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Hamartomatous polyposis syndromes
Kevin M Zbuk and Charis Eng*
S U M M A RY
The hamartomatous polyposis syndromes are a heterogeneous group of
disorders that share an autosomal-dominant pattern of inheritance and are
characterized by hamartomatous polyps of the gastrointestinal tract. These
syndromes include juvenile polyposis syndrome, Peutz–Jeghers syndrome
and the PTEN hamartoma tumor syndrome. The frequency and location
of the polyps vary considerably among syndromes, as does the affected
patient’s predisposition to the development of gastrointestinal and other
malignancies. Although the syndromes are uncommon, it is important
for the clinician to recognize these disorders because they are associated
with considerable morbidity and mortality, not only from malignancy but
also from nonmalignant manifestations such as bleeding, intussusception,
and bowel obstruction. Each hamartomatous polyposis syndrome has its
own distinctive organ-specific manifestations and each requires a different
surveillance strategy, which makes accurate diagnosis crucial for appropriate
patient management. The availability of clinical genetic testing for these
disorders means that appropriate recognition allows for timely referral
for cancer genetic counseling, and often allows for predicative testing in
at-risk family members. Promisingly, an understanding of the molecular
pathogenesis of these disorders offers insights into the mechanisms
underlying the development of sporadic malignancy, and enables rational
selection of targeted therapies that warrant further investigation.
Keywords cancer, hamartomatous polyposis syndromes, inherited
Review criteria
This Review is based on a PubMed search performed in January 2007 with the
following terms alone or in combination: “hamartomatous polyps”, “hamartomas”,
“juvenile polyposis syndrome”, “juvenile polyps”, “Peutz–Jeghers syndrome”,
“Cowden syndrome”, “Bannayan–Riley–Ruvalcaba syndrome”, “BRRS”, “PTEN
hamartoma tumor syndrome”, “small bowel polyps”, “PTEN”, “BMPR1A”, “LKB1”,
“SMAD4”, “germline”, “mTOR inhibitors”, “rapamcyin”. Full-length, original
research and review articles published in English were used.
cme
KM Zbuk is a Cancer Genomic Medicine Fellow and Crile Fellow at the
Genomic Medicine Institute, Cleveland Clinic and C Eng is Chair and Director
of the Genomic Medicine Institute and Director of the Center for Personalized
Genetic Healthcare, Cleveland Clinic and Professor and Vice Chairman,
Department of Genetics, Case Western Reserve University School of Medicine,
Cleveland, OH, USA.
Correspondence
*Cleveland Clinic Genomic Medicine Institute, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA
[email protected]
Received 22 February 2007 Accepted 14 June 2007
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doi:10.1038/ncpgasthep0902
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Continuing Medical Education online
Medscape, LLC is pleased to provide online continuing
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Learning objectives
Upon completion of this activity, participants should be
able to:
1 Identify the different autosomal dominant types of
hamartomatous polyposis syndromes.
2 Describe the risk for cancer associated with juvenile
polyposis syndrome.
3 List clinical features of and cancer risks associated
with Peutz–Jeghers syndrome.
4 List the types of cancers that Cowden’s syndrome
predisposes to.
5 Describe surveillance strategies recommended for
the hamartomatous polyposis syndrome PTEN
hamartoma tumor syndrome.
INTRODUCTION
The hereditary gastrointestinal polyposis syn­­
dromes can be broadly divided into those in
which the polyps are predominantly adenomatous
and those in which the polyps are pre­dominantly
hamartomatous. Hamartomatous polyps are
composed of the normal cellular elements of
the gastrointestinal tract, but have a markedly
distorted architecture. The hamarto­matous poly­
posis syndromes are a hetero­geneous group of
disorders that are inherited in an autosomal­dominant manner. The syndromes include juvenile
polyposis syndrome (JPS), Peutz–Jeghers syn­­drome (PJS), and PTEN hamartoma tumor
syn­­drome (PHTS). PHTS includes Cowden syn­­
drome, Bannayan–Riley–Ruvalcaba syndrome
(BRRS), and all syndromes in which there are
germline PTEN mutations.
