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23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
Table 23.1 (continued)
Polyposis syndromes
Syndrome Gene(s)
SPS Unknown Serrated
Nonpolyposis syndromes
Lynch
syndrome
Familial
CRC type X
With permission from Kalady MF, Heald B.Diagnostic approach to hereditary colorectal cancer syndromes. Clin Colon
Rectal Surg. 2015;28(4):205–14. © Thieme
FA P familial adenomatous polyposis, MAP MUTYH-associated polyposis, JPS juvenile polyposis syndrome, PJP
Peutz-Jeghers polyposis, PHTS PTEN hamartoma tumor syndromes, SPS serrated polyposis syndrome, CRC colorectal
cancer, HHT hereditary hemorrhagic telangiectasia, AD autosomal dominant, AR autosomal recessive
MLH1,
MSH2,
MSH6, PMS2,
EPCAM
Unknown Adenoma AD Amsterdam criteria positive,
Main polyp
type Inheritance Predominant clinical ndings
polyps
Adenoma AD Microsatellite-unstable CRC, advanced
Unknown >20 serrated polyps;
Any serrated polyp and family history
of SPS;
>5 serrated polyps proximal to the
sigmoid, 2 are >1cm diameter
adenomas; gastric, duodenal, small
bowel, transitional cell, gall bladder,
pancreas, endometrial, and ovarian
cancer
microsatellite-stable tumors
Approximate
CRC risk
25–40%
60–80%
12%
305
Adenomatous Polyposis Syndromes
Familial Adenomatous Polyposis
Clinical Presentation
• FAP is an autosomal-dominant inherited disease
that occurs in approximately 1 in 10,000 live
births and affects both genders equally and all
races. The hallmark feature of FAP is colorectal
adenomatous polyposis, but the phenotype varies per patient, even within the same family.
• Severe FAP is characterized by thousands of
colorectal adenomas. Often times there is little
normal mucosa between the adenomatous polyps. Mild polyposis is described as having
between 100 and 1000 colorectal adenomas.
Patients with fewer than 100 adenomas are
considered to have attenuated FAP.Figure23.3
provides an example of moderate to severe
polyposis.
• Nearly 100% of patients with FAP will
develop CRC if left untreated.
• FAP is a multisystem disease and may present
with various extracolonic lesions. Two specic subtypes of FAP are based on a specic
constellation of extracolonic manifestations.
Fig. 23.3 Moderate to severe polyposis in the resected
specimen of a 22-year-old woman with familial adenomatous polyposis
Gardner’s syndrome is FAP with desmoid
tumors, osteomas, epidermoid cysts, or
extranumery teeth. Turcot’s syndrome is FAP
associated with malignant tumors of the central nervous system. Both syndromes are also
caused by mutations in APC.
Underlying Genetics
• FAP is caused by an inherited mutation in the
APC gene on chromosome 5q21. As patients
306
are born with only one functional copy of the
“gatekeeper” gene, loss of the second allele
via sporadic mechanisms leads to rapid development of hundreds to thousands of colorectal
adenomas.
• More than 850 different mutations have been
described, most of which produce a stop
codon that ceases protein translation which
yields a truncated APC protein. Depending on
the location of the “stop,” the truncated protein has variable functional abilities, likely
accounting for some of phenotypic variation
seen with different mutations. About 25% of
patients with FAP have a “de novo” mutation
and thus have no family history.
Diagnosis
• FAP may be diagnosed genetically or clinically. Genetic testing reveals an APC germline
mutation in approximately 80% of cases.
Indications for genetic counseling referral and
testing include a family history of FAP, personal history of more than ten adenomas, personal history of adenomas, and an extracolonic
manifestation of FAP.
• For at-risk individuals in families with a
known mutation, genetic testing is directed for
that mutation.
• Approximately 20% of patients will not have
an identied germline mutation but still have
the clinical phenotype.
CRC Risk
• FAP carries a near 100% CRC risk. Cancers
develop at a median age of 39. The goal of
surveillance and intervention is to reduce the
risk of death from colorectal cancer via
colectomy or proctocolectomy before cancers
develop. The risk of CRC in attenuated FAP is
approximately 70%, and cancers develop at a
relatively later age (average 58 years) compared to classical FAP.
