330

Hamartomatous Polyps and Associated

Syndromes
Molly M. Cone, MD1

1 Division of Colon and Rectal Surgery, Department of General Surgery, Address for correspondence Molly M. Cone, MD, Division of Colon and
Vanderbilt University Medical Center, Nashville, Tennessee Rectal Surgery, Department of General Surgery, Vanderbilt University
Medical Center, 1161, 21st Avenue South, D5248 MCN Nashville, TN
Clin Colon Rectal Surg 2016;29:330–335. 37232 (e-mail: [email protected]).

Abstract Hamartomatous polyps of the gastrointestinal tract can occur sporadically, however, for
Keywords several hereditary syndromes, their presence is one of the major clinical features. Peutz–
► hamartomatous Jeghers syndrome, juvenile polyposis syndrome, and the PTEN hamartoma syndromes

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polyposis are autosomal dominant inherited disorders that predispose to formation of such
► Peutz–Jeghers polyps, especially in the colon and rectum. These can lead to increased colorectal cancer
syndrome risk and should be followed and managed appropriately. In this article, the three major
► juvenile polyposis hereditary hamartomatous syndromes are described, including presentation, colorectal
► PTEN surveillance, and management.

Hamartomatous polyp syndromes are a group of hereditary colorectal cancer (CRC). There are several hypotheses for the
conditions that include hamartomatous polyps of the gastroin- mechanism by which hamartomatous polyps become malig-
testinal tract as one of their more prominent features. The term nant. First is that it follows a hamartoma-carcinoma sequence,
hamartoma was introduced in 1904 by German pathologist similar to adenoma-carcinoma, in that a polyp grows larger,
Albrecht1 stemming from the Greek word hamartia, translated dysplasia develops, followed eventually by invasive carcinoma.
as “a failure,” meaning a tumor made from malformed cells, However, there is little known molecular data to support this
considered a developmental error. A hamartoma resembles a theory.4 A second theory is that cancer results not from the
neoplasm, but grows at the same rate as normal cells.2 The first polyps themselves, but from asymmetrical stem cell divisions,
histologic description of a colonic hamartoma is attributed to leading to altered stem cell lineage turnover rates and acceler-
Horrilleno et al in 1957 who stated that they are “characterized ated progression to cancer. In Peutz–Jeghers polyps, the progen-
by a proliferation of both glandular and stromal elements, itor zone in the intestinal crypts is expanded, which contributes
usually associated with marked vascularity and variable to this process.5 A third hypothesis is based on the idea that
amounts of cellular infiltration composed of lymphocytes, plas- hamartomatous polyps may develop foci of adenomas, which
ma cells, and polymorphonuclear leukocytes with a frequent then can proceed to malignant degeneration.6
preponderance of eosinophils.”3 Most hamartomatous polyps of the colon and rectum,
The umbrella of hamartomatous polyposis covers a rare occur in the setting of an inherited syndrome, but they can
group of genetic disorders, including Peutz–Jeghers syn- also be sporadic. In the pediatric population, solitary juvenile
drome (PJS), juvenile polyposis syndrome (JPS), and PTEN hamartomatous polyps are the most common type encoun-
hamartoma tumor syndromes which, in turn, encompasses tered during colonoscopy (70.5% of polyps found).7 In adults,
Bannayan–Riley–Ruvalcaba syndrome (BRRS) and Cowden Mesiya et al did a retrospective analysis of sporadic hamar-
syndrome (CS). Hamartomatous polyps can also occur tomas in their colonoscopy patients over an 11-year period.
sporadically, unrelated (to the best of our knowledge) to They found that 0.15% of patients had sporadic hamartomas
the aforementioned syndromes. with a mean age of diagnosis at 55 years, and that the most
Hamartomatous polyps can cause symptoms of bleeding or common indication for colonoscopy in these patients was
intussusception and obstruction as they are best known to do in rectal bleeding (68%). The majority of these polyps were
PJS, however, these syndromes also carry an increased risk of located in the rectosigmoid, and 36% of patients had a

Issue Theme Colorectal Polyps and Copyright © 2016 by Thieme Medical DOI http://dx.doi.org/
Polyposis Syndromes; Guest Editor: Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0036-1582441.
Paul E. Wise, MD, FACS, FASCRS New York, NY 10001, USA. ISSN 1531-0043.
Tel: +1(212) 584-4662.
 Hamartomatous Polyps and Associated Syndromes Cone 331

concomitant adenomatous polyp. In all those affected, there

was only one hamartomatous polyp per person.8 Sporadic,
singular hamartomatous polyps are not thought to confer an
increased risk of cancer.9

