended pancreatic cancer surveillance in Peutz-Jeghers syndrome?
We suggest annual pancreatic cancer surveillance with either magnetic resonance cholangiopancreatography or endoscopic ultrasound starting
at age 35 years. (Weak recommendation, low quality of evidence)
Juvenile Polyposis Syndrome
Who should undergo a genetic evaluation for juvenile polyposis syndrome?
We recommend genetic evaluation for any individual with 1) 5 or more juvenile polyps of the colon or rectum; or 2) 2 or more juvenile polyps in
other parts of the gastrointestinal tract; or (3) any number of juvenile polyps and 1 or more first-degree relatives with juvenile polyposis
syndrome. (Strong recommendation, low quality of evidence)
Which organs should undergo surveillance when caring for a patient with juvenile polyposis syndrome?
Juvenile polyposis syndrome patients are at increased risk for cancer in multiple organs including cancer of the colon and stomach.
Given this risk, we recommend patients with juvenile polyposis syndrome undergo surveillance of the colon and stomach. (Strong
recommendation, low quality of evidence)
At what age should colonoscopic and upper endoscopic surveillance begin in individuals identified with juvenile polyposis syndrome?
We suggest initiating colonoscopic and upper endoscopic surveillance at age 12–15 years, or earlier if symptomatic. Surveillance should be
repeated every 1–3 years depending on polyp burden. (Weak recommendation, low quality of evidence)
Which patients with juvenile polyposis syndrome should undergo screening for hereditary hemorrhagic telangiectasia?
We suggest patients with SMAD4 pathogenic variants be clinically evaluated for HHT at the time of the diagnosis, including screening for and
appropriate management of cerebral and pulmonary AVMs. (Weak recommendation, low quality of evidence)
PTEN hamartoma tumor syndrome
Which gastrointestinal findings should prompt a genetic evaluation for PTEN hamartoma tumor syndrome?
We recommend individuals with multiple gastrointestinal hamartomas or ganglioneuromas undergo genetic evaluation for Cowden’s syndrome
and related conditions. (Strong recommendation, low quality of evidence)
(continued on the next page)

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Gastrointestinal hamartomatous polyposis syndromes

TABLE 1. Continued

Which organs should undergo surveillance for cancer when caring for a patient with PTEN hamartoma tumor syndrome?
In PTEN hamartoma tumor syndrome, patients are at increased risk for cancer in multiple organs, including cancer of the breast, thyroid, kidney,
uterus, colon, and skin.
Given this risk, we recommend a multi-disciplinary approach to cancer surveillance in these organs. (Strong recommendation, low quality of
evidence)
What is the recommended colonoscopic surveillance in individuals identified with PTEN hamartoma tumor syndrome?
We suggest colonoscopy surveillance to begin at age 35 years (or 10 years younger than age of any relative with colorectal cancer), repeated at
intervals no greater than 5 years, depending on polyp burden. (Weak recommendation, low quality of evidence)
NOTE. Specific circumstances may merit modification of the recommendations. In cases where very-early-onset cancers develop, the above statements may be modified to start
surveillance 10 years earlier than the youngest cancer diagnosis in the family.

CANCER FAMILY HISTORY ASSESSMENT AND
REFERRAL FOR GENETIC TESTING IN
GASTROENTEROLOGY PRACTICE
Question: Which individuals with hamartomatous
polyps should be referred for genetic evaluation?
Recommendation: We recommend patients with
any of the following undergo a genetic evaluation: 2
or more lifetime hamartomatous polyps, a family history
of hamartomatous polyps, or a cancer associated with a
hamartomatous polyposis syndrome in first- or second-
degree relatives. Genetic testing (if indicated) should be
performed using a multigene panel test. (Strong recom-
mendation, low quality of evidence)
Hereditary cancer syndromes account for approximately
5%–10% of new cancer diagnoses and many of the cancers
that arise in families with undiagnosed hereditary cancer
syndromes are preventable. The identification of individ-
uals with a hereditary gastrointestinal cancer syndrome re-
quires a thorough evaluation of the patient’s personal and
family history of cancer. The collection and assessment of
family cancer history is a valuable tool for cancer intercep-
tion and prevention and can be critical in the identification
of genetic susceptibility. An accurate family history is one
that collects the following information: 1) type of cancer,
2) age at diagnosis of each primary cancer, 3) lineage
(maternal or paternal), 4) ethnicity (people of some ethnic-
ities, such as those with Ashkenazi Jewish ancestry, are at
greater risk for certain cancers), and 5) results of any pre-
vious cancer-related genetic testing.2
Features of a patient’s personal history and clinical char-
acteristics may suggest an inherited susceptibility to can-
cer. Although it is not rare to identify individuals with an
isolated hamartomatous polyp (particularly an isolated
juvenile polyp), other features may prompt further evalua-
tion for an underlying hereditary syndrome. Features asso-
ciated with the hamartomatous polyposis syndromes are
outlined in detail in this document and include early age
at cancer onset, multiple cancers in close relatives, unusual
numbers of hamartomatous polyps, or associated dermato-
logic findings. Genetic evaluation may include genetic
counseling and/or genetic testing.
Genetic counseling is a key component to hereditary
cancer risk assessment. The purpose of genetic coun-
seling is to educate individuals about the genetic and bio-
logic factors that are related to a patient’s cancer
diagnosis or risk of disease. Counseling helps an individ-
ual understand the relevant genetic, medical, and psycho-
social information to make informed decisions about their
health care. This includes reviewing and expanding the
following: family history information, elements of genetic
testing, tailored cancer risks associated with a pathogenic
variant, impact on medical management, reproductive is-
sues and options, confidentiality of results, risks with ge-
netic discrimination, potential significance of test results
for other family members, and other pertinent topics.
Practice guidelines from the American College of Medical
Genetics and Genomics and National Society of Genetic
Counselors are available for details regarding the ele-
ments and process of genetic counseling.3 Although
traditional models of genetic evaluation and testing
included a certified genetic counselor, alternative
models exist and are emerging that include provisions
for pretest counseling to be provided by physicians and
other health care providers in order to deal with the
increasing demand for genetic testing. If a patient is
found to be a carrier of a germline pathogenic variant, or
the results are ambiguous due to the finding of a variant
of uncertain significance, the help of a genetics provider
for post-test counseling and education is recommended.
In the current era, the vast majority of genetic testing for in-
herited cancer risk predisposition is performed using a
multigene panel testing approach.4 Some patients or
families may elect to decline genetic testing due to
concerns about risk to confidentiality and insurance; in
these cases, surveillance may still be indicated in the
presence of a concerning clinical and/or family history.
If a germline pathogenic variant is identified, other fam-
ily members should be offered testing for clarification of
their own risk. This testing may facilitate initiation of
screening for associated cancers before symptomatic man-
ifestations occur and reduce the morbidity and mortality
associated with the syndrome. For example, early small
bowel surveillance may find a polyp that could be removed
from a child with a pathogenic variant in STK11 before

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leading to intussusception. It is important to recognize that
genetic testing may not identify pathogenic variants in
every family suspected of a hereditary syndrome. However,
there may be clinical features in the family history that sug-
gest a familial predisposition to cancer and suggest more
intensive surveillance recommendations. Referral to Cen-
ters of Excellence might be particularly helpful when ge-
netic testing results are ambiguous in the setting of
suspicious features and prophylactic surgery is being
considered. Lastly, in the era of multigene panel testing,
there may be a scenario in which a germline variant is
found incidentally associated with an unsuspected syn-
drome. In these cases, patients may be eligible for cancer
screening and surveillance as outlined. However, pheno-
type and cancer risk compared with patients with classic fa-
milial features are not established and are areas of active
research. Enlisting the assistance of a genetic specialist
may be particularly helpful in interpreting ambiguous re-
sults and providing management recommendations in
these cases.
When children are identified with a hamartomatous pol-
yposis syndrome, their transition of care to adulthood
for cancer surveillance is a unique aspect that bears consid-
eration. It is imperative to transition adolescents with
life-long medical conditions from child-centered to adult-
centered care. Preparation for this transition takes place
throughout childhood and adolescence to achieve inde-
pendent health management in adulthood. Steps required
are individualized based on the developmental needs of
the patient. Inherited conditions involve generational fac-
tors, as multiple family members may be affected. Health
care providers can assist in the transition of care by coordi-
nating screening and surveillance to ensure patients
receive recommended care.5
GASTROINTESTINAL HAMARTOMATOUS
POLYPOSIS SYNDROMES
The hamartomatous polyposis syndromes are rare entities
with an estimated prevalence of 1/100,000–200,000,6,7 but
this has not been measured directly in any population. The
term hamartoma implies a non-neoplastic tumor with a
markedly distorted architecture composed of an abnormal
mixture of cells and tissue normally present in that particular
area. The diagnosis is based on the presence of a pathogenic
germline variant or meeting clinical criteria for the syndrome.
The hamartomatous polyposis syndromes are distinct from
Lynch syndrome and the adenomatous polyposis syndromes,
based on the presence of hamartomas (Figures 1 and 2).
Certain hamartomatous polyps of the gut have a unique
histopathological appearance, such as those associated with
PJS, PTEN, JPS, and HMPS.8 Hamartomas are not typically
characterized by dysplasia, but some evidence suggests the
existence of a hamartoma–carcinoma pathway in some of
these polyps.
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Gastrointestinal hamartomatous polyposis syndromes
PEUTZ-JEGHERS SYNDROME
Question: Who should undergo a genetic evaluation
for Peutz-Jeghers syndrome?
Recommendation: We recommend genetic evalua-
tion for any individual with the following: 1) 2 or more
histologically confirmed Peutz-Jeghers polyps, 2) any
number of Peutz-Jeghers polyps in an individual who
has a family history of Peutz-Jeghers syndrome in a
first-degree relative, 3) characteristic mucocutaneous
pigmentation in a person with a family history of
Peutz-Jeghers syndrome, and 4) any number of Peutz-
Jeghers polyps in a person with the characteristic muco-
cutaneous pigmentation of Peutz-Jeghers syndrome.
(Strong recommendation, low quality of evidence)
Clinical features
PJS was the first hamartomatous polyposis syndrome
described, by Peutz in Holland in 1921 and by Jeghers,
McKusick, and Katz in the United States in 1949.9 The
clinical recognition of PJS was facilitated by the
characteristic mucocutaneous freckling around the mouth
and multiple cerebriform-appearing polyps due to smooth
muscle bands coursing through the polyp (Figures 1A and
2A–C, and Table 2). Hamartomatous polyps vary in size and
may have a characteristic histologic structure, which makes
it possible to distinguish the PJ polyp. PJ polyps are typically
composed of branching bands of smooth muscle covered
by hyperplastic glandular mucosa.10 PJS polyps may develop
in the stomach, small intestine, and colon. Rectal bleeding
with anemia is the most common presentation, followed by
abdominal pain, diarrhea, and intussusception. The clinical
management in early life is initially focused on preventing
complications of small bowel polyposis–related obstruction
and bleeding and, in adulthood, the focus is primarily on
management of cancer risk.
Diagnosis
The diagnostic clinical features of PJS include the pres-
ence of 2 or more histologically confirmed PJ polyps; any
number of PJ polyps in an individual who has a family his-
tory of PJS in a first-degree relative; characteristic mucocu-
taneous pigmentation in a person with a family history of
PJS; or any number of PJ polyps in a person with the char-
acteristic mucocutaneous pigmentation of PJS.11
Genetics
In 1997, a genetic locus for PJS was mapped to chromo-
some 19p13.3,12 which in 1998 led to the cloning of the
STK11 (serine/threonine kinase) gene, which encodes the
LKB1 (liver kinase B1) protein, and linkage to PJS.13
STK11 functions like a tumor suppressor gene, regulates
cell growth via adenosine monophosphate–activated pro-
tein kinase,14 and negatively regulates mTOR signaling.15
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Gastrointestinal hamartomatous polyposis syndromes

Figure 1. Histologic characteristics of polyps. hamartomatous polyps. Images courtesy of Drs Aaron Pollett and Thomas Plesec. A, Peutz-Jeghers polyp:
pathognomonic broad bands of mucosal smooth muscle seen throughout the lesion. B, Juvenile polyp: characteristic chronic inflammatory infiltrate and
cystic dilatation. C, Adenomatous polyp: characteristic hypercellularity with glandular crowding, enlarged nuclei, increased mitotic activity and reduced
goblet cells. By definition, all tubular adenomas show epithelial dysplasia. D, Ganglioneuroma: benign neuroectodermal tumor composed of ganglion and
Schwann cells.

PJS is inherited in an autosomal dominant fashion with an herited from the unaffected parent in a somatic tissue accord-
inactivating germline pathogenic variant inherited from the ing to the classic “two-hit” model of Knudson.16 However, loss
affected parent. It was initially assumed that the polyps of the wild-type allele (ie, the second hit) is not an obligatory
occurred after the loss of the second, wild-type, allele in- feature of PJ polyps.17 Moreover, recent data in mice indicate

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 Gastrointestinal hamartomatous polyposis syndromes

Figure 2. Endoscopic images of hamartomatous polyposis syndromes. Endoscopic photos provided courtesy of Swati Patel, MD, Gregory Idos, MD, and
Carol Burke, MD. A, Peutz-Jeghers small bowel polyps. B, Peutz-Jeghers gastric polyps. C, Peutz-Jeghers colon polyps. D, Juvenile polyposis gastric
polyps. E, Juvenile polyposis colon polyp. F, Cowden syndrome associated–esophageal glycogenic acanthosis. G, Cowden syndrome small bowel polyps.
H, Cowden syndrome colon polyps. I, Cowden syndrome gastric polyps.

that the presence of a single inactivating germline pathogenic for the formation of the polyps in these mice. Furthermore,
variant (ie, haploinsufficiency), as occurs in individuals with conditional knockout of the STK11 gene targeted to gastroin-
PJS, promotes the development of gastrointestinal testinal smooth muscle cells yields the same polyposis pheno-
polyposis, and that loss of the wild-type allele is not necessary type in mice.18 Evidence suggests that LKB1 deficiency in

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Gastrointestinal hamartomatous polyposis syndromes

TABLE 2. Clinical features of gastrointestinal hamartomatous polyposis syndromes

“Commercially
Syndrome available gene testing” Polyps Clinical features

PJS STK11 Peutz-Jeghers polyps (pathologically Childhood: Labial pigmentation; gastrointestinal

characteristic) bleeding and intussusception
Adults: Increased risk for multiple cancers
JPS SMAD4 or BMPR1A Juvenile (inflammatory) polyps; juvenile polyps Childhood: Gastrointestinal bleeding, auto-amputation
and inflammatory polyps are pathologically of polyps; anemia
indistinct Adults: CRC and gastric cancer
CS PTEN (inactivation) Hyperplastic polyps; juvenile-like polyps; Childhood: none
WWP1 (gain-of-function) ganglioneuromas; lipomas; Adults: multiple cancer risks
hamartomas;adenomas
BRRS PTEN Same as for CS Developmental delay, hemangiomas, lipomas,
gastrointestinal polyps
HMPS GREM1 (duplication Pathologically mixed with features of adenoma, Increased risk of colonic polyposis and CRC
upstream of promoter) hyperplastic polyps, inflammatory polyps

either T cells19 or mesenchymal cells18,19 leads to immune cell
proliferation in the stroma. Stromal deficiency of LKB1 leads
to tumor formation (in mice) via the interleukin-11–JAK/
STAT3 (Janus kinase/signal transducer and activator of
transcription 3) pathway, and administration of the JAK1/2
inhibitor ruxolitinib dramatically reduces polyposis in
mice.20 The phenomenon of stromal-driven epithelial polyp
development may be referred to as a “landscaper” genetic
effect.21 These discoveries raise the possibility of
the development of novel preventive pharmacological
interventions for patients.
Genotype–phenotype relationships reveal that missense
alterations in STK11 are associated with later onset of symp-
toms than other sequence variations.11,22 Some of the
germline pathogenic variants in STK11 are Alu-mediated
deletions and inversions.23 Deletions and inversions are
likely to completely inactivate a gene, whereas a missense
pathogenic variant may have an intermediate effect on
protein function. Approximately 15% of STK11 pathogenic
variants in PJS involve large genetic deletions.24 Therefore,
genetic diagnostic platforms must include strategies to
detect these types of germline variations; at least some of
the “missing” germline pathogenic variants may involve
obscure rearrangements of the STK11 gene.
Cancer risk
Question: Which organs should undergo surveil-
lance when caring for a patient with Peutz-Jeghers
syndrome?
Recommendation: Patients with Peutz-Jeghers syn-
drome are at increased risk for cancer in multiple or-
gans, including cancer of the breast, small bowel,
colon, stomach, pancreas, ovaries, testes, and lungs.
Given this risk, we recommend a multidisciplinary
approach to cancer surveillance in these organs. (Strong
recommendation, low quality of evidence)
Very high lifetime risks of cancer occur in multiple or-
gans in patients with PJS, inside and outside the gut. Intra-
tubular large-cell hyalinizing Sertoli cell neoplasms, ovarian
sex cord tumors, and adenoma malignum of the uterine
cervix, although not common, are linked to PJS25 (Table 3).
The lifetime risk of colon, stomach, and small bowel can-
cer has been estimated at 12%–39%, 29%, and 13% respec-
tively6,26–28 (Table 3). Most CRCs occur after the mid-20s
(range, 27–71 years, median age 46 years), but these malig-
nancies have been reported in teenage years as well.26
Mean age at diagnosis of gastric adenocarcinoma ranges
between 30 and 40 years and of small intestinal cancer
between 37 and 42 years.26,27,29
In a meta-analysis of 210 cases reported in 6 publications
(retrospective cohort studies with kindred-based ascertain-
ment from the United States, United Kingdom, and The
Netherlands) on PJS that were based on clinical and histologic
criteria with varying types of ascertainment, the relative risk
(RR) for any cancer was 15.2 (95% confidence limits [CL], 2
and 19) compared with a variety of time period–specific
U.S.-based registries. Significantly increased age-adjusted
cancer risks were noted for the small intestine (RR, 520;
95% CL, 220 and 1306; cumulative risk [CR], 13%), stomach
(RR, 213; 95% CL, 96 and 368; CR, 29%), pancreas (RR, 132;
95% CL, 44 and 261; CR, 36%), colon (RR, 84; 95% CL, 47
and 137; CR, 39%), esophagus (RR, 57; 95% CL, 2.5 and 557;
CR, 0.5%), ovary (RR, 27; 95% CL, 7.3 and 68; CR, 21%),
lung (RR, 17.0; 95% CL, 5.4 and 39; CR, 15%), uterus (RR,
16.0; 95% CL, 1.9 and 56; CR, 9%), testes (RR, 4.5; 95% CL,
0.12 and 25; CR, 9%), and breast (RR, 15.2; 95% CL, 7.6 and
27; CR, 54%).26 Mean age at the time of cancer diagnosis
was 42.9 years. The absolute risk of developing any cancer
between the ages of 15 and 64 was estimated to be 93%.
The risk of cancer in PJS was revisited in 2 follow-up
studies that included some who were members of the orig-
inal cohort.28,30 The lattermost report included some of
the original 210 cases and expanded to 419 cases, in

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 Gastrointestinal hamartomatous polyposis syndromes

TABLE 3. Risk of cancer in hamartomatous polyposis syndromes

Site General population risk,* % Syndrome risk, % Mean age at diagnosis, y Reference

PJS
Colorectal 4.3 39 42–46 26, 29
Stomach <1 29 30–40 26, 29
Small bowel <1 13 37–42 26, 29
Breast 12.9 32–54 37–59 26, 28, 29
Ovarian (mostly SCTAT) 1.2 21 28 26
Cervix (adenoma malignum) <1 10–23 34–40 26
Uterus 3.1 9 43 26, 29
Pancreas 1.7 11–36 41–52 26, 28, 29, 32
Testicular (Sertoli cell tumor) <1 9 6-9 26, 29
Lung 6.3 7–17 47 26, 28, 29
JPS
Colon 4.3 39 44 86
Stomach <1 5–21 54 65, 67, 89
CS
Breast 12.9 25–85 38–46 100, 101, 102
Thyroid 1.3 3–38 31–38 100, 101, 102
Uterus 3.1 5–28 25 95, 100, 101, 102
Kidney (renal cell) 1.7 15–34 40 97, 100, 104
Colon 4.3 9–18 35 100–103, 106
Melanoma 2.3 6 3y 100, 101
HMPS
Colon 4.3 Increased d 119–121
SCTAT, Sex cord tumors with annular tubules.
*National Cancer Institute. Surveillance, Epidemiology, and End Results Cancer Statistics Review 1975–2017. Lifetime risk (%) of being diagnosed with cancer by site, 2017.
yYoungest age of onset.

which 297 had confirmed germline pathogenic variants in
STK11.28 The cumulative incidences of cancer by decade
from age 20 to 70 years were 2%, 5%, 17%, 31%, 60%,
and 85% respectively, confirming the initial estimates and
tumor spectrumdpredominantly the gastrointestinal tract
and breast. Cancer risks were the same in those with a
clinical diagnosis but no detectable germline pathogenic
variant in the STK11 gene.
Several collaborative studies from Europe and the
United States again found similar risks for cancer.29,31 A
systematic review of 20 cohort studies looking at 1644
patients with PJS confirmed at least 1 cancer in >90% of
patients with PJS at a mean age of 42 years.29 CRC was
the most commonly diagnosed tumor, followed by
cancers of the breast, small intestine, stomach, lung,
pancreas, cervix, ovary, bile ducts, and testicles. A
multicenter study from Italy of 119 STK11 pathogenic
variant carriers reported an overall RR for cancer of 22.0
in women (in part because of additional risks for cervical
cancers) and 8.6 in men, compared with an Italian-based
general population registry, and a cumulative risk of cancer
reaching 89% by age 65 years.27 A more recent study from
China confirmed elevated cancer risks (albeit somewhat
lower than the American and European data), early age
of onset, and a similar tumor spectrum.32
Surveillance of affected individuals
The effectiveness of cancer surveillance in PJS has not
been evaluated in controlled studies. Consequently, sur-
veillance recommendations have been developed by
consensus groups and expert opinion analyzing cancer
risks and published organ-specific surveillance protocols
(Tables 3 and 4).11,33–35
Question: How and when should small bowel sur-
veillance be performed in Peutz-Jeghers syndrome?
Recommendation: We recommend that baseline
small bowel surveillance using video capsule endoscopy
or magnetic resonance enterography be performed be-
tween ages 8 and 10 years or earlier if the patient is
symptomatic. If no polyps are found at the initial exam-
ination, surveillance should resume at age 18 years.
Because of the risk of small bowel intussusception,
small bowel surveillance in adulthood is recommended
to continue throughout life every 2–3 years. (Strong
recommendation, low quality of evidence)

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Gastrointestinal hamartomatous polyposis syndromes

TABLE 4. Surveillance guidelines in hamartomatous polyposis syndromes

ACG 2015 NCCN 2020 ESPGHAN 2019 USMSTF 2020

Age of Interval, Age of Interval, Age of Interval, Age of Interval, Evidence
Examination initiation, y y initiation, y y initiation, y y initiation, y y grade

JPS
Colonoscopy 12–15 1–3 15 2–3 12–15 d 12–15 1–3 Low
Upper endoscopy 12–15 1–3 15 2–3 Late teens* d 12–15 1–3 Low
Screen for vascular lesions 6 mo d 6 mo d At diagnosis d 6 moy d d
PJS
Colonoscopy 8, 18z 3 Late teens 2–3 8 3 8–10, 18z 2–3 Very low
z
Upper endoscopy 8, 18 3 Late teens 2–3 8 3 8–10, 18z 2–3 Very low
z z
VCE 8, 18 3 w8–10x 2–3 8 3 8, 18 2–3 Low
CT or MRE of small bowel d d w8–10x 2–3 d d d d d
MRI/MRCP or EUS of 30 1–2 w30–35{ 1–2 d d 35 1 Low
pancreas
MRI and/or mammogram 25 1 w25 1 d d d d d
Physical examination Birth to 1 w10 1 d d d d d
teenage
Pelvic examination and Pap 25jj 1 w18–20 1 d d d d d
smear
Testicular examination Birth to 1 w10 1 d d d d d
teenage
PHTS
Colonoscopy 15 2 35 5 d d 35 5 Low
Upper endoscopy 15 2–3 d d d d d d d
Thyroid examination and Adolescence 1 7 1 d d d d d
US
MRI and/or mammogram 30–35 1 30-35 1 d d d d d
Endometrial sampling 30–35 1 d 1–2 d d d d d
Urinalysis or renal US 18 1 40 1–2 d d d d d
Skin examination w18 1 At diagnosis 1 d d d d d
ACG, American College of Gastroenterology; CT, computed tomography; ESPGHN, European Society for Paediatric Gastroenterology Hepatology and Nutrition; EUS, endoscopic
ultrasound; MRCP, magnetic resonance cholangiopancreatography; NCCN, National Comprehensive Cancer Network.
*Upper gastrointestingal screening in JPS SMAD4 carriers is indicated in asymptomatic patients starting in late teens. For non-SMAD4 JPS patients, upper endoscopic screening is
only indicated if the patient has relevant symptoms or anemia not explained by colonic polyps.
ySMAD4 mutation carriers should be clinically evaluated for HHT at the time of the diagnosis, including screening for, and appropriate management of, cerebral and pulmonary
AVMs.
z
First procedure at 8 years of age; if polyps present, repeat every 3 years; if no polyps, restart at 18 years of age and every 3 years.
xBaseline at age 8–10 years of age with follow-up interval based on findings but at least by age 18 years of age, then every 2–3 years, although this may be individualized by at
least age 18 years, then every 2–3 years, although this may be individualized, or with symptoms).
{Based on clinical judgment, early initiation age may be considered, such as 10 years younger than the earliest age of onset in the family.
jjACG 2015 Guidelines recommend transvaginal ultrasound as part of surveillance beginning at age 25 years.