The hamartomatous polyposis syndromes are
uncommon—together, they account for fewer
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than 1% of colon cancer cases in North America.1
Nonetheless, it is important that these syndromes
are recognized and managed appropriately for
several reasons. First, most of these syndromes
are associated with a markedly increased risk for
the development of colon cancer. Second, they are
associated with the development of extra-colonic
manifestations, both malignant and nonmalig­
nant, which often result in considerable morbidity
and mortality. Insights into the molecular patho­
genesis of malignancy in these rare disorders have
advanced our knowledge of the patho­genesis of
their sporadic counterparts. This advancement is
illustrated by the evolution of the concept of the
hamartoma to carcinoma sequence,2 which is an
alternative sequence to the adenoma to carcinoma
paradigm of colo­rectal cancer pathogenesis.
Although the field of hamartomatous polyposis
is broad, in this Review we discuss the diagnosis
and clinical features of the different hamartoma­
tous polyposis syndromes, the risk of malignancy
associated with each syndrome, appropriate
surveillance recommendations, and what is
known about the genetics of these syndromes.
Other disorders that are associated with the
presence of hamartomatous polyps are briefly
discussed, and the Review additionally summa­
rizes the potential for targeted therapy of hamarto­
matous polyposis syndromes and the malignant
potential of hamartomatous polyps.
PEUTZ–JEGHERS SYNDROME
Diagnosis and clinical features
PJS, which has an incidence of 1 in 150,000 in
North America and Western Europe,3 is charac­
terized by the presence of hamartomatous polyps
in the gastrointestinal tract, and is associated
with a distinctive mucocutaneous pigmentation.
Polyps occur most commonly in the small intes­
tine (64%), although involvement of the colon
(53%), stomach (49%), and rectum (32%) is also
seen.4 Polyps have also been found in the upper
and lower respiratory tract and bladder.5 There
are usually fewer than 20 polyps present in each
case, and the polyps vary in size from several
millimeters to more than 5 cm in diameter.6
Patients usually present with PJS in the second
or third decade of life, and the presenting symp­
toms include abdominal pain, rectal bleeding,
anemia, small intestinal intussusception, bowel
obstruction, and rectal prolapse of polyps.5
The characteristic pigmentation, which is
usually dark blue to dark brown in color, is present
in 95% of patients with PJS and is most commonly
september 2007 vol 4 no 9 ZBUK AND ENG seen on the vermillion border of the lips, the
buccal mucosa, and the hands and feet.4 Perinasal,
perianal, genital, and peri­orbital pigmentation
can also be observed, but this pigmentation often
fades after puberty. In contrast to the lentigines
seen in individuals with PJS, common freckles
spare the buccal mucosa, and are usually rare
around the lips and nose.
The diagnostic criteria for PJS include the pres­
ence of characteristic mucocutaneous pigmenta­
tion, the presence of small-bowel hamartomatous
polyps and a family history of PJS. Patients need
to fulfill two of these three criteria for a clinical
diagnosis of PJS to be made.7
On endoscopy, the polyps seen in patients
with PJS have no defining features, although
they can develop long stalks that predispose the
intestine to intussusception.5 Microscopically,
extensive smooth-muscle proliferation, with an
elongated, arborized pattern of polyp forma­
tion, can be seen (Figure 1).8 This characteristic
microscopic appearance of PJS polyps enables
experienced gastrointestinal pathologists to
confirm the clinical diagnosis.
Cancer risk
PJS is associated with a markedly increased risk
of malignancy that is not confined to the gastro­
intestinal tract. A meta-analysis found that,
compared with the general population, patients
with PJS have a relative risk (RR) of greater than
15 for developing any type of cancer.9 According
to this meta-analysis, the cumulative risk of
develop­­ing any type of cancer was 93% by the time
a PJS patient was 65 years old. Very high RRs for
the development of cancer were observed for the
small intestine (520), stomach (213), pancreas
(132), colon (84), and esophagus (57), with RRs
of greater than 10 for the development of breast,
lung and ovarian cancer.
A follow-up study restricted to patients with
PJS who had a germline mutation in the tumor
suppressor gene STK11 (also known as LKB1)
confirmed that these patients have a very high
risk of developing cancer.10 The cumulative risk
of developing any type of cancer was 81%
by the time these patients were 70 years of age,
the cumulative risk of developing any gastro­
intestinal cancer (including small intestine,
colorectal, esophageal and pancreatic cancer)
was 66% by the time they were 70 years of age,
and for female patients the cumulative risk of
developing breast cancer was 32% by the time
they were 60 years of age.10
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by advances in capsule and double-balloon endo­
scopy. Although the precise role of these tech­
niques in the management of patients with PJS
has not yet been established, they will undoubt­
edly prove useful in the nonsurgical treatment
of patients with polyps of the small intestine,13
and might replace surveillance performed by
small-bowel barium follow-through.
