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COLON
271
Surveillance Colonoscopy after Endoscopic Resection of a Malignant Polyp
alignant polyp is a polyp with invasive cancer invading the
A m
submucosa (pT1). An invasive adenocarcinoma arising in a
pedunculated or sessile polyp may be adequately treated by endoscopic en bloc polypectomy alone if the cancer invades only the
submucosa and possesses favorable histologic features. Favorable histologic features include well or moderately differentiated
tumors, absence of lymphatic or vascular invasion, and negative
resection margins. If any adverse histologic features are noted,
the risk of lymph node involvement is increased substantially and
surgical resection is required. If the lesion is removed piecemeal
and the adequacy of resection cannot be confirmed, surgical
resection should also be considered. National recommendations
for the postpolypectomy intervals for persons who have adenomas with invasive cancer and favorable prognostic features may
be as short as 3 to 6 months to ensure that no residual polyp tissue
remains.
Surveillance Colonoscopy in Patients with Colorectal Cancer
S
urveillance of patients with resected CRC has two potential roles.
One is the detection of recurrences of the primary cancer at an early
stage, allowing curative treatment, and the second is the detection
of metachronous colorectal neoplasms. Colonoscopy performed at
annual or shorter intervals has not been shown to provide a survival
benet in persons with colon cancer, likely because of the relatively
low rates of anastomotic or intraluminal recurrence (2% to 4% in
the case of colon cancer), and because the majority of recurrences
detected are incurable. erefore, the primary benet of surveillance
colonoscopy is detecting and resecting metachronous neoplasms,
particularly in the rst 2 years aer surgical resection.
Patients with colon cancer that has been resected to achieve a
cure should undergo a high-quality preoperative colonoscopy to rule
out synchronous lesions. According to the USMSTF, in the case of
an obstructive cancer, the colonoscopy should be performed 3 to 6
months aer surgery if no unresectable metastasis was found during
surgery. Subsequent surveillance colonoscopy should be performed 1
year aer surgical resection or aer the initial colonoscopy that was
performed to clear the colon of synchronous neoplasia. If results are
normal, the colonoscopy is repeated at 3 years, and if ndings of that
colonoscopy are normal, then the subsequent examination should be
performed in 5 years.
Many clinicians distinguish between rectal and colon cancer
because local recurrence rates for rectal cancer can be 10 times that
of colon cancer. e USMSTF recommends that patients treated with
low anterior resection for rectal cancer undergo endoscopic ultrasound or exible sigmoidoscopy at 3- to 6-month intervals for the
rst 2 years aer resection for the purpose of detecting a surgically
curable recurrence.
Surveillance Colonoscopy in Patients with
Inflammatory Bowel Disease
P
atients with inflammatory bowel disease are at increased risk of
CRC. The degree of risk depends on the duration and anatomic
extent of the inflammation. After 10 years of pancolitis, the risk
of CRC has been reported to rise by 0.5% to 1% per year. The
ACG recommends annual or biannual surveillance colonoscopy
after 8 to 10 years of colitis or after 12 to 15 years of left-sided
colitis. Patients with primary sclerosing cholangitis and ulcerative
colitis have an increased risk of CRC, and a colonoscopy is advisable at the diagnosis of primary sclerosing cholangitis and then
annually.
Surveillance Colonoscopy in Patients with a Family History of Colorectal Cancer or Adenomatous Polyps
atients with a family history of either CRC or adenomatous pol-
P
yps in a first-degree relative before age 60 years or in 2 or more
first-degree relatives at any age should begin colonoscopy at age
40 years or 10 years before the youngest case in the family. The
recommended interval for colonoscopy is every 5 years if the
examination is normal. In patients with a family history of either
CRC or adenomatous polyps in a first-degree relative after age 60
years or in more than two second-degree relatives, it is recommended that screening begin with any average-risk option. The
ACG advocates colonoscopy every 10 years as the preferred CRC
screening strategy, and in this group, it recommends beginning at
age 50 years rather than at the USMSTF suggested age of 40 years.
The interval for colonoscopy should be altered according to the
size, number, and pathologic features of lesions detected on each
examination.
WHEN SHOULD SCREENING
AND
SURVEILLANCE STOP IN THE
AVERAGE-RISK POPULATION?
W
ith age, the risk of colonoscopy increases and its benets wane.
Both screening and surveillance should stop when the risk outweighs
the benet. e USPSTF recommends against screening in patients
85 years or older and suggests individualized decisions in patients
between 75 and 85 years based on patient comorbidities and life
expectancy. e USMSTF recognizes that persons with advanced
neoplasia are at an increased risk of metachronous CRC and are a
group that could benet from colonoscopy aer the age of 85 years.
Decisions about ongoing colonoscopy need to be individualized.
CONCLUSION
C incidence and mortality have been steadily declining in the
CR
United States, which is attributed to increases in the use of CRC
screening and removal of colorectal polyps. Colonoscopy every 10
years is considered the gold standard CRC prevention screening test
but must be considered within the preference of the patient. e optimal and most eective screening test is the one that is actually performed. Randomized controlled trials demonstrate both a reduction
in CRC incidence and mortality with the use of fecal occult blood
testing and exible sigmoidoscopy.
Ultimately, the eectiveness of screening depends on adherence and the performance of high-quality examinations. It is recommended that all endoscopists monitor key colonoscopy quality
indicators.
g g e
u
S
A
hlquist DA, Zou H, Domanico M, etal. Next-generation stool DNA test ac-
curately detects colorectal cancer and large adenomas. Gastroenterology.