Gastrointestinal polyposis and cancer surveillance with esophagogastroduodenoscopy (EGD),

Gastric, small bowel, and colorectal polyposis occur in
88%–100% of patients, with the majority appearing in
the small bowel (60%–90%) and colon (50%–64%).36
Polyps can vary in number (1–100) and size (0.1–3 cm in
diameter) and age of onset of symptoms may vary. Polyp
growth begins in childhood by age 10 years (33%), with
most experiencing symptoms such as bleeding,
abdominal pain, intussusception, or obstruction (68%)
by age 18 years.37 In affected or at-risk individuals, early
colonoscopy, and small bowel imaging with video
capsule endoscopy (VCE) and/or magnetic resonance en-
terography (MRE) is recommended to begin at age 8
years.11,33–35
Intussusception is rare in children younger than 5
years, and the precise risk of intussusception between 5
and 18 years of age is unknown. Retrospective registry
data report that 23 of 34 adults with PJS (68%) had under-
gone laparotomy by the age of 18 years, 70% of which

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were performed as an emergency. By the age of 10 years,
30% had required a laparotomy.37 In a single-institution
study of 379 pediatric patients who underwent pneumatic
reduction for intussusception (from all causes), one-
quarter required operative management.38 There is a
paucity of studies that assess modalities to evaluate the
small bowel in patients with PJS. Retrospective data
comparing VCE to small bowel barium studies have
reported VCE as a useful diagnostic tool in PJS. A
retrospective study from France included 27 children
who underwent at least 1 VCE.39 The authors found VCE
was a useful diagnostic tool, however, findings at VCE may
not predict future bowel obstructions. Although VCE may
not predict future bowel obstructions, it has a greater
sensitivity in detecting small bowel polyps compared with
MRE and provides patients with another alternative if they
are unable to undergo MRE. Ten children with PJS with
polyps >15 mm identified by VCE and MRE underwent
single-balloon enteroscopy.40 In this small study, single-
balloon enteroscopy was effective for treating small bowel
polyps. Further larger, multicenter studies are warranted
to accurately determine the safety of therapeutic single-
balloon enteroscopy in children.7 Based on the published
data, VCE or MRE is recommended between ages 8 and 10
years in asymptomatic patients. Investigations should
commence earlier if patients have symptoms. If no polyps
are found on the baseline investigation, repeat small
bowel evaluation may commence at age 18 years. If polyps
are found, further investigation and surveillance should be
individualized based on polyp size and location. Because
of the risk of small bowel intussusception, small bowel
surveillance in adulthood continues throughout life every
2–3 years. If polyps are present in the colon or stomach,
EGD or colonoscopy is continued as necessary every 2–3
years.
Question: What is the recommended approach to
endoscopic surveillance of the stomach, duodenum,
and colon in Peutz-Jeghers syndrome?
Recommendation: We suggest a baseline upper
gastrointestinal endoscopy between the ages of 8 and
10 years, which could be performed at the time of
capsule placement for small bowel surveillance or if
polyps are identified on magnetic resonance enterogra-
phy. Although the initiation age for colonoscopy remains
uncertain, we also suggest initiation of colonoscopy at
the same time as esophagogastroduodenoscopy. In
those in whom characteristic polyps are detected, both
colonoscopy and esophagogastroduodenoscopy should
be repeated every 2–3 years. In those in whom there
are no Peutz-Jeghers polyps at baseline, surveillance is
repeated at age 18 years, or sooner should symptoms
arise, and then every 3 years. (Weak recommendation,
very low quality of evidence)
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Gastrointestinal hamartomatous polyposis syndromes
Management of polyposis
Although the malignant potential of PJ polyps is un-
known and the evidence of benefit from gastrointestinal
surveillance is not robust, endoscopic removal of polyps
is recommended to prevent polyp-related complications
and to reduce the risk of cancer. In a study of long-term
outcomes of gastrointestinal procedures from a PJ polypo-
sis registry, investigators tracked the results of 776 proced-
ures among 63 patients with PJS at a median age of 20
years (range, 3–59 years). A total of 2461 polypectomies
were performed; more than 1000 polyps were removed
during colonoscopy and more than 400 polyps were
removed during EGD, and the remaining polyps were
removed by means of enteroscopy or laparotomy of the
small bowel.41 A substantial proportion of patients
required intervention for removal of large polyps and the
authors concluded that surveillance reduced polyp
burden and likelihood of polyp-related complications,
and provided cancer surveillance. Therefore, we recom-
mend polypectomy for polyps in the stomach and colorec-
tum that are >0.5 cm in size on endoscopic surveillance
and an attempt to remove all polyps if endoscopically
feasible.33,35,42,43
In the small bowel, balloon enteroscopy and MRE have
similar diagnostic yields for lesions
15 mm, but endos-
copy permits polyp removal.43 Consequently, removal,
preferably by enteroscopy, of small intestinal polyps that
are symptomatic or rapidly growing, or asymptomatic
polyps that are >1.0–1.5 cm in size, has been
recommended.33,35,37,42,44,45 Surgery is often needed
when small bowel intussusception occurs. Some
authorities recommend an attempt to clear the small
intestine of polyps during laparotomy by means of
intraoperative endoscopy with polypectomy or, for larger
polyps, by means of enterotomy. This “clean sweep”
approach appears to decrease the need for recurrent
small bowel surgery.46 Thus, the early management focus
is on large hamartomatous polyps and their tendency to
obstruct the gut or bleed. As children grow older and
transition into adulthood, the focus shifts to managing
the cancer risk.
Question: What size polyps found on small bowel
imaging in Peutz-Jeghers syndrome should be removed?
Recommendation: We recommend polypectomy
of small bowel polyps that are symptomatic
or
10 mm to prevent intussusception and other com-
plications, such as bleeding. (Strong recommendation,
low quality of evidence)
Breast cancer
Invasive ductal adenocarcinoma poses the greatest risk
of early malignancy to patients with PJS (24%–54% lifetime
risk in women) and often presents at a young age (range,
19–61 years in 1 study).26,47 The risk of breast cancer in
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Gastrointestinal hamartomatous polyposis syndromes
women with PJS is within the same range as women
affected by BRCA-1 or BRCA-2 pathogenic variants (40%–
85% lifetime risk for breast cancer).26,48 Therefore,
consensus opinion surveillance recommendations by
groups that include breast cancer experts49,50 include
monthly breast self-examination starting at age 18 years,
biannual clinical breast examination starting at age 25
years, annual breast magnetic resonance imaging (MRI)
from ages 25–29 years, and mammography with consider-
ation of tomosynthesis (3-dimensional mammography)
alternating every 6 months with breast MRI with contrast
from ages 30 to 75 years.6,11 The option of
prophylactic mastectomy might be discussed on a case-
by-case basis, factoring in family history. In patients with
PJS, referral to a breast cancer specialist for management
of breast cancer surveillance is reasonable, and a multidis-
ciplinary approach including a breast surgeon is recom-
mended when prophylactic mastectomy is being
considered.
Question: What is the recommended pancreatic
cancer surveillance in Peutz-Jeghers syndrome?
Recommendation: We suggest annual pancreatic
cancer surveillance with either magnetic resonance
cholangiopancreatography or endoscopic ultrasound
starting at age 35 years. (Weak recommendation, low
quality of evidence)
Pancreas cancer
Pancreatic cancer is the third most frequently occurring
malignancy in patients with PJS. The lifetime risk of
pancreatic ductal adenocarcinoma is between 11% and
36%, presenting, on average, at ages 41–52 years, with
95% of cases occurring after age 24 years.6,26,28,51,52 PJS
is associated with the highest relative risk of all
pancreatic cancer syndromes, with the exception of
hereditary pancreatitis (25%–40% lifetime risk).43
Consequently, a high-risk pancreatic surveillance protocol
is recommended. The consensus recommendations of
the International Cancer of the Pancreas Screening Con-
sortium53 recommend pancreas MRI/magnetic resonance
cholangiopancreatography and/or endoscopic ultrasound
every 1–2 years starting from age 40 years, for which
evidence suggests that these cancers can be found in
earlier stages.54 The National Comprehensive Cancer
Network Guidelines recommend initiating pancreatic
cancer surveillance between the ages of 30 and 35 years.
Due to reports of pancreatic cancer diagnoses in patients
with PJS before the age of 40 years,26 the USMSTF
suggests initiating annual surveillance at age 35 years
with MRI/magnetic resonance cholangiopancreatography
and/or endoscopic ultrasound. Ideally, these
examinations would alternate on an annual basis, as they
are complementary. In addition, routine fasting glucose
and hemoglobin A1c at initiation of screening is
1036 GASTROINTESTINAL ENDOSCOPY Volume 95, No. 6 : 2022
recommended by the Cancer of the Pancreas Screening
Consortium. At the current time, the USMSTF awaits
definitive data before making a recommendation
regarding fasting glucose and hemoglobin A1c. Recent
updates to the Cancer of the Pancreas Screening
Guidelines detail surveillance protocols and management
recommendations based on imaging and endoscopic
findings.55
Gynecological cancers
The lifetime risks for ovarian, uterine, and cervical can-
cer are estimated at 21%, 9%, and 10%–23%, respectively,
with mean age at presentation of 28–35 years, 43 years,
and 34–40 years, respectively.6,26,27 Of note, almost all
ovarian tumors in patients with PJS are sex cord tumors
with annular tubules, and rarely cystadenomas or
granulosa cell tumors. Sex cord tumors with annular
tubule neoplasms are a heterogeneous group of benign
or malignant neoplasms, but the tumors rarely have
lymph node metastasis.26 Also, an unusual percentage of
cervical cancers in patients with PJS are adenoma
malignum, a rare, well-differentiated, cervical adenocarci-
noma that is associated with a poor prognosis and difficult
to diagnose on Pap smear. A high level of suspicion is
required for diagnosis.56 Recommendations for
gynecological surveillance are pelvic examination with
Pap smear and transvaginal ultrasound annually starting
at age 25 years.33,35
Testicles
The estimated risk of testicular cancer in male patients
with PJS is 9%, mean age at diagnosis is 9 years (range,
3–20 years).6,26,27 These tumors present as testicular
masses. The tumors are Sertoli cell tumors that can
cause gynecomastia and other signs of hyperestrogenism
and occasionally virilization and/or accelerated height
growth.26 Accelerated height velocity can be challenging
to detect as adolescents have “growth spurts” as part of
normal maturation and development. Expert opinion
recommends annual history and physical examination
(including self-examination) with observation for femi-
nizing changes and examination of the testicles6,34,35;
based on the range of age at diagnosis of this tumor,
examination should start from birth. Ultrasound of the
testicles every 2 years from birth to age 12 years has
been suggested.44
Lung
The lifetime risk of lung cancer in patients with PJS has
been estimated between 7% and 17%,6,26–28,30 compared
with 0.2%–0.6% in nonsmokers in the general
population.57 The cumulative risk of lung cancer in PJS
surpasses 5% by age 55 years.6 Of note, lung cancer risk
in patients with PJS has not been calculated with
adjustment for smoking status. The RRs of lung cancer in
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patients with PJS compared with nonsmokers are similar to
people with a more than 30 pack-year history of smoking
who have quit for 10–15 years (hazard ratio, 14.8).58
Currently, the American College of Chest Physicians,
American Society of Clinical Oncology, and American
Cancer Society recommend low-dose computed tomogra-
phy annually for individuals with this level of cumulative
risk for lung cancer from ages 55 to 74 years.59,60 There
are no data to show benefit of lung cancer surveillance in
patients with PJS. Lung cancer surveillance with annual
low-dose computed tomography, as performed in smokers
at high risk for lung cancer, may be considered in patients
with PJS. Smoking cessation counseling in patients with PJS
is advisable to mitigate risk.33,34
Chemoprevention
Currently, there are no known chemopreventive agents
in clinical practice that slow or prevent the development of
intestinal polyps and cancers in PJS. Pathogenic variants in
the STK11 gene decrease inhibition of mTOR leading to
the development of intestinal polyps. A trial examining
the oral selective mTOR inhibitor, everolimus, was
stopped prematurely because of poor patient accrual.
Only 2 patients were enrolled, 1 with pancreatic cancer
that progressed and another patient who withdrew from
the protocol because of severe complications from the
medication.61
In a murine model of PJS, treatment with celecoxib, a
COX2 inhibitor, resulted in a >50% reduction in polyp
burden. When used in patients with PJS with diffuse polyp-
osis in the body of the stomach (tens to hundreds), 2 of 6
had a significant reduction in polyp number, as assessed by
5 independent evaluators, after administering celecoxib
(200 mg twice per day for 6 months).62
Summary
PJS is associated with a very high cumulative lifetime
risk of cancer of multiple organs, including, but not limited
to, the gastrointestinal tract. Intensive surveillance is rec-
ommended to prevent and manage complications of pol-
yposis and identify cancer at an early stage. The
development of polyposis and the cancer risks may be a
reflection of the effects of haploinsufficiency of the LKB1
protein, for which there are possible medical therapies to
be explored. It is unclear whether the basic mechanisms
responsible for hamartoma formation in younger life are
the same as those that create the risks for cancer later in
life. Simulation models and clinical trials are needed to
optimize endoscopic surveillance frequencies and the use
of imaging modalities in adults. In addition, collaborative
multicenter consortia may help facilitate chemoprevention
trials in the future.
www.giejournal.org
Gastrointestinal hamartomatous polyposis syndromes
JUVENILE POLYPOSIS SYNDROME
Question: Who should undergo a genetic evaluation
for juvenile polyposis syndrome?
Recommendation: We recommend genetic evalua-
tion for any individual with 1) 5 or more juvenile polyps
of the colon or rectum; 2) 2 or more juvenile polyps in
other parts of the gastrointestinal tract; or 3) any num-
ber of juvenile polyps and 1 or more first-degree rela-
tives with juvenile polyposis syndrome. (Strong
recommendation, low quality of evidence)
Clinical features
JPS is an autosomal dominant inherited condition in
which multiple juvenile polyps are found in the colorectum
(98% of affected patients) (Figure 1B), stomach (14%),
jejunum and ileum (7%), and duodenum (7%).63–65 The
incidence of JPS is between 1 in 100,000 and 1 in
160,000 individuals.65 The polyps in JPS vary in size from
small sessile nodules to pedunculated lesions that are
3
cm in diameter. Histologically, the typical juvenile polyp
has a distinctive cystic architecture, dilated mucus-filled
glands, a prominent lamina propria, and Paneth cells en-
meshed within a dense infiltration of inflammatory cells.
In patients with germline pathogenic variants in SMAD4,
additional features of gastric polyposis, gastric cancer,
and a JPS–hereditary hemorrhagic telangiectasia (HHT)
overlap syndrome are common. The management of JPS
is based on decreasing the risk of bleeding and gastric
and colorectal cancer through polypectomy. Patients with
JPS-HHT overlap syndrome should have lifelong HHT sur-
veillance. One study also demonstrated that as many as
38% may have thoracic aorta abnormalities.66
Juvenile polyps are most often solitary and are not syn-
dromic, occurring sporadically in infants and children. A
typical history associated with a solitary juvenile polyp is
the asymptomatic passing of a polyp into an infant’s diaper.
Juvenile polyps appear endoscopically to have a smooth
red surface, may be sessile or pedunculated, and patholog-
ically are characterized by cystic dilatation of mucus-filled
glands suspended in an inflamed stroma (Figures 1B and
2D and E). These lesions may also be called retention
polyps or inflammatory polyps because of their
microscopic appearance.
Diagnosis
The diagnosis of JPS is made based on clinical criteria or
identification of a germline pathogenic variant in SMAD4 or
BMPR1A. The clinical diagnosis of JPS is made when a per-
son has any 1 of the following: 1) 5 or more juvenile polyps
of the colon or rectum; 2) any number of juvenile polyps in
parts of the gastrointestinal tract other than the colon; or
3) any number of juvenile polyps and 1 or more first-
degree relatives with JPS.65
Volume 95, No. 6 : 2022 GASTROINTESTINAL ENDOSCOPY 1037
Gastrointestinal hamartomatous polyposis syndromes
Genetics
JPS is an autosomal dominant disorder with approxi-
mately 75% of cases inherited from a parent and 25% rep-
resenting de novo pathogenic variants.64 Approximately
60% of patients with JPS have a pathogenic variant in the
BMPR1A or SMAD4 gene.67 Rarely (1 in 1,000,000)
individuals develop features of JPS and PHTS, known as
juvenile polyposis of infancy, due to a large deletion
encompassing both the BMPR1A and PTEN genes.
In a study from the Cleveland Clinic of 35 patients with
JPS, germline pathogenic variants in SMAD4 and BMPR1A
were associated with similar colonic polyposis phenotypes,
but SMAD4 pathogenic variant carriers were more likely to
have more gastric polyps, and an 11% risk of gastrointes-
tinal cancer.68 However, no gastric cancers were reported
in patients with BMPR1A pathogenic variants in 8
patients followed for a mean of 11 years.
However, germline pathogenic variants in other genes
may cause a hamartomatous polyp phenotype. In a study
of 49 patients referred to the Cleveland Clinic for unex-
plained hamartomatous or hyperplastic polyps, germline
pathogenic variants were found in multiple genes,
including endoglin (ENG, a gene associated with HHT),
STK11 (the PJS gene), SMAD4, BMPR1A, and PTEN.69 In a
later study from this group of 603 patients with a
“moderate load of gastrointestinal polyps” with at least 1
confirmed to be a hamartoma or hyperplastic polyp, 13%
were found to have a germline pathogenic variant in at
least 1 of the genes listed above and 20% of the cohort
had a personal history of CRC.70
As discussed in the context of PJS, it has been tradi-
tionally thought that a germline pathogenic variant asso-
ciated with a hereditary colon cancer syndrome did not
change the biology of the normal tissues and a second
(somatic) hit was required for a tumor to form. In fact,
allelic loss of the SMAD4 locus was found in the epithelial
component of juvenile polyps of patients with JPS
(together with a germline pathogenic variant in SMAD4)
using in situ hybridization, but not in the inflammatory
or stromal cells. This was compatible with the Knudson
2-hit model.71 However, another group has reported
that SMAD4 haploinsufficiency (ie, a lower dose of the
gene product due to the specific type of germline
pathogenic variant) causes the JPS phenotype in
humans, supported by data from mice.72 However, just
as in PJS, being haploinsufficient for SMAD4 (ie, just the
germline pathogenic variant), is associated with partially
diminished transforming growth factor–b signaling, at
least in mice,72 as this alters proliferation in T cells,
which contributes to the development of polyps and
cancer.73,74 Specific deletion of SMAD4 in mouse T cells
leads to up-regulation of the Th17-inflammatory pathway
in the stroma, and the growth of large polyps in the
gastrointestinal tracts of mice.73,74 This raises the
question of whether there is abnormal regulation of
1038 GASTROINTESTINAL ENDOSCOPY Volume 95, No. 6 : 2022
immune cells in JPS, and may explain the inflammatory
appearance of juvenile polyps independent of abnormal
biology in the epitheliumdanother landscaper
mechanism, as discussed above for PJS. These
observations may have important clinical implications
for future attempts to halt the appearance or growth of
the inflammatory polyps. However, allelic loss (ie, a
somatic variants as the second hit) occurs in at least
some polyps of JPS patients.75,76
Juvenile polyposis syndrome–hereditary
hemorrhagic telangiectasia overlap syndrome
HHT occurs in approximately 15%–81% of patients with a
germline SMAD4 pathogenic variant.77,78 The clinical
features of HHT, such as epistaxis, obscure gastrointestinal
bleeding, digital clubbing, visceral arteriovenous
malformations (AVMs), and mucocutaneous telangiectasias
should be sought in SMAD4 patients. International
guidelines (outlined below) recommend that surveillance
and treatment for HHT complications are necessary for all
SMAD4 carriers.79
Juvenile polyposis of infancy
Juvenile polyposis of infancy is a severe form of juvenile
polyposis. This disease presents in the first 2 years of life
with diarrhea, abdominal pain, rectal bleeding, refractory
anemia, hypoalbuminemia, and enteropathy. Case reports
indicate that a large deletion in the long arm of chromo-
some 10 (10q23), encompassing the PTEN and BMPR1A
genes, is associated with the development of the dis-
ease.69,80–83
Question: Which organs should undergo surveil-
lance when caring for a patient with juvenile polyposis
syndrome?
Recommendation: Patients with juvenile polyposis
syndrome are at increased risk for cancer in multiple or-
gans, including cancer of the colon and stomach.
Given this risk, we recommend patients with juvenile
polyposis syndrome undergo surveillance of the colon
and stomach. (Strong recommendation, low quality
of evidence)
Gastrointestinal polyposis and cancer
In a retrospective chart review study of 257 children
with juvenile polyps at a single-referral center, patients pre-
sented at a median age of 5.6 years, and at colonoscopy
39% had multiple polyps.84 Among 192 patients who
underwent complete colonoscopy at initial diagnosis, 117
(60.9%) had a single polyp and 75 (39.1%) had multiple
polyps. These lesions recurred in 21 of 47 patients
(44.7%) after an initial eradication, including 3 of 18
presenting with a single polyp, and neoplasia was found
in 3.9% of lesions. Patients with JPS often have a variable
presentation of polyp distribution, which may occur
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throughout the colon and/or stomach and the cancer risk
is attributable to the presence of dysplasia in the polyps.
One study of 78 juvenile polyps from 12 patients with
JPS and 34 patients with sporadic juvenile polyps
reported that dysplasia was present in 31% of the polyps
from patients with JPS but in none of the polyps from
patients with sporadic juvenile polyps.85 Dysplasia in
polyps from patients with JPS was associated with
somatic variants in the APC gene.85 In a longitudinal
study from St Mark’s Hospital of 44 patients with JPS
from 30 kindreds, a total of 787 polyps (juvenile and
adenomatous) were resected, and 65 of 787 (8.3%)
contained mild/moderate architectural dysplasia, and 20
additional polyps (2.5%) were adenomatous.65