Genetics
mm
Figure 1 A typical Peutz–Jeghers syndrome polyp
demonstrating the arborizing pattern of smoothmuscle proliferation. Abbreviation: mm, muscularis
mucosa. Permission obtained from Macmillan
Publishers Ltd © Bronner (2003)79 Modern
Pathology 16: 359–365.
PJS also predisposes females to development
of cervical adenoma malignum, a rare and very
aggressive adenocarcinoma of the cervix.11 In
addition, females with PJS commonly develop
benign ovarian sex-cord tumors with annular
tubules, whereas males with PJS are predisposed
to development of Sertoli-cell testicular tumors;12
although neither of these two tumor types is
malignant, they can cause symptoms related to
increased estrogen production.
Germline mutations of STK11 are documented
in up to 70–80% of patients with PJS; up to
15% of cases have germline deletions of all or
part of STK11.14 Although the classic clinical and
histopathologic features of PJS might sometimes
obviate the need for genetic testing, analysis of
germline STK11 mutations can be helpful when
the clinical features are subtle or when the histo­
logical diagnosis is in question.15 STK11 encodes
a serine–threonine kinase that modulates cellular
proliferation, controls cell polarity, and seems
to have an important role in responding to low
cellular energy levels.16 In the performance of this
last role, the STK11 protein is involved in the inhi­
bition of AMP-activated protein kinase (AMPK),
and signals downstream to inhibit the mTOR
(mammalian target of rapamycin; also known as
FRAP; FKBP12-rapamycin complex-associated
protein) pathway;17 the mTOR pathway is dysreg­
ulated in patients with PJS and in patients with
PHTS (Figure 3). Genotype–phenotype correlation
suggests that patients with PJS who have mutations
in STK11 that result in truncation of the encoded
STK11 protein have a significantly earlier age of
onset than those who have a missense mutation or
no detectable mutation of STK11.18 Interestingly,
heterozygous Stk11 knockout mice develop
hamartomatous polyps in the stomach and small
intestine, but the predominant malignancy they
develop is hepato­cellular carcinoma, which is not a
malignancy characteristic of human PJS.19
Surveillance recommendations
Surveillance recommendations for the hamarto­
matous polyposis syndromes are based on expert
opinion, but no randomized trials have evaluated
the efficacy of surveillance for the management of
these disorders. The surveillance recommenda­
tions for patients with PJS are complex, and focus
on the increased risk of gastrointestinal, gyneco­
logic, breast, and testicular neoplasms. A strategy
proposed in 2006 by Giardiello and Trimbath is
illustrated in Figure 2.8
Surveillance and management of polyposis of
the small intestine has been markedly improved
PTEN HAMARTOMA TUMOR SYNDROME
Diagnosis and clinical features
The term PHTS was developed to unify the hetero­
geneous group of disorders that are all caused by
germline mutations of the tumor suppressor gene
PTEN.20 PHTS encompasses the dis­­orders Cowden
syndrome, BRRS, and Proteus syndrome. Several
other disorders have also been associated with
germline PTEN mutations, but a detailed discus­
sion of this group of disorders is beyond the scope
of this Review, and the prevalence of polyposis in
many of these disorders is unknown.
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Gastrointestinal polyps/malignancies
Both sexes
UGI endoscopy and small-bowel series every 2–3 years
Colonoscopy every 2–3 years
EUS pancreas +/– CT scan/
CA19–9 every 1–2 years
Breast cancer
Females
Monthly breast self-examination
Annual mammogram and
breast MRI and semi-annual
clinical examination
Benign and malignant ovarian neoplasia
Annual TVUS and CA125
AdenoCA cervix and ovarian neoplasia
Benign ovarian neoplasia
Pelvic examination and Pap smear
Annual Hx and Px
Males
Sertoli tumor testes
Annual Hx and Px
Consider US testes every 2 years
Birth
8 years
12 years
18 years
21 years
25 years
Figure 2 The suggested age-range-specific surveillance recommendations for patients with Peutz–Jeghers
syndrome. Abbreviations: EUS, endoscopic ultrasound; Hx, history; Pap smear, Papanicolaou smear;
Px, physical examination; TVUS, transvaginal ultrasound; UGI, upper gastrointestinal; US, ultrasound.
Adapted from data presented in Reference 8.