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Allison JE, Sakoda LC, Levin TR, et al. Screening for colorectal neoplasms
with new fecal occult blood tests: update on performance characteristics.
J Natl Cancer Inst. 2007;99(19):1462–1470.
Atkin W, Dadswell E, Wooldrage K, etal. Computed tomographic colonog-
raphy versus colonoscopy for investigation of patients with symptoms
suggestive of colorectal cancer (SIGGAR): a multicentre randomised trial.
Lancet. 2013;381(9873):1194–1202.
Atkin WS, Edwards R, Kralj-Hans I, etal. Once-only exible sigmoidoscopy
screening in prevention of colorectal cancer: a multicentre randomised
controlled trial. Lancet. 2010;375(9726):1624–1633.
Baxter NN, Goldwasser MA, Paszat LF, etal. Association of colonoscopy and
death from colorectal cancer. Ann Intern Med. 2009;150(1):1–8.
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Corley DA, Jensen CD, Marks AR, etal. Adenoma detection rate and risk of
colorectal cancer and death. N Engl J Med. 2014;370:1298–1306.
Davila RE, Rajan E, Adler D, etal. ASGE guideline: the role of endoscopy in
the diagnosis, staging, and management of colorectal cancer. Gastrointest
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Hawkins NJ, Ward RL. Sporadic colorectal cancers with microsatellite insta-
bility and their possible origin in hyperplastic polyps and serrated adenomas. J Natl Cancer Inst. 2001;93(17):1307–1313.
Kaminski MF, Regula J, Kraszewska E, etal. Quality indicators for colonosco-
py and the risk of interval cancer. N Engl J Med. 2010;362(19):1795–1803.
Kim DH, Pickhardt PJ, Taylor AJ, etal. CT colonography versus colonoscopy
for the detection of advanced neoplasia. N Engl J Med. 2007;357(14):
1403–1412.
Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer
pathogenesis. Gastroenterology. 2010;138(6):2088–2100.
Levin B, Lieberman DA, McFarland B, etal. Screening and surveillance for
the early detection of colorectal cancer and adenomatous polyps, 2008: a
joint guideline from the American Cancer Society, the US Multi-Society
Task Force on Colorectal Cancer, and the American College of Radiology.
Gastroenterology. 2008;134(5):1570–1595.
Lieberman DA, Rex DK, Winawer SJ, etal. Guidelines for colonoscopy sur-
veillance aer screening and polypectomy: a consensus update by the
US Multi-Society Task Force on Colorectal Cancer. Gastroenterology.
2012;143(3):844–857.
Pohl H, Srivastava A, Bensen SP, et al. Incomplete polyp resection during
colonoscopy-results of the complete adenoma resection (CARE) study.
Gastroenterology. 2013;144(1):74–80.e1.
Rex DK, Johnson DA, Anderson JC, etal. American College of Gastroenter-
ology guidelines for colorectal cancer screening 2009 [corrected]. Am J
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Robertson DJ, Lieberman DA, Winawer SJ, etal. Colorectal cancers soon aer
colonoscopy: a pooled multicohort analysis. Gut. 2014;63(6):949–956.
Schoen RE, Pinsky PF, Weissfeld JL, et al. Colorectal-cancer incidence
and mortality with screening exible sigmoidoscopy. N Engl J Med.
2012;366(25):2345–2357.
Segnan N, Armaroli P, Bonelli L, etal. Once-only sigmoidoscopy in colorectal
cancer screening: follow-up ndings of the Italian randomized controlled
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ventive Services Task Force Recommendation statement. Ann Intern Med.
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Zauber AG, Winawer SJ, O’Brien MJ, et al. Colonoscopic polypectomy
and long-term prevention of colorectal-cancer deaths. N Engl J Med.
2012;366(8):687–696.
G
M
C C
INTRODUCTION
ancer is a disorder of cellular growth and differentiation that is
C
due to a loss of function of regulatory pathways and feedback loops.
Colorectal cancer is an excellent example of this mechanism because
access via colonoscopy to the spectrum of premalignant lesions in
the colon and rectum allows demonstration and study of the process.
Sporadic colorectal cancer arises from pre-existing benign lesions
that begin small and gradually enlarge as they transition histologically
and biologically toward cancer via an adenoma-carcinoma or a serrated polyp-carcinoma sequence. In 1988, Bert Vogelstein published
a sequence of genetic abnormalities that appeared to correlate with
the histologic adenoma to carcinoma sequence. Subsequent research
has conrmed Vogelstein’s observations and has expanded knowledge and understanding of the genetics of colorectal carcinogenesis.
It is now known that at least three dierent genetic mechanisms lead
to colorectal cancer, producing cancers of dierent biology. Understanding the molecular genetics of colorectal neoplasia is important.
Fostering an understanding of the molecular genetics of colorectal
neoplasia is the purpose of this chapter.
GROWTH CONTROL
N
ormal cell growth is regulated tightly by multiple redundant systems that are conserved from one species to another. Multiple dysfunctional genetic events need to accumulate in an epithelium before
clinical eects of growth deregulation are noticeable. Each colorectal
cancer is genetically unique and has accumulated mutations in an
average of 90 dierent genes. Only a small number of these mutations
are driver mutations, which are responsible for the carcinogenesis.
Most are “passenger” mutations.