Patients with JPS are at increased risk for cancer princi-
pally in the stomach and colon (Table 3). In a small cohort
of patients with JPS (n Z 84) relative to age-, sex-, and
race-matched controls, the RR of CRC was estimated to
be 34 (95% CL, 14.4 and 65.7), with a cumulative lifetime
risk of CRC reaching 38.7%.86 The CRCs were diagnosed
at a mean age of 43.9 years. Interestingly, no other
gastrointestinal cancers were noted in this cohort, but
the numbers were small and the duration of the study
was short. Individuals with gastric polyposis, usually in
association with pathogenic variants in SMAD4 are also at
risk for gastric cancer, with the lifetime risk estimated to
be at least 30% and median age of diagnosis is 58 years;
this has not been reported in association with BMPR1A
pathogenic variants.67,87–91 Estimates of gastrointestinal
cancer risk range from 11%68 to 55%,89 but none of the
studies are prospective long-term studies (which would
lead to underestimates), and all are prone to referral-
based ascertainment bias (overestimates).
Question: At what age should colonoscopic and up-
per endoscopic surveillance begin in individuals identi-
fied with juvenile polyposis syndrome?
Recommendation: We suggest initiating colono-
scopic and upper endoscopic surveillance at age 12–
15 years, or earlier if symptomatic. Surveillance should
be repeated every 1–3 years depending on polyp
burden. (Weak recommendation, low quality of evi-
dence)
Management of polyposis
The goal of surveillance in JPS is to mitigate symptoms
related to the disorder and decrease the risk of complica-
tions from the manifestations, including cancer. Colonos-
copy should be first performed at age 12–15 years and
repeated every 1–3 years, depending on polyp burden
found, with removal of all polyps when feasible or at least
all polyps
5 mm. Upper endoscopy should be first per-
formed at age 12–15 years and repeated every 1–3 years
depending on polyp burden found, with removal of
polyps
5 mm. Due to the possible presence of intestinal
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Gastrointestinal hamartomatous polyposis syndromes
telangiectasias, an annual history and physical examination
and complete blood counts to monitor for rectal bleeding
and/or anemia should begin at age 12–15 years in patients
with a germline SMAD4 pathogenic variant.
Endoscopic polypectomy is recommended for colo-
rectal polyposis management. Surgery with colectomy
and ileorectal anastomosis is recommend for patients
with CRC, endoscopically unmanageable colon polyp
burden, and uncontrolled anemia from colonic bleeding.33
In some cases, proctocolectomy is necessary for rectal
cancer or advanced polyp burden of the rectum.
Colectomy in patients with JPS should be reserved for
patients with polyp burdens that cannot be managed by
polypectomy, persistent blood loss leading to severe
anemia or hypoalbuminemia, or cancer. A decision to
proceed to colectomy should be reviewed with
gastroenterologists and surgeons with expertise in caring
for individuals with hereditary polyposis syndromes.
The risk of gastric cancer is a concern in patients with
JPS with SMAD4 pathogenic variants and gastric polypo-
sis. There is a paucity of published data evaluating the
stomach and small bowel in pediatric patients with JPS.
Those with upper gastrointestinal symptoms, or with
anemia not explained by colonic polyps, should undergo
evaluation with upper endoscopy.92 In pediatric patients
without SMAD4 pathogenic variants, according to the
existing data, gastroscopy is not indicated unless the
child has symptoms.92 In asymptomatic patients with
SMAD4 pathogenic variants, it is prudent to assess the
upper tract between the ages of 12 and 15 years. At
the time of this publication, it is uncertain as to
whether BMPR1A pathogenic variants are associated
with gastric cancer risk, and that pending new
evidence, upper endoscopy surveillance is suggested at
intervals similar to those recommended for SMAD4
carriers. In adults, partial or complete gastrectomy is
indicated in patients with gastric cancer, high-grade
dysplasia, inability to adequately survey or endoscopi-
cally control polyposis, persistent anemia or gastrointes-
tinal bleeding from gastric polyposis or angioectasia,
symptoms of gastric outlet obstruction, or protein-
losing gastropathy.63,64
Question: Which patients with juvenile polyposis
syndrome should undergo screening for hereditary
hemorrhagic telangiectasia?
Recommendation: We suggest patients with
SMAD4 pathogenic variants be clinically evaluated for
hereditary hemorrhagic telangiectasia at the time of
the diagnosis, including screening for and appropriate
management of cerebral and pulmonary arteriovenous
malformations. (Weak recommendation, low quality
of evidence)
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Gastrointestinal hamartomatous polyposis syndromes
Management of juvenile polyposis syndrome–
hereditary hemorrhagic telangiectasia
As recommended by HHT Foundation International,
patients with SMAD4 pathogenic variants should be
screened for vascular findings associated with HHT.79,93
Children with possible or confirmed HHT should be
screened for brain AVMs at the time of diagnosis and
undergo at least 1 follow-up MRI at puberty because brain
AVM development appears to correlate with times of
growth. Lung AVM screening and surveillance is recom-
mended at diagnosis and then every 3–5 years with pulse
oximetry testing and consideration of transthoracic
contrast echocardiogram. In adulthood, surveillance
should include annual hemoglobin or hematocrit for all
patients older than 35 years. Transthoracic contrast echo-
cardiogram as a screen for pulmonary AVMs should be per-
formed at the time of diagnosis, within 5 years preceding
planned pregnancy, after pregnancy, and otherwise every
5–10 years. Physicians should consider referring these pa-
tients to HHT Centers of Excellence for this evaluation.
Brain MRI with and without contrast should be performed
at birth or at the time of diagnosis to screen for cerebral
vascular malformations.
Chemoprevention
No known effective chemoprevention strategies exist
for the development of polyposis in patients with JPS.
Summary
BMPR1A and SMAD4 gene alterations are responsible for
JPS, yet only 60% of patients will have a pathogenic alter-
ation identified. The clinical overlap syndromes include
JPS-HHT in patients with a SMAD4 pathogenic variant and
juvenile polyposis of infancy in patients with a combined
BMPR1A and PTEN deletion. The symptoms of JPS are usu-
ally related to bleeding from colorectal polyposis or in
SMAD4-related JPS to gastric polyposis or manifestations
of HHT. Cancer risk in JPS is elevated, mainly in the colon
and stomach (39%–68%), and is largely associated with
SMAD4 pathogenic variants.94 Excess risk of
nongastrointestinal cancer is not reported in JPS.
PTEN-HAMARTOMA TUMOR SYNDROME
Clinical features
Question: Which gastrointestinal findings should
prompt a genetic evaluation for PTEN hamartoma tu-
mor syndrome?
Recommendation: We recommend individuals
with multiple gastrointestinal hamartomas or ganglio-
neuromas undergo genetic evaluation for Cowden’s
syndrome and related conditions. (Strong recommen-
dation, low quality of evidence)
1040 GASTROINTESTINAL ENDOSCOPY Volume 95, No. 6 : 2022
PHTS includes a variety of phenotypic variations known
as CS, BRRS, and Proteus syndrome. The clinical diagnosis
of the PHTS is made in patients meeting the revised diag-
nostic criteria, which include the presence of hamartomas
of the skin and gastrointestinal tract (see Figures 1D and
2F–H), mucocutaneous lesions, macrocephaly, and an
increased risk of benign and malignant lesions of the
breast, thyroid, and endometrium.95
Diagnosis
The genetic diagnosis of PHTS is established with a
germline pathogenic variant in the phosphatase and
tensin homolog (PTEN) gene. The clinical criteria for the
diagnosis of CS is complex, and can be found at the
National Comprehensive Cancer Network website.49 The
discussion for this article will focus on the manifestations
and management of patients with a confirmed diagnosis
of PHTS.
Genetics
Question: Which organs should undergo surveil-
lance for cancer when caring for a patient with PTEN ha-
martoma tumor syndrome?
Recommendation: In PTEN hamartoma tumor syn-
drome, patients are at increased risk for cancer in mul-
tiple organs, including cancer of the breast, thyroid,
kidney, uterus, colon, and skin.
Given this risk, we recommend a multidisciplinary
approach to cancer surveillance in these organs. (Strong
recommendation, low quality evidence)
The PTEN gene encodes a dual-function phosphatase
that negatively regulates the growth-promoting activity of
the phosphatidylinositol 3-kinase pathway. The PHTS fam-
ily of syndromes are caused by inactivating pathogenic
variants in PTEN, making it a classic tumor suppressor
gene.96 Germline pathogenic variants in the PTEN gene
lead to heterogeneous phenotypes called PHTS, which
includes CS, BRRS, and some cases of the PTEN-related
Proteus syndrome (not considered further here).97,98
Germline pathogenic variants in PTEN are associated
with other systemic nonpolyposis phenotypes, including
abnormalities of the central nervous system and skeleton,
but these will not be discussed here in detail. Patients
with CS are also at risk for dysplastic cerebellar gangliocy-
toma (Lhermitte-Duclos disease), but the specific genetic
basis of this and the other protean manifestations of germ-
line pathogenic variants in PTEN are not yet understood.
Interestingly, gain-of-function germline pathogenic variants
in the WWP1 gene, an E3 ubiquitin ligase commonly up-
regulated in cancers, inhibits the activity of PTEN, causes
a CS-like syndrome (oligopolyposis and cancer-prone
phenotype), and provides some insight into what may be
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responsible for PHTS in the absence of germline variants in
PTEN.99
Cancer risk
Cancer risks for patients with germline pathogenic vari-
ants in PTEN are very high. The International Cowden Con-
sortium reported in 2012 on 368 individuals with germline
pathogenic variants in PTEN. Elevated standardized inci-
dence ratios (SIRs) were found for carcinomas of the
breast (SIR, 25.4; 95% CL, 19.8 and 32.0), thyroid (SIR,
51.1; 95% CL, 38.1 and 67.1), endometrium (SIR, 42.9;
95% CL, 28.1 and 62.8), colorectum (SIR, 10.3; 95% CL,
5.6 and 17.4), kidney (SIR, 30.6; 95% CL, 17.8 and 49.4),
and melanoma (SIR, 8.5; 95% CL, 4.1 and 15.6). This led
to cumulative lifetime risks for cancer of the breast at
85.2% (95% CL, 71.4% and 99.1%), thyroid 35.2% (95%
CL, 19.7% and 50.7%), endometrium 28.2% (95% CL,
17.1% and 39.3%), colorectum 9.0% (95% CL, 3.8% and
14.1%), kidney 33.6% (95% CL, 10.4% and 56.9%), and mel-
anoma 6% (95% CL, 1.6% and 9.4%).100
A multicenter study from France estimated cancer risks
in 154 patients with a germline pathogenic variant in
PTEN.101 SIRs for female breast cancer were 39.1 (95%
confidence interval [CI], 24.8–58.6), thyroid cancer 43.2
(95% CI, 19.7–82.1) in women and 199.5 (95% CI, 106.39–
342.03) in men, melanoma 28.3 (96% CI, 7.6–35.4) in
women and 39.4 (95% CI, 10.6–100.9) in men, and
endometrial cancer 48.7 (95% CI, 9.8–142.3). Estimated
cumulative lifetime risks by age 70 years were 85% for any
cancer, 77% for female breast cancer, and 38% for thyroid
cancer. Median age for developing cancer was 36 years.
Although 85% were reported to have colonic polyps of
any variety, risks for gastrointestinal cancer were not
reported to be elevated in this series. However, a review
of 211 patients with CS from the Mayo Clinic, including a
review of the literature, reported a 16% lifetime risk for
CRC. In this study, only 46% had a proven germline
pathogenic variant in PTEN, and the cumulative risk for
any cancer by age 70 years was 89%.102
In a study of 2548 patients who met “relaxed” Interna-
tional Cowden’s Consortium criteria for CS with 5 or
more gastrointestinal polyps in which at least 1 was consid-
ered hyperplastic or hamartomatous, germline pathogenic
variants in PTEN were found in 127 (5%).103 At endoscopy,
gastrointestinal polyps were found throughout the gut, and
one-half were considered “hyperplastic.” In this group,
13% of those who underwent colonoscopy developed
CRC (7.1% of the entire series of patients), all before age
50 years (the youngest was 35 years old), with a SIR for
CRC of 224.1 (95% CI, 109.3–411.3).
A multicenter study from 9 countries of 180 carriers of
germline pathogenic variants in PTEN estimated the cumu-
lative risk of any cancer or Lhermitte-Duclos disease by age
60 years was 56% for men and 87% for women.104
Increased risk was reported for cancers of the breast,
thyroid, endometrium, skin, kidneys, colorectum, and
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Gastrointestinal hamartomatous polyposis syndromes
lungs. An earlier report from this group on 156 patients
reported that benign gastrointestinal polyps were found
in 31% of patients at a mean age of 38 years (range, 18–
62 years) and most were considered “hamartomas.”105
The cumulative risk of developing polyps was 70% by
age 60 years. The cumulative risk of developing CRC was
18% by age 60 years (occurring between ages 53 and 62
years), suggesting that surveillance colonoscopy might
not be necessary in early adult life.
Gastrointestinal polyps and polyposis
Gastrointestinal polyps are frequently found in patients
with germline pathogenic variants in PTEN, with variable
prevalence. Estimates suggest that 35%–93% of patients
with CS have gastrointestinal polyps, but in some reports
the germline basis of the disease was not known and a uni-
form interpretation of nonadenomatous polyps had not
been established.103,106 The wide range of estimated polyp
prevalence is probably a reflection of the heterogeneity of
the disease and challenges in making definitive
diagnoses outside of germline tests. Gastrointestinal
polyps include hyperplastic polyps, inflammatory polyps,
ganglioneuromas, lipomas, adenomas, and the nonspecific
term hamartomas.
A prospective study of 127 PTEN pathogenic variant car-
riers from 2548 subjects in an International Cowden Con-
sortium study in which 69 underwent endoscopic studies
found that 64 (93%) had gastrointestinal polyps.103 Of
that group, one-half had hyperplastic polyps, but all of
the above-listed polyps (plus adenomas) were also found.
The number of polyps ranged from 1 to “innumerable,”
and were distributed throughout the gut.
BRRS is caused by germline pathogenic variants in the
PTEN gene.98,107 It is a pediatric condition associated
with macrocephaly, developmental delay, gastrointestinal
hamartomatous polyps, and pigmented macules on the
toes and glans penis. It has also been called the
Bannayan-Zonana or Ruvalcaba-Riley-Smith syndrome.
Inexplicably, members of the same family may have fea-
tures of either BRRS or CS,108 and some cases of BRRS
do not have detectable pathogenic variants in PTEN.109
Confusing overlap between CS and JPS can occur when,
as mentioned above, a chromosomal deletion occurs on
chromosome 10q22.3-q24.1. This leads to the loss of
both PTEN and BMPR1A28; a situation that can also look
like BRRS, also known as juvenile polyposis of infancy
(see section on JPS).110,111
In a smaller study of 19 patients with CS (in which only
12 were shown to have germline pathogenic variants in
PTEN), pan-colonic polyps were found in 58%, pan-
gastrointestinal polyps in 42%, and the pathological inter-
pretation of the polyps included inflammatory polyps in
95%, but also adenomas, lipomas, and ganglioneuromas.112
Moreover, there was more than 1 pathological variety in
79% of patients, indicating the clinical heterogeneity in
this entity. Esophageal glycogenic acanthosis is also
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Gastrointestinal hamartomatous polyposis syndromes
found in PHTS, which is a benign condition and there is no
reported increased risk for esophageal cancer.113
Question: What is the recommended colonoscopic
surveillance in individuals identified with PTEN hamar-
toma tumor syndrome?
Recommendation: We suggest colonoscopy sur-
veillance to begin at age 35 years (or 10 years younger
than age of any relative with colorectal cancer),
repeated at intervals no greater than 5 years, depending
on polyp burden. (Weak recommendation, low quality
of evidence)
Surveillance of affected individuals
Surveillance recommendations are provided in Table 4.
The assessment at diagnosis of CS/PHTS should include a
complete (and especially dermatologic and neurologic)
clinical examination, mammography and breast MRI,
thyroid ultrasound, transvaginal ultrasound, upper
gastrointestinal endoscopy, colonoscopy, and renal
ultrasound. Although there are no data regarding risk-
reduction surgery in women with CS, the option for risk-
reducing mastectomy and hysterectomy should be dis-
cussed on a case-by-case basis.
The risk of CRC in patients with CS is estimated to be up
to 9%–18% lifetime risk with mean age at diagnosis of 44
years, but ranging from 35 to 49 years.100,102,103,105,114,115
Consequently, expert opinion recommends colonoscopy
starting at age 35 years unless symptomatic or if a close
relative has had colon cancer before age 40 years, then
start 10 years before the earliest known colon cancer in
the family and repeat every 5 years or more frequently if
the patient is symptomatic or polyps are found. This
recommendation differs from a recent American College
of Gastroenterology Guideline,32 which recommends
initiating colonoscopy at age 15 years. Recent evidence
suggesting later onset of significant colon cancer risk
informed our recommendations.
Colectomy is rarely required in patients with CS and is
reserved for patients with CRC or in whom surveillance
and clearing of premalignant lesions is not endoscopically
feasible.
Breast cancer
The management of breast cancer risk begins at age 25
years with clinical breast examination every 6–12 months;
annual mammography and breast MRI surveillance starting
between ages 30 and 35 years or 5–10 years before the
earliest known breast cancer in the family.49 In patients
with PHTS, referral to a breast cancer specialist for
management of breast cancer surveillance is reasonable
and a multidisciplinary approach, including a breast
surgeon, is recommended when prophylactic mastectomy
is being considered.
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Endometrial cancer
The management of endometrial cancer risk begins be-
tween the ages of 30 and 35 years. Endometrial cancer can
often be detected early on the basis of symptoms, and
women should be educated regarding seeking medical atten-
tion on the basis of symptoms, including abnormal uterine
bleeding or postmenopausal bleeding. Endometrial biopsy
is sensitive and specific for endometrial cancer and surveil-
lance via biopsy every 1–2 years can be considered.33,49
Thyroid cancer
An annual thyroid ultrasound should be performed,
beginning at the time of PHTS diagnosis (including in
childhood).33,49
Renal cancer
The recommended management of kidney cancer risk is
an annual renal ultrasound and/or renal MRI starting at age
40 years if there is a family history of renal cancer, or every
2 years if not.33,49
Melanoma
The management of melanoma risk includes an annual
clinical skin examination beginning at age 18 years.33
Summary
Germline pathogenic variants in PTEN are associated
with variety of gastrointestinal hamartomatous polyps
and a markedly increased risk of cancer, but largely in
nongastrointestinal organs. There is a moderate increase
in the risk of CRC, but it may be that the age of risk is
such that colonoscopic surveillance can be withheld until
age 35 years or later or 10 years younger than the age
of the youngest relative with CRC. However, the reports
of CRC risk have been variable,95,116 and no surveillance
recommendation has been rigorously evaluated. The
principal organs at risk for cancer include the breast,
thyroid, endometrium, and colorectum.
HEREDITARY MIXED POLYPOSIS SYNDROME
The genetic basis of the disease and cancer risk
HMPS is a rare autosomal dominant disease reported in
only a few families. It is characterized by attenuated colonic
polyposis. The polyps include adenomas, hyperplastic, and
a particular polyp with an admixture of variable histologies
including adenomatous, hyperplastic, juvenile, and mixed
polyps.117 In the original HMPS kindred described by
Whitelaw et al,118 13 members were diagnosed with CRC
and 23 developed multiple polyps of several different
histologic types (adenomatous, hyperplastic, and
juvenile). HMPS has been associated with large
duplications of the promoter region or entire GREM1
gene.119–121 These unusual pathogenic variants increase
the expression of the gene product, which then inhibits
the bone morphogenetic protein (BMP) pathway.119 This
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 Gastrointestinal hamartomatous polyposis syndromes

TABLE 5. Areas requiring further investigation in hamartomatous polyposis syndromes

1. Discover the germline variants in families with clinically recognizable syndromes who do not have germline mutations in the genes known to be
associated with these syndromes.
2. Understand the effects of haplo-insufficiency of STK11 in PJS and the SMAD4 in JPS on the development of polyposis.
3. Identify safe and effective pharmacological interventions for the inhibition of polyp formation children and adults with the hamartomatous pol-
yposis syndromes.
4. Determine whether pharmacological intervention can mitigate cancer risk in PJS and JPS in adults (independent of the polyposis risk).
5. Develop simulation models in adults with a hamartomatous polyposis syndrome to determine the optimal endoscopic frequency.
6. Design and implement studies to determine the best imaging modalities and surveillance intervals in adults with a hamartomatous polyposis
syndrome.
7. Determine whether the hamartomatous phenotype in pediatric patients predicts the cancer risk in adulthood.
8. Perform outcomes studies evaluating the transition of care in pediatric polyposis patients entering adult life, including outcomes such as compli-
ance with surveillance.
9. Determine difference in phenotype and cancer risk in individuals who meet clinical criteria, but do not have an identifiable pathogenic variant
compared to those with a germline pathogenic variant in a hamartomatous polyposis syndrome.
10. Determine the lifetime cancer risks in patients with a pathogenic variant, but without clinical manifestations (those identified incidentally on multi-
gene panel testing).
11. Quantify the frequency of mosaicism as a cause of the hamartomatous polyposis syndromes.
12. Determine the optimal modality of small bowel evaluation in individuals with PJS.

promoter duplication was found in 0.7% of Ashkenazi Jews
in Israel who met clinical criteria for Lynch syndrome.120
The largest series reported 4 families with 16 affected
members; the onset of polyposis starts in the late 20s,
which is when colonoscopic surveillance should begin.122
There are not enough data to know the optimal
surveillance intervals or whether extraintestinal neoplasia
is a risk. The underlying genetic basis of the majority of
HMPS families is unknown.
myeloproliferative disease) may have therapeutic poten-
tial in patients with PJS.21 Also, LKB1 activity inhibits the
activation of adenosine monophosphate–dependent pro-
tein kinase. Loss of LKB1 activity results in adenosine
monophosphate–dependent protein kinase activation
with up-regulation of mTORC1 signaling contributing
to growth of PJS polyposis. Targeting of adenosine
monophosphate–dependent protein kinase activation is
currently being investigated.123