Cowden syndrome is an uncommon, underrecognized disorder with an estimated incidence
of 1 per 200,000 of the population, at least in
Europe and North America;21 the syndrome
confers an increased risk of breast, thyroid,
and endometrial cancer. Other features of the
disorder include the following: macrocephaly;
gastrointestinal polyps; benign breast, thyroid,
and endometrial manifestations; and character­
istic mucocutaneous lesions (Table 1). Many of
the benign manifestations are hamartomatous
in nature, and Cowden syndrome has previously
been referred to as the multiple hamartoma
syndrome. Operational diagnostic criteria for
Cowden syndrome are updated annually by the
National Comprehensive Cancer Network.22
BRRS is characterized by the presence of
multiple lipomas, gastrointestinal hamartoma­
tous polyps, macrocephaly, hemangiomas,
developmental delay and, in males, pigmented
macules on the glans penis.23 Formal diagnostic
criteria have not been established.
Proteus syndrome is a complex multisystem
disorder that is characterized by congenital
mal­­formations, hemihypertrophy, hamarto­matous
overgrowths, epidermal nevi and hypero­stosis.24
Historically, it was felt that gastrointestinal
polyps were more commonly seen in patients
with BRRS than in patients with Cowden
syndrome, as these polyps are present in
approximately 50% of patients with BRRS.23 It
is possible, however, that asymptomatic polyps
are at least as common in patients with Cowden
syndrome. Series have suggested that diminu­
tive colonic polyps, mostly present distal to the
hepatic flexure, occur in 60–90% of patients
with Cowden syndrome.25–27 One small study
of patients with this syndrome, which has been
presented in abstract form only, reported that
such polyps have a markedly varied histology,
with adenomatous, juvenile, hyperplastic,
lipomatous, and ganglio­neuro­matous polyps all
being described.26 Whether such varied polyp
pathology is common in patients with Cowden
syndrome is, however, questioned by some in
he field.
Another manifestation of Cowden syndrome
is glycogenic acanthosis. This manifestation is
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P13K
PIP2
PIP3
TSC1
AKT
TSC2
Rapamycin
CCI-779
PTEN
STK11
AMPK
mTOR
Protein synthesis
Angiogenesis
Figure 3 Signaling pathways dysregulated in patients with Peutz–Jeghers
syndrome or PTEN hamartoma tumor syndrome. PTEN and STK11 both
downregulate the mTOR pathway, a growth promoting pathway, which when
dysregulated contributes to the pathogenesis of PJS and PHTS. Both PTEN
and STK11 act indirectly on mTOR through modulation of the TSC1–TSC2
complex upstream of mTOR. By contrast, the mTOR inhibitors, which include
rapamycin and CCI-779, inhibit mTOR directly, downstream of both PTEN and
STK11, making them potentially useful agents for the treatment of both PJS
and PHTS. Abbreviations: AKT, protein kinase B; AMPK, AMP-activated protein
kinase; mTOR, mammalian target of rapamycin (also known as FRAP; FKBP12rapamycin complex-associated protein); PI3K, phosphoinositide-3 kinase; PIP2,
phosphoinositol 4,5-bisphosphate; PIP3, phosphoinositol 3,4,5-trisphosphate;
PHTS, PTEN hamartoma tumor syndrome; PJS, Peutz–Jegher syndrome; PTEN,
phosphatase and tensin homolog, deleted on chromosome TEN; STK11, serine–
threonine protein kinase 11 (also known as LKB1); TSC1, tuberous sclerosis 1
protein; TSC2, tuberous sclerosis 2 protein.
Table 1 Common manifestations of Cowden syndrome.29
Feature
Percentage of patients affected
Mucocutaneous manifestations
Trichilemmomas
Papillomatous papules
Acral keratosis
99%
Breast lesions
Fibrocystic breast disease
Adenocarcinoma
76% of affected females
Macrocephaly
30–40%
Thyroid abnormalities
Multinodular goiter
Adenomas
Thyroid carcinoma (usually follicular)
50–67%
30–50% of affected females
Gastrointestinal lesions
Hamartomatous polyps
Esophageal glycogenic acanthosis
Genitourinary abnormalities
Multiple uterine leiomyomas (fibroids) and/or
bicornuate uterus
One study sought to classify patients with
gastrointestinal polyposis syndromes on the
basis of the germline mutation status of several
genes known to confer predisposition to gastro­
intestinal polyps.15 All the patients studied had
more than five colo­rectal polyps in their life­
time, one of which was either hamartomatous
or hyperplastic. Germline PTEN mutations were
identi­­fied in 2 of the 23 patients (9%) who had a
combination of hyperplastic and adenomatous
polyps. These two patients had features remini­
scent of Cowden syndrome, but did not meet
diagnostic criteria.