Normal cell growth is a balance between proteins that stimulate
(coded for by proto-oncogenes) and proteins that inhibit (coded for
by tumor suppressor genes). When that balance is disturbed, carcinogenesis can occur. Tumor suppressor genes and proto-oncogenes
are organized into various signal transduction pathways that react
to extracellular signals and transmit them to the cell nucleus, where
an appropriate response is generated. Four main signal transduction
pathways are involved in colorectal adenocarcinoma: wnt/wingless,
epidermal growth factor (EGF), transforming growth factor (TGF)-β,
and p53-mediated cell cycle arrest/apoptosis and DNA repair. Al l must
be inactivated or overstimulated for cancer to develop. Overstimulation occurs by mutation or DNA hypomethylation. Inactivation of
tumor suppressor genes happens through mutations, chromosomal
instability (loss of heterozygosity), and DNA hypermethylation.
Mutations are permanent structural changes in genes. ese
changes may have no eect on gene function (coding of their protein;
called polymorphisms), or they may be deleterious, with an impact on
function. Mutations may be inherited (the cause of hereditary colorectal cancer) or acquired. ey may be acquired as a result of lifestyle or
James M.
vironmental factors (e.g., smoking and drinking alcohol), chance,
en
or defects in DNA repair. Because each cell has two copies of each
gene, both copies of a tumor suppressor gene must be inactivated for
gene expression to be lost. e time taken to inactivate both copies
from environmental or lifestyle causes is one reason why carcinogenesis in the colon takes so long to occur. When one copy is lost as a result
of inheritance of a mutation, the time for inactivation is reduced.
Chromosomal instability is reected in loss of heterozygosity—
that is, chromosomal events by which chromosomal instability allows
chromosomal deletion or rearrangements, including nondisjunction, duplication, or translocation. e function of the genes on the
re a
rrangedchromosomes may be lost. Mutations in
chromosomal instability, the most common molecular mechanism in
colorectal cancer (70% of cancers are a result of chromosomal instability) and a characteristic of hereditary cancers in FAP, MYH-associated polyposis, and polymerase proofreading polyposis (Table 56-1).
Hypermethylation inactivates genes by abrogating expression. e
gene is structurally normal, but the addition of extra methyl groups
to CpG base pairs in the gene promoter stops expression and production of the protein. DNA methylation is a normal phenomenon
and a way in which gene expression is controlled to suit the changing
needs of organ function. Hypomethylation, leading to unstable DNA,
was one of the early causes of colorectal carcinogenesis described by
Vogelstein. However, it is promoter hypermethylation that plays a
key role in the production of colorectal cancer via the histologic precursor of serrated polyps. About 15% to 18% of sporadic colorectal
cancers arise in this way. ey are known as CpG island methylation
phenotype (CIMP) cancers.
Church
APC c
an promote
DNA REPAIR
ach time a cell divides, the DNA is replicated. e delity of rep-
E
lication is extremely important to preservation of a normal cell line
and is protected by a series of DNA repair mechanisms. Loss of DNA
repair results in mutations as the unrepaired DNA is transmitted into
daughter cells, potentially aecting hundreds of genes. ree types
of DNA repair are involved in colorectal carcinogenesis: mismatch
repair, base excision repair, and polymerase proofreading. Defective
DNA mismatch repair is seen as a dominantly inherited phenomenon in Lynch syndrome and as a sporadic cause of microsatellite
instability in 15% to 18% of colorectal cancers. Microsatellite instability results from unrepaired mismatches in DNA microsatellites, a
cause of mutations in multiple genes.
CLINIC
e molecular prole of any colorectal cancer is relevant to clinical
care because the cancer biology is set by the mechanisms of carcinogenesis. Chromosomal instability causes aneuploid cancers that
AL SIGNIFICANCE
273
274
Molecular Genetics of colorect
cancer
al
TABLE 56-1: Mechanisms of Colorectal Carcinogenesis
Mechanism Cause of the Mechanism Initiating Mutation Driv
hromosomal instability APC mutation APC APC, KRAS, SMAD4,
C
ers
TP53 mutations; loss of
heterozygosity
% Sporadic Colorectal
Cancers
60% colon, 90% rectum
Chromosomal instability Defective DNA polymer-
POLD1, POLE APC <1%
ase proofreading
Chromosomal instability GC:AT transversions MYH APC, KRAS 1%-2%
Methylation CpG island methylation ? BRAF, MLH1 18%
Microsatellite instability DNA mismatch repair
dysfunction
Defective DNA Repair Sporadic Mutation
MLH1, PMS2, MSH2,
MSH6
COMPLEXITY
APC, TGFβIIR 18%
is chapter has been written in simple terms in an attempt to make
the concepts understandable, with the mechanisms of colorectal carcinogenesis laid out in Figure 56-1. However, biology is never this
Deleterious Mutation Tumor Suppressor
Gene Inactivation
simple. e distinctions between the dierent mechanisms and pathways are blurred at best, and multiple mechanisms and pathways can
be active in one patient at the same time. erefore, although the
basic principles apply and patients can generally be sorted according
to the broad molecular characterization of the cancer, no series falls
Promoter Hypermethylation
Sporadic Mutation
Loss of Heterozygosity
Oncogene
activation
Signal
transduction failure
CANCER
neatly into theoretical categories.
g g e
u
S
B
Kalady MF, Sanchez JA, Manilich E, etal. Divergent oncogenic changes inu-
Rex DK, Ahnen DJ, Baron JA, etal. Serrated lesions of the colorectum: re-
Sanchez JA, Krumroy L, Plummer S, etal. Genetic and epigenetic classica-
S t
ogaert J, Prenen H. Molecular genetics of colorectal cancer. Ann Gastroen-
terol. 2014;27(1):9–14.
ence survival dierences between colon and rectal adenocarcinomas. Dis
Colon Rectum. 2009;52(6):1039–1045.
view and recommendations from an expert panel. Am J Gastroenterol.