FUTURE RESEARCH CONSIDERATIONS Juvenile polyposis syndrome

The hamartoma syndromes are rare and it is difficult
for single institutions or even collaborative centers to
accumulate enough cases and follow them prospectively
long enough to develop robust conclusions about cancer
risk. Modeling, simulation, and collaborative multicenter
clinical studies can be used to help clarify the benefits
and risks of various interventions and surveillance pro-
grams. The management of these diseases changes
dramatically when the patient matures from childhood
to adulthooddwhich is where almost all of the cancer
risk lies. Important knowledge gaps are listed in Table 5
and expanded upon below.
Of note is the mouse model of juvenile polyposis
created by a conditional knockout of the SMAD4 gene
only in T-cell populations.73 These animals spontaneously
developed massive polyps within the gastroduodenal
region. The epithelium in the polyps contained increased
expression of pro-inflammatory cytokines, particularly
interleukin-11, a cytokine known to promote gastric
epithelial cell survival and hyperplasia with evidence of
increased TH17 cell activity. This suggests possible thera-
peutic targets for the future chemoprevention of juvenile
polyposis.
SUMMARY AND CONCLUSIONS

Peutz-Jeghers syndrome Among the gastrointestinal hamartomatous polyposis

As indicated above, STK11/LKB1 pathogenic variants
result in up-regulation of inflammatory cytokines and
promotion of overgrowth of both stromal and normal
gastrointestinal epithelium, driving polyp formation
(Table 5). Up-regulation of cytokines is associated with
hyperactivation of JAK-STAT, which contributes to
inflammation and cancer. Inhibition of JAK-STAT signifi-
cantly reduced polyp growth in mice. Consequently, the
JAK inhibitor ruxolitinib (already clinically approved for
syndromes, PJS is the best understood. The polyps are
readily identified as PJ polyps pathologically, and only 1
known gene (STK11) is associated with this entity. The
phenotype is clinically distinct. Not all patients (or fam-
ilies) have detectable germline pathogenic variants in
STK11, so additional genes in this pathway are possibly
contributors to this entity. The polyps may evolve
through an expansion of elements of the gut stroma
due to haploinsufficiency of STK11. In children, the

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Gastrointestinal hamartomatous polyposis syndromes
main risks are for gastrointestinal obstruction and
bleeding. Later in adult life, a very high risk of intestinal
and extraintestinal cancers exists. The major organs at
risk for cancer (in order of decreasing relative risk)
include the small intestine, stomach, pancreas, colon,
esophagus, ovary, lung, uterus, and breast, with estimated
lifetime risks for any cancer reaching >90%. The ovaries
and testes are also at risk for rare variant tumors. The
screening and surveillance strategies change dramatically
when the children reach adulthood.
JPS has principal risks for obstruction and bleeding in
the pediatric ages, but the management in adults shifts
to cancer risks in the stomach and colon. Importantly, un-
like PJS, the gastrointestinal cancers tend to arise within
the juvenile polyps, suggesting that polyp removal might
prevent cancer. Cancer risk is linked to germline patho-
genic variants in the SMAD4 gene rather than the BMPR1A
gene. The polyps are histologically inflammatory in nature,
and their growth may be driven by haploinsufficiency of
SMAD4 in the immune cells of the polyp stroma. The man-
agement focuses on the polyps in children and cancers
later in life, when endoscopic approaches are the mainstay
of surveillance.
The hamartoma syndromes associated with germline
pathogenic variants in PTEN raise a completely different
clinical challenge. Although nearly all patients with PHTS
have a variety of different hamartomatous gastrointestinal
polyps, studies suggest an increased risk of cancer in this
setting.100,103 The extracolonic cancer risks are greatest
for the breast, thyroid, melanoma, and endometrium.
The absolute risk for CRC appears to be increased,
ranging from 9% to 18% during a lifetime, and the rest of
the gastrointestinal tract does not have an established
increase in cancer risk. The age for beginning
surveillance for CRC remains to be determined, but the
early onset of CRC provides some suggestions. Be aware
that the PTEN gene and BMPR1A are located near one
another on chromosome 10q, and that large-scale chromo-
somal deletions could adversely affect both genes, compli-
cating the clinical picture. Long-term prospective studies of
mutation carriers are still needed to further clarify the risk
of cancer and the role of surveillance in these syndromes.
With increases in genetic testing and evaluation, future
studies will be conducted with more robust cohorts of
genetically characterized, less heterogeneous populations.
However, there is also a need to study patients and families
with unusual phenotypes where no genotype can be
found.
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Abbreviations used in this paper: AVM, arteriovenous malformation; BMP,
bone morphogenetic protein; BRRS, Bannayan-Riley-Ruvalcaba
syndrome; CI, confidence interval; CL, confidence limits; CR, cumulative
risk; CRC, colorectal cancer; CS, Cowden’s syndrome; EGD,
esophagogastroduodenoscopy; GRADE, Grading of Recommendations
Assessment, Development and Evaluation; HHT, hereditary hemorrhagic
telangiectasia; HMPS, hereditary mixed polyposis syndrome; JPS, juvenile
polyposis syndrome; MRE, magnetic resonance enterography; MRI,
magnetic resonance imaging; PHTS, PTEN hamartoma tumor
syndrome; PJS, Peutz-Jeghers syndrome; RR, relative risk; SIR,
standardized incidence ratio; USMSTF, U.S. Multi-Society Task Force on
Colorectal Cancer; VCE, video capsule endoscopy.
CONFLICTS OF INTEREST: The authors disclose no conflicts of interest relative
to the current work since 2016. These authors disclose the following industry
relationships (consulting, research, reimbursement) without conflict of interest
relevant to the current work since 2016: C. Richard Boland: Ambry Genetics.
Gregory Idos: Myriad Genetics, Inc. Carol Burke: Salix Pharmaceuticals, Ferring
Pharmaceuticals, Aries Pharmaceuticals, Pfizer, Cancer Prevention Pharma-
ceuticals, Janssen Pharmaceuticals, SLA Pharma AG, and Freenome Holdings,
Inc. Samir Gupta: Freenome Holdings, Inc, Guardant Health, Inc, CellMax, Inc,
www.giejournal.org
Gastrointestinal hamartomatous polyposis syndromes
and Mallinckrodt Pharmaceuticals. Brian C. Jacobson: Motus, GI, Dark
Canyon LLC, and Remedy Partners. Aasma Shaukat: Iterative Scopes, Free-
nome Holdings Inc. Swati G. Patel: Olympus America, Freenome Holdings
Inc, ERBE USA. Sapna Syngal: Myriad Genetics, Inc, DC Health, Inc, and Glaxo-
Smith Kline, Inc. Douglas Robertson: Covidien, Freenome Holdings, Inc, and
Amadix. The remaining authors disclose no conflicts.
This article is being published jointly in Gastrointestinal Endoscopy, Gastro-
enterology, and The American Journal of Gastroenterology. The article is
identical except for minor stylistic and spelling differences in keeping
with each journal’s style. Citations from any of the 3 journals can be
used when citing this article.
*Authors share co-first authorship.
Copyright ª 2022 by the American Society for Gastrointestinal Endoscopy,
the American Gastroenterological Association, and the American College of
Gastroenterology
0016-5107/$36.00
https://doi.org/10.1016/j.gie.2022.02.044
Current affiliations: Division of Gastroenterology, University of California-
San Diego School of Medicine, San Diego, California (1), Divisions of
Gastroenterology and Clinical Cancer Genomics, Center for Precision Med-
icine, City of Hope National Medical Center, Duarte, California (2), The Zane
Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontar-
io, Canada (3), Division of Gastroenterology, Hepatology and Nutrition,
Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
(4), Division of Gastroenterology, Department of Medicine, The Johns Hop-
kins University School of Medicine, Baltimore, Maryland (5), Veterans Af-
fairs Medical Center, White River Junction, Vermont (6), Geisel School of
Medicine at Dartmouth, Hanover, New Hampshire (7), University of Con-
necticut, Farmington, Connecticut (8), Department of Gastroenterology,
Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio (9), Veterans
Affairs Puget Sound Health Care System, Seattle, Washington (10), Univer-
sity of Washington School of Medicine, Seattle, Washington (11), Division
of Gastroenterology and Hepatology, New York University Langone
Health, New York, New York (12), Veterans Affairs Medical Center, San Die-
go, California (13), University of California San Diego, La Jolla, California
(14), Veterans Affairs San Diego Healthcare System, San Diego, California
(15), Division of Gastroenterology, Massachusetts General Hospital, Boston,
Massachusetts (16), University of Colorado School of Medicine, Rocky
Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
(17), Minneapolis Veterans Affairs Health Care System, Minneapolis, Minne-
sota (18), University of Minnesota, Minneapolis, Minnesota (19), Brigham
and Women’s Hospital, Boston Massachusetts (20), Dana-Farber Cancer
Institute, Boston Massachusetts (21), Harvard Medical School, Boston Mas-
sachusetts (22).
Correspondence to: C. Richard Boland, MD, University of California San
Diego, 9444 Medical Center Drive, East Campus Office Building, Room 2-
065, La Jolla, California 92037. E-mail: crboland@health.ucsd.edu.
Volume 95, No. 6 : 2022 GASTROINTESTINAL ENDOSCOPY 1047
 Chinese Journal of Plastic and Reconstructive Surgery 3 (2021) 147–149

Contents lists available at ScienceDirect

Chinese Journal of Plastic and Reconstructive Surgery

journal homepage: www.keaipublishing.com/en/journals/chinese-
journal-of-plastic-and-reconstructive-surgery

A case of labial lentigines in Peutz-Jeghers syndrome treated using a

Q-switched alexandrite laser
Shuai Yang, Hong Xu, Ying Zhang, Changbo Tao, Peisheng Jin *
Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China

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

Keywords: Peutz-Jeghers syndrome (PJS) is a polygenic autosomal dominant disease characterized by multiple gastroin-
Labial lentigines testinal polyps and pigmentation of the mucosa and skin. While there are a few reports regarding successful
Peutz-jeghers syndrome treatment of intestinal polyps in PJS, there is little research regarding treatment of mucocutaneous melanosis.
Q-switched alexandrite laser
This study investigated the many advantages of using a Q-switched alexandrite laser to treat mucocutaneous
Treatment
melanosis. In this case, a 19-year-old male with PJS presented with labial lentigines and received two Q-switched
alexandrite laser treatments in 2018. Subsequently, the efficacy of the treatment was evaluated. The result of the
evaluation was that, after the two laser treatments, the labial lentigines were successfully removed, and there
were no complications.

1. Introduction
Peutz-Jeghers syndrome (PJS) is a polygenic autosomal dominant
disease characterized by multiple gastrointestinal polyps, in addition to
pigmentation of the mucosa and skin.1–5 In patients with PJS, irregularly
pigmented macules of varying sizes and colors can be found on the
vermillion border of the lip, palate, perioral skin, buccal mucosa, and
tongue. Common treatments, such as cryosurgery, surgical excision,
electrodesiccation, dermabrasion, and carbon dioxide or argon laser
ablation, commonly result in incomplete removal of the macules, scar-
ring, or changes in normal pigmentation. Although there are a few re-
ports regarding successful treatment of intestinal polyps in patients with
PJS,6,7 there is little research regarding treatment of the associated
mucocutaneous melanosis.8–10 This study reports a case of labial lenti-
gines in a patient with PJS that was treated using a Q-switched alexan-
drite laser.
2. Case presentation
A 19-year-old male with PJS presented to the plastic surgery outpa-
tient clinic at the Affiliated Hospital of Xuzhou Medical University with
labial lentigines. The disease had been detected in the patient around the
age of 5 years. Several black-pigmented macules begin to appear on the
lips, and the size of the pigmented macules gradually increased, until
eventually they extended over the entire lip (Fig. 1). The patient had not
received prior treatment for labial lentigines. Digital photographs were
taken before each treatment and at each subsequent visit to evaluate
treatment efficacy.
The subject provided informed consent prior to treatment. The
treatment area was identified as the labial lentigines. The face was
cleaned, disinfected with 75% alcohol, and dried. A Q-switched alexan-
drite laser with a 755-nm wavelength and a 50-ns pulse duration setting
was used. All treatments were performed using a 2-mm spot size and
fluence between 4 and 9 J/cm.2 No topical anesthesia was needed before
the operation, although topical antibiotic ointment was applied to the
treated site to prevent possible infection after the operation. The patient
was advised to be vigilant about sun protection, and a follow-up was
performed to evaluate the treatment efficacy and complications.
The labial lentigines immediately disappeared or faded after the first
laser irradiation. Their surfaces became whitish, and grayish patches
were seen at the treated site, accompanied by edema. Crust formed
within 1–2 days and sloughed off after one week. The treatment interval
was 3 months, and the first treatment effect was evaluated prior to the
second treatment (Fig. 2). The second treatment used the same protocol
as the first, and long-term follow-up was conducted after the final
treatment. Fig. 3 shows a photograph taken 1 year after the final treat-
ment. The labial lentigines were removed successfully without recur-
rence, scar formation, or other complications.

* Corresponding author. Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Huai-hai West Road, Xuzhou 221002, Jiangsu, China.
E-mail address: 100000401006@xzhmu.edu.cn (P. Jin).

https://doi.org/10.1016/j.cjprs.2021.09.006
Received 1 September 2021; Accepted 8 September 2021
Available online 20 October 2021
2096-6911/© 2021 China Medical Cosmetology Press Co. Ltd. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access
article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
S. Yang et al. Chinese Journal of Plastic and Reconstructive Surgery 3 (2021) 147–149

Fig. 1. Before treatment, black-pigmented macules extended over the entire lip.

successfully without recurrence, scar formation, or other complications.

In clinical practice, there are also reports of successful cases of applying
Q-switched Nd-YAG laser treatment and Q-switched ruby laser treat-
ment, which provide additional options for the treatment of mucocuta-
neous melanosis in PJS.

4. Conclusion

Our study supports the use of a Q-switched alexandrite laser for safe
and effective treatment of labial lentigines in PJS.

Fig. 2. On follow-up after the first treatment, the patient’s labial lentigines were
Ethics Declarations
reduced in size and lightened in color.
Ethics approval and consent to participate

The need for ethical approval was waived as this is a case report.

Consent for publication

The patient gave written informed consent to publish the data con-
tained within this study.

Competing interest

The authors declare that they have no competing interests.

Authors’ contributions

Yang S: Data curation, Writing-Original draft. Tao C: Investigation. Xu

H: Resources. Zhang Y: Investigation. Jin P: Supervision.

References
Fig. 3. At a follow-up assessment one year after the last treatment, the labial
lentigines were removed successfully without recurrence, scar formation, or
other complications. The patient satisfaction was excellent.
3. Discussion
Pigmentation of mucosa and skin, along with multiple gastrointes-
tinal polyps, is characteristic of PJS. Mucocutaneous melanosis in PJS
seriously affects the physical and mental health of patients,1–5 but its
treatment still perplexes the majority of clinicians. Previous treatments,
such as surgical excision, electrodesiccation, cryosurgery, dermabrasion,
and carbon dioxide or argon laser ablation, commonly result in incom-
plete removal of the polyps, scarring, or changes in normal pigmenta-
tion.6,7,11,12 In this case, we treated labial lentignes with a Q-switched
alexandrite laser and achieved a satisfactory therapeutic outcome.
Long-term follow-up suggests that the labial lentigines were removed
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Editorial Announcement—Electronic Manuscript Submission

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To submit a manuscript, please proceed to the Editorial Manager website at https://www.editorialmanager.com/cjprs. New instructions for authors
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CLINICAL PRACTICE GUIDELINES

Diagnosis and Management of Cancer Risk in the
Gastrointestinal Hamartomatous Polyposis Syndromes:
Recommendations From the US Multi-Society Task Force
on Colorectal Cancer
C. Richard Boland,1,* Gregory E. Idos,2,* Carol Durno,3,4 Francis M. Giardiello,5
Joseph C. Anderson,6,7,8 Carol A. Burke,9 Jason A. Dominitz,10,11 Seth Gross,12
Samir Gupta,13,14,15 Brian C. Jacobson,16 Swati G. Patel,17 Aasma Shaukat,18,19
Sapna Syngal,20,21,22 and Douglas J. Robertson6,7
1
Division of Gastroenterology, University of California-San Diego School of Medicine, San Diego, California; 2Divisions of
Gastroenterology and Clinical Cancer Genomics, Center for Precision Medicine, City of Hope National Medical Center, Duarte,
California; 3The Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; 4Division of
Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;
5
Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland;
6
Veterans Affairs Medical Center, White River Junction, Vermont; 7Geisel School of Medicine at Dartmouth, Hanover, New
Hampshire; 8University of Connecticut, Farmington, Connecticut; 9Department of Gastroenterology, Hepatology and Nutrition,
Cleveland Clinic, Cleveland, Ohio; 10Veterans Affairs Puget Sound Health Care System, Seattle, Washington; 11University of
Washington School of Medicine, Seattle, Washington; 12Division of Gastroenterology and Hepatology, New York University
Langone Health, New York, New York; 13Veterans Affairs Medical Center, San Diego, California; 14University of California San
Diego, La Jolla, California; 15Veterans Affairs San Diego Healthcare System, San Diego, California; 16Division of
Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; 17University of Colorado School of Medicine,
Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado; 18Minneapolis Veterans Affairs Health Care
System, Minneapolis, Minnesota; 19University of Minnesota, Minneapolis, Minnesota; 20Brigham and Women’s Hospital, Boston,
Massachusetts; 21Dana-Farber Cancer Institute, Boston, Massachusetts; and 22Harvard Medical School, Boston, Massachusetts

The gastrointestinal hamartomatous polyposis syndromes are
rare, autosomal dominant disorders associated with an
increased risk of benign and malignant intestinal and extra-
intestinal tumors. They include Peutz-Jeghers syndrome, ju-
venile polyposis syndrome, the PTEN hamartoma tumor
syndrome (including Cowden’s syndrome and Bannayan-Riley-
Ruvalcaba syndrome), and hereditary mixed polyposis syn-
drome. Diagnoses are based on clinical criteria and, in some
cases, confirmed by demonstrating the presence of a germline
pathogenic variant. The best understood hamartomatous pol-
yposis syndrome is Peutz-Jeghers syndrome, caused by germ-
line pathogenic variants in the STK11 gene. The management is
focused on prevention of bleeding and mechanical obstruction
of the small bowel by polyps and surveillance of organs at
gastrointestinal and colonic polyposis, colon cancer, and other
extraintestinal manifestations and cancers. Due to the relative
rarity of the hamartomatous polyposis syndromes, recom-
mendations for management are based on few studies. This U.S
Multi-Society Task Force on Colorectal Cancer consensus
statement summarizes the clinical features, assesses the
*Authors share co-first authorship.
Abbreviations used in this paper: AVM, arteriovenous malformation; BMP,
bone morphogenetic protein; BRRS, Bannayan-Riley-Ruvalcaba syn-
drome; CI, confidence interval; CL, confidence limits; CR, cumulative risk;
CRC, colorectal cancer; CS, Cowden’s syndrome; EGD, esophagogas-
troduodenoscopy; GRADE, Grading of Recommendations Assessment,
Development and Evaluation; HHT, hereditary hemorrhagic telangiectasia;
CLINICAL PRACTICE GUIDELINES

increased risk for cancer. Juvenile polyposis syndrome is
caused by a germline pathogenic variant in either the SMAD4 or
BMPR1A genes, with differing clinical courses. Patients with
SMAD4 pathogenic variants may have massive gastric polypo-
sis, which can result in gastrointestinal bleeding and/or
protein-losing gastropathy. Patients with SMAD4 mutations
usually have the simultaneous occurrence of hereditary hem-
orrhagic telangiectasia (juvenile polyposis syndrome–
hereditary hemorrhagic telangiectasia overlap syndrome)
that can result in epistaxis, gastrointestinal bleeding from
mucocutaneous telangiectasias, and arteriovenous malforma-
tions. Germline pathogenic variants in the PTEN gene cause
overlapping clinical phenotypes (known as the PTEN hamar-
toma tumor syndromes), including Cowden’s syndrome and
related disorders that are associated with an increased risk of
HMPS, hereditary mixed polyposis syndrome; JPS, juvenile polyposis
syndrome; MRE, magnetic resonance enterography; MRI, magnetic
resonance imaging; PHTS, PTEN hamartoma tumor syndrome; PJS,
Peutz-Jeghers syndrome; RR, relative risk; SIR, standardized incidence
ratio; USMSTF, US Multi-Society Task Force on Colorectal Cancer; VCE,
video capsule endoscopy.
This article is being published jointly in Gastroenterology, Gastrointestinal
Endoscopy, and The American Journal of Gastroenterology. The article is
identical except for minor stylistic and spelling differences in keeping with
each journal’s style. Citations from any of the 3 journals can be used when
citing this article.
Most current article
© 2022 by the American Gastroenterological Association,
the American Society for Gastrointestinal Endoscopy, and
the American College of Gastroenterology
0016-5085/$36.00
https://doi.org/10.1053/j.gastro.2022.02.021
 2064 Boland et al
current literature, and provides guidance for diagnosis,
assessment, and management of patients with the hamar-
tomatous polyposis syndromes, with a focus on endoscopic
management.
T he gastrointestinal hamartomatous polyposis syn-
dromes are rare, autosomal dominant disorders
associated with an increased risk of benign and malignant
intestinal and extraintestinal tumors. Nevertheless, there
has been tremendous progress in recent years, both in un-
derstanding the underlying genetics that underpin these
disorders and in elucidating the biology of associated pre-
malignant and malignant conditions. Emerging data in
affected populations focus increasingly on those with
defined cancer susceptibility germline pathogenic variants
leading to less heterogeneity in terms of quantifying cancer
risk.
The US Multi-Society Task Force on Colorectal Cancer
(USMSTF) is a group of colorectal cancer (CRC) content
experts appointed by the American College of Gastroenter-
ology, American Gastroenterological Association, and
American Society for Gastrointestinal Endoscopy, supple-
mented at times by other experts to complement existing
expertise. In this USMSTF Consensus Statement, the
gastrointestinal hamartomatous polyposis syndromes were
chosen because of recent progress in understanding these
diseases. The following entities reviewed are: Peutz-Jeghers
syndrome (PJS), juvenile polyposis syndrome (JPS), PTEN
hamartoma tumor syndrome (PHTS, including Cowden’s
syndrome [CS] and Bannayan-Riley-Ruvalcaba syndrome
[BRRS]), and hereditary mixed polyposis syndrome (HMPS).
Germline alterations are known to cause each of these dis-
orders, but the diagnosis can also be made on the basis of
clinical criteria.
Although there are essentially no long-term prospective
controlled studies of comparative effectiveness of manage-
ment strategies for these syndromes, there have been
consensus statements by expert panels that made manage-
ment recommendations for these disorders. The goal of this
USMSTF Statement was to review the literature focusing on
the most recent data, synthesize both the data and the sug-
gested approaches to diagnosis and management by other
expert groups, and present the consensus recommendations
of the USMSTF (Table 1). Review of summary tables, con-
ference calls, and revisions of iterative drafts, including
CLINICAL PRACTICE GUIDELINES
recommendation statements, were used to reach consensus,
at which time documents were forwarded to Governing
Boards for approval. As our USMSTF is a group of individuals
with expertise in gastroenterology and gastrointestinal ma-
lignancies, we have reserved our management recommen-
dations to these areas and defer to other expert groups’
recommendations for other cancers (which are reviewed
here). This document therefore recommends clinical ap-
proaches to diagnosing and managing these conditions that
affect children and adults, focuses on cancer risk, and pro-
vides insights into future research opportunities.
Gastroenterology Vol. 162, No. 7
Methods
A computer-aided PubMed search was performed from 2000
to 2018, with additional back searches as required, and consisted
of the following search terms: hamartoma, hamartomatous polyp,
hamartoma syndrome, Peutz-Jeghers syndrome, juvenile polyp,
juvenile polyposis, Cowden’s syndrome, Cowden’s disease, PTEN-
hamartoma, Bannayan-Riley-Ruvalcaba syndrome, hyperplastic
polyposis, serrated polyposis, and hereditary mixed polyposis
syndrome. Only English-language articles were reviewed. Pub-
lished articles were selected on the basis of relevance to the
diagnosis or clinical management of these diseases. Emphasis
was placed on the risk for gastrointestinal cancer in these dis-
orders to gain consensus on rational and reasonable strategies
for management once these diseases are diagnosed in a family.
The document was approved by the governing boards of each of
the sponsoring gastroenterology societies.
The USMSTF approach to an adapted use of Grading of
Recommendations Assessment, Development and Evaluation
(GRADE) has been described previously.1 In brief, the GRADE
process categorizes the quality of the evidence as high, mod-
erate, low, or very low on the basis of the strength of under-
lying studies, and that categorization can be adjusted on the
basis of study limitations. For example, randomized trials begin
as high-quality evidence and observational studies as low-
quality evidence, but their quality may be adjusted up or
down on the basis of specific study factors. Although the
GRADE process entails a formal meta-analysis to assess the
quality of evidence for each recommendation, the USMSTF
employs a modified, qualitative approach for this assessment.
The GRADE process separates evaluation of the quality of the
evidence to support a recommendation from the strength of
that recommendation. This is done in recognition of the fact
that, although the quality of the evidence can influence the
strength of the recommendation, other factors can influence a
recommendation, such as adverse effects, patient preferences,
values, and cost. Generally, strong recommendations mean that
most informed patients would choose the recommended man-
agement. Weak recommendations mean that patients’ choices
will vary according to their values and preferences, and clini-
cians should ensure that patient care is in keeping with their
values and preferences. When the quality of the evidence to
support a recommendation is low or very low, or if there is a
close balance between desirable and undesirable consequences,
then usually only a weak recommendation would be warranted.
Weaker recommendations are indicated by phrases such as “we
suggest,” and stronger recommendations are typically stated as
“we recommend.”
However, the relative infrequency of, and absence of
controlled prospective trials of the interventions (eg, to prevent
cancer) in, these syndromes leave all of the recommendations
without a robust basis of underlying evidence. Thus, all of the
interventional recommendations fall (at best) into the “low
quality of evidence” GRADE category, indicating that the true
effect of the interventions may be markedly different than
estimated at this time, and that further research is likely to
impact or change our confidence in the effects. As such, this
review is intended to establish a starting point for future
research into the care of patients with the hamartomatous
polyposis syndromes.
June 2022 Gastrointestinal Hamartomatous Polyposis Syndromes 2065