Cancer risk
Among the different PHTS disorders, cancer risk
has been clearly documented only in patients
with Cowden syndrome. In female patients the
syndrome is associated with up to a 50% life­
time risk of developing breast cancer25 and a
5–10% risk of developing endometrial cancer.29
The risk of developing breast cancer might also be
increased for male patients with the syndrome,30
and all patients with the syndrome have a 10%
lifetime risk of developing follicular thyroid
cancer.25 The risk of colon cancer associated
with Cowden syndrome is not well characterized.
One case report described a patient with Cowden
syndrome who had a PTEN mutation and meta­
chronous colon carcinomas, both of which
appeared to arise from within hamartomatous
polyps.31 In addition, the authors reported the
presence of a somatic mutation (i.e. the ‘second
hit’ according to the two-hit hypothesis of cancer
development) in PTEN within the carcinoma. In
a large cohort of patients with PTEN mutations, a
modestly increased RR for the development of
colon cancer has been noted (Pilarski R and Eng C,
unpublished data); however, further research is
necessary to confirm this association.
3–10%
Surveillance recommendations
30%
44% of affected females
recognized as elevated gray-white plaques in
the distal mucosa of the esophagus that, on
histo­logical examination, demonstrate epithe­
lial thickening associated with the prolifera­
tion of large glycogen-filled squamous cells.28
Current clinical opinion is that, irrespective of
their phenotype, all patients who have germline
PTEN mutations should be monitored by use of
the surveillance recommendations established
for Cowden syndrome.29 At present, the National
Comprehensive Cancer Network guidelines for
Cowden syndrome make no specific recommen­
dations for gastrointestinal system screening
(Table 2), but rather focus largely on the increased
risk of breast, thyroid and endo­­metrial cancer.22
Nevertheless, these guidelines are updated annu­
ally, and will incorporate screening for colorectal
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Table 2 We do not have permission to reproduce this table
on the website. Please refer to the print issue of the journal.
To view the most recent and complete version of these
surveillance recommendations, go online to www.nccn.org.
cancer if ongoing research confirms that patients
with Cowden syndrome are at an increased risk
of colon cancer.
Genetics
Germline PTEN mutations are found in 85%
of patients with Cowden syndrome and in
more than 60% of patients with BRRS.20,32,33
Mutations have been detected in the promoter
region of PTEN in patients with Cowden
syndrome, whereas deletions of all or part of
PTEN (not normally detectable by conven­
tional polymerase chain reaction) have been
documented in patients with BRRS.34 The
PTEN protein is a ubiquitously expressed, dual­specificity phosphatase that has both lipid and
protein phosphatase activity. The lipid phos­
phatase activity of PTEN is best characterized; its
major substrate is phosphoinositol tri­phosphate.
By regulating the levels of phosphoinositol
triphosphate, PTEN acts as a negative regulator of
the AKT pathway.35 As a tumor suppressor, PTEN
has a crucial role in the control of cell growth,
proliferation and angiogenesis (reviewed by
Waite and Eng36), and somatic PTEN mutations
are prevalent in various malig­nancies.37
september 2007 vol 4 no 9 ZBUK AND ENG Mouse models often provide helpful comple­
mentary insights into the human disease; however,
although mouse models of Pten deficiency are
available their usefulness in helping to dissect the
pathogenesis of human PHTS and/or Cowden
syndrome is limited. Heterozygous Pten+/– mice
develop hamartomatous polyps of the gastro­
intestinal tract, but the spectrum of neoplasia and
malignancies observed bears little resemblance
to that seen with Cowden syndrome; mice often
develop thymic and peripheral lymphomas and
prostate cancer at a young age.35,38
JUVENILE POLYPOSIS SYNDROME
Diagnosis and clinical features
JPS is characterized by the presence of multiple
juvenile polyps. These polyps are named for their
histological appearance and can occur at any age.