2012;107(9):1315–1329.
tions dene clinical phenotypes and determine patient outcomes in colorectal cancer. Br J Surg. 2009;96(10):1196–1204.
e d
R
e
a d i n g
FIGURE 56-1
rise from adenomas and accounts for 90% of rectal cancers. Micro
a
atellite instability is associated with right-sided colon cancers, which
s
Mechanisms of color
ectal carcinogenesis.
show lymphocytic inltration and have a better than expected prognosis. CpG island methylation causes almost exclusively right-sided
cancers that arise from serrated polyps, some of which also have
microsatellite instability. eir prognosis depends on the presence
of a BRAF mutation (worse), and their response to 5-uorouracil
chemotherapy depends on whether the microsatellites are unstable
(unresponsive).
-
P
S
INTR
ODUCTION
H
ereditary colorectal cancer syndromes account for approximately
5% of all colorectal cancers. Traditionally they have been categorized
according to the number and histologic features of colorectal polyps
in aected patients, although there is signicant blurring of the distinction between “polyposis” and “nonpolyposis” syndromes. e most
common hereditary syndrome of colorectal cancer (Lynch syndrome)
is not usually associated with polyposis and is the subject of a separate
chapter. In this chapter, polyposis syndromes will be discussed.
REGISTRIES
olyposis syndromes are rare, with the most common, familial adeno-
P
matous polyposis (FAP), found in 1:8000 live births. e syndromes
are complex, with variable and sometimes confusing genotypes and
a spectrum of overlapping phenotypes. e aims of management of
aected patients are prevention of death from cancer with maintenance
of optimal quality of life. Achieving these aims depends on aggressive
investigation of the family, lifelong surveillance of all aected members,
and the choice of appropriate investigations and procedures. Lapses in
surveillance allow cancers to occur, and inappropriate management
risks destruction of quality of life. Caring for families aected by hereditary polyposis syndromes takes a team of experienced experts, such
as those found at registries and cancer centers throughout the United
States. Patients with hereditary polyposis can be referred to such centers for a second opinion or for denitive care. Patients then return to
local caregivers for continued care. Even in the absence of a registry or
cancer center, genetic counseling is important as a prelude to testing
and as part of the interpretation of the results.
DEFINITIONS
Polyposis” simply means “a lot” of polyps. In practical terms, a
“
patient has adenomatous polyposis if more than 100 synchronous
adenomas are present, and he or she has serrated polyposis (SPS) if
more than 20 synchronous serrated polyps are present. Fewer adenomas (10 to 100) can be classied as oligopolyposis or attenuated polyposis, and in these cases, cumulative polyp counts are relevant. A
description of the polyposis syndromes, their genotypes, and a summary of their phenotypes is provided in Table 57-1.
F
AMILIAL ADENOMATOUS POLYPOSIS
F
AP was the rst syndrome of hereditary colorectal cancer to be
described. FAP is due to dominant inheritance of a mutation in the
tumor suppressor gene APC, a key part of the wnt/wingless signal
transduction pathway. APC forms a complex with AXIN and GSK,
James M.
degrades cytoplasmic β catenin and stops it from entering the nucleus,
where it would stimulate downstream growth-enhancing pathways.
Dysfunctional APC means that β catenin–induced stimulation of
cell growth happens inappropriately. APC has other important functions, including roles in chromosomal segregation and microtubule
formation. Mutations in APC promote chromosomal instability, and
sporadic APC mutations are an initiating event in sporadic colorectal
neoplasia.
FAP is dominantly inherited with 100% penetrance, which means
that if a relative has inherited the mutation, the chance of them
expressing the disease clinically is 100%. Although the mutation is
dominantly inherited, 25% of patients do not have a family history,
in some cases because of adoption, nonpaternity, or ignorance; biologic explanations include mosaicism or a new mutation occurring
at conception. e lack of a family history is a signicant problem
for aected patients because it denies them awareness of risk. Such
patients usually present serendipitously with symptoms or when typical extracolonic manifestations are recognized. Up to 60% of patients
with a “new” mutation have cancer at the time of presentation.
Genetic T
A di
tion in APC. e chances of detecting a mutation in patients with
classic FAP are greater than 80%. Finding the mutation in a clinically
aected patient means that at-risk relatives can be tested. If relatives
do not carry the family mutation, they are excused from high-risk
surveillance. If no APC mutation is found, large deletions and deletions in promoter 1B need to be excluded. Other genetic causes of
polyposis can be sought (e.g., mutations in MYH, mismatch repair
genes, and POLD1 and POLE). If no genetic cause of the polyposis
is identied, every at-risk relative must be screened with exible sigmoidoscopy yearly.
Genetic testing is usually performed at puberty because this is the
time that screening starts. Earlier testing can be performed if hepatoblastoma screening is contemplated.
Genotype/Phenotype
part from excusing unaected patients from surveillance and con-
A
rming the disease in mutation carriers, knowing the genotype can
help predict the phenotype of the syndrome. e 5′ and 3′ mutations
are associated with attenuated polyposis, whereas mutations in the
middle of the gene are associated with classic or profuse polyposis.