Table 1.Questions and Recommendations of Best Practice

Which individuals with hamartomatous polyps should be referred for genetic evaluation?
We recommend patients with any of the following undergo a genetic evaluation: 2 or more lifetime hamartomatous polyps, a family history of
hamartomatous polyps, or a cancer associated with a hamartomatous polyposis syndrome in first or second-degree relatives. Genetic
testing (if indicated) should be performed using a multigene panel test. (Strong recommendation, low quality of evidence)
Peutz-Jeghers syndrome
Who should undergo a genetic evaluation for Peutz-Jeghers syndrome?
We recommend genetic evaluation for any individual with the following: 1) 2 or more histologically confirmed Peutz-Jeghers polyps, 2) any
number of Peutz-Jeghers polyps in an individual who has a family history of Peutz-Jeghers syndrome in a first-degree relative, 3)
characteristic mucocutaneous pigmentation in a person with a family history of Peutz-Jeghers syndrome, 4) any number of Peutz-
Jeghers polyps in a person with the characteristic mucocutaneous pigmentation of Peutz-Jeghers syndrome. (Strong
recommendation, low quality of evidence)
Which organs should undergo surveillance when caring for a patient with Peutz-Jeghers syndrome?
Patients with Peutz-Jeghers syndrome are at increased risk for cancer in multiple organs including cancer of the breast, small bowel,
colon, stomach, pancreas, ovaries, testes, and lungs.
Given this risk, we recommend a multidisciplinary approach to cancer surveillance in these organs (Strong recommendation, low
quality of evidence)
How and when should small bowel surveillance be performed in Peutz-Jeghers syndrome?
We recommend that baseline small bowel surveillance using video capsule endoscopy or magnetic resonance enterography be performed
between ages 8-10 years or earlier if the patient is symptomatic. If no polyps are found at the initial examination, surveillance should
resume at age 18. Because of the risk of small bowel intussusception, small bowel surveillance in adulthood is recommended to
continue throughout life every 2-3 years. (Strong recommendation, low quality of evidence)
What is the recommended approach to endoscopic surveillance of the colon, stomach, and duodenum in Peutz-Jeghers syndrome?
We suggest a baseline upper gastrointestinal endoscopy between the ages of 8 and 10 years, which could be performed at the time of
capsule placement for small bowel surveillance or if polyps are identified on magnetic resonance enterography. Although the initiation
age for colonoscopy remains uncertain, we also suggest initiation of colonoscopy at same time as esophagogastroduodenoscopy. In
those in whom characteristic polyps are detected, both colonoscopy and esophagogastroduodenoscopy should be repeated every 2–
3 years. In those in whom there are no Peutz-Jeghers polyps at baseline, surveillance is repeated at age 18 years, or sooner should
symptoms arise, and then every 3 years. (Weak recommendation, very low quality of evidence)
What size polyps found on small bowel imaging in Peutz-Jeghers syndrome should be removed?
We recommend polypectomy of small bowel polyps that are symptomatic or
10 mm to prevent intussusception and other complications,
such as bleeding.(Strong recommendation, low quality of evidence)
What is the recommended pancreatic cancer surveillance in Peutz-Jeghers syndrome?
We suggest annual pancreatic cancer surveillance with either magnetic resonance cholangiopancreatography or endoscopic ultrasound
starting at age 35 years. (Weak recommendation, low quality of evidence)
Juvenile Polyposis Syndrome
Who should undergo a genetic evaluation for juvenile polyposis syndrome?
We recommend genetic evaluation for any individual with 1) 5 or more juvenile polyps of the colon or rectum; or 2) 2 or more juvenile
polyps in other parts of the gastrointestinal tract; or (3) any number of juvenile polyps and 1 or more first-degree relatives with juvenile
polyposis syndrome. (Strong recommendation, low quality of evidence)
Which organs should undergo surveillance when caring for a patient with juvenile polyposis syndrome?
Juvenile polyposis syndrome patients are at increased risk for cancer in multiple organs including cancer of the colon and stomach.
Given this risk, we recommend patients with juvenile polyposis syndrome undergo surveillance of the colon and stomach. (Strong
recommendation, low quality of evidence)
At what age should colonoscopic and upper endoscopic surveillance begin in individuals identified with juvenile polyposis syndrome?
We suggest initiating colonoscopic and upper endoscopic surveillance at age 12–15 years, or earlier if symptomatic. Surveillance should
be repeated every 1–3 years depending on polyp burden. (Weak recommendation, low quality of evidence)
Which patients with juvenile polyposis syndrome should undergo screening for hereditary hemorrhagic telangiectasia?
We suggest patients with SMAD4 pathogenic variants be clinically evaluated for HHT at the time of the diagnosis, including screening for
and appropriate management of cerebral and pulmonary AVMs. (Weak recommendation, low quality of evidence)
CLINICAL PRACTICE GUIDELINES

PTEN hamartoma tumor syndrome

Which gastrointestinal findings should prompt a genetic evaluation for PTEN hamartoma tumor syndrome?
We recommend individuals with multiple gastrointestinal hamartomas or ganglioneuromas undergo genetic evaluation for Cowden’s
syndrome and related conditions. (Strong recommendation, low quality of evidence)
Which organs should undergo surveillance for cancer when caring for a patient with PTEN hamartoma tumor syndrome?
In PTEN hamartoma tumor syndrome, patients are at increased risk for cancer in multiple organs, including cancer of the breast, thyroid,
kidney, uterus, colon, and skin.
Given this risk, we recommend a multi-disciplinary approach to cancer surveillance in these organs. (Strong recommendation, low
quality of evidence)
What is the recommended colonoscopic surveillance in individuals identified with PTEN hamartoma tumor syndrome?
We suggest colonoscopy surveillance to begin at age 35 years (or 10 years younger than age of any relative with colorectal cancer),
repeated at intervals no greater than 5 years, depending on polyp burden. (Weak recommendation, low quality of evidence)

NOTE. Specific circumstances may merit modification of the recommendations. In cases where very-early-onset cancers
develop, the above statements may be modified to start surveillance 10 years earlier than the youngest cancer diagnosis in the
family.
 2066 Boland et al
Cancer Family History Assessment and
Referral for Genetic Testing in
Gastroenterology Practice
Question: Which individuals with hamartomatous polyps
should be referred for genetic evaluation?
Recommendation: We recommend patients with any of
the following undergo a genetic evaluation: 2 or more
lifetime hamartomatous polyps, a family history of
hamartomatous polyps, or a cancer associated with a
hamartomatous polyposis syndrome in first- or second-
degree relatives. Genetic testing (if indicated) should be
performed using a multigene panel test. (Strong
recommendation, low quality of evidence)
Hereditary cancer syndromes account for approximately
5%–10% of new cancer diagnoses and many of the cancers
that arise in families with undiagnosed hereditary cancer
syndromes are preventable. The identification of individuals
with a hereditary gastrointestinal cancer syndrome requires
a thorough evaluation of the patient’s personal and family
history of cancer. The collection and assessment of family
cancer history is a valuable tool for cancer interception and
prevention and can be critical in the identification of genetic
susceptibility. An accurate family history is one that collects
the following information: 1) type of cancer, 2) age at
diagnosis of each primary cancer, 3) lineage (maternal or
paternal), 4) ethnicity (people of some ethnicities, such as
those with Ashkenazi Jewish ancestry, are at greater risk for
certain cancers), and 5) results of any previous cancer-
related genetic testing.2
Features of a patient’s personal history and clinical
characteristics may suggest an inherited susceptibility to
cancer. Although it is not rare to identify individuals with an
isolated hamartomatous polyp (particularly an isolated ju-
venile polyp), other features may prompt further evaluation
for an underlying hereditary syndrome. Features associated
with the hamartomatous polyposis syndromes are outlined
in detail in this document and include early age at cancer
onset, multiple cancers in close relatives, unusual numbers
of hamartomatous polyps, or associated dermatologic find-
ings. Genetic evaluation may include genetic counseling
and/or genetic testing.
Genetic counseling is a key component to hereditary
cancer risk assessment. The purpose of genetic counseling is
CLINICAL PRACTICE GUIDELINES
to educate individuals about the genetic and biologic factors
that are related to a patient’s cancer diagnosis or risk of
disease. Counseling helps an individual understand the
relevant genetic, medical, and psychosocial information to
make informed decisions about their health care. This in-
cludes reviewing and expanding the following: family his-
tory information, elements of genetic testing, tailored cancer
risks associated with a pathogenic variant, impact on med-
ical management, reproductive issues and options, confi-
dentiality of results, risks with genetic discrimination,
potential significance of test results for other family mem-
bers, and other pertinent topics. Practice guidelines from
Gastroenterology Vol. 162, No. 7
the American College of Medical Genetics and Genomics and
National Society of Genetic Counselors are available for
details regarding the elements and process of genetic
counseling.3 Although traditional models of genetic evalua-
tion and testing included a certified genetic counselor,
alternative models exist and are emerging that include
provisions for pretest counseling to be provided by physi-
cians and other health care providers in order to deal with
the increasing demand for genetic testing. If a patient is
found to be a carrier of a germline pathogenic variant, or the
results are ambiguous due to the finding of a variant of
uncertain significance, the help of a genetics provider for
post-test counseling and education is recommended. In the
current era, the vast majority of genetic testing for inherited
cancer risk predisposition is performed using a multigene
panel testing approach.4 Some patients or families may elect
to decline genetic testing due to concerns about risk to
confidentiality and insurance; in these cases, surveillance
may still be indicated in the presence of a concerning clin-
ical and/or family history.
If a germline pathogenic variant is identified, other
family members should be offered testing for clarification of
their own risk. This testing may facilitate initiation of
screening for associated cancers before symptomatic man-
ifestations occur and reduce the morbidity and mortality
associated with the syndrome. For example, early small
bowel surveillance may find a polyp that could be removed
from a child with a pathogenic variant in STK11 before
leading to intussusception. It is important to recognize that
genetic testing may not identify pathogenic variants in every
family suspected of a hereditary syndrome. However, there
may be clinical features in the family history that suggest a
familial predisposition to cancer and suggest more intensive
surveillance recommendations. Referral to Centers of
Excellence might be particularly helpful when genetic
testing results are ambiguous in the setting of suspicious
features and prophylactic surgery is being considered.
Lastly, in the era of multigene panel testing, there may be a
scenario in which a germline variant is found incidentally
associated with an unsuspected syndrome. In these cases,
patients may be eligible for cancer screening and surveil-
lance as outlined. However, phenotype and cancer risk
compared with patients with classic familial features are not
established and are areas of active research. Enlisting the
assistance of a genetic specialist may be particularly helpful
in interpreting ambiguous results and providing manage-
ment recommendations in these cases.
When children are identified with a hamartomatous
polyposis syndrome, their transition of care to adulthood for
cancer surveillance is a unique aspect that bears consider-
ation. It is imperative to transition adolescents with life-long
medical conditions from child-centered to adult-centered
care. Preparation for this transition takes place throughout
childhood and adolescence to achieve independent health
management in adulthood. Steps required are individualized
based on the developmental needs of the patient. Inherited
conditions involve generational factors, as multiple family
members may be affected. Health care providers can assist
June 2022
in the transition of care by coordinating screening and
surveillance to ensure patients receive recommended care.5
Gastrointestinal Hamartomatous
Polyposis Syndromes
The hamartomatous polyposis syndromes are rare en-
tities with an estimated prevalence of 1/100,000–
200,000,6,7 but this has not been measured directly in any
population. The term hamartoma implies a non-neoplastic
tumor with a markedly distorted architecture composed of
an abnormal mixture of cells and tissue normally present in
that particular area. The diagnosis is based on the presence
of a pathogenic germline variant or meeting clinical criteria
for the syndrome. The hamartomatous polyposis syndromes
are distinct from Lynch syndrome and the adenomatous
polyposis syndromes, based on the presence of hamartomas
(Figures 1 and 2). Certain hamartomatous polyps of the gut
have a unique histopathological appearance, such as those
associated with PJS, PHTS, JPS, and HMPS.8 Hamartomas are
not typically characterized by dysplasia, but some evidence
suggests the existence of a hamartoma–carcinoma pathway
in some of these polyps.
Peutz-Jeghers Syndrome
Question: Who should undergo a genetic evaluation for
Peutz-Jeghers syndrome?
Recommendation: We recommend genetic evaluation
for any individual with the following: 1) 2 or more
histologically confirmed Peutz-Jeghers polyps, 2) any
number of Peutz-Jeghers polyps in an individual who
has a family history of Peutz-Jeghers syndrome in a
first-degree relative, 3) characteristic mucocutaneous
pigmentation in a person with a family history of Peutz-
Jeghers syndrome, and 4) any number of Peutz-Jeghers
polyps in a person with the characteristic
mucocutaneous pigmentation of Peutz-Jeghers
syndrome. (Strong recommendation, low quality of
evidence)
Clinical Features
PJS was the first hamartomatous polyposis syndrome
described, by Peutz in Holland in 1921 and by Jeghers,
McKusick, and Katz in the United States in 1949.9 The
clinical recognition of PJS was facilitated by the character-
istic mucocutaneous freckling around the mouth and mul-
tiple cerebriform-appearing polyps due to smooth muscle
bands coursing through the polyp (Figures 1A and 2A–C,
and Table 2). Hamartomatous polyps vary in size and may
have a characteristic histologic structure, which makes it
possible to distinguish the PJ polyp. PJ polyps are typically
composed of branching bands of smooth muscle covered by
hyperplastic glandular mucosa.10 PJS polyps may develop in
the stomach, small intestine, and colon. Rectal bleeding with
Gastrointestinal Hamartomatous Polyposis Syndromes 2067
anemia is the most common presentation, followed by
abdominal pain, diarrhea, and intussusception. The clinical
management in early life is initially focused on preventing
complications of small bowel polyposis–related obstruction
and bleeding and, in adulthood, the focus is primarily on
management of cancer risk.
Diagnosis
The diagnostic clinical features of PJS include the pres-
ence of 2 or more histologically confirmed PJ polyps; any
number of PJ polyps in an individual who has a family his-
tory of PJS in a first-degree relative; characteristic muco-
cutaneous pigmentation in a person with a family history of
PJS; or any number of PJ polyps in a person with the
characteristic mucocutaneous pigmentation of PJS.11
Genetics
In 1997, a genetic locus for PJS was mapped to chro-
mosome 19p13.3,12 which in 1998 led to the cloning of the
STK11 (serine/threonine kinase) gene, which encodes the
LKB1 (liver kinase B1) protein, and linkage to PJS.13 STK11
functions like a tumor suppressor gene, regulates cell
growth via adenosine monophosphate–activated protein
kinase,14 and negatively regulates mTOR signaling.15
PJS is inherited in an autosomal dominant fashion with
an inactivating germline pathogenic variant inherited from
the affected parent. It was initially assumed that the polyps
occurred after the loss of the second, wild-type, allele
inherited from the unaffected parent in a somatic tissue
according to the classic “two-hit” model of Knudson.16
However, loss of the wild-type allele (ie, the second hit) is
not an obligatory feature of PJ polyps.17 Moreover, recent
data in mice indicate that the presence of a single inacti-
vating germline pathogenic variant (ie, haploinsufficiency),
as occurs in individuals with PJS, promotes the development
of gastrointestinal polyposis, and that loss of the wild-type
allele is not necessary for the formation of the polyps in
these mice. Furthermore, conditional knockout of the STK11
gene targeted to gastrointestinal smooth muscle cells yields
the same polyposis phenotype in mice.18 Evidence suggests
that LKB1 deficiency in either T cells19 or mesenchymal
cells18,19 leads to immune cell proliferation in the stroma.
Stromal deficiency of LKB1 leads to tumor formation (in
mice) via the interleukin-11–JAK/STAT3 (Janus kinase/
signal transducer and activator of transcription 3) pathway,
CLINICAL PRACTICE GUIDELINES
and administration of the JAK1/2 inhibitor ruxolitinib
dramatically reduces polyposis in mice.20 The phenomenon
of stromal-driven epithelial polyp development may be
referred to as a “landscaper” genetic effect.21 These dis-
coveries raise the possibility of the development of novel
preventive pharmacological interventions for patients.
Genotype–phenotype relationships reveal that missense
alterations in STK11 are associated with later onset of
symptoms than other sequence variations.11,22 Some of the
germline pathogenic variants in STK11 are Alu-mediated
deletions and inversions.23 Deletions and inversions are
 2068 Boland et al Gastroenterology Vol. 162, No. 7
CLINICAL PRACTICE GUIDELINES

Figure 1. Histologic characteristics of polyps. hamartomatous polyps. Images courtesy of Drs Aaron Pollett and Thomas
Plesec. (A) Peutz-Jeghers polyp: pathognomonic broad bands of mucosal smooth muscle seen throughout the lesion. (B)
Juvenile polyp: characteristic chronic inflammatory infiltrate and cystic dilatation. (C) Adenomatous polyp: characteristic
hypercellularity with glandular crowding, enlarged nuclei, increased mitotic activity and reduced goblet cells. By definition, all
tubular adenomas show epithelial dysplasia. (D) Ganglioneuroma: benign neuroectodermal tumor composed of ganglion and
Schwann cells.

likely to completely inactivate a gene, whereas a missense genetic diagnostic platforms must include strategies to
pathogenic variant may have an intermediate effect on detect these types of germline variations; at least some of
protein function. Approximately 15% of STK11 pathogenic the “missing” germline pathogenic variants may involve
variants in PJS involve large genetic deletions.24 Therefore, obscure rearrangements of the STK11 gene.
June 2022 Gastrointestinal Hamartomatous Polyposis Syndromes 2069

CLINICAL PRACTICE GUIDELINES

Figure 2. Endoscopic images of hamartomatous polyposis syndromes. Endoscopic photos provided courtesy of Swati Patel,
MD, Gregory Idos, MD, and Carol Burke, MD. (A) Peutz-Jeghers small bowel polyps. (B) Peutz-Jeghers gastric polyps. (C)
Peutz-Jeghers colon polyps. (D) Juvenile polyposis gastric polyps. (E) Juvenile polyposis colon polyp. (F) Cowden syndrome
associated–esophageal glycogenic acanthosis. (G) Cowden syndrome small bowel polyps. (H) Cowden syndrome colon
polyps. (I) Cowden syndrome gastric polyps.
 2070 Boland et al Gastroenterology Vol. 162, No. 7

Table 2.Clinical Features of Gastrointestinal Hamartomatous Polyposis Syndromes

“Commercially available
Syndrome gene testing” Polyps Clinical features

PJS STK11 Peutz-Jeghers polyps Childhood: Labial pigmentation; gastrointestinal

(pathologically
characteristic)
JPS SMAD4 or BMPR1A Juvenile (inflammatory)
polyps; juvenile polyps and
inflammatory polyps are
pathologically indistinct
CS PTEN (inactivation) Hyperplastic polyps; juvenile-
WWP1 (gain-of-function) like polyps;
ganglioneuromas; lipomas;
hamartomas;adenomas
BRRS PTEN Same as for CS
HMPS GREM1 (duplication Pathologically mixed with
upstream of promoter) features of adenoma,
hyperplastic polyps,
inflammatory polyps
bleeding and intussusception
Adults: Increased risk for multiple cancers
Childhood: Gastrointestinal bleeding, auto-
amputation of polyps; anemia
Adults: CRC and gastric cancer
Childhood: none
Adults: multiple cancer risks
Developmental delay, hemangiomas, lipomas,
gastrointestinal polyps
Increased risk of colonic polyposis and CRC

Cancer Risk
Question: Which organs should undergo surveillance
when caring for a patient with Peutz-Jeghers syndrome?
Recommendation: Patients with Peutz-Jeghers
syndrome are at increased risk for cancer in multiple
organs, including cancer of the breast, small bowel,
colon, stomach, pancreas, ovaries, testes, and lungs.
Given this risk, we recommend a multidisciplinary
approach to cancer surveillance in these organs. (Strong
recommendation, low quality of evidence)
Very high lifetime risks of cancer occur in multiple or-
gans in patients with PJS, inside and outside the gut. Intra-
tubular large-cell hyalinizing Sertoli cell neoplasms, ovarian
sex cord tumors, and adenoma malignum of the uterine
cervix, although not common, are linked to PJS25 (Table 3).
The lifetime risk of colon, stomach, and small bowel
cancer has been estimated at 12%–39%, 29%, and 13%
respectively6,26–28 (Table 3). Most CRCs occur after the mid-
CLINICAL PRACTICE GUIDELINES
age-adjusted cancer risks were noted for the small intestine
(RR, 520; 95% CL, 220 and 1306; cumulative risk [CR],
13%), stomach (RR, 213; 95% CL, 96 and 368; CR, 29%),
pancreas (RR, 132; 95% CL, 44 and 261; CR, 36%), colon
(RR, 84; 95% CL, 47 and 137; CR, 39%), esophagus (RR, 57;
95% CL, 2.5 and 557; CR, 0.5%), ovary (RR, 27; 95% CL, 7.3
and 68; CR, 21%), lung (RR, 17.0; 95% CL, 5.4 and 39; CR,
15%), uterus (RR, 16.0; 95% CL, 1.9 and 56; CR, 9%), testes
(RR, 4.5; 95% CL, 0.12 and 25; CR, 9%), and breast (RR,
15.2; 95% CL, 7.6 and 27; CR, 54%).26 Mean age at the time
of cancer diagnosis was 42.9 years. The absolute risk of
developing any cancer between the ages of 15 and 64 was
estimated to be 93%.
The risk of cancer in PJS was revisited in 2 follow-up
studies that included some who were members of the
original cohort.28,30 The lattermost report included some of
the original 210 cases and expanded to 419 cases, in which
297 had confirmed germline pathogenic variants in
STK11.28 The cumulative incidences of cancer by decade
from age 20 to 70 years were 2%, 5%, 17%, 31%, 60%, and
85% respectively, confirming the initial estimates and tu-