Peutz–Jeghers Syndrome
In 1921 Peutz published an original report on his observations of
two brothers, as well as a study of the literature to date,
associating intestinal polyps with skin and mucosal pigmenta-
tions transmitted via a pattern of inheritance.10 Jeghers et al then
chronicled their experience with similar patients, helping to
distinguish the syndrome as a distinct entity.11
Clinical features of PJS include mucocutaneous melanic
pigmentation and intestinal polyposis. To diagnose PJS, a
patient must have two or more hamartomatous polyps in
the gastrointestinal tract or have a family history of PJS with

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either one confirmed PJS polyp or typical perioral pigmenta-
tion.6 PJS polyps are most prevalent in the small intestine
(range, 70–95%) but may also be present in the large intestine
(range, 24–50%) and stomach (25%). Polyps typically develop
Fig. 1 Peutz–Jeghers polyp histology. While large colonic Peutz–
around the time of early adolescence. They also have been
Jeghers polyps may contain abundant smooth muscle fibers, smaller
reported to form in the nares, pelvis, gall bladder, urinary polyps (as shown here) typically show areas of epithelial overgrowth
bladder, and lungs.12,13 The other well-known manifestation is relative to the stroma with large branching crypts. In contrast to
the perioral pigmentation, which often predates polyp forma- juvenile polyps, there is little inflammation in crypts or stroma. (Image
tion. Typically described as dark blue to dark brown macules courtesy of Dr. Kay Washington.)
that appear around the mouth, eyes, nostrils, perianal area, and
on the buccal mucosa, these lesions tend to fade with age.12 risk, to date, there is no surveillance protocol that has been
The incidence of PJS is reported to be around 1/120,000 shown to decrease cancer incidence or increase survival.15
and is inherited in an autosomal dominant pattern.14 The Thus, surveillance guidelines are empiric and based on the
only identified genetic mutation associated with PJS is in the risk of gastrointestinal complications and cancer.18 Specifi-
LKB1 gene (also known by the Human Genome Organization cally for gastrointestinal cancers, surveillance should include
name STK11, as discussed in the article “Polyp Genetics” a colonoscopy and upper endoscopy every 2 to 3 years
by Drs Klos and Dharmarajan, on pp. 289–295), located on beginning in the late teens. Also, recommended is a small
chromosome 19p13.3 and is found in at least 75% of PJS bowel visualization with a computed tomography or magnet-
patients, thus suggesting additional unidentified gene loci ic resonance imaging enterography starting at the age of
leading to the other 25%. With approximately 55% of patients 10 years and repeated every 2 to 3 years.19 Additional
having an identified affected parent, the rate of de novo PJS recommendations published by the American College of
may be as high as 45%.15 Gastroenterology (ACG) in their 2015 practice guidelines
The PJS polyp displays characteristic histologic morpholo- include an initial upper endoscopy and colonoscopy begin-
gy to help distinguish it from other hamartomatous polyps. ning at the age of 8 years. If there are polyps that are
Microscopically, there is a prominent arborizing pattern of endoscopically manageable then surveillance should contin-
smooth muscle derived from the underlying muscularis ue every 3 years. If there are no polyps, then surveillance
mucosae. Some PJS polyps demonstrate a phenomenon called should restart at the age of 18 years and continue every
enteritis cystica profunda, also called pseudoinvasion or 3 years. Similarly, a capsule endoscopy is recommended for
epithelial misplacement. This can simulate invasive adeno- the small bowel. There are also recommendations for surveil-
carcinoma but is a benign process. ►Fig. 1 depicts a micro- lance of the pancreas, breast, ovary/uterus/cervix, and
scopic view of a PJS polyp. testicular tumors that can be accessed on the National
The perceived increase in risk for development of cancer in Comprehensive Cancer Network (NCCN) Web site or through
patients with PJS has changed over time. Estimates as low as 2 the ACG practice guidelines.18,19
to 3% for intestinal cancer were published in a 1974 JAMA Treatment of PJS polyps includes endoscopic removal of
article.16 However, in a meta-analysis published by Giardiello polyps, and newer adjuncts such as double balloon entero-
et al in 2000, the cumulative risk of developing any cancer in scopy make the reach of endoscopic therapy greater. If the
PJS by age 64 is 93% with a cumulative risk of CRC of 39%.17 colonic polyps are not able to be managed endoscopically, or if
Other cancers associated with PJS include foregut, pancreatic, neoplastic changes are found, then total abdominal colectomy
breast, gynecologic, testicular, and lung.6,13 with ileorectal anastomosis should be considered (assuming
Because of the markedly increased risk of cancer, surveil- the polyps are not in the rectum, in which case total procto-
lance is very important in patients with PJS. Despite this high colectomy may be indicated).18

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332 Hamartomatous Polyps and Associated Syndromes Cone

Familial Juvenile Polyposis Syndrome Clinical features of JPS include multiple juvenile hamartom-
atous polyps in the intestinal tract and histologic features
In 1939, the first confirmed JPS patient was described by which are demonstrated in ►Fig. 2. A patient may have
Diamond. After symptoms of constipation and hematochezia, minimal symptoms, or may complain of bleeding, obstruction,
a 30-month-old child was found to have a large prolapsing polyp or diarrhea. Anemia and potentially protein-losing enteropa-
in the rectum.20 In 1948, another child was described as having thies can also be a consequence of JPS-associated polyposis.12
juvenile polyps throughout the stomach, colon, and rectum,21 Specifically, the SMAD4 mutation may give rise to a combined
and in 1962 British pathologist Morson was the first to define the juvenile polyposis-hereditary hemorrhagic telangiectasia
histologic difference between juvenile, Peutz–Jeghers, adenoma- (HHT) syndrome,25,26 so screening for associated vascular
tous, and solitary/inflammatory polyps.22 lesions within the first 6 months of life is recommended
JPS is inherited in an autosomal dominant pattern with with this mutation. A clinical diagnosis of JPS is considered
approximately 75% of the patients having a family history of when they meet at least one of the three criteria: at least three
JPS, the remainder are thought to be de novo.23 The inci- juvenile polyps of the colon; multiple juvenile polyps found
dence is between 1/100,000 to 1/160,000 people.18 Two throughout the gastrointestinal tract; and/or any number of
genetic mutations have been identified in patients with JPS juvenile polyps with a family history of JPS.19
including in SMAD4 and BMPR1A. Both the genes are part of Intestinal cancer in patients with JPS has been reported for
the transforming growth factor/bone morphogenetic years, but there was hesitancy to propose that the hamar-

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protein (BMP) signal pathway,12,24 as discussed earlier in tomatous polyps themselves increased this risk.27 In 1978,
this issue. Liu et al published a case report of a 16-year-old male patient

Fig. 2 Juvenile polyp histology. (a) Low power: Juvenile polyps are rounded and contain abundant stroma in addition to cystically dilated crypts.
(b) High power: The dilated crypts are lined by columnar to flattened colonic epithelium and may contain numerous inflammatory cells. (Image
courtesy of Dr. Kay Washington.)

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 Hamartomatous Polyps and Associated Syndromes Cone 333

with JPS who had a hamartomatous juvenile polyp with a to be two distinct conditions, recent literature supports them
focus of signet ring cell carcinoma.28 Since that time there are representing one condition with variable expression and
several additional publications that provide evidence that penetrance. Lachlan et al showed that both conditions can
juvenile polyps do have malignant potential. Similar to other be caused by the same mutation in the same gene, can be
hamartomatous syndromes, there are speculations about the present in different members of the same family, and have
pathway to carcinogenesis. Subramony et al showed that in many clinical features in common.33 The mutation is inher-
juvenile polyps < 1 cm, the histology was of a juvenile polyp, ited in an autosomal dominant fashion. Similar to the other
but in polyps between 1 and 2.9 cm, there was an increased hamartomatous syndromes, the polyps found in the PTEN
incidence of epithelium with mild-to-moderate dysplasia, syndromes were historically not thought to increase malig-
and if the polyp was > 3 cm, the majority of the polyps nancy in the colon and rectum.32 Now it is believed to
were lined by mostly dysplastic epithelium which closely increase the risk of CRC by 9 to 16% with an average age at
resembled adenomas.29 Overall, the estimated lifetime risk of diagnosis of 44 to 48 years. Colorectal polyp prevalence is as
CRC varies in JPS, but published rates range from 38 to 68% high as 90% in patients with PTEN mutations.32 The histology
with the lifetime risk of gastric cancer being 21%.30,31 of polyps found includes most commonly hamartomas (29%)
Surveillance recommendations as per the NCCN and ACG but also ganglioneuromas, adenomas, and inflammatory
practice guidelines include a colonoscopy and upper endos- polyps.18 The specific morphology of a PTEN polyp can be
copy at age 12 to 15 years and repeated annually if polyps are seen in ►Fig. 3.

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found. If no polyps are found, it should be repeated every 2 to Clinically, macrocephaly is the most consistent feature
3 years. In patients with known SMAD4 mutations, screening seen in patients with a PTEN mutation with 80 to 100% of
for vascular lesions associated with HHT should begin within patients expressing this trait.33 Looking at the component
the first 6 months of life. Similar to PJS, if the colonic polyps conditions separately, BRRS is usually diagnosed in childhood
are unable to be controlled endoscopically or demonstrate and is often accompanied by delayed motor and intellectual
malignant degeneration, a total abdominal colectomy or total development.33 The general criteria that have been used
proctocolectomy with or without reconstruction is historically for diagnosis of BRRS include macrocephaly,
recommended.18,19 hamartomas (including at least one lipoma, hemangioma,
or intestinal polyp), and pigmented macules of the glans
penis in males.6,33 However, with the recent change in
PTEN Hamartoma Tumor Syndromes
thinking to encompass all PTEN abnormalities under the
The phosphatase and tensin homolog gene located on chro- same heading, BRRS and CS can be diagnosed clinically by
mosome 10 is also known as PTEN. PTEN is a tumor suppressor the revised PTEN hamartoma tumor syndrome diagnostic
gene that is active in many pathways involved in cellular criteria outlined in ►Table 1.19,34
growth.32 The most commonly reported conditions caused by CS is thought to be the most common of the PTEN
a mutation in this gene are CS and BRRS. At one time thought syndromes with a prevalence estimate of 1/200,000 to 1/

Fig. 3 PTEN/Cowden polyp histology. Hamartomatous polyps in Cowden syndrome may resemble juvenile polyps but are often relatively
nondescript. In this example, the polyp contains slightly distorted crypts in a fibrotic lamina propria. (Image courtesy of Dr. Kay Washington.)

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334 Hamartomatous Polyps and Associated Syndromes Cone

Table 1 Revised PTEN hamartoma tumor syndrome clinical diagnostic criteria

Major criteria Minor criteria

Breast cancer Autism spectrum disorder
Endometrial cancer (epithelial) Colon cancer
Thyroid cancer (follicular) Esophageal glycogenic acanthuses ( 3)
GI hamartomas (including ganglioneuromas, Lipomas ( 3)
but excluding hyperplastic polyps;  3)
Lhermitte–Duclos disease (adult) Intellectual disability (i.e., IQ  75)
Macrocephaly ( 97th percentile) Renal cell carcinoma
Macular pigmentation of the glans penis Testicular lipomatosis
Multiple mucocutaneous lesions (any of the following): Thyroid cancer (papillary or follicular variant of papillary)
• Multiple trichilemmomas (3) Thyroid structural lesions (adenoma, multinodular goiter)
• Acral keratosis (3 palmoplantar keratotic pits and/or acral
hyperkeratotic papules) Vacular anomalies (including multiple intracranial
• Mucocutaneous neuromas (3) developmental venous anomalies)

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• Oral papillomas, multiple (3) OR biopsy proven OR dermatol-
ogist diagnosed
Operational diagnosis in and individual (either of the following):
1. Three or more major criteria, but one must include macrocephaly, Lhermitte–Duclos disease, or GI hamartomas
2. Two major and three minor criteria
Operational diagnosis in a family where one individual meets revised PHTS clinical diagnostic criteria or has a PTEN mutation
(any of the following):
1. Any two major criteria with or without minor criteria
2. One major and two minor criteria
3. Three minor criteria

Abbreviations: GI, gastrointestinal; IQ, intelligence quotient; NCCN, National Comprehensive Cancer Network; PHTS, PTEN hamartoma tumor
syndrome.
Source: Adapted from NCCN guidelines and Pilarski et al.19,34

250,000.32 It is generally diagnosed in adulthood. This age polyps are generally not a major feature. These include heredi-
difference from BRRS is likely because children with macro- tary disorders such as neurofibromatosis type 1 (von Reck-
cephaly and no learning or motor problems are unlikely to linghausen disease) that can demonstrate gastrointestinal
come to medical attention at an early age and thus simply ganglioneuromatosis (a type of hamartoma). Most gastroin-
demonstrates a variable presentation based on the age of testinal involvement is usually incidental and asymptomatic.12
developing signs and symptoms. Multiple endocrine neoplasia type 2B can also demonstrate
For surveillance of the PTEN hamartoma tumor syndromes, gastrointestinal ganglioneuromatosis in up to 40% and can
there is some discrepancy in recommendations. According to the become symptomatic.12 Basal cell nevus syndrome (BCNS),
ACG practice guidelines, a colonoscopy should be done at least also called Gorlin syndrome, is characterized by multiple basal
every 2 years, starting at age 15, which is similar for endoscopy of cell carcinomas and other cancers such as medulloblastoma.
the upper gastrointestinal tract. Additionally, the thyroid, breast, Multiple gastric hamartomatous polyps have been described in
uterus, kidneys, and skin (for melanoma) should be surveyed. BCNS, however, the polyps are not a major characteristic and
These recommendations are based on expert opinion.18 The most families have no gastrointestinal manifestations.12 The
NCCN guidelines site category 2A evidence (lower-level evi- hereditary mixed polyposis syndrome is made up of a
dence, uniform NCCN consensus that the intervention is appro- variety of colorectal tumors, including atypical juvenile polyps,
priate) and suggest colonoscopy starting at age 35 and repeated hyperplastic/serrated polyps, adenomas, and carcinomas.12
every 5 years or more frequently if symptomatic or polyps are Cronkhite–Canada Syndrome is also characterized by hamar-
found.19 They also have recommendations for breast, tomatous polyps in the intestinal tract, but this is not heredi-
uterus, thyroid, kidney, and skin surveillance. Again, similar to tary and appears to be more autoimmune or inflammatory in
the other syndromes, colectomy should be performed for endo- nature.12,13 It is a very rare syndrome with an estimated
scopically uncontrollable polyps, high grade dysplasia, or cancer. incidence of one per million and is characterized primarily
by diffuse hamartomatous polyps of the gastrointestinal tract,
cutaneous hyperpigmentation, dystrophic involvement of the
Other Syndromes
fingernails, and alopecia. Because of its rarity, there is little
There are several other documented syndromes that have been data for optimal screening, but annual endoscopic evaluation is
associated with hamartomatous polyps, but the colorectal generally recommended.35

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 Hamartomatous Polyps and Associated Syndromes Cone 335

Chemoprevention 15 Riegert-Johnson D, Gleeson F, Westra W, et al. Peutz-Jeghers

Syndrome. In: Riegert-Johnson D, Boardman L, Hefferon T, Roberts
There are no current recommendations for chemoprevention in M, eds. Cancer Syndromes. Bethesda, MD: National Center for
Biotechnology Information; 2009
the hamartomatous polyposis syndromes. While difficult to
16 Reid JD. Intestinal carcinoma in the Peutz-Jeghers syndrome. JAMA
study with their infrequent incidence, there is ongoing thought 1974;229(7):833–834
and research for potential targets to reduce polyp growth and 17 Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of
progression. For JPS, COX-2 may be a target, and for PJS, COX-2 or cancer in familial Peutz-Jeghers syndrome. Gastroenterology
mTOR may be targets. For PTEN hamartoma tumor syndrome, 2000;119(6):1447–1453
18 Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW;
the P13K, AKT1, mTOR, or PDK1 pathways may be targets for
American College of Gastroenterology. ACG clinical guideline: Genetic
chemoprevention or therapeutic interventions.36 Further stud-
testing and management of hereditary gastrointestinal cancer syn-
ies are ongoing looking at each of these pathways as targets for dromes. Am J Gastroenterol 2015;110(2):223–262, quiz 263
therapies for each of these hamartoma syndromes. 19 National Comprehensive Cancer Network. Genetic/familial high-
risk assessment: Colorectal 2015. Available at: http://www.nccn.
org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed
September 18, 2015
Acknowledgment
20 Diamond M. Adenoma of the rectum in children report of a case in
I would like to thank Kay Washington, MD, PhD of the a thirty month old girl. Am J Dis Child 1939;57(2):360–367
Vanderbilt Department of Pathology for the images and 21 Ravitch MM. Polypoid Adenomatosis of the Entire Gastrointestinal

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their descriptions. Tract. Ann Surg 1948;128(2):283–298
22 Morson B. Some peculiarities in the histology of intestinal polyps.
Dis Colon Rectum 1962;5(5):337–344
23 Calva D, Howe J. Juvenile Polyposis. In: Riegert-Johnson D, Board-
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