The presence of isolated juvenile polyps in the
colorectum is relatively common; up to 2% of chil­
dren who are under 10 years of age have an isolated
juvenile polyp.39,40 The diagnosis of JPS, therefore,
requires the presence of more than three to five
juvenile polyps in the colorectum, or the presence
of juvenile polyps throughout the gastrointestinal
tract, or the presence of any number of juvenile
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cancer might be as high as 40–50%;43 a study by
Brosens et al. demonstrated that, compared with
the general population, patients with JPS have
a RR for colon cancer of 34, with a mean age at
diagnosis of 43 years.48 There are probably also
increased risks of gastric cancer, carcinoma of
the small intestine and possibly pancreatic cancer
associ­ated with JPS, although there were no upper
gastrointestinal malignancies detected in the
cohort described by Brosens et al.43,48
Figure 4 A typical juvenile polyp demonstrating
gland dilatation, inflammatory cell infiltrate and
absence of smooth-muscle proliferation. Permission
obtained from Macmillan Publishers Ltd © Bronner
(2003)79 Modern Pathology 16: 359–365.
polyps in an individual who has a family history of
juvenile polyposis syndrome.41,42 The appearance
of the polyps associated with JPS can be indistin­
guishable from that of those seen in other hamarto­
matous polyposis syndromes (especially those in
Cowden syndrome), and the features of these
syndromes should, therefore, be carefully sought
when evalu­ating a patient with suspected JPS.
On endoscopy, the characteristic juvenile polyp
is spherical in shape, often pedunculated, and has
a smooth and often shiny appearance.1 Juvenile
polyps can reach several centimeters in diameter.
At the microscopic level, these polyps appear as
mucous-filled, dilated glands that are often associ­
ated with inflammatory cell infiltration (Figure 4).41
Unlike the PJS polyp there is no smooth-muscle
proliferation. Most juvenile polyps occur in the
colon and rectum; the frequency of polyps in
the stomach and small intestine is less than 20%,43
although individuals who have SMAD4 muta­
tions (see below) have a much higher frequency of
upper gastro­intestinal polyps than this.44,45 Tens
to hundreds of polyps are often present in affected
individuals, and a diagnosis of JPS is usually
made before a patient reaches 20 years of age.46
Common presenting symptoms include rectal
bleeding, anemia, abdominal pain, obstruction,
and less commonly rectal prolapse of polyps.47
Cancer risk
The predisposition to the development of malig­
nancy conferred by JPS seems to be confined
to malignancies of the gastrointestinal system.
Colorectal cancer is by far the most common
malignancy that develops, and the lifetime risk
of an individual with JPS developing this form of
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Surveillance recommendations
There are several surveillance recommenda­
tions for individuals affected with JPS.43,49 First,
affected individuals should be monitored for rectal
bleeding, anemia, abdominal pain, constipation,
diarrhea, or change in stool size, shape, and/or
color; these symptoms might warrant additional
investigation including endo­­scopy. Second, CBC,
colonoscopy, and upper endoscopy should begin by
the time the affected individual is 15 years of age.
Third, if screening results are negative, screening
should be repeated in 3 years’ time. Fourth, if only a
few polyps are identified, they should be removed;
screening should then be performed annually
until no additional polyps are found, at which
time screening every 3 years can resume. Fifth, if
the polyp burden or dysplastic changes necessitate
colectomy, or gastrectomy/small-bowel resection,
subsequent screening should be performed annu­
ally until no additional polyps are found, at which
time screening every 3 years can resume.
Importantly, there have been families with
SMAD4 mutations described (see below) that
have family members with both JPS and heredi­
tary hemorrhagic telangectasia.50 This situ­ation
indicates the need to screen patients with SMAD4
mutations for occult vascular mal­­formations;
however, a discussion of the details of this is
beyond the scope of this Review.
Genetics
Germline mutations of SMAD4, BMPR1A, and
ENG have all been described in patients with
JPS, and all three genes encode proteins that
are involved in the transforming growth factor
(TGF-)β signaling pathway.15 The TGF-β sign­
aling pathway is an important modulator of many
cellular processes, including proliferation, differ­
entiation and adhesion (reviewed by Waite and
Eng51), and TGF-β itself has a major role in the
control of colonic epithelial growth.52
The importance of the TGF-β pathway in
colon cancer development is illustrated by the
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finding that somatic mutations of the TGF-β
receptor II are present in most colorectal cancers
from patients with Lynch syndrome, and are also
common in sporadic colorectal cancers that exhibit
microsatellite instability. In addition, somatic
mutations in the part of the gene that encodes
the kinase domain of TGF-β receptor II are seen
in approximately 15% of sporadic microsatellite
stable colorectal cancers.53 Somatic mutations of
other members of the TGF-β signaling pathway,
including SMAD2 and SMAD4, are found in
sporadic colon cancers; SMAD4 mutations are
more commonly found in advanced malignancy
or metastasis. Although such mutations occur
only in approximately 15% of sporadic colorectal
cancers, loss of heterozygosity at 18q, the region
containing both of the SMAD2 and SMAD4 loci,
is found in up to 70% of adenocarcinomas and
in at least 10% of early adenomas.54 It is possible,
but yet to be confirmed, that such mutations
occur at increased frequency in patients with JPS,
representing a somatic ‘second hit’ within the
TGF-β pathway.