20s (range, 27–71 years, median age 46 years), but these
malignancies have been reported in teenage years as well.26
Mean age at diagnosis of gastric adenocarcinoma ranges
between 30 and 40 years and of small intestinal cancer
between 37 and 42 years.26,27,29
In a meta-analysis of 210 cases reported in 6 publica-
tions (retrospective cohort studies with kindred-based
ascertainment from the United States, United Kingdom,
and The Netherlands) on PJS that were based on clinical and
histologic criteria with varying types of ascertainment, the
relative risk (RR) for any cancer was 15.2 (95% confidence
limits [CL], 2 and 19) compared with a variety of time
period–specific US-based registries. Significantly increased
mor spectrum—predominantly the gastrointestinal tract
and breast. Cancer risks were the same in those with a
clinical diagnosis but no detectable germline pathogenic
variant in the STK11 gene.
Several collaborative studies from Europe and the United
States again found similar risks for cancer.29,31 A systematic
review of 20 cohort studies looking at 1644 patients with PJS
confirmed at least 1 cancer in >90% of patients with PJS at a
mean age of 42 years.29 CRC was the most commonly diag-
nosed tumor, followed by cancers of the breast, small intes-
tine, stomach, lung, pancreas, cervix, ovary, bile ducts, and
testicles. A multicenter study from Italy of 119 STK11 path-
ogenic variant carriers reported an overall RR for cancer of
June 2022 Gastrointestinal Hamartomatous Polyposis Syndromes 2071

Table 3.Risk of Cancer in Hamartomatous Polyposis Syndromes

Site General population risk,a % Syndrome risk, % Mean age at diagnosis, y Reference

PJS
Colorectal 4.3 39 42–46 26, 29
Stomach <1 29 30–40 26, 29
Small bowel <1 13 37–42 26, 29
Breast 12.9 32–54 37–59 26, 28, 29
Ovarian (mostly SCTAT) 1.2 21 28 26
Cervix (adenoma malignum) <1 10–23 34–40 26
Uterus 3.1 9 43 26, 29
Pancreas 1.7 11–36 41–52 26, 28, 29, 32
Testicular (Sertoli cell tumor) <1 9 6-9 26, 29
Lung 6.3 7–17 47 26, 28, 29
JPS
Colon 4.3 39 44 86
Stomach <1 5–21 54 65, 67, 89
CS
Breast 12.9 25–85 38–46 100, 101, 102
Thyroid 1.3 3–38 31–38 100, 101, 102
Uterus 3.1 5–28 25 95, 100, 101, 102
Kidney (renal cell) 1.7 15–34 40 97, 100, 104
Colon 4.3 9–18 35 100–103, 106
Melanoma 2.3 6 3b 100, 101
HMPS
Colon 4.3 Increased — 119–121

SCTAT, sex cord tumors with annular tubules.

a
National Cancer Institute. Surveillance, Epidemiology, and End Results Cancer Statistics Review 1975–2017. Lifetime risk (%)
of being diagnosed with cancer by site, 2017.
b
Youngest age of onset.

22.0 in women (in part because of additional risks for cer-
vical cancers) and 8.6 in men, compared with an Italian-based
general population registry, and a cumulative risk of cancer
reaching 89% by age 65 years.27 A more recent study from
China confirmed elevated cancer risks (albeit somewhat
lower than the American and European data), early age of
onset, and a similar tumor spectrum.32
Surveillance of Affected Individuals
The effectiveness of cancer surveillance in PJS has not
been evaluated in controlled studies. Consequently, sur-
veillance recommendations have been developed by
consensus groups and expert opinion analyzing cancer risks
and published organ-specific surveillance protocols
Gastrointestinal Polyposis and Cancer
Gastric, small bowel, and colorectal polyposis occur in
88%–100% of patients, with the majority appearing in the
small bowel (60%–90%) and colon (50%–64%).36 Polyps
can vary in number (1–100) and size (0.1–3 cm in diameter)
and age of onset of symptoms may vary. Polyp growth be-
gins in childhood by age 10 years (33%), with most expe-
riencing symptoms such as bleeding, abdominal pain,
intussusception, or obstruction (68%) by age 18 years.37 In
affected or at-risk individuals, early surveillance with
esophagogastroduodenoscopy (EGD), colonoscopy, and
small bowel imaging with video capsule endoscopy (VCE)
and/or magnetic resonance enterography (MRE) is recom-
mended to begin at age 8 years.11,33–35
CLINICAL PRACTICE GUIDELINES

(Tables 3 and 4).11,33–35 Intussusception is rare in children younger than 5 years,

Question: How and when should small bowel surveillance
be performed in Peutz-Jeghers syndrome?
Recommendation: We recommend that baseline small
bowel surveillance using video capsule endoscopy or
magnetic resonance enterography be performed
between ages 8 and 10 years or earlier if the patient is
symptomatic. If no polyps are found at the initial
examination, surveillance should resume at age 18
years. Because of the risk of small bowel
intussusception, small bowel surveillance in adulthood is
recommended to continue throughout life every 2–3
years. (Strong recommendation, low quality of evidence)
and the precise risk of intussusception between 5 and 18
years of age is unknown. Retrospective registry data report
that 23 of 34 adults with PJS (68%) had undergone lapa-
rotomy by the age of 18 years, 70% of which were per-
formed as an emergency. By the age of 10 years, 30% had
required a laparotomy.37 In a single-institution study of 379
pediatric patients who underwent pneumatic reduction for
intussusception (from all causes), one-quarter required
operative management.38 There is a paucity of studies that
assess modalities to evaluate the small bowel in patients
with PJS. Retrospective data comparing VCE to small bowel
barium studies have reported VCE as a useful diagnostic tool
 CLINICAL PRACTICE GUIDELINES

2072 Boland et al
Table 4.Surveillance Guidelines in Hamartomatous Polyposis Syndromes

ACG 2015 NCCN 2020 ESPGHAN 2019 USMSTF 2020

Age of Age of Age of Age of Evidence

Examination initiation, y Interval, y initiation, y Interval, y initiation, y Interval, y initiation, y Interval, y grade

JPS
Colonoscopy 12–15 1–3 15 2–3 12–15 — 12–15 1–3 Low
Upper endoscopy 12–15 1–3 15 2–3 Late teensa — 12–15 1–3 Low
Screen for vascular lesions 6 mo — 6 mo — At diagnosis — 6 mob — —
PJS
Colonoscopy 8, 18c 3 Late teens 2–3 8 3 8–10, 18c 2–3 Very low
Upper endoscopy 8, 18 c 3 Late teens 2–3 8 3 8–10, 18c 2–3 Very low
VCE 8, 18 c 3 w8–10d 2–3 8 3 8, 18c 2–3 Low
CT or MRE of small bowel — — w8–10d 2–3 — — — — —
MRI/MRCP or EUS of pancreas 30 1–2 w30–35e 1–2 — — 35 1 Low
MRI and/or mammogram 25 1 w25 1 — — — — —
Physical examination Birth to teenage 1 w10 1 — — — — —
Pelvic examination and Pap smear 25f 1 w18–20 1 — — — — —
Testicular examination Birth to teenage 1 w10 1 — — — — —
PHTS
Colonoscopy 15 2 35 5 — — 35 5 Low
Upper endoscopy 15 2–3 — — — — — — —
Thyroid examination and US Adolescence 1 7 1 — — — — —
MRI and/or mammogram 30–35 1 30-35 1 — — — — —
Endometrial sampling 30–35 1 — 1–2 — — — — —
Urinalysis or renal US 18 1 40 1–2 — — — — —
Skin examination w18 1 At diagnosis 1 — — — — —

ACG, American College of Gastroenterology; CT, computed tomography; ESPGHN, European Society for Paediatric Gastroenterology Hepatology and Nutrition; EUS,
endoscopic ultrasound; MRCP, magnetic resonance cholangiopancreatography; NCCN, National Comprehensive Cancer Network.
a
Upper gastrointestingal screening in JPS SMAD4 carriers is indicated in asymptomatic patients starting in late teens. For non-SMAD4 JPS patients, upper endoscopic

Gastroenterology Vol. 162, No. 7

screening is only indicated if the patient has relevant symptoms or anemia not explained by colonic polyps.
b
SMAD4 mutation carriers should be clinically evaluated for HHT at the time of the diagnosis, including screening for, and appropriate management of, cerebral and
pulmonary AVMs.
c
First procedure at 8 years of age; if polyps present, repeat every 3 years; if no polyps, restart at 18 years of age and every 3 years.
d
Baseline at age 8–10 years of age with follow-up interval based on findings but at least by age 18 years of age, then every 2–3 years, although this may be individualized by
at least age 18 years, then every 2–3 years, although this may be individualized, or with symptoms).
e
Based on clinical judgment, early initiation age may be considered, such as 10 years younger than the earliest age of onset in the family.
f
ACG 2015 Guidelines recommend transvaginal ultrasound as part of surveillance beginning at age 25 years.
June 2022
in PJS. A retrospective study from France included 27 chil-
dren who underwent at least 1 VCE.39 The authors found
VCE was a useful diagnostic tool, however, findings at VCE
may not predict future bowel obstructions. Although VCE
may not predict future bowel obstructions, it has a greater
sensitivity in detecting small bowel polyps compared with
MRE and provides patients with another alternative if they
are unable to undergo MRE. Ten children with PJS with
polyps >15 mm identified by VCE and MRE underwent
single-balloon enteroscopy.40 In this small study, single-
balloon enteroscopy was effective for treating small bowel
polyps. Further larger, multicenter studies are warranted
to accurately determine the safety of therapeutic single-
balloon enteroscopy in children.7 Based on the pub-
lished data, VCE or MRE is recommended between ages 8
and 10 years in asymptomatic patients. Investigations
should commence earlier if patients have symptoms. If no
polyps are found on the baseline investigation, repeat
small bowel evaluation may commence at age 18 years. If
polyps are found, further investigation and surveillance
should be individualized based on polyp size and location.
Because of the risk of small bowel intussusception, small
bowel surveillance in adulthood continues throughout life
every 2–3 years. If polyps are present in the colon or
stomach, EGD or colonoscopy is continued as necessary
every 2–3 years.
Question: What is the recommended approach to
endoscopic surveillance of the stomach, duodenum, and
colon in Peutz-Jeghers syndrome?
Recommendation: We suggest a baseline upper
gastrointestinal endoscopy between the ages of 8 and
10 years, which could be performed at the time of
capsule placement for small bowel surveillance or if
polyps are identified on magnetic resonance
enterography. Although the initiation age for
colonoscopy remains uncertain, we also suggest
initiation of colonoscopy at the same time as
esophagogastroduodenoscopy. In those in whom
characteristic polyps are detected, both colonoscopy
and esophagogastroduodenoscopy should be repeated
every 2–3 years. In those in whom there are no Peutz-
Jeghers polyps at baseline, surveillance is repeated at
age 18 years, or sooner should symptoms arise, and
then every 3 years. (Weak recommendation, very low
quality of evidence)
Management of Polyposis
Although the malignant potential of PJ polyps is un-
known and the evidence of benefit from gastrointestinal
surveillance is not robust, endoscopic removal of polyps is
recommended to prevent polyp-related complications and
to reduce the risk of cancer. In a study of long-term out-
comes of gastrointestinal procedures from a PJ polyposis
registry, investigators tracked the results of 776 procedures
among 63 patients with PJS at a median age of 20 years
(range, 3–59 years). A total of 2461 polypectomies were
performed; more than 1000 polyps were removed during
colonoscopy and more than 400 polyps were removed
Gastrointestinal Hamartomatous Polyposis Syndromes 2073
during EGD, and the remaining polyps were removed by
means of enteroscopy or laparotomy of the small bowel.41 A
substantial proportion of patients required intervention for
removal of large polyps and the authors concluded that
surveillance reduced polyp burden and likelihood of polyp-
related complications, and provided cancer surveillance.
Therefore, we recommend polypectomy for polyps in the
stomach and colorectum that are >0.5 cm in size on endo-
scopic surveillance and an attempt to remove all polyps if
endoscopically feasible.33,35,42,43
In the small bowel, balloon enteroscopy and MRE have
similar diagnostic yields for lesions
15 mm, but endoscopy
permits polyp removal.43 Consequently, removal, preferably
by enteroscopy, of small intestinal polyps that are symp-
tomatic or rapidly growing, or asymptomatic polyps that are
>1.0–1.5 cm in size, has been recommended.33,35,37,42,44,45
Surgery is often needed when small bowel intussusception
occurs. Some authorities recommend an attempt to clear the
small intestine of polyps during laparotomy by means of
intraoperative endoscopy with polypectomy or, for larger
polyps, by means of enterotomy. This “clean sweep”
approach appears to decrease the need for recurrent small
bowel surgery.46 Thus, the early management focus is on
large hamartomatous polyps and their tendency to obstruct
the gut or bleed. As children grow older and transition into
adulthood, the focus shifts to managing the cancer risk.
Question: What size polyps found on small bowel
imaging in Peutz-Jeghers syndrome should be removed?
Recommendation: We recommend polypectomy of
small bowel polyps that are symptomatic or
10 mm to
prevent intussusception and other complications, such
as bleeding. (Strong recommendation, low quality of
evidence)
Breast Cancer
Invasive ductal adenocarcinoma poses the greatest risk
of early malignancy to patients with PJS (24%–54% lifetime
risk in women) and often presents at a young age (range,
19–61 years in 1 study).26,47 The risk of breast cancer in
women with PJS is within the same range as women affected
by BRCA-1 or BRCA-2 pathogenic variants (40%–85% life-
time risk for breast cancer).26,48 Therefore, consensus
opinion surveillance recommendations by groups that
include breast cancer experts49,50 include monthly breast
CLINICAL PRACTICE GUIDELINES
self-examination starting at age 18 years, biannual clinical
breast examination starting at age 25 years, annual breast
magnetic resonance imaging (MRI) from ages 25–29 years,
and mammography with consideration of tomosynthesis (3-
dimensional mammography) alternating every 6 months
with breast MRI with contrast from ages 30 to 75 years.6,11
The option of prophylactic mastectomy might be discussed
on a case-by-case basis, factoring in family history. In pa-
tients with PJS, referral to a breast cancer specialist for
management of breast cancer surveillance is reasonable,
and a multidisciplinary approach including a breast surgeon
is recommended when prophylactic mastectomy is being
considered.
 2074 Boland et al
Question: What is the recommended pancreatic cancer
surveillance in Peutz-Jeghers syndrome?
Recommendation: We suggest annual pancreatic cancer
surveillance with either magnetic resonance
cholangiopancreatography or endoscopic ultrasound
starting at age 35 years. (Weak recommendation, low
quality of evidence)
Pancreas Cancer
Pancreatic cancer is the third most frequently occurring
malignancy in patients with PJS. The lifetime risk of
pancreatic ductal adenocarcinoma is between 11% and
36%, presenting, on average, at ages 41–52 years, with 95%
of cases occurring after age 24 years.6,26,28,51,52 PJS is
associated with the highest relative risk of all pancreatic
cancer syndromes, with the exception of hereditary
pancreatitis (25%–40% lifetime risk).43 Consequently, a
high-risk pancreatic surveillance protocol is recommended.
The consensus recommendations of the International Can-
cer of the Pancreas Screening Consortium53 recommend
pancreas MRI/magnetic resonance cholangiopancreatog-
raphy and/or endoscopic ultrasound every 1–2 years
starting from age 40 years, for which evidence suggests that
these cancers can be found in earlier stages.54 The National
Comprehensive Cancer Network Guidelines recommend
initiating pancreatic cancer surveillance between the ages of
30 and 35 years. Due to reports of pancreatic cancer di-
agnoses in patients with PJS before the age of 40 years,26 the
USMSTF suggests initiating annual surveillance at age 35
years with MRI/magnetic resonance cholangiopancreatog-
raphy and/or endoscopic ultrasound. Ideally, these exami-
nations would alternate on an annual basis, as they are
complementary. In addition, routine fasting glucose and
hemoglobin A1c at initiation of screening is recommended
by the Cancer of the Pancreas Screening Consortium. At the
current time, the USMSTF awaits definitive data before
making a recommendation regarding fasting glucose and
hemoglobin A1c. Recent updates to the Cancer of the
Pancreas Screening Guidelines detail surveillance protocols
and management recommendations based on imaging and
endoscopic findings.55
Gynecological Cancers
CLINICAL PRACTICE GUIDELINES
The lifetime risks for ovarian, uterine, and cervical can-
cer are estimated at 21%, 9%, and 10%–23%, respectively,
with mean age at presentation of 28–35 years, 43 years, and
34–40 years, respectively.6,26,27 Of note, almost all ovarian
tumors in patients with PJS are sex cord tumors with
annular tubules, and rarely cystadenomas or granulosa cell
tumors. Sex cord tumors with annular tubule neoplasms are
a heterogeneous group of benign or malignant neoplasms,
but the tumors rarely have lymph node metastasis.26 Also,
an unusual percentage of cervical cancers in patients with
PJS are adenoma malignum, a rare, well-differentiated, cer-
vical adenocarcinoma that is associated with a poor prog-
nosis and difficult to diagnose on Pap smear. A high level of
Gastroenterology Vol. 162, No. 7
suspicion is required for diagnosis.56 Recommendations for
gynecological surveillance are pelvic examination with Pap
smear and transvaginal ultrasound annually starting at age
25 years.33,35
Testicles
The estimated risk of testicular cancer in male patients
with PJS is 9%, mean age at diagnosis is 9 years (range, 3–
20 years).6,26,27 These tumors present as testicular masses.
The tumors are Sertoli cell tumors that can cause gyneco-
mastia and other signs of hyperestrogenism and occasion-
ally virilization and/or accelerated height growth.26
Accelerated height velocity can be challenging to detect as
adolescents have “growth spurts” as part of normal matu-
ration and development. Expert opinion recommends
annual history and physical examination (including self-
examination) with observation for feminizing changes and
examination of the testicles6,34,35; based on the range of age
at diagnosis of this tumor, examination should start from
birth. Ultrasound of the testicles every 2 years from birth to
age 12 years has been suggested.44
Lung
The lifetime risk of lung cancer in patients with PJS has
been estimated between 7% and 17%,6,26–28,30 compared
with 0.2%–0.6% in nonsmokers in the general population.57
The cumulative risk of lung cancer in PJS surpasses 5% by
age 55 years.6 Of note, lung cancer risk in patients with PJS
has not been calculated with adjustment for smoking status.
The RRs of lung cancer in patients with PJS compared with
nonsmokers are similar to people with a more than 30 pack-
year history of smoking who have quit for 10–15 years
(hazard ratio, 14.8).58 Currently, the American College of
Chest Physicians, American Society of Clinical Oncology, and
American Cancer Society recommend low-dose computed
tomography annually for individuals with this level of cu-
mulative risk for lung cancer from ages 55 to 74 years.59,60
There are no data to show benefit of lung cancer surveil-
lance in patients with PJS. Lung cancer surveillance with
annual low-dose computed tomography, as performed in
smokers at high risk for lung cancer, may be considered in
patients with PJS. Smoking cessation counseling in patients
with PJS is advisable to mitigate risk.33,34
Chemoprevention
Currently, there are no known chemopreventive agents
in clinical practice that slow or prevent the development of
intestinal polyps and cancers in PJS. Pathogenic variants in
the STK11 gene decrease inhibition of mTOR leading to the
development of intestinal polyps. A trial examining the oral
selective mTOR inhibitor, everolimus, was stopped prema-
turely because of poor patient accrual. Only 2 patients were
enrolled, 1 with pancreatic cancer that progressed and
another patient who withdrew from the protocol because of
severe complications from the medication.61
In a murine model of PJS, treatment with celecoxib, a
COX2 inhibitor, resulted in a >50% reduction in polyp
burden. When used in patients with PJS with diffuse
June 2022
polyposis in the body of the stomach (tens to hundreds), 2
of 6 had a significant reduction in polyp number, as
assessed by 5 independent evaluators, after administering
celecoxib (200 mg twice per day for 6 months).62
Summary
PJS is associated with a very high cumulative lifetime
risk of cancer of multiple organs, including, but not limited
to, the gastrointestinal tract. Intensive surveillance is rec-
ommended to prevent and manage complications of polyp-
osis and identify cancer at an early stage. The development
of polyposis and the cancer risks may be a reflection of the
effects of haploinsufficiency of the LKB1 protein, for which
there are possible medical therapies to be explored. It is
unclear whether the basic mechanisms responsible for
hamartoma formation in younger life are the same as those
that create the risks for cancer later in life. Simulation
models and clinical trials are needed to optimize endoscopic
surveillance frequencies and the use of imaging modalities
in adults. In addition, collaborative multicenter consortia
may help facilitate chemoprevention trials in the future.
Juvenile Polyposis Syndrome
Question: Who should undergo a genetic evaluation for
juvenile polyposis syndrome?
Recommendation: We recommend genetic evaluation
for any individual with 1) 5 or more juvenile polyps of
the colon or rectum; 2) 2 or more juvenile polyps in
other parts of the gastrointestinal tract; or 3) any
number of juvenile polyps and 1 or more first-degree
relatives with juvenile polyposis syndrome. (Strong
recommendation, low quality of evidence)
Clinical Features
JPS is an autosomal dominant inherited condition in
which multiple juvenile polyps are found in the colorectum
(98% of affected patients) (Figure 1B), stomach (14%),
jejunum and ileum (7%), and duodenum (7%).63–65 The
incidence of JPS is between 1 in 100,000 and 1 in 160,000
individuals.65 The polyps in JPS vary in size from small
sessile nodules to pedunculated lesions that are
3 cm in
diameter. Histologically, the typical juvenile polyp has a
distinctive cystic architecture, dilated mucus-filled glands, a
prominent lamina propria, and Paneth cells enmeshed
within a dense infiltration of inflammatory cells. In patients
with germline pathogenic variants in SMAD4, additional
features of gastric polyposis, gastric cancer, and a JPS–
hereditary hemorrhagic telangiectasia (HHT) overlap syn-
drome are common. The management of JPS is based on
decreasing the risk of bleeding and gastric and colorectal
cancer through polypectomy. Patients with JPS-HHT overlap
syndrome should have lifelong HHT surveillance. One study
also demonstrated that as many as 38% may have thoracic
aorta abnormalities.66
Gastrointestinal Hamartomatous Polyposis Syndromes 2075
Juvenile polyps are most often solitary and are not
syndromic, occurring sporadically in infants and children. A
typical history associated with a solitary juvenile polyp is
the asymptomatic passing of a polyp into an infant’s diaper.
Juvenile polyps appear endoscopically to have a smooth red
surface, may be sessile or pedunculated, and pathologically
are characterized by cystic dilatation of mucus-filled glands
suspended in an inflamed stroma (Figures 1B and 2D and
E). These lesions may also be called retention polyps or
inflammatory polyps because of their microscopic
appearance.
Diagnosis
The diagnosis of JPS is made based on clinical criteria or
identification of a germline pathogenic variant in SMAD4 or
BMPR1A. The clinical diagnosis of JPS is made when a per-
son has any 1 of the following: 1) 5 or more juvenile polyps
of the colon or rectum; 2) any number of juvenile polyps in
parts of the gastrointestinal tract other than the colon; or 3)
any number of juvenile polyps and 1 or more first-degree
relatives with JPS.65
Genetics
JPS is an autosomal dominant disorder with approxi-
mately 75% of cases inherited from a parent and 25%
representing de novo pathogenic variants.64 Approximately
60% of patients with JPS have a pathogenic variant in the
BMPR1A or SMAD4 gene.67 Rarely (1 in 1,000,000) in-
dividuals develop features of JPS and PHTS, known as ju-
venile polyposis of infancy, due to a large deletion
encompassing both the BMPR1A and PTEN genes.
In a study from the Cleveland Clinic of 35 patients with
JPS, germline pathogenic variants in SMAD4 and BMPR1A
were associated with similar colonic polyposis phenotypes,
but SMAD4 pathogenic variant carriers were more likely to
have more gastric polyps, and an 11% risk of gastrointes-
tinal cancer.68 However, no gastric cancers were reported in
patients with BMPR1A pathogenic variants in 8 patients
followed for a mean of 11 years.
However, germline pathogenic variants in other genes
may cause a hamartomatous polyp phenotype. In a study of
49 patients referred to the Cleveland Clinic for unexplained
hamartomatous or hyperplastic polyps, germline pathogenic
variants were found in multiple genes, including endoglin
(ENG, a gene associated with HHT), STK11 (the PJS gene),
CLINICAL PRACTICE GUIDELINES
SMAD4, BMPR1A, and PTEN.69 In a later study from this
group of 603 patients with a “moderate load of gastroin-
testinal polyps” with at least 1 confirmed to be a hamartoma
or hyperplastic polyp, 13% were found to have a germline
pathogenic variant in at least 1 of the genes listed above and
20% of the cohort had a personal history of CRC.70
As discussed in the context of PJS, it has been tradi-
tionally thought that a germline pathogenic variant associ-
ated with a hereditary colon cancer syndrome did not
change the biology of the normal tissues and a second (so-
matic) hit was required for a tumor to form. In fact, allelic
loss of the SMAD4 locus was found in the epithelial
component of juvenile polyps of patients with JPS (together
 2076 Boland et al
with a germline pathogenic variant in SMAD4) using in situ
hybridization, but not in the inflammatory or stromal cells.
This was compatible with the Knudson 2-hit model.71
However, another group has reported that SMAD4 hap-
loinsufficiency (ie, a lower dose of the gene product due to
the specific type of germline pathogenic variant) causes the
JPS phenotype in humans, supported by data from mice.72
However, just as in PJS, being haploinsufficient for SMAD4
(ie, just the germline pathogenic variant), is associated with
partially diminished transforming growth factor–b
signaling, at least in mice,72 as this alters proliferation in T
cells, which contributes to the development of polyps and
cancer.73,74 Specific deletion of SMAD4 in mouse T cells
leads to up-regulation of the Th17-inflammatory pathway in
the stroma, and the growth of large polyps in the gastro-
intestinal tracts of mice.73,74 This raises the question of
whether there is abnormal regulation of immune cells in JPS,
and may explain the inflammatory appearance of juvenile
polyps independent of abnormal biology in the epi-
thelium—another landscaper mechanism, as discussed
above for PJS. These observations may have important
clinical implications for future attempts to halt the appear-
ance or growth of the inflammatory polyps. However, allelic
loss (ie, a somatic variants as the second hit) occurs in at
least some polyps of JPS patients.75,76
Juvenile Polyposis Syndrome–Hereditary
Hemorrhagic Telangiectasia Overlap Syndrome
HHT occurs in approximately 15%–81% of patients with
a germline SMAD4 pathogenic variant.77,78 The clinical fea-
tures of HHT, such as epistaxis, obscure gastrointestinal
bleeding, digital clubbing, visceral arteriovenous malfor-
mations (AVMs), and mucocutaneous telangiectasias should
be sought in SMAD4 patients. International guidelines
(outlined below) recommend that surveillance and treat-
ment for HHT complications are necessary for all SMAD4
carriers.79
Juvenile Polyposis of Infancy
Juvenile polyposis of infancy is a severe form of juvenile
polyposis. This disease presents in the first 2 years of life
with diarrhea, abdominal pain, rectal bleeding, refractory
anemia, hypoalbuminemia, and enteropathy. Case reports
indicate that a large deletion in the long arm of chromosome
CLINICAL PRACTICE GUIDELINES
10 (10q23), encompassing the PTEN and BMPR1A genes, is
associated with the development of the disease.69,80–83
Question: Which organs should undergo surveillance
when caring for a patient with juvenile polyposis
syndrome?
Recommendation: Patients with juvenile polyposis
syndrome are at increased risk for cancer in multiple
organs, including cancer of the colon and stomach.
Given this risk, we recommend patients with juvenile
polyposis syndrome undergo surveillance of the colon
and stomach. (Strong recommendation, low quality of
evidence)
Gastroenterology Vol. 162, No. 7
Gastrointestinal Polyposis and Cancer
In a retrospective chart review study of 257 children
with juvenile polyps at a single-referral center, patients
presented at a median age of 5.6 years, and at colonoscopy
39% had multiple polyps.84 Among 192 patients who un-
derwent complete colonoscopy at initial diagnosis, 117
(60.9%) had a single polyp and 75 (39.1%) had multiple
polyps. These lesions recurred in 21 of 47 patients (44.7%)
after an initial eradication, including 3 of 18 presenting with
a single polyp, and neoplasia was found in 3.9% of lesions.
Patients with JPS often have a variable presentation of polyp
distribution, which may occur throughout the colon and/or
stomach and the cancer risk is attributable to the presence
of dysplasia in the polyps. One study of 78 juvenile polyps
from 12 patients with JPS and 34 patients with sporadic
juvenile polyps reported that dysplasia was present in 31%
of the polyps from patients with JPS but in none of the
polyps from patients with sporadic juvenile polyps.85
Dysplasia in polyps from patients with JPS was associated
with somatic variants in the APC gene.85 In a longitudinal
study from St Mark’s Hospital of 44 patients with JPS from
30 kindreds, a total of 787 polyps (juvenile and adenoma-
tous) were resected, and 65 of 787 (8.3%) contained mild/
moderate architectural dysplasia, and 20 additional polyps
(2.5%) were adenomatous.65
Patients with JPS are at increased risk for cancer prin-
cipally in the stomach and colon (Table 3). In a small cohort
of patients with JPS (n ¼ 84) relative to age-, sex-, and race-
matched controls, the RR of CRC was estimated to be 34
(95% CL, 14.4 and 65.7), with a cumulative lifetime risk of
CRC reaching 38.7%.86 The CRCs were diagnosed at a mean
age of 43.9 years. Interestingly, no other gastrointestinal
cancers were noted in this cohort, but the numbers were
small and the duration of the study was short. Individuals
with gastric polyposis, usually in association with patho-
genic variants in SMAD4 are also at risk for gastric cancer,
with the lifetime risk estimated to be at least 30% and
median age of diagnosis is 58 years; this has not been re-
ported in association with BMPR1A pathogenic var-
iants.67,87–91 Estimates of gastrointestinal cancer risk range
from 11%68 to 55%,89 but none of the studies are pro-
spective long-term studies (which would lead to un-
derestimates), and all are prone to referral-based
ascertainment bias (overestimates).
Question: At what age should colonoscopic and upper
endoscopic surveillance begin in individuals identified
with juvenile polyposis syndrome?
Recommendation: We suggest initiating colonoscopic
and upper endoscopic surveillance at age 12–15 years,
or earlier if symptomatic. Surveillance should be
repeated every 1–3 years depending on polyp burden.
(Weak recommendation, low quality of evidence)
Management of Polyposis
The goal of surveillance in JPS is to mitigate symptoms
related to the disorder and decrease the risk of
June 2022
complications from the manifestations, including cancer.
Colonoscopy should be first performed at age 12–15 years
and repeated every 1–3 years, depending on polyp burden
found, with removal of all polyps when feasible or at least
all polyps
5 mm. Upper endoscopy should be first per-
formed at age 12–15 years and repeated every 1–3 years
depending on polyp burden found, with removal of polyps