FAP Extracolonic Manifestations
• Upper gastrointestinal tract: Approximately
90% of patients with FAP develop duodenal
adenomas. Despite the high incidence of adenomas, only about 5–10% of patients will
M. F. Kalady and Y. NancyYou
Fig. 23.4 Different manifestations of desmoid disease.
(a) Abdominal wall desmoid occurring 1year after total
proctocolectomy for familial adenomatous polyposis. (b)
Resected abdominal wall desmoid. (c) Large intra-abdominal desmoid arising from the root of the small bowel mesentery. (d) Sheetlike desmoid tumor arising in the
mesentery with associated desmoid reaction (Photos in (c)
and (d) courtesy of Dr. James Church)
develop periampullary cancer. Non-neoplastic
gastric fundic gland polyps are a common
nding, occurring in about 50% of patients.
These have a minimal risk of malignancy.
Rare gastric cancers in FAP are felt to develop
from gastric adenomas that form in the gastric
antrum in about 10% of FAP patients.
• Desmoids: Desmoid disease affects approximately 5% of patients with FAP.About half of
FAP-associated desmoid tumors arise intraabdominally in bowel mesentery, and 40%
develop in the abdominal wall. The remainder
presents in the back, neck, or limbs. Desmoids
can manifest as at, brous, sheet-like lesions
or as dened discrete masses (see Fig.23.4).
• Thyroid cancer: Although the risk of thyroid
cancer in FAP is only 2%, it doubles the risk
of that for the general population. The incidence is 17 times higher in women than in
men, and it develops at a young mean age of
27 years. The primary histology is papillary
carcinoma.
• Other malignant tumors: There are several
rare extracolonic malignant tumors associated
with FAP that have a higher incidence than the
general population. These include pancreatic
adenocarcinomas (relative risk 4.5, lifetime
risk 1.7%), hepatoblastoma in children (RR
23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
307
7500–7500, absolute risk 2%), and medulloblastoma (RR 7, lifetime risk 0.025%).
• Other benign lesions: Several benign lesions
are associated with FAP that do not necessarily require intervention but can be used to help
make a diagnosis. Congenital hypertrophy of
the retinal pigment epithelium (CHRPE) is
characterized as well-delineated grayish-black
or brown oval spots seen in 60–85% of FAP
patients. Bony lesions including dental abnormalities and mandibular and skull osteomas
are found in approximately 20% of patients.
Multiple cutaneous and subcutaneous lesions
are associated with FAP including epidermoid
cysts, lipomas, and bromas. These are
benign, and intervention is not necessary
unless they cause symptoms. The presence of
these on the face, scalp, and extremities rather
than on the back in young patients should
raise suspicion for possible FAP.
Management
Screening
• Colorectal: The goal of colorectal screening
and surveillance in FAP is to limit CRC risk by
timely intervention and surgical referral.
Screening should be done on all individuals
with a genetic diagnosis or in rst-degree relatives of persons with a clinical diagnosis of
FAP.If no genetic mutation is found in a family but they have a clinical diagnosis, all rstdegree relatives should be screened. Screening
begins at age 12 and can be initiated with exible proctosigmoidoscopy. If polyps are seen, a
full colonoscopy is warranted. If no polyps are
identied on the initial proctosigmoidoscopy,
the exam should be repeated every 1–2years
or earlier if symptoms develop. For those without a genetic diagnosis, rst-degree relatives
who are not found to have any polyps by age
40 can safely be transitioned to screening
guidelines for the general population.
• Duodenal and gastric: Upper gastrointestinal
endoscopic screening is a key part of FAP disease management. Screening is done with a
side-viewing endoscope and should begin at
age 20–25 years. Screening intervals are
Table 23.2 Scores of duodenal adenoma characteristics
and management recommendations according to
Spigelman criteria
Duodenal disease grading scale (points assigned)
Assigned
points
Number of
polyps
Size of
polyps
(mm)
Histology Tubular Tubulovillous Villous
Dysplasia Mild Moderate Severe
Recommendations based on Spigelman score
Total points Spigelman
0 0 Repeat endoscopy in
1–4 I Repeat endoscopy in
5–6 II Repeat endoscopy in
7–8 III Repeat endoscopy in
9–12 IV Surgical evaluation
1 2 3
1–4 5–20 >20
1–4 5–10 >10
Recommendation
stage
5years
5years
2–3years
6–12months
based on the Spigelman staging system
(Table23.2).
• Desmoids: There are no recommendations for
routine screening for desmoid disease.
• Thyroid: Annual thyroid screening by ultrasound should be recommended to FAP
patients.
Treatment
Colorectal
• The goals of FAP treatment are to remove or
limit the CRC risk while maximizing quality
of life. As CRC is near certain, surgical
removal is the mainstay of treatment.
Timing ofSurgery
• Patients with symptoms should be offered surgery both to treat the symptoms and to prophylactically treat potential occult cancer. For
asymptomatic teenagers with FAP, surgery
can be reasonably delayed until the late teen
years or early twenties when they have reached
physical and emotional maturity. CRC before
the age of 20 is extremely rare and is usually
308
M. F. Kalady and Y. NancyYou
accompanied by symptoms. Since cancer risk
increases with age, patients diagnosed in their
third decade or beyond should be offered surgery at the time of diagnosis.
• Delaying surgery in an asymptomatic patient
with low polyp burden may be considered in
specic circumstances: women who wish to
have children and avoid the risk of decreased
fecundity following proctectomy; morbidly
obese patients who wish to lose weight to
make restorative proctocolectomy with ileal
pouch-anal anastomosis (IPAA) a more feasible option; and patients who have desmoids in
their family, as most desmoids develop after
surgery. Deferral of surgery should only be
done in patients who are asymptomatic, motivated, and adherent to surveillance protocols.
Extent ofResection
• For patients without evidence of rectal cancer,
surgical options include colectomy with ileorectal anastomosis (IRA) or total proctocolectomy (TPC) with or without restoration of
gastrointestinal tract. Decisions are made
based on balancing future cancer risk with
quality of life associated with bowel function,
as valued by both the patient and surgeon.
TPC removes all or nearly all at-risk mucosa
and almost completely eliminates future CRC
risk. Restoration of the gastrointestinal tract
via an ileal pouch-anal anastomosis (IPAA)
results in more frequent bowel movements,
higher incidence of incontinence, and
decreased quality of life compared to colectomy and IRA.The improved function of an
IRA is countered by cancer risk in the residual
rectum. Patient selection is key to minimizing
risk. An IRA is the preferred approach for
patients who have a relatively low colorectal
polyp burden. Conversely, APC mutations at
codons 1309 and 1328 are associated with
severe polyposis and are independent risk factors for proctectomy after TAC in FAP.
• For patients who develop rectal cancer, total
proctocolectomy should be performed with
restoration of the gastrointestinal tract via an
IPAA when possible. In the presence of stage
IV disease with limited life expectancy, a
proctectomy alone may be considered if there
is no cancer in the colon and the polyp burden
is minimal or controlled. If the rectal cancer is
locally advanced and radiotherapy is required,
it should be utilized in the preoperative period
or not at all, especially if a restorative proctocolectomy is planned, as postoperative radiotherapy is associated with toxicity and risk of
ileal pouch loss. If an IPAA is not planned,
and radiotherapy is not given preoperatively,
an omental pedicle ap or pelvic inlet mesh
should be considered to occlude the small
bowel from the pelvis in case postoperative
radiotherapy is unexpectedly required.
• In the presence of colon cancer and metastatic
disease, decisions regarding whether to proceed
with proctocolectomy instead of just colectomy
should be based on the likelihood of cure and
risk of metachronous cancer in the rectum if left
in situ. Patients with locally advanced primary
tumors (or those with possible metastatic disease) with minimal rectal polyp burden may be
better served by abdominal colectomy and IRA
(or proctocolectomy and ileostomy) versus
restorative proctocolectomy– where complications of surgery are more common and may
delay administration of adjuvant chemotherapy.
• Debate exists over the use of mucosectomy
and handsewn anastomosis versus doublestapled anastomosis during TPC and IPAA as
a means of reducing the risk of subsequent
rectal cancer. Mucosectomy to the dentate line
theoretically removes all colorectal mucosa at
risk for neoplasia. However, this technique
potentially fails if an incomplete mucosectomy results in residual mucosal cells, which
are present in up to 20% of patients. This risk
must be balanced against the cancer risk from
a small anal transition zone that remains following a stapled IPAA.It may be preferable to
have any at-risk mucosa in the lumen of the
gut, where it can be observed over time, rather
than implanted outside the ileal pouch at the
time of mucosectomy, where it cannot be
observed. In cases of rectal dysplasia or rectal
cancer, many clinicians advocate mucosectomy, although denitive data regarding
reduction in cancer risk are lacking.
23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
309
Duodenal Adenomas
• Duodenal adenomas can progress to cancer,
but this rate is relatively low, and, as such, the
lesions can usually be managed endoscopically. The Spigelman staging system estimates
duodenal cancer risk based on several factors
as given in Table23.2. Early-stage lesions may
safely be surveyed with low risk of cancer.
However, those with Spigelman stage IV disease have a 36% risk of adenocarcinoma.
Adenocarcinoma, persistent or recurrent highgrade dysplasia, or Spigelman stage IV disease
warrants consideration of surgery. Surgical
options include pancreaticoduodenectomy or
pancreas-preserving duodenectomy.
Desmoid Disease
• Staging and medical therapy. Desmoid disease can be clinically devastating and is the
second cause of death in FAP.Clinically, presentation ranges from asymptomatic to severe
pain, obstruction, or stulization. Treatment
depends on symptoms, desmoid location, size,
and extent of disease. Church has proposed a
staging system for abdominal desmoids
(Table 23.3). The Cleveland Clinic uses this
staging system to guide medical management.
Stage I desmoids are either observed or treated
with a nonsteroidal anti-inammatory drug
such as sulindac (150–200 mg twice daily).
Stage II desmoid treatment includes sulindac
and antiestrogen therapy, such as raloxifene
(60 mg twice daily). Stage III desmoids are
usually treated with chemotherapy agents
such as methotrexate and vinorelbine or Doxil.
Stage IV desmoids are difcult to control and
Table 23.3 Proposed intra-abdominal desmoid disease
clinical staging system
Disease
stage Clinical characteristics
I Asymptomatic disease, not growing,
and<10cm in maximum diameter
II Minimally symptomatic and not growing
or>10cm in maximum diameter
III Symptomatic disease, slowly growing, or
obstructive complications
IV Symptomatic disease and rapidly growing
or severe complications (e.g., stula)
are treated with more aggressive anti-sarcoma
chemotherapy such as Doxil or Adriamycin.
Although desmoid tumors are radiosensitive,
the close proximity to the small bowel limits
its use due to toxicity.
• Surgical therapy. Surgery for abdominal desmoids is usually reserved for treatment of disease complications such as bowel obstruction,
enterocutaneous stula, and ureteric obstruction. If possible, resection to negative margins
is the goal. Intra-abdominal tumors are frequently located at the root of the small bowel
mesentery and are often not resectable due to
the proximity to critical small bowel blood
supply. Surgery is usually the rst-line treatment for symptomatic abdominal wall desmoids. Due to the location, these tumors are
usually able to be safely resected with minimal complications. The defect in the abdominal wall may need to be closed with tissue
aps or mesh.
Thyroid Neoplasia
• Thyroid disease may be detected in FAP by
evaluation of symptoms or routine ultrasound
screening. Since cancers tend to be multifocal,
patients with thyroid cancer should be considered for total thyroidectomy and radioiodine
ablation.
Evaluation ofAt-Risk Relatives
• As FAP is autosomal dominantly inherited, all
rst-degree relatives of an FAP patient have a
50% chance of also having the disease.
Therefore, all rst-degree relatives in an FAP
family should be evaluated. Due to the implications of both positive and negative results,
pretest counseling, preferably with a genetic
counselor, should be done. Potentially affected
family members should be evaluated at the
time of diagnosis or for children, when they
reach the age of 12.
• If the proband (rst affected relative) has a
known APC mutation, then germline DNA
testing of at-risk relatives is appropriate.
• If the proband does not have a detectable
mutation, then genetic testing for APC mutations in the family is not indicated. At-risk
310
M. F. Kalady and Y. NancyYou
relatives should undergo screening by colonoscopy. For at-risk children, exible sigmoidoscopy should be considered at age
12years. Subsequent testing intervals for children depend on ndings at the initial proctosigmoidoscopy. If polyps are seen, a full
colonoscopy is warranted. If no polyps are
identied, the exam should be repeated every
1–2years or earlier if symptoms develop. For
those families without a genetic diagnosis,
rst-degree relatives who are not found to
have any polyps by age 40 can safely be transitioned to screening guidelines for the general population.
MUTYH-Associated Polyposis
Clinical Presentation
• The syndrome is primarily characterized by
multiple colorectal adenomas and an increased
risk for CRC at a younger age (40s–50s), but
the colorectal polyp phenotype is highly variable. Moderate polyposis (less than 100 adenomas) is the most common phenotype.
Polyposis is not necessary for an MAP diagnosis and as many as 20% of patients present
with colorectal cancer without a history of
colorectal polyps or synchronous polyps.
• Despite the similar colorectal phenotype to
FAP, patients with MAP are less likely to have
the extracolonic manifestations that are commonly seen in FAP. Approximately 20% of
patients with MAP will have duodenal polyposis, and gastric fundic polyps are rare.
Osteomas, desmoids, and CHRPE are not
associated with MAP.
Underlying Genetics
• MAP is the only hereditary CRC syndrome
with an autosomal recessive inheritance pattern, and thus family history may help guide
counseling and testing in patients who are suspected of having MAP. MAP is caused by
inherited biallelic mutations in the MUTYH
gene, which codes for a base excision repair
protein. Approximately 1–2% of the general
population carries a MUTYH mutation.
Diagnosis
• MAP diagnosis is conrmed by genetic testing for mutations in the MUTYH gene.
Germline MUTYH testing should be offered to
patients who have a recessive pattern of family history of colorectal cancer or polyposis,
who have a clinical phenotype of FAP or
attenuated FAP but test negative for an APC
mutation, or who have a personal history of
>10 colorectal adenomas. Nearly 30% of
patients with a clinical phenotype of FAP
without an identied APC mutation have biallelic MUTYH mutations.
CRC Risk
• The cumulative lifetime risk of developing
colorectal cancer for patients with biallelic
MUTYH mutations is estimated at 75% for
males and 72% for females by age 70. Onset
of cancer is earlier than sporadic colorectal
cancer, with the mean age of diagnosis
reported between 45 and 56years old.
• The risk of CRC for monoallelic MUTYH carriers continues to be dened. Data from the
Colon Cancer Family Registry estimate the
cumulative lifetime risk of developing CRC
for people with monoallelic MUTYH mutations at 7.2% for males and 5.6% for females
by age 70.
Extracolonic Cancer Risk
• The spectrum of extracolonic neoplasia in
MAP continues to be dened. An increased
risk of upper gastrointestinal polyps and cancers is consistently reported. About 17% of
cases have duodenal adenomas with a lifetime
duodenal cancer risk of 4%. The overall incidence of malignancy outside the gastrointestinal tract is 38%, almost double that of the
general population. The most common
extraintestinal cancers are bladder, ovarian,
and skin cancers with standard incidence
ratios of 7.2, 5.7, and 2.8, respectively. Some
23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
311
studies report an increased risk of thyroid cancer and sebaceous gland tumors.
Management
Screening
• Most cases of MAP are diagnosed at the time
of CRC detection. In the rare cases when an
individual is diagnosed with biallelic MUTYH
mutations but does not have an indication for
colectomy, colonoscopy screening should
begin at age 25–30 years. If no neoplasia is
identied on the exam, it should be repeated
every 3–5 years with consideration for
decreasing the interval with advancing age.
Any polyps found on colonoscopy should be
removed and examined histologically. When
polyps are present, the interval is shortened to
1–2years depending on the ndings. Patients
with a polyp burden that cannot be controlled
endoscopically should be referred for consideration of colectomy.
• Esophagoduodenoscopy with side-viewing
gastroscope should be performed to evaluate
for duodenal adenomatous neoplasia. This
screening should start at age 30 years and
repeated every 3–5years if the exam is normal.
For patients with duodenal adenomas, management is similar to the recommendations for
FAP patients with duodenal adenomas. The
American College of Gastroenterology also
recommends annual thyroid ultrasound screening in patients with MAP.
• There is no consensus regarding screening for
monoallelic carriers. Some clinicians have
suggested screening these people by colonoscopy every 5years, beginning 10years earlier
than the youngest patient aficted with CRC
in the family.
noscopy. Surgical options include total
abdominal colectomy, subtotal colectomy, or
proctocolectomy. A segmental colectomy may
be considered in certain circumstances such as
metastatic cancer or medical comorbidities
that preclude extended resection. Any remaining colorectum should be surveyed annually,
with removal of subsequent polyps.
• Despite the recommendation to consider subtotal or total abdominal colectomy for patients
with curable colon cancer, and proctocolectomy for patients with curable rectal cancer,
there are no prospective data that show
extended resection reduces the risk of death
from metachronous colorectal cancers. It is
unlikely that denitive studies will be performed, given the rarity of the diagnosis.
Evaluation ofAt-Risk Relatives
• As this syndrome is autosomal recessive,
patients must have two abnormal alleles to
manifest the disease. Different from other
inherited colorectal cancer syndromes, it is the
siblings of patients with MAP that are at
greatest risk, rather than the parents or chil-
dren. Each sibling of an affected individual
has a 25% chance of also having the disease.
• Genetic counseling and testing for specic
MUTYH mutation in the family should be
offered at the age of 18years to reduce morbidity and mortality through early diagnosis
and treatment. Children of biallelic patients
will be at least a monoallelic carrier.
Approximately 1% of the general population is
a monoallelic carrier. If the spouse of the
affected patient is a carrier, then each offspring
has a 50% chance of having MAP. Therefore,
the partner of the affected patient should be
tested to evaluate risk to the offspring.
Treatment
• The phenotype dictates treatment in
MAP. Indications for surgery include CRC,
high-grade dysplasia in an adenoma that cannot be removed endoscopically, or a polyp
burden that cannot be safely managed by colo-
Polymerase Proofreading-Associated Polyposis
A new syndrome has recently been reported as
polymerase proofreading-associated polyposis
312
M. F. Kalady and Y. NancyYou
(PPAP). This syndrome continues to be dened
and has only been characterized in a few families.
It is inherited in an autosomally dominant fashion
and caused by a germline mutation in proofreading regions of one of two DNA polymerases,
POLE and POLD1. The clinical phenotype is one
of oligo-adenomatous polyposis and early-age
CRC and endometrial cancer. Guidelines are in
evolution, but expert opinions support surveillance via colonoscopy every 1–2years starting at
age 20–25 and EGD every 3years. For females
with a POLD1 mutation, endometrial cancer
screening by ultrasound is recommended starting
at age 40years.
Hamartomatous Polyposis Syndromes
• Hamartomas are non-neoplastic growths of an
abnormal mixture of tissue that is normally
found at that anatomic site. Juvenile polyps
and Peutz-Jeghers polyps are hamartomatous
polyps in the small bowel and colorectum.
Although these lesions are generally not considered neoplastic, they can be the hallmark of
inherited hamartomatous polyposis syndromes such as juvenile polyposis syndrome
(JPS), Peutz-Jeghers syndrome (PJS), and the
PTEN hamartoma tumor syndrome (PHTS).
These syndromes are rare but clinically
important as they predispose to colorectal and
other cancers.
Juvenile Polyposis Syndrome
Clinical Presentation
• Juvenile polyps are usually round, smooth,
cherry-red lesions that are often pedunculated
on a long stalk. An abundance and overgrowth
of the lamina propria with mucin-lled spaces
are the characteristic histologic features.
Chronic inammatory cells are often seen
which can lead to an inaccurate diagnosis of
inammatory polyp. Juvenile polyps occur
throughout the gastrointestinal tract including
the stomach, small bowel, colon, and rectum,
starting in the rst or second decade of life.
The number of polyps varies from a few to
hundreds. Symptoms are related to the polyps
and most commonly include acute or chronic
gastrointestinal bleeding, iron-deciency anemia, prolapsed rectal polyps, abdominal pain,
or diarrhea.
• JPS is also associated with extracolonic congenital malformations such as cardiac and cranial abnormalities, duplication of the renal
pelvis, cleft palate, gut malrotation, and polydactyly. JPS along with a SMAD4 mutation
may present as hereditary hemorrhagic telangiectasia (HHT). HHT may manifest with skin
and mucosal telangiectasias; cerebral, pulmonary, and hepatic arteriovenous malformations; and an increased risk of associated
hemorrhage.
Underlying Genetics
• JPS is an autosomal dominantly inherited disease caused by germline mutations in
BMPR1A or SMAD4. About 60% of JPS cases
are familial, while the remaining 40% occur
sporadically.
Diagnosis
• JPS diagnosis is based on clinical criteria
which include the following: (1) more than
ve juvenile polyps of the colon or rectum, (2)
juvenile polyps in the extracolonic gastrointestinal tract, or (3) any number of juvenile
polyps and a positive family history. Patients
who satisfy any of these criteria should be
offered genetic counseling and genetic testing.
A causative germline mutation is identied in
approximately 50% of cases.
CRC andExtracolonic Risk
• JPS patients have an approximately 50% lifetime CRC risk, with reports of varying incidence between 17% and 68%. The mean age
of CRC diagnosis is 43years, but CRC may
develop at a young age, and there is a case
report of CRC in a 15-year-old patient. The
stomach, duodenum, pancreas, and jejunum
are at increased risk for cancer in JPS. The
risk of gastric or duodenal cancer is 15–21%.
23 Molecular Basis ofColorectal Cancer andOverview ofInherited Colorectal Cancer Syndromes
313
SMAD4 associations are associated with a
higher risk of extracolonic cancer compared to
patients with BMPR1A mutations.
Management
Screening
• Screening by colonoscopy should begin at age
12–15, or earlier if symptoms are present. The
interval between colonoscopies depends on
the exam ndings. If there are no polyps, colonoscopy should be repeated in 2–3years. Any
polyps seen should be removed at colonoscopy and examined histologically. When polyps are present and removed, colonoscopy
should be done annually until an exam is clear,
after which, the interval may be extended to
every 2–3 years. Upper gastrointestinal
screening should begin between ages 15 and
25 or earlier if symptoms develop. Endoscopic
management principles follow those as given
for adenomas of the upper GI tract.
Treatment
• Surgical indications include the presence of
high-grade dysplasia or cancer, or if the polyp
burden cannot be effectively managed endoscopically. Prophylactic colectomy may be
considered for patients with poor surveillance
compliance or those with a family history of
CRC.For colorectal disease, surgical options
include colectomy and ileorectal anastomosis,
subtotal colectomy with ileosigmoid anastomosis, or total proctocolectomy.
• Surgery for the upper gastrointestinal tract is
indicated for signicant symptoms, malignancy, or development of protein-losing gastropathy or enteropathy. For gastric disease,
subtotal gastrectomy is usually done. For
small bowel disease, treatment is segmental
resection.
tion, then siblings of the parent as well as siblings of the proband should be tested as they
have a 50% chance of also having the mutation. Children of the proband should also be
tested after counseling and testing in the early
teenage years. If a mutation is not found in the
family, at-risk individuals should be initially
screened for gastrointestinal polyps and followed accordingly based on results.
Peutz-Jeghers Syndrome
Clinical Presentation
• Nearly 90% of PJS patients will develop hamartomatous polyps, most commonly in the
small bowel, followed by the colon, stomach,
and rectum in decreasing frequency. Polyps
vary in size from a few millimeters to several
centimeters and tend to become pedunculated
as they grow larger.
• Peutz-Jeghers polyps differ histologically
from juvenile polyps in that they arise due to
an overgrowth of the muscularis mucosa,
rather than the lamina propria. They have less
inammatory inltrate and less mucin than
juvenile polyps. Multiple branching of the
muscularis mucosa gives the histologic
appearance of a tree under the microscope.
• Although the polyp burden is usually low
(<20), the larger size of the polyp often causes
symptoms of obstruction, pain, gastrointestinal bleeding, polyp prolapse peranus, or small
bowel intussusception. Symptoms usually
develop by the teen years or early twenties.
• The classical extraintestinal lesion seen in PJS
is benign mucocutaneous pigmentation, which
is present in approximately 95% of cases. The
pigmentation is usually a small, dark-brown
or blue-brown macule that is obvious in
infancy but may fade in adolescence.
Evaluation ofAt-Risk Relatives
• If a specic mutation is identied in an individual, all at-risk family members should be
counseled and tested for that mutation.
Approximately 75% of patients will have an
affected parent. If a parent carries the muta-
Underlying Genetics
• PJS is autosomal dominantly inherited and
caused by germline mutations in STK11. This
gene encodes a member of the serine/threonine kinase family, which functions as a tumor
suppressor.
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M. F. Kalady and Y. NancyYou
Diagnosis
• PJS is a clinical diagnosis based on meeting
any one of the following World Health
Organization criteria: (1) three or more histologically conrmed Peutz-Jeghers polyps, (2)
any number of Peutz-Jeghers polyps with a
family history of PJS, (3) characteristic, prominent, mucocutaneous pigmentation with a
family history of PJS, or (4) any number of
Peutz-Jeghers polyps and characteristic prominent, mucocutaneous pigmentation. An individual meeting any of the above criteria should
be offered genetic counseling and testing.
CRC andExtracolonic Risk
• Patients with PJS have an increased risk of
developing colorectal and extracolonic cancers. PJS patients have more than 90% estimated lifetime risk of developing cancer of
some type. The risk for developing breast,
colon, pancreatic, and gastric cancer is 54%,
39%, 36%, and 29%, respectively. In addition,
males are at risk for Sertoli cell testicular
tumors and women for sex cord tumors with
annular tubules of the ovary and adenoma
malignum of the cervix.
Management
Surveillance
• Given the broad spectrum of disease in PJS,
surveillance is complex and includes multiple
organs. Randomized controlled trials have not
been performed to evaluate the efcacy of
cancer surveillance protocols, and published
recommendations are based on expert
opinion.
• The NCCN recommends starting screening at
age 8–10 years via evaluation of the small
bowel, with the interval exam based on ndings. If initial exam is normal, then the repeat
evaluation is recommended at age 18 years
and then at 2–3year intervals. Males should
undergo annual testicular physical examination starting at age 10 years, and females
should undergo annual pelvic examination
and Papanicolaou stain starting at age
18–20years. Women should have breast phys-
ical examinations every 6months and yearly
mammogram and breast MRI starting at age
25years. Colonoscopy and upper endoscopy
should be in the late teens and repeated every
2–3years for both genders. Pancreatic cancer
screening involves endoscopic ultrasound or
MRCP along with serum CA19-9 every
1–2years starting at age 25–30years.
Polypectomy
• Endoscopic intervention plays a key role in
the management of PJS. Polypectomy treats
polyp-related symptoms and prophylactically
prevents development of symptoms. As with
the surveillance guidelines, intervention recommendations are based on expert opinion.
Asymptomatic gastric or colonic polyps larger
than 1cm should be removed endoscopically.
Small bowel polyps larger than 1–1.5cm or
those that have grown rapidly from prior exam
should be removed to decrease future complications such as bleeding and intussusception.
Some symptomatic polyps may be beyond the
reach of conventional endoscopy, and intervention may require push enteroscopy or combined laparoscopy/laparotomy with endoscopy
in the operating room, which allows guidance
of the endoscope further distally into the small
bowel.
Surgery
• Surgery is most commonly reserved for symptoms, the most common being obstruction and
bleeding in the small bowel. Obstruction is
often caused by intussusception. Most cases
resolve spontaneously, but if the obstruction
persists more than a few hours, surgery is
required. The goal of surgery is to remove the
affected segment, preserving as much bowel
as possible. If surgery is required, a “clean
sweep” at surgery is recommended to reduce
the need for future operations. This technique
involves evaluating the entire small bowel and
removing all polyps. An endoscope may be
placed through the open resection ends of the
bowel or via an enterotomy.
• As in the other syndromes, the development of
high-grade dysplasia, colorectal cancer, or an