Desmoid tumors are more severe with 3′ mutations, which are also
associated with Gardner syndrome (polyposis, epidermoid cysts,
osteoma, dental anomalies, and desmoids). Congenital hypertrophy
of the retinal pigmented epithelium (CHRPE) is found with muta
ions in the middle of the gene. Some investigators have indicated
t
esting
agnosis of FAP can be conrmed by testing for a germline muta-
Church
275
-
276
PolyPosis syndr
omes
TABLE 57-1: Syndromes of Hereditary Polyposis
Colorectal
ome
Syndr
rofuse FAP >1000 adenomas APC
P
Polyp Count Genotype Phenotype
(codon 1309)
Colorectal, gastric, small intestinal
neoplasia; desmoid disease; benign
and malignant tumors of thyroid, skin,
bone, brain, liver, and pancreas
Classical FAP 100-1000
APC Same
adenomas
Attenuated FAP 10-100
adenomas
APC
(5′ and 3′ mutations)
Same
MAP Any adenomas MYH Same
PPAP >5 adenomas POLD1
POLE
Young age of onset, microsatellite stable
colorectal cancer; endometrial cancer
(POLE)
Juvenile polyposis >5 juvenile polyps SMAD4
BMPR1A
Gastric and colorectal hamartomas and
cancer
ENG
Peutz-Jeghers Peutz-Jegher polyps/small bowel > colorectum STK11 Oral/cutaneous pigmentation, cancers of
the breast, pancreas, stomach, ovary,
testis, and small intestine
Hereditary mixed
polyposis
SPS >20 serrated polyps of any size anywhere; any
>5 adenomas, serrated polyps, and hamartomas
(the hamartoma is important)
GREM1 expression
Unknown
serrated polyps and a family history of SPS >5
serrated polyps proximal to the sigmoid, 2 of
which are >10 mm
F
A P, Familial adenomatous polyposis; MAP, MYH-associated polyposis; PPA P, polymerase proofreading-associated polyposis; SPS, serrated polyposis.
hat the genotype can be used to plan surgery, but surgery should
t
always be determined by the colonic polyposis phenotype.
Color
ectal Cancer in Familial Adenomatous
Polyposis
n all patients with FAP who are untreated, a microsatellite stable, chro-
I
mosomal unstable colorectal cancer will develop at an average age of
40 years. e age range is wide, although cancer in teenagers is rare.
e cancer risk is proportional to the severity of the polyposis, with
cancer in attenuated FAP occurring much later than with profuse FAP.
Surveillance and prophylactic surgery aim to prevent cancer.
Surveillance begins at diagnosis or at puberty. Patients who are
part of a family with established FAP undergo genetic testing, and
yearly colonoscopic surveillance is targeted to mutation carriers. If no
mutation is detectable, all at-risk relatives are screened with exible
sigmoidoscopy until adenomas are found (and colonoscopy starts)
or until they reach their mid twenties, when surveillance schedules
can be eased. Prophylactic surgery is performed if the colorectal polyps are symptomatic, profuse, or unstable (i.e., increase in size to >1
cm, display severe dysplasia, or increase in number). Children with
mild polyposis can be followed up yearly, and elective surgery can be
performed when physical and emotional maturity is reached and the
time is right from a nancial and psychological point of view.
It is critical to remember that FAP cannot be cured by surgery,
many patients with FAP are asymptomatic and young, and the prophylactic operation should not worsen quality of life.
Surgical Options for the Large Bowel
e two main surgical options for the large bowel are colectomy and
ileorectal anastomosis (IRA) and proctocolectomy and ileal pouch–
anal anastomosis (IPAA). e respective indications, advantages, and
disadvantages of each option are shown in Table 57-2.
IPAA can be stapled or hand sewn aer an anal mucosectomy. A
stapled IPAA oers better bowel function but leaves anal transitional
zone (ATZ) epithelium, in which cancer may develop. A hand-sewn
anastomosis is more dicult to perform and to survey. If adenomas
are present in the ATZ at index surgery, then there is no choice but to
perform a mucosectomy. However, postoperative surveillance is critical for all patients because anastomotic cancers have been reported
aer both stapled and hand-sewn IPAA.
Laparoscopic technique oers major advantages for young, active,
asymptomatic patients with FAP. However, laparoscopic pouches are
tricky. Making the pouch reach to the anus can be an issue, especially
when desmoid disease is present. Desmoid disease prevents IPAA in
about 15% of patients presenting for a proctectomy and IPAA aer
an initial IRA.
Extracolonic Manifestations
H
ereditary colorectal cancer syndromes are associated with multiple
extracolonic manifestations because of the eect of the germline
mutation on other organs. ose associated with polyposis are mentioned in Table 57-1.
COLON
TABLE 57-2: Two Main Options for Prophylactic Treatment of the Large Bowel in Familial Adenomatous
Polyposis
Option Indications Contraindications Advantages Disadvantages
olectomy and
C
ileorectal
anastomosis
<20 rectal adenomas; <1000
colonic adenomas; high
risk of desmoid disease
>20 rectal adenomas;
rectal cancer
Relatively normal bowel
function; no pelvic dissection (no impact on sexual
function or fecundity); less
complex and complicated
surgery; no stoma
Rectal mucosa at risk for
progressive neoplasia
and cancer
277
Proctocolectomy and
ileal pouch–anal
anastomosis
olorectal cancer is the most common cause of death in persons
C
with FAP, followed by desmoid disease and ampullary carcinoma.
Desmoid disease is discussed in Chapter 58.
Ampullar
A
lmost all patients with FAP have duodenal adenomas, and duodenal/ampullary cancer will develop in about 10% if they are not treated.