5 mm. Due to the possible presence of intestinal telangi-
ectasias, an annual history and physical examination and
complete blood counts to monitor for rectal bleeding and/or
anemia should begin at age 12–15 years in patients with a
germline SMAD4 pathogenic variant.
Endoscopic polypectomy is recommended for colorectal
polyposis management. Surgery with colectomy and ileor-
ectal anastomosis is recommend for patients with CRC,
endoscopically unmanageable colon polyp burden and
uncontrolled anemia from colonic bleeding.33 In some
cases, proctocolectomy is necessary for rectal cancer or
advanced polyp burden of the rectum. Colectomy in pa-
tients with JPS should be reserved for patients with polyp
burdens that cannot be managed by polypectomy, persis-
tent blood loss leading to severe anemia or hypo-
albuminemia, or cancer. A decision to proceed to colectomy
should be reviewed with gastroenterologists and surgeons
with expertise in caring for individuals with hereditary
polyposis syndromes.
The risk of gastric cancer is a concern in patients with
JPS with SMAD4 pathogenic variants and gastric polyposis.
There is a paucity of published data evaluating the stomach
and small bowel in pediatric patients with JPS. Those with
upper gastrointestinal symptoms, or with anemia not
explained by colonic polyps, should undergo evaluation
with upper endoscopy.92 In pediatric patients without
SMAD4 pathogenic variants, according to the existing data,
gastroscopy is not indicated unless the child has symp-
toms.92 In asymptomatic patients with SMAD4 pathogenic
variants, it is prudent to assess the upper tract between the
ages of 12 and 15 years. At the time of this publication, it is
uncertain as to whether BMPR1A pathogenic variants are
associated with gastric cancer risk, and that pending new
evidence, upper endoscopy surveillance is suggested at
intervals similar to those recommended for SMAD4 carriers.
In adults, partial or complete gastrectomy is indicated in
patients with gastric cancer, high-grade dysplasia, inability
to adequately survey or endoscopically control polyposis,
persistent anemia or gastrointestinal bleeding from gastric
polyposis or angioectasia, symptoms of gastric outlet
obstruction, or protein-losing gastropathy.63,64
Question: Which patients with juvenile polyposis
syndrome should undergo screening for hereditary
hemorrhagic telangiectasia?
Recommendation: We suggest patients with SMAD4
pathogenic variants be clinically evaluated for hereditary
hemorrhagic telangiectasia at the time of the diagnosis,
including screening for and appropriate management of
cerebral and pulmonary arteriovenous malformations.
(Weak recommendation, low quality of evidence)
Gastrointestinal Hamartomatous Polyposis Syndromes 2077
Management of Juvenile Polyposis Syndrome–
Hereditary Hemorrhagic Telangiectasia
As recommended by HHT Foundation International, pa-
tients with SMAD4 pathogenic variants should be screened
for vascular findings associated with HHT.79,93 Children
with possible or confirmed HHT should be screened for
brain AVMs at the time of diagnosis and undergo at least 1
follow-up MRI at puberty because brain AVM development
appears to correlate with times of growth. Lung AVM
screening and surveillance is recommended at diagnosis
and then every 3–5 years with pulse oximetry testing and
consideration of transthoracic contrast echocardiogram. In
adulthood, surveillance should include annual hemoglobin
or hematocrit for all patients older than 35 years. Trans-
thoracic contrast echocardiogram as a screen for pulmonary
AVMs should be performed at the time of diagnosis, within 5
years preceding planned pregnancy, after pregnancy, and
otherwise every 5–10 years. Physicians should consider
referring these patients to HHT Centers of Excellence for
this evaluation. Brain MRI with and without contrast should
be performed at birth or at the time of diagnosis to screen
for cerebral vascular malformations.
Chemoprevention
No known effective chemoprevention strategies exist for
the development of polyposis in patients with JPS.
Summary
BMPR1A and SMAD4 gene alterations are responsible for
JPS, yet only 60% of patients will have a pathogenic alter-
ation identified. The clinical overlap syndromes include JPS-
HHT in patients with a SMAD4 pathogenic variant and ju-
venile polyposis of infancy in patients with a combined
BMPR1A and PTEN deletion. The symptoms of JPS are
usually related to bleeding from colorectal polyposis or in
SMAD4-related JPS to gastric polyposis or manifestations of
HHT. Cancer risk in JPS is elevated, mainly in the colon and
stomach (39%–68%), and is largely associated with SMAD4
pathogenic variants.94 Excess risk of nongastrointestinal
cancer is not reported in JPS.
PTEN-Hamartoma Tumor Syndrome
Clinical Features
CLINICAL PRACTICE GUIDELINES
Question: Which gastrointestinal findings should prompt
a genetic evaluation for PTEN hamartoma tumor
syndrome?
Recommendation: We recommend individuals with
multiple gastrointestinal hamartomas or
ganglioneuromas undergo genetic evaluation for
Cowden’s syndrome and related conditions. (Strong
recommendation, low quality of evidence)
PHTS includes a variety of phenotypic variations known
as CS, BRRS, and Proteus syndrome. The clinical diagnosis of
 2078 Boland et al
the PHTS is made in patients meeting the revised diagnostic
criteria, which include the presence of hamartomas of the
skin and gastrointestinal tract (see Figures 1D and 2F–H),
mucocutaneous lesions, macrocephaly, and an increased
risk of benign and malignant lesions of the breast, thyroid,
and endometrium.95
Diagnosis
The genetic diagnosis of PHTS is established with a
germline pathogenic variant in the phosphatase and tensin
homolog (PTEN) gene. The clinical criteria for the diagnosis
of CS is complex, and can be found at the National
Comprehensive Cancer Network website.49 The discussion
for this article will focus on the manifestations and man-
agement of patients with a confirmed diagnosis of PHTS.
Genetics
Question: Which organs should undergo surveillance for
cancer when caring for a patient with PTEN hamartoma
tumor syndrome?
Recommendation: In PTEN hamartoma tumor
syndrome, patients are at increased risk for cancer in
multiple organs, including cancer of the breast, thyroid,
kidney, uterus, colon, and skin.
Given this risk, we recommend a multidisciplinary
approach to cancer surveillance in these organs. (Strong
recommendation, low quality evidence)
The PTEN gene encodes a dual-function phosphatase
that negatively regulates the growth-promoting activity of
the phosphatidylinositol 3-kinase pathway. The PHTS
family of syndromes are caused by inactivating pathogenic
variants in PTEN, making it a classic tumor suppressor
gene.96 Germline pathogenic variants in the PTEN gene
lead to heterogeneous phenotypes called PHTS, which in-
cludes CS, BRRS, and some cases of the PTEN-related
Proteus syndrome (not considered further here).97,98
Germline pathogenic variants in PTEN are associated
with other systemic nonpolyposis phenotypes, including
abnormalities of the central nervous system and skeleton,
but these will not be discussed here in detail. Patients with
CS are also at risk for dysplastic cerebellar gangliocytoma
(Lhermitte-Duclos disease), but the specific genetic basis of
CLINICAL PRACTICE GUIDELINES
this and the other protean manifestations of germline
pathogenic variants in PTEN are not yet understood.
Interestingly, gain-of-function germline pathogenic vari-
ants in the WWP1 gene, an E3 ubiquitin ligase commonly
up-regulated in cancers, inhibits the activity of PTEN,
causes a CS-like syndrome (oligopolyposis and cancer-
prone phenotype), and provides some insight into what
may be responsible for PHTS in the absence of germline
variants in PTEN.99
Cancer Risk
Cancer risks for patients with germline pathogenic var-
iants in PTEN are very high. The International Cowden
Gastroenterology Vol. 162, No. 7
Consortium reported in 2012 on 368 individuals with
germline pathogenic variants in PTEN. Elevated standard-
ized incidence ratios (SIRs) were found for carcinomas of
the breast (SIR, 25.4; 95% CL, 19.8 and 32.0), thyroid (SIR,
51.1; 95% CL, 38.1 and 67.1), endometrium (SIR, 42.9; 95%
CL, 28.1 and 62.8), colorectum (SIR, 10.3; 95% CL, 5.6 and
17.4), kidney (SIR, 30.6; 95% CL, 17.8 and 49.4), and mel-
anoma (SIR, 8.5; 95% CL, 4.1 and 15.6). This led to cumu-
lative lifetime risks for cancer of the breast at 85.2% (95%
CL, 71.4% and 99.1%), thyroid 35.2% (95% CL, 19.7% and
50.7%), endometrium 28.2% (95% CL, 17.1% and 39.3%),
colorectum 9.0% (95% CL, 3.8% and 14.1%), kidney 33.6%
(95% CL, 10.4% and 56.9%), and melanoma 6% (95% CL,
1.6% and 9.4%).100
A multicenter study from France estimated cancer risks
in 154 patients with a germline pathogenic variant in
PTEN.101 SIRs for female breast cancer were 39.1 (95%
confidence interval [CI], 24.8–58.6), thyroid cancer 43.2
(95% CI, 19.7–82.1) in women and 199.5 (95% CI, 106.39–
342.03) in men, melanoma 28.3 (96% CI, 7.6–35.4) in
women and 39.4 (95% CI, 10.6–100.9) in men, and endo-
metrial cancer 48.7 (95% CI, 9.8–142.3). Estimated cumu-
lative lifetime risks by age 70 years were 85% for any
cancer, 77% for female breast cancer, and 38% for thyroid
cancer. Median age for developing cancer was 36 years.
Although 85% were reported to have colonic polyps of any
variety, risks for gastrointestinal cancer were not reported
to be elevated in this series. However, a review of 211 pa-
tients with CS from the Mayo Clinic, including a review of
the literature, reported a 16% lifetime risk for CRC. In this
study, only 46% had a proven germline pathogenic variant
in PTEN, and the cumulative risk for any cancer by age 70
years was 89%.102
In a study of 2548 patients who met “relaxed” Interna-
tional Cowden’s Consortium criteria for CS with 5 or more
gastrointestinal polyps in which at least 1 was considered
hyperplastic or hamartomatous, germline pathogenic vari-
ants in PTEN were found in 127 (5%).103 At endoscopy,
gastrointestinal polyps were found throughout the gut, and
one-half were considered “hyperplastic.” In this group, 13%
of those who underwent colonoscopy developed CRC (7.1%
of the entire series of patients), all before age 50 years (the
youngest was 35 years old), with a SIR for CRC of 224.1
(95% CI, 109.3–411.3).
A multicenter study from 9 countries of 180 carriers of
germline pathogenic variants in PTEN estimated the cumu-
lative risk of any cancer or Lhermitte-Duclos disease by age
60 years was 56% for men and 87% for women.104
Increased risk was reported for cancers of the breast, thy-
roid, endometrium, skin, kidneys, colorectum, and lungs. An
earlier report from this group on 156 patients reported that
benign gastrointestinal polyps were found in 31% of pa-
tients at a mean age of 38 years (range, 18–62 years) and
most were considered “hamartomas.”105 The cumulative
risk of developing polyps was 70% by age 60 years. The
cumulative risk of developing CRC was 18% by age 60 years
(occurring between ages 53 and 62 years), suggesting that
surveillance colonoscopy might not be necessary in early
adult life.
June 2022
Gastrointestinal Polyps and Polyposis
Gastrointestinal polyps are frequently found in patients
with germline pathogenic variants in PTEN, with variable
prevalence. Estimates suggest that 35%–93% of patients
with CS have gastrointestinal polyps, but in some reports
the germline basis of the disease was not known and a
uniform interpretation of nonadenomatous polyps had not
been established.103,106 The wide range of estimated polyp
prevalence is probably a reflection of the heterogeneity of
the disease and challenges in making definitive diagnoses
outside of germline tests. Gastrointestinal polyps include
hyperplastic polyps, inflammatory polyps, ganglioneuromas,
lipomas, adenomas, and the nonspecific term hamartomas.
A prospective study of 127 PTEN pathogenic variant
carriers from 2548 subjects in an International Cowden
Consortium study in which 69 underwent endoscopic
studies found that 64 (93%) had gastrointestinal polyps.103
Of that group, one-half had hyperplastic polyps, but all of
the above-listed polyps (plus adenomas) were also found.
The number of polyps ranged from 1 to “innumerable,” and
were distributed throughout the gut.
BRRS is caused by germline pathogenic variants in the
PTEN gene.98,107 It is a pediatric condition associated with
macrocephaly, developmental delay, gastrointestinal
hamartomatous polyps, and pigmented macules on the toes
and glans penis. It has also been called the Bannayan-
Zonana or Ruvalcaba-Riley-Smith syndrome. Inexplicably,
members of the same family may have features of either
BRRS or CS,108 and some cases of BRRS do not have
detectable pathogenic variants in PTEN.109 Confusing over-
lap between CS and JPS can occur when, as mentioned
above, a chromosomal deletion occurs on chromosome
10q22.3-q24.1. This leads to the loss of both PTEN and
BMPR1A28; a situation that can also look like BRRS, also
known as juvenile polyposis of infancy (see section on
JPS).110,111
In a smaller study of 19 patients with CS (in which only
12 were shown to have germline pathogenic variants in
PTEN), pan-colonic polyps were found in 58%, pan-
gastrointestinal polyps in 42%, and the pathological inter-
pretation of the polyps included inflammatory polyps in
95%, but also adenomas, lipomas, and ganglioneuromas.112
Moreover, there was more than 1 pathological variety in
79% of patients, indicating the clinical heterogeneity in this
entity. Esophageal glycogenic acanthosis is also found in
PHTS, which is a benign condition and there is no reported
increased risk for esophageal cancer.113
Question: What is the recommended colonoscopic
surveillance in individuals identified with PTEN
hamartoma tumor syndrome?
Recommendation: We suggest colonoscopy
surveillance to begin at age 35 years (or 10 years
younger than age of any relative with colorectal cancer),
repeated at intervals no greater than 5 years, depending
on polyp burden. (Weak recommendation, low quality of
evidence)
Gastrointestinal Hamartomatous Polyposis Syndromes 2079
Surveillance of Affected Individuals
Surveillance recommendations are provided in Table 4.
The assessment at diagnosis of CS/PHTS should include a
complete (and especially dermatologic and neurologic)
clinical examination, mammography and breast MRI, thyroid
ultrasound, transvaginal ultrasound, upper gastrointestinal
endoscopy, colonoscopy, and renal ultrasound. Although
there are no data regarding risk-reduction surgery in
women with CS, the option for risk-reducing mastectomy
and hysterectomy should be discussed on a case-by-case
basis.
The risk of CRC in patients with CS is estimated to be up
to 9%–18% lifetime risk with mean age at diagnosis of 44
years, but ranging from 35 to 49 years.100,102,103,105,114,115
Consequently, expert opinion recommends colonoscopy
starting at age 35 years unless symptomatic or if a close
relative has had colon cancer before age 40 years, then start
10 years before the earliest known colon cancer in the
family and repeat every 5 years or more frequently if the
patient is symptomatic or polyps are found. This recom-
mendation differs from a recent American College of
Gastroenterology Guideline,32 which recommends initiating
colonoscopy at age 15 years. Recent evidence suggesting
later onset of significant colon cancer risk informed our
recommendations.
Colectomy is rarely required in patients with CS and is
reserved for patients with CRC or in whom surveillance and
clearing of premalignant lesions is not endoscopically
feasible.
Breast Cancer
The management of breast cancer risk begins at age 25
years with clinical breast examination every 6–12 months;
annual mammography and breast MRI surveillance starting
between ages 30 and 35 years or 5–10 years before the
earliest known breast cancer in the family.49 In patients with
PHTS, referral to a breast cancer specialist for management of
breast cancer surveillance is reasonable and a multidisci-
plinary approach, including a breast surgeon, is recom-
mended when prophylactic mastectomy is being considered.
Endometrial Cancer
The management of endometrial cancer risk begins be-
tween the ages of 30 and 35 years. Endometrial cancer can
CLINICAL PRACTICE GUIDELINES
often be detected early on the basis of symptoms, and women
should be educated regarding seeking medical attention on
the basis of symptoms, including abnormal uterine bleeding
or postmenopausal bleeding. Endometrial biopsy is sensitive
and specific for endometrial cancer and surveillance via bi-
opsy every 1–2 years can be considered.33,49
Thyroid Cancer
An annual thyroid ultrasound should be performed,
beginning at the time of PHTS diagnosis (including in
childhood).33,49
 2080 Boland et al
Renal Cancer
The recommended management of kidney cancer risk is
an annual renal ultrasound and/or renal MRI starting at age
40 years if there is a family history of renal cancer, or every
2 years if not.33,49
Melanoma
The management of melanoma risk includes an annual
clinical skin examination beginning at age 18 years.33
Summary
Germline pathogenic variants in PTEN are associated
with variety of gastrointestinal hamartomatous polyps and a
markedly increased risk of cancer, but largely in non-
gastrointestinal organs. There is a moderate increase in the
risk of CRC, but it may be that the age of risk is such that
colonoscopic surveillance can be withheld until age 35 years
or later or 10 years younger than the age of the youngest
relative with CRC. However, the reports of CRC risk have
been variable,95,116 and no surveillance recommendation
has been rigorously evaluated. The principal organs at risk
for cancer include the breast, thyroid, endometrium, and
colorectum.
Hereditary Mixed Polyposis Syndrome
The Genetic Basis of the Disease and Cancer
Risk
HMPS is a rare autosomal dominant disease reported in
only a few families. It is characterized by attenuated colonic
polyposis. The polyps include adenomas, hyperplastic, and a
particular polyp with an admixture of variable histologies
including adenomatous, hyperplastic, juvenile, and mixed
polyps.117 In the original HMPS kindred described by
Whitelaw et al,118 13 members were diagnosed with CRC
and 23 developed multiple polyps of several different his-
tologic types (adenomatous, hyperplastic, and juvenile).
HMPS has been associated with large duplications of the
promoter region or entire GREM1 gene.119–121 These un-
usual pathogenic variants increase the expression of the
gene product, which then inhibits the bone morphogenetic
protein (BMP) pathway.119 This promoter duplication was
found in 0.7% of Ashkenazi Jews in Israel who met clinical
criteria for Lynch syndrome.120 The largest series reported
4 families with 16 affected members; the onset of polyposis
CLINICAL PRACTICE GUIDELINES
starts in the late 20s, which is when colonoscopic surveil-
lance should begin.122 There are not enough data to know
the optimal surveillance intervals or whether extraintestinal
neoplasia is a risk. The underlying genetic basis of the ma-
jority of HMPS families is unknown.
Future Research Considerations
The hamartoma syndromes are rare and it is difficult for
single institutions or even collaborative centers to accu-
mulate enough cases and follow them prospectively long
enough to develop robust conclusions about cancer risk.
Modeling, simulation, and collaborative multicenter clinical
Gastroenterology Vol. 162, No. 7
studies can be used to help clarify the benefits and risks of
various interventions and surveillance programs. The
management of these diseases changes dramatically when
the patient matures from childhood to adulthood—which is
where almost all of the cancer risk lies. Important knowl-
edge gaps are listed in Table 5 and expanded upon below.
Peutz-Jeghers Syndrome
As indicated above, STK11/LKB1 pathogenic variants
result in up-regulation of inflammatory cytokines and pro-
motion of overgrowth of both stromal and normal gastro-
intestinal epithelium, driving polyp formation (Table 5). Up-
regulation of cytokines is associated with hyperactivation of
JAK-STAT, which contributes to inflammation and cancer.
Inhibition of JAK-STAT significantly reduced polyp growth
in mice. Consequently, the JAK inhibitor ruxolitinib (already
clinically approved for myeloproliferative disease) may have
therapeutic potential in patients with PJS.21 Also, LKB1 ac-
tivity inhibits the activation of adenosine monophosphate–
dependent protein kinase. Loss of LKB1 activity results in
adenosine monophosphate–dependent protein kinase acti-
vation with up-regulation of mTORC1 signaling contributing
to growth of PJS polyposis. Targeting of adenosine
monophosphate–dependent protein kinase activation is
currently being investigated.123
Juvenile Polyposis Syndrome
Of note is the mouse model of juvenile polyposis created
by a conditional knockout of the SMAD4 gene only in T-cell
populations.73 These animals spontaneously developed
massive polyps within the gastroduodenal region. The
epithelium in the polyps contained increased expression of
pro-inflammatory cytokines, particularly interleukin-11, a
cytokine known to promote gastric epithelial cell survival
and hyperplasia with evidence of increased TH17 cell ac-
tivity. This suggests possible therapeutic targets for the
future chemoprevention of juvenile polyposis.
Summary and Conclusions
Among the gastrointestinal hamartomatous polyposis
syndromes, PJS is the best understood. The polyps are
readily identified as PJ polyps pathologically, and only 1
known gene (STK11) is associated with this entity. The
phenotype is clinically distinct. Not all patients (or families)
have detectable germline pathogenic variants in STK11, so
additional genes in this pathway are possibly contributors
to this entity. The polyps may evolve through an expansion
of elements of the gut stroma due to haploinsufficiency of
STK11. In children, the main risks are for gastrointestinal
obstruction and bleeding. Later in adult life, a very high risk
of intestinal and extraintestinal cancers exists. The major
organs at risk for cancer (in order of decreasing relative
risk) include the small intestine, stomach, pancreas, colon,
esophagus, ovary, lung, uterus, and breast, with estimated
lifetime risks for any cancer reaching >90%. The ovaries
and testes are also at risk for rare variant tumors. The
June 2022 Gastrointestinal Hamartomatous Polyposis Syndromes 2081