The prevalences of germline mutations of
BMPR1A and SMAD4 are 20% each in patients
with JPS.55 The prevalence of germline ENG
mutations is currently unknown, but germ­
line ENG mutations seem to predispose to the
develop­ment of JPS in early childhood.15 One
additional study has documented missense varia­
tion in ENG in patients with JPS who are younger
than 10 years of age, but it is not clear whether
these variants are pathogenic.56
In addition, several cases of JPS of infancy,
characterized by generalized polyposis and often
diagnosed in the first 2 years of life, have been
associated with germline deletions that encom­
pass both PTEN and BMPR1A.15,57–59 These
patients’ clinical features often overlap with
those seen in patients with Cowden syndrome
and BRRS. These patients usually present with a
fulminant disease course characterized by intus­
susception, rectal bleeding, and protein-losing
enteropathy, which is often fatal early in life. The
similarity of the polyps associated with JPS and
Cowden syndrome initially led to speculation
that PTEN mutations might cause some cases of
JPS. It is now realized however, that these cases
were in fact Cowden syndrome cases that were
not recognized as such.60,61
Genotype–phenotype correlation analyses
have demonstrated that patients who have
SMAD4 mutations are more likely to develop
massive upper gastrointestinal polyps and have
september 2007 vol 4 no 9 ZBUK AND ENG a family history of upper gastrointestinal poly­
posis than are those patients who have BMPR1A
mutations.44,45 The Smad4+/– mouse exhibits
a phenotype that is similar to that of human
JPS; this mouse develops multiple gastric and
small intestinal polyps that are very similar histo­
logically to juvenile polyps, although no polyps
are seen in the colon.62 Moreover, areas of adeno­
carcinoma are also seen in the stomach and small
intestine. Heterozygous Bmpr1a knockout mice
appear grossly normal,63 while the Eng+/– hetero­
zygous knockout mouse exhibits features of
hereditary hemorrhagic telangiectasia, but does
not develop overt gastrointestinal polyps.64 It
is not clear from the literature, however, how
carefully either of these mice models was exam­
ined for evidence of polyposis, as their generation
preceded by several years the recognition of ENG
and BMPR1A mutations as causes of JPS.
OTHER DISORDERS
Several other disorders are associated with
hamarto­­matous polyps of the gastrointestinal
tract. A detailed discussion of these dis­orders
is not possible in this Review, but they are
mentioned briefly.
Multiple endocrine neoplasia type 2B is
charac­­terized by medullary thyroid cancer, pheo­
chromo­cytoma, marfinoid habitus, and multiple
ganglioneuromas. The ganglioneuromas affect
the gastrointestinal tract in approximately 40% of
affected patients65 and can lead to constipation,
diarrhea, abdominal pain and bowel obstruction.
Similarly, in patients with neurofibro­­
matosis type 1, neurofibromas can involve
the gastro­intestinal tract, and sometimes lead
to gastro­intestinal bleeding and/or abdominal
pain.66 The basal cell nevus syndrome (Gorlin
syndrome), which is characterized by multiple
cutaneous basal cell carcinomas, has been associ­
ated with multiple gastric hamartomatous
polyps,67 but many affected families have no
gastrointestinal manifestations.
Finally, hereditary mixed polyposis is charac­
terized by polyps of mixed histological types,
which include atypical juvenile polyps, hyper­
plastic polyps, sessile serrated adenomas, adeno­
matous polyps. Hereditary mixed polyposis
also confers a predisposition to colorectal carci­
noma.68 Evidence has suggested that in some
families the CRAC1 locus is involved,69 but we
suspect that this syndrome is heterogeneous, as
supported by a report of BMPR1A mutations
occurring in a family with this disorder.49
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review
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TARGETED THERAPEUTICS
The potential of targeted therapies for the treat­
ment of hamartomatous polyposis syndromes
deserves discussion given the relatively robust
molecular characterization of these disorders.
The most promising agents at this point in time
are those that modulate the mTOR pathway,
a target directly relevant to PHTS as well as to
PJS (Figure 3).
The mTOR inhibitor rapamycin has demon­
strated efficacy for the treatment of neoplastic
manifestations of the hamartomatous condi­
tion tuberous sclerosis.70 This condition results
from germline mutations of TSC1 or TSC2, and
the proteins encoded by these genes also down­
regulate the mTOR pathway.70 Rapamycin and
the related drug CCI-779 have been successfully
used as prophylactic treatment for transplant
rejection, and have been studied extensively in
early trials to investigate the treatment of various
malignancies.71 The drugs have proven reason­
ably safe and well tolerated, especially when used
as monotherapy.71 There have, however, been no
published trials on the use of mTOR inhibitors
in hamartomatous polyposis syndromes. Some
preliminary data suggest that cyclo-oxygenase 2
inhibitors might also show promise in the
treatment of both JPS and PJS.72,73
MALIGNANT POTENTIAL OF
HAMARTOMATOUS POLYPS
The malignant potential of hamartomatous
polyps is not known and is an important and
unresolved issue. For JPS and Cowden syndrome
there has been documentation of patients who
have both adenomatous and hamartomatous
polyps, and malignant transformation might be
occurring within adenomatous polyps in this
situation.15 An alternative hypothesis is that
hamartomatous polyps might undergo adenoma­
tous followed by carcinomatous transformation,
or possibly transform directly from hamartomas
to carcinomas.2,74,75
In patients with PJS, PHTS, or JPS hamarto­
matous polyps have been detected that contain
areas of adenoma and/or carcinoma.2,31,75,76
Hamartomatous polyps have traditionally been
viewed as nonmalignant, and in the case of PJS
it has been argued that germline STK11 muta­
tions lead to altered cell polarity, which results in
mucosal prolapse.77 In this model, the hamarto­
matous polyp develops as an epiphenomenon
and is nonneoplastic; the occurrence of cancer
or adenomas within a hamartomatous polyp is
500 nature clinical practice GASTROENTEROLOGY & HEPATOLOGY
© 2007 Nature Publishing Group
coincidental. Abnormalities in cell polarity are
believed to underlie the predisposition to malig­
nancy, possibly through the association between
altered cell polarity and expansion of the stem cell
compartment of the colon.78 Similar debate exists
regarding the malignant potential of juvenile
polyps in patients with JPS. Further research is
necessary to resolve these conflicting hypo­theses.
CONCLUSIONS
Advances in the understanding of the genetic
etio­logies of the hamartomatous polyposis
syndromes has led to the availability of clinical
genetic testing, which has revolutionized the
practice of cancer genetics for these disorders,
and has important implications for affected
individuals and at-risk family members. An
important challenge will be to determine the
underlying pathomechanisms involved for those
affected patients who have no currently identifi­
able genetic mutation. Such efforts will not only
benefit the small number of patients affected by
these disorders, but will also serve to increase
knowledge of the mechanisms underlying the
development of sporadic malignancies.
Key points
■ Hamartomatous polyposis syndromes are inherited
autosomal-dominant syndromes that confer
predisposition to cancers and have divergent
clinical features, but often involve interconnected
molecular pathways
■ Juvenile polyposis syndrome is caused by germline
mutations of SMAD4, BMPR1A and ENG, and it
predisposes individuals to colon cancer, and, to a
lesser extent, upper gastrointestinal malignancies
■ Cowden syndrome, the most common PTEN
hamartoma tumor syndrome, is caused by
germline PTEN mutations and is characterized
by benign and malignant breast, thyroid and
endometrial manifestations, in addition to
macrocephaly and characteristic mucocutaneous
findings
■ Peutz–Jeghers syndrome is caused by germline
STK11 mutations and is associated with a
markedly increased risk of gastrointestinal, breast
and gynecologic malignancies
■ Timely diagnosis of hamartomatous polyposis
syndromes allows for appropriate surveillance
and management, which varies considerably
between syndromes
■ Clinical testing for germline mutations should occur
in the setting of appropriate genetic counseling and
offer predictive testing for family members
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Acknowledgments
KM Zbuk is a Crile Fellow of
the Cleveland Clinic, USA.
C Eng is a recipient of the
Doris Duke Distinguished
Clinical Scientist Award and
is supported by grants from
the US National Institutes of
Health, US National Cancer
Institute and the American
Cancer Society.
Désirée Lie, University
of California, Irvine, CA,
is the author of and is
solely responsible for the
content of the learning
objectives, questions and
answers of the Medscapeaccredited continuing
medical education activity
associated with this article.
Competing interests
The authors declared no
competing interests.
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