Duodenal surveillance begins at age 20 years and continues according to the ndings at the prior examination. Duodenal adenomatosis
is scored according to adenoma number, size, and histology of the
adenomas, expressed as a Spigelman grade. Grade I is the mildest form
of duodenal polyposis and is usually followed by repeat esophagogastroduodenoscopy in 3 to 5 years. Grade II requires follow-up in 3 years,
grade III in 1 year, and grade IV, which is associated with a 36% incidence of cancer, is an indication to consider prophylactic surgery.
Treatment of duodenal adenomas is endoscopic or surgical. An
endoscopic or transduodenal polypectomy is associated with a high
rate of recurrence. e lowest recurrence rates follow pancreas-preserving duodenectomy, which is the operation of choice for stage IV
duodenal polyposis. Although a pancreas-preserving duodenectomy
results in signicant morbidity, the morbidity is less than for a Whipple procedure, which should be reserved for patients with cancer.
No eective agent exists for chemoprevention of duodenal adenomas, although celecoxib has shown a weak eect.
e stomach may exhibit three manifestations of FAP. Fundic
gland polyps are found in more than 90% of patients. ese polyps
are hyperplastic, although low-grade dysplasia can be found in 40%.
Gastric adenomas are found in 10% of patients with FAP, usually in
the antrum. ese adenomas may be precursors of gastric cancer.
Gastric cancer is rare in Western countries but much more common
in Asia. Esophagogastroduodenoscopy (EGD) screening and removal
of gastric adenomas is part of upper gastrointestinal surveillance.
y Cancer and Duodenal Adenomas
>20 rectal polyps; >1000
colon polyps; curable
rectal cancer; good anal
function
Advanced rectal cancer;
weak anal sphincters
Maintains per anal defecation;
minimizes cancer risk
enal Masses
Adr
A
drenal tumors are oen seen in patients with FAP who are having
computed tomography scans for other reasons. ese tumors are
generally benign, nonfunctional adenomas and are not treated. Adrenal tumors greater than 5 cm may need to be resected.
Brain T
F
ticular astrocytoma and glioblastoma. This combination has
been referred to as Turcot syndrome, although this term includes
patients with Lynch syndrome in whom a medulloblastoma
develops.
umors
AP is associated with an increased risk of brain tumors, in par-
Range of function from
good to bad; risk of
pouch and anal transition zone neoplasia;
temporary ileostomy;
risk of complications
(including pelvic nerve
damage and reduced
fecundity)
Hepatoblastoma
A h
epatoblastoma is a rare tumor that aects boys with FAP from
infancy to age 6 years. Screening is controversial because it means
that genetic testing is performed in infancy. Liver ultrasound and
serum alpha fetoprotein can lead to early diagnosis, but even without
screening the tumor is rarely fatal.
Gar
dner-Type Manifestations
A s
et of extraintestinal manifestations associated with FAP was identied by Utah genetics professor Eldon Gardner and came to bear
his name. ese manifestations include desmoid tumors, osteomas,
dental anomalies (extra teeth), and epidermoid cysts. is association
is useful because the presence of some of these manifestations predicts a high risk of desmoid tumors. None needs to be treated unless
symptomatic.
yroid Cancer
Th
AP is associated with a high risk of papillary thyroid cancer, which
F
is more common in women than in men. Screening with ultrasound
is eective in achieving early diagnosis, and nodules larger than 1 cm
in diameter are biopsied by ne-needle aspiration. Screening begins
at diagnosis and continues yearly. When cancer is diagnosed, a thyroidectomy should be performed.
Congenital Hyper
trophy of the Retinal Pigmented
Epithelium
E can be dened as the presence of four or more hyper- or
CHRP
hypopigmented spots involving both eyes. e spots have no functional eect, and CHRPE is most signicant as a marker of disease.
Alert ophthalmologists may diagnose FAP.
278
PolyPosis syndr
omes
Surveillance
S
urveillance is key to preventing cancer and relies on good compliance on the part of the patient and hard work from a registry
or clinical coordinator on the part of the registry. The large bowel
is surveyed yearly, unless the presence of advanced neoplasia
requires more frequent examinations. The upper gastrointestinal
tract is checked regularly, with a frequency dependent on findings of the previous examination. Severe duodenal polyposis is
associated with an increased risk of small intestinal polyps, and
capsule endoscopy is indicated. Thyroid screening is performed
ye a rly.
The IRA
Yearly proctoscopy is performed with a exible scope aer two enemas. No sedation is required. e anastomosis should be checked,
along with the terminal ileum for 15 cm. Small ulcers are common
and do not mean that Crohn disease is present. Polyp size, number,
and location should be noted. Polyps measuring less than 5 mm can
be counted but not treated, as long as the patient is compliant with
screening. Larger polyps should be removed. Flat red velvety areas
should be biopsied, especially in scarred rectums. e other side of
the rectal valves should be checked.
The IPAA
Yearly pouchoscopy is performed with a flexible scope after two
enemas. The anus may be stenotic and tender, especially after
a hand-sewn anastomosis. In this case a pediatric gastroscope
may be used, along with Xylocaine jelly as a lubricant. The scope
should be passed into the afferent ileum, and one must be aware
of the difference between lymphoid follicles and adenomas: if in
doubt, a biopsy should be performed. The top of the pouch and
then the pouch itself should be checked. Ulcers are normal and
do not necessarily mean that Crohn disease is present. Particular
attention should be directed to the ATZ and anus. Retroversion of
the scope may be possible and may detect ATZ polyps more easily. Polyps larger than 5 mm should be removed. If the ATZ has
extensive polyposis, polypectomy or a mucosal strip and pouch
advancement may need to be performed after induction of general
anesthesia.
Oligopolyposis/Attenuated Familial Adenomatous Polyposis
e presence of fewer than 100 synchronous adenomas is termed oli-
gopolyposis or attenuated polyposis. is condition occurs in persons
with FAP in the setting of a 5′ or 3′ mutation. Polyps are generally
more right sided, and cancer develops later than with classic FAP.
Sometimes the polyps are hard to see, and chromoendoscopy of the
right colon has been recommended.
Genetic testing is less productive of a germline mutation in
patients with attenuated polyposis, and the dierentials of MYH-
associated polyposis (MAP), polymerase proofreading-associated
polyposis (PPAP), and even Lynch syndrome are relevant. Table 57-3
is an amalgam of data from two recent studies and shows that oligopolyposis can be explained genetically in APC mutation–negative
patients.
Whereas mutations at either end of the gene have a mild polyposis
phenotype, they are associated with severe duodenal polyposis (5′)
and symptomatic desmoid disease (3′). EGD screening is therefore
critical, and surgery in patients with a 3′ mutation must be performed
in the context of a high desmoid risk, which means that when the
polyp size and histologic features indicate surgery, a laparoscopic IRA
or an open pouch is favored.
TABLE 57-3: Genotypes of Patients with Oligopoly-
posis: Number of Adenomas
Genotype <10 (%) 10-19 (%) 20-99 (%) 100-999 (%)
APC 4 5 10 56
MYH b
iallelic 2 4 7 7
MYH mono-
allelic
Lynch 8.0 6.3 5.6 6.5
Tota l 16 17.3 24.6 70.5
rover etal., JAMA/Hackaman etal., ASCO 2013.
G
MYH-ASSOCIA
MYH co
which repairs oxidative damage to the DNA. Loss of MYH prevents
DNA repair and allows the persistence of G-C: T-A transversions
throughout the genome. Transversions in APC are mutations that
cause a mild form of adenomatous polyposis. However, other genes
can be aected as well, leading to a variety of presentations. MAP
is a notorious mimic and may present as sporadic colorectal cancer,
young age of onset colorectal cancer, FAP, SPS, Lynch syndrome, and
familial colorectal cancer type X. Patients who are diagnosed clinically with FAP but do not have an APC mutation may actually have
MAP.
show dominant inheritance. The recessive pattern of inheritance
means that both parents are carriers and usually are unaffected.
Siblings are at 25% risk of MAP. Children of a proband will be
carriers unless the unaffected spouse is a carrier, in which case
the children have a 50% chance of inheriting the syndrome. The
incidence of a monoallelic MYH mutation (carrier status) is 2%.
The risk of colorectal cancer associated with carrier status is controversial. Some studies report a twofold increase in risk, and
thus performing screening colonoscopy early in carriers is worth
considering.
many years. However, some patients have 100 to 1000 adenomas.
Extracolonic manifestations of MAP have not been well dened,
but gastroduodenal polyps, small bowel cancer, thyroid cancer, and
abdominal desmoids have been described.
requires a resection, and if the diagnosis is already made, then the
choice of surgery is the same as for FAP. e main dierence is that
patients with MAP are older, and thus comorbidities become an issue.
Patients with MAP sometimes undergo a segmental colectomy for an
apparently sporadic cancer and then face colonoscopic surveillance
of an increasingly unstable colon. e alternative is completion colectomy. e cost of keeping the colon is a yearly colonoscopy. Polyps
with severe dysplasia are a relative indication to abandon endoscopy
and choose surgery.
teria, and thyroid screening is valuable in detecting the papillary
cancers.
lance colonoscopy must be uncompromising. A “fair” preparation is
not to be tolerated. Polyps oen have a low prole, are pale, and can
be easily missed. Performing surveillance colonoscopy at short intervals (in 6 months) is worthwhile until the endoscopist is sure that no
dangerous missed lesions are present.
des for a protein involved in the base excision repair pathway,
MAP is recessively inherited, but aspects of the family can
Colorectal polyposis is usually attenuated and can be absent for
e polyps drive management of patients with MAP. Cancer
EGD screening is appropriate as determined by Spigelman cri-
As with all patients who have hereditary colon cancer, surveil-
2 2 2 1
TED POLYPOSIS (MAP)
COLON
279
YMERASE PROOFREADING–
POL
ASSOCIATED POLYPOSIS
PAP is a syndrome that was described in 2013 as dominant inheritance
P
of young age at onset, microsatellite stable colorectal (and endometrial) cancer, and oligo-adenomatous polyposis as a result of a germline mutation in one of two spell-checking genes (POLD1 and POLE)
involved in DNA replication. PPAP therefore enters the dierential of
familial colorectal cancer type X, oligopolyposis, and colorectal cancer
with a young age of onset. Germline testing is available through some
genetic panels and is likely to be increasingly available in the future.
Because only a few families with this syndrome have been
reported, its full phenotype and its optimal treatment are as yet
unknown. Treatment principles remain set, however: treat colorectal
cancer by resection and prevent it either via colonoscopic polypectomy or resection.
SERRA
PS is a syndrome characterized by multiple serrated polyps, a high
S
risk of colorectal cancer, and a family history of colorectal cancer,
but generally a lack of dominant inheritance. Our knowledge of SPS
is limited by the lack of a genotype. Without the irrefutable denition that a deleterious germline mutation brings, it is necessary to
dene the syndrome by phenotype, which has suggested at least two
dierent variants—one with multiple, small, le-sided serrated polyps (usually hyperplastic), and another with fewer numbers of rightsided, larger, sessile serrated adenomas/polyps.
Serrated polyps show a saw-toothed pattern of the colorectal
epithelium that is due to a failure of apoptosis and accumulation of
colonocytes that should have been shed. ey consist of hyperplastic polyps (generally small, le sided, and minimally associated with
cancer), sessile serrated adenomas/polyps (larger, right sided, more
disorganized in their proliferation, and precursors of a methylator
[CpG island methylator phenotype] cancer), and traditional serrated
adenomas (rare, with unusual serrated proliferation and adenomatous dysplasia, and precancerous).
An arbitrary denition of SPS proposed by the World Health
Organization includes patients with more than 20 serrated polyps of
any size or distribution, patients with any serrated polyp and a family
history of SPS, and patients with ve or more serrated polyps proximal to the sigmoid colon, at least two of which are larger than 10
mm. However, these denitions may underestimate risk because of
the presence of multiple serrated polyps in patients whose phenotype
does not quite meet the criteria. Cumulative polyp counts can contribute to patient numbers, and thus the diagnosis can be made aer
a series of surveillance examinations.
Although patients tend to sort themselves into le-sided SPS and
right-sided SPS (usually sessile serrated adenomatous/polyps polyposis and mixed SPS), the risk of colon cancer and the rate of family
history of cancer are similar (a colon cancer risk of 25% to 30% and a
family history of 25% to 28%). Extracolonic cancers t no particular
pattern and include unusual cancers such as prostate and leukemia.
e goal of SPS treatment is to prevent cancer, which can be
achieved by surgery or by colonoscopic polypectomy. Colonoscopic
management is dicult because serrated polyps are dicult to see
and can grow quite large. Cancers generally arise later in life but can
arise quickly from missed or rapidly growing polyps. No association
has been found with gastric, duodenal, or small bowel polyposis.
HAMAR
lorectal hamartoma is an overgrowth of a tissue component that
A co
is normally present in the bowel wall. It is benign but can be associated with colorectal cancer, especially in the context of a syndrome of
TED POLYPOSIS
TOMATOUS POLYPOSES
polyposis. e three main hereditable syndromes of hamartomatous
polyposis are Peutz-Jegher polyposis, juvenile polyposis, and PTEN
tumor hamartoma syndromes.
eutz-Jegher Polyposis
P
Peutz-Jegher polyps are overgrowths of the muscularis mucosae.
e polyps have a typical appearance, with branching bers of
the muscularis mucosae extending through the lobulations of the
polyp. Peutz-Jegher polyposis (PJP) is associated with dominant
inheritance, and more than 80% of cases have a germline mutation
in STK11. PJP is a global growth disorder. Polyps occur preferentially in the small bowel but also in the colon, rectum, and stomach. ere is a high risk of cancer in several organs, including the
stomach, small bowel, colon and rectum, breast, pancreas, ovary,
and testis.
Children with PJP have characteristic mucocutaneous pigmentation on their lips. is pigmentation fades as they approach their 20s
but is one of three clinical diagnostic criteria for PJP. e other two
criteria are the presence of more than one Peutz-Jegher polyp and a
family history of PJP. Patients need to meet two of these three criteria
to qualify for genetic testing.
Patients with PJP usually present in childhood with a complication of their small bowel polyps. is complication is sometimes
abdominal pain and sometimes a full-blown small bowel obstruction as a result of intussusception. Persons with intussusception must
undergo surgery and resection of the polyp. Diagnosis of the syndrome before a surgical complication has occurred raises the possibility of management by enteroscopy and polypectomy. Surgery for
PJP is most eective when it removes or destroys all visible polyps (a
clean sweep), which minimizes recurrent symptoms due to enlarging
polyps. A polyp-focused approach risks multiple laparotomies, with
associated comorbidity.
Surveillance of patients with PJP is complicated because of the
multiple organs at risk for cancer. Current guidelines can be found in
the Suggested Reading list.
uvenile Polyposis
J
J
uvenile polyps are the most common intestinal polyp in children.
Solitary polyps may bleed and autoamputate. e presence of ve or
more juvenile polyps, or any number of juvenile polyps with a family
history of juvenile polyposis (JPS), denes JPS. JPS can be dened
genetically by the identication of a germline mutation in either
SMAD4 or BMPR1A. Both genes play important roles in the trans-
orming growth factor-β signal transduction pathway, and mutations
f
are found in more than 40% of cases of JPS. Patients with a SMAD4
mutation tend to have more aggressive upper gastrointestinal manifestations and are at high risk of having hereditary hemorrhagic
telangiectasia. All SMAD4 mutation carriers should undergo hemorrhagic telangiectasia screening.
Histologically, juvenile polyps represent an overgrowth of
the lamina propria. They characteristically have prominent
inflammatory cells and large mucus spaces. They are sometimes
reported as “inflammatory” polyps, which may cause diagnostic
confusion.
Patients with JPC are primarily aected by colorectal polyposis and may present with symptoms such as bleeding and diarrhea.
Sometimes the uid loss from the polyps is severe. e stomach is
also aected and may contain masses of polyps. Patients who have
undergone a proctocolectomy and creation of an ileal pouch oen
are found to have polyps in the pouch. Colorectal cancer risk is signicantly high in JPS, and patients usually undergo a colectomy and
IRA or a proctocolectomy and IPAA. Colonoscopic surveillance is