Table 5.Areas Requiring Further Investigation in Hamartomatous Polyposis Syndromes

1. Discover the germline variants in families with clinically recognizable syndromes who do not have germline mutations in the genes known
to be associated with these syndromes.
2. Understand the effects of haplo-insufficiency of STK11 in PJS and the SMAD4 in JPS on the development of polyposis.
3. Identify safe and effective pharmacological interventions for the inhibition of polyp formation children and adults with the hamartomatous
polyposis syndromes.
4. Determine whether pharmacological intervention can mitigate cancer risk in PJS and JPS in adults (independent of the polyposis risk).
5. Develop simulation models in adults with a hamartomatous polyposis syndrome to determine the optimal endoscopic frequency.
6. Design and implement studies to determine the best imaging modalities and surveillance intervals in adults with a hamartomatous pol-
yposis syndrome.
7. Determine whether the hamartomatous phenotype in pediatric patients predicts the cancer risk in adulthood.
8. Perform outcomes studies evaluating the transition of care in pediatric polyposis patients entering adult life, including outcomes such as
compliance with surveillance.
9. Determine difference in phenotype and cancer risk in individuals who meet clinical criteria, but do not have an identifiable pathogenic
variant compared to those with a germline pathogenic variant in a hamartomatous polyposis syndrome.
10. Determine the lifetime cancer risks in patients with a pathogenic variant, but without clinical manifestations (those identified incidentally on
multigene panel testing).
11. Quantify the frequency of mosaicism as a cause of the hamartomatous polyposis syndromes.
12. Determine the optimal modality of small bowel evaluation in individuals with PJS.

screening and surveillance strategies change dramatically
when the children reach adulthood.
JPS has principal risks for obstruction and bleeding in
the pediatric ages, but the management in adults shifts to
cancer risks in the stomach and colon. Importantly, unlike
PJS, the gastrointestinal cancers tend to arise within the
juvenile polyps, suggesting that polyp removal might pre-
vent cancer. Cancer risk is linked to germline pathogenic
variants in the SMAD4 gene rather than the BMPR1A gene.
The polyps are histologically inflammatory in nature, and
their growth may be driven by haploinsufficiency of SMAD4
in the immune cells of the polyp stroma. The management
focuses on the polyps in children and cancers later in life,
when endoscopic approaches are the mainstay of
surveillance.
The hamartoma syndromes associated with germline
pathogenic variants in PTEN raise a completely different
clinical challenge. Although nearly all patients with PHTS
have a variety of different hamartomatous gastrointestinal
polyps, studies suggest an increased risk of cancer in this
setting.100,103 The extracolonic cancer risks are greatest for
the breast, thyroid, melanoma, and endometrium. The ab-
solute risk for CRC appears to be increased, ranging from
9% to 18% during a lifetime, and the rest of the gastroin-
patients and families with unusual phenotypes where no
genotype can be found.
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Correspondence
Address correspondence to: C. Richard Boland, MD, University of California
San Diego, 9444 Medical Center Drive, East Campus Office Building, Room
2-065, La Jolla, California 92037. e-mail: crboland@health.ucsd.edu
Conflicts of interest
The authors disclose no conflicts of interest relative to the current work since
2016. These authors disclose the following industry relationships (consulting,
research, reimbursement) without conflict of interest relevant to the current
work since 2016: C. Richard Boland: Ambry Genetics. Gregory Idos: Myriad
Genetics, Inc. Carol Burke: Salix Pharmaceuticals, Ferring Pharmaceuticals,
Aries Pharmaceuticals, Pfizer, Cancer Prevention Pharmaceuticals, Janssen
Pharmaceuticals, SLA Pharma AG, and Freenome Holdings, Inc. Samir
Gupta: Freenome Holdings, Inc, Guardant Health, Inc, CellMax, Inc, and
Mallinckrodt Pharmaceuticals. Brian C. Jacobson: Motus, GI, Dark Canyon
LLC, and Remedy Partners. Aasma Shaukat: Iterative Scopes, Freenome
Holdings Inc. Swati G. Patel: Olympus America, Freenome Holdings Inc,
ERBE USA. Sapna Syngal: Myriad Genetics, Inc, DC Health, Inc, and
GlaxoSmith Kline, Inc. Douglas Robertson: Covidien, Freenome Holdings,
Inc, and Amadix. The remaining authors disclose no conflicts.
CLINICAL PRACTICE GUIDELINES
 CASE REPORT – OPEN ACCESS
International Journal of Surgery Case Reports 79 (2021) 286–290

Contents lists available at ScienceDirect

International Journal of Surgery Case Reports

journal homepage: www.casereports.com

Peutz-Jeghers syndrome in a woman presenting as intussusception: A

case report
Erwin Syarifuddin a , Rina Masadah b , Ronald Erasio Lusikooy a , Warsinggih a,∗ ,
Julianus Aboyaman Uwuratuw a , Muhammad Faruk c
a
Division of Digestive, Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
b
Department of Pathology Anatomy, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
c
Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia

a r t i c l e i n f o a b s t r a c t

Article history: INTRODUCTION: Peutz-Jeghers syndrome (PJS) is an uncommon autosomal dominant syndrome with a
Received 16 December 2020 variable to high penetrance that leads to the development of polyps within the gastrointestinal mucosa.
Received in revised form 14 January 2021 Here we report a case of an adult female suffering jejunoileal intussusception due to PJS.
Accepted 14 January 2021
PRESENTATION OF CASE: A 30-year-old woman came to an emergency department with a small bowel
Available online 18 January 2021
obstruction caused by intussusception. The patient underwent an emergency exploratory laparotomy. An
intussusception at the level of 60 cm from the ligamentum treitz was revealed, and the intussusception
Keywords:
small bowel segment was not viable; we decided to perform segmental jejunoileal resection with the
Peutz-Jeghers syndrome
Intussusception
Bishop-Koop procedure, and the specimen histopathology of the segmental jejunoileal resection showed
Hamartoma a typical hamartomatous polyp features. Two month later, diagnostic endoscopy showed multiple polyps
Polyps (between 5 and 15 mm) in the large bowel. The polyps were removed with endoscopic polypectomy
Case report and examined histopathologically, showing characteristics of PJS. Further detailed family history was
obtained, and similar skin lesions were detected on our patient’s child (since birth). Although endoscopy
screening identified multiple polyps in the child’s ileum and large bowel, he was not suffering from
abdominal symptoms.
CONCLUSION: In patients with intussusception at a young age, PJS can be caused by the presence of a
hamartoma polyp as a trigger for intussusception. If there are multiple polyps found in the gastrointestinal
mucosa and other pathognomonic signs are found, such as hyperdense macular lesions on the lip and
buccal mucosa, such cases should be confirmed as PJS.
© 2021 The Author(s). Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
Peutz-Jeghers syndrome (PJS) is an uncommon autosomal dom-
inant syndrome with a variable to high penetrance that leads to
the development of polyps within the colon and rectum, and only
a small number of cases have been reported in the literature [1].
PJS affects around 1 in 8300 to 200,000 births [2]. PJS was first
reported by Peutz in 1921 [3,4], and subsequently, detailed case PJS
by Jeghers, McKusick, and Katz in 1949 [5]. This syndrome consists
of the association of gastrointestinal polyps mucocutaneous pig-
mentation and a familial incidence [6]. In PJS, the gastrointestinal
(GI) tract develops hamartomatous polyps, which occur most com-
monly in the small bowel, colon, and rectum (≥ 90% of cases), and
less commonly in the stomach or urinary tract [7]. Hamartomas can
range from 5 to 50 mm in diameter (median size, 35 mm). Hamar-
tomas are associated with intussusception, bleeding, anemia, and
obstruction [8].
Here, we report the uncommon case of a female suffering
jejunoileal intussusception due to PJS, in line with the updated
consensus-based surgical case report (SCARE) guidelines [9].
2. Case presentation

A 30-year-old woman came to an emergency department with

∗ Corresponding author at: Warsinggih Division of Digestive, Department of
Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Jalan Perintis
Kemerdekaan KM 11, Makassar, 90245, Indonesia.
E-mail addresses: erwinsyarifuddin@yahoo.com (E. Syarifuddin),
r.masadah@med.unhas.ac.id (R. Masadah), ronaldlusikooy@gmail.com
(R.E. Lusikooy), kbd.warsinggih@gmail.com ( Warsinggih),
boyuwuratuw@gmail.com (J.A. Uwuratuw), faroex8283@gmail.com (M. Faruk).
the chief complaint of intermittent episodes of colicky abdomi-
nal pain with tarry stool 4 weeks before admission. From the vital
signs, the patient was tachycardic and hypotensive. On physical
examination, she had an of pigmentation in the oral cavity (Fig. 1).
The abdomen was less distended, with increased bowel sound,
tenderness, and hypertimpanic on percussion. The digital rectal

https://doi.org/10.1016/j.ijscr.2021.01.053
2210-2612/© 2021 The Author(s). Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
 CASE REPORT – OPEN ACCESS
E. Syarifuddin et al.
Fig. 1. Mucocutaneous pigmentation on the buccal mucosa and lips.
examination revealed normal limits. Blood investigation showed
anemia (hemoglobin level, 7.6 g/dl). An abdominal X-ray showed a
small bowel obstruction.
The patient underwent an emergency exploratory laparotomy.
We (the digestive surgeon and residents) detected a jejunoileal
intussusception caused by multiple polyps at ∼60 cm from the lig-
amentum treitz (Fig. 2A and B), and the milking procedure was
successfully performed, but a 40-cm segment of the jejunoileal
intussusception was not viable. Therefore, we decided to perform
segmental resection and, through this, found multiple polyps in
the borderline resection of the mucosa proximal jejunum and dis-
tal ileum. We decided to extend the resection until we no longer
found polyps. We decided to perform the Bishop-Koop procedure
(Fig. 3A). The specimen was sent for histopathological examination
and described as a typical hamartomatous polyp (Fig. 3B). She was
given an intravenous broad-spectrum antibiotic, and analgesics
drugs were administered for 5 days.
Postoperatively, the patient had satisfactory progress, tolerat-
ing oral feeding, and was discharged on the seventh postoperative
day. Two month later, we performed diagnostic endoscopy; there
were multiple polyps in the large bowel measuring 5–15 mm,
without any features of intussusceptions (Fig. 4). This polyp was
removed with endoscopic polypectomy. Histopathological exam-
ination revealed a polyp characteristic of PJS consisting of a
branching framework of connective tissue and smooth muscle lined
by the normal intestinal epithelium. Further detailed family history
was obtained, and similar skin lesions were detected on her child
(since birth). Although endoscopy screening performed identified
multiple polyps (< 5 mm) in the ileum and large bowel, the child
was not suffering from abdominal symptoms (Fig. 5).
3. Discussion
PJS is an inherited polyposis syndrome in which multiple char-
acteristic polyps occur in the gastrointestinal (GI) tract, associated
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International Journal of Surgery Case Reports 79 (2021) 286–290
with mucocutaneous pigmentation, especially of the vermilion bor-
der of the lips. PJS is an autosomal dominant disease caused by a
germline mutation in the STK11 (LKB1) gene [8]. The estimation of
the population prevalence of PJS differs between studies, ranging
from 1 in 8300 to 1 in 280,000 individuals. The probable prevalence
is around 1 in 100,000 people [2].
The diagnosis of PJS can be made in patients with hamartoma-
tous polyp(s) with at least two of the following clinical criteria
also present: labial melanin deposits, a family history of the syn-
drome, and small bowel polyposis. The syndrome appears equally
in males and females and is found in all racial groups [6]. The clin-
ical manifestation of PJS is characterized by asymptomatic periods
interspersed with complications, such as abdominal pain, intus-
susception often leading to intestinal obstruction, polyp extrusion
through the rectum, and bleeding, which is often occult [7,10,11].
Small bowel obstruction is the presenting complaint in half of
the cases, and relaparotomy due to polyp-induced complications
occurs commonly and might do so at quite short intervals [10].
In addition to polyposis, previous studies have reported an
increased risk of GI and extra-GI malignancies in PJS patients, com-
pared with that of the general population [7]. The PJS is associated
with an increased risk of gastrointestinal and non-gastrointestinal
malignancies. A meta-analysis involving six studies and 210
patients showed a cumulative risk of 93% from 15 to 64 years for all
types of malignancies. Thus, the relative risk of an individual with
SPJ to present neoplasia in any region, compared with the general
population, is up to 15 times higher [11,12]. The most frequent
neoplasm in patients with PJS is the colonic tumor (57%), followed
by breast (45%), pancreas (36%), stomach (29%), ovary (21%), small
intestine (13%), and uterus (10%) tumors [11,13]. Among gastroin-
testinal cancers, increased cancer risk was indicated for the colon,
stomach, small intestine, and pancreas. Also, female PJS patients
are at greater risk of gastrointestinal and gynecological cancers,
ovarian cancer, cervical cancer, uterine cancer, and breast cancer.
Meanwhile, the high risk of pulmonary cancer, renal cancer, pro-
static cancer, bone cancer, and leukemia has also been reported.
There is wide variability in cancer risk estimates, as reviewed in a
recent meta-analysis study [14].
Until recently, PJS was considered a benign condition and was
treated conservatively. Repeated laparotomies were considered
risky and ineffective because of the continuous growth of the
polyps. Patients were, therefore, treated surgically only when acute
bowel obstruction occurred [10].
More recently, the management approach has changed, becom-
ing more aggressive. When the diagnosis of PJS is histologically
confirmed, we suggest that all polyps should be removed with the
aim of preventing intussusception with gangrene requiring resec-
tion, which might lead to short-bowel syndrome [10].
Most publications recommend polypectomy for polyps in the
stomach or colon that are greater than 1 cm in size noted dur-
ing endoscopic surveillance. Surgery has been recommended for
symptomatic or rapidly growing small intestinal polyps or asymp-
tomatic polyps greater than 1–1.5 cm in size. Some experts suggest
a clean sweep. This can be facilitated by concomitant interopera-
tive endoscopy with polypectomy or, in the case of larger polyps,
enterotomy. The clean sweep approach appears to decrease the
need for recurrent small bowel surgery. Recently, the use of double-
balloon enteroscopy for removal of small bowel PJS polyps has been
reported and might decrease the need for laparotomy [14].
In our case, the patient was admitted to the hospital with intus-
susception. The exploratory laparotomy revealed intussusception
with the small bowel segment not viable. Small bowel resection
was performed and continued with the Bishop-Koop procedure
due to prevent short bowel syndrome. We did not perform an end-
to-end anastomosis because the patient had hypovolemic shock
 CASE REPORT – OPEN ACCESS
E. Syarifuddin et al. International Journal of Surgery Case Reports 79 (2021) 286–290

Fig. 2. (A) Intussusception ileojejenal and (B) hamartoma of the ileum.

Fig. 3. (A) The Bishop-Koop procedure of the jejunum; (B) The histopathological findings reveal hamartoma, with a typical PJS polyp demonstrating an arborizing pattern of
growth of smooth-muscle (HE staining, magnification 4×); and (C) Histopathological findings revealed an edematous appearance of the intestinal mucosa with inflammatory
lymphocytes, histiocytes, and very dense plasma cells. In the layer below, there appears pigment hemosiderin. There is no evidence of dysplasia or malignancy (HE staining,
magnification 40×).

Fig. 4. Colonoscopy with more than 50 polyps scattered throughout the colon and rectum.

288
 CASE REPORT – OPEN ACCESS
E. Syarifuddin et al.
Fig. 5. On the patient’s male child, we detected: (A) pigmentations of the lips and oral mucosa; and (B) polyp in the large bowel detected by endoscopy screening.
preoperative and anemia, and we found edema in the small bowel
mucosa.
4. Conclusion
In patients with intussusception at a young age, a hamartoma
polyp might have been the trigger for intussusception. If there are
multiple polyps found in the GI mucosa together with other pathog-
nomonic signs, such as hyperdense macular lesions on the lip and
buccal mucosa, such cases should be confirmed as PJS.
Declaration of Competing Interest
The authors declare that they have no conflict of interests.
Funding
No funding or sponsorship was received for this study or publi-
cation of this article.
Ethical Approval
The study is exempt from ethical approval in our institution.
Consent
Written informed consent was obtained from the patient for
publication of this case report and accompanying images. A copy
of the written consent is available for review by the Editor-in-Chief
of this journal on request.
Author contribution
Erwin Syarifuddin, Julianus A. Uwuratuw, and Muhammad
Faruk: study concept, surgical therapy for this patient. Erwin
Syarifuddin, Rina Masadah, and Muhammad Faruk: Data collec-
tion, Writing-Original draft preparation. Ronald E. Lusikooy and
Warsinggih: senior author and the manuscript reviewer. Erwin
Syarifuddin and Muhammad Faruk: Editing and Writing. All
authors read and approved the final manuscript.
Registration of research studies
Not applicable.
289
International Journal of Surgery Case Reports 79 (2021) 286–290
Guarantor
Erwin Syarifuddin.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgment
We acknowledge Robert Christeven, M.D, for her help in provid-
ing us with the linguistic assistance for this case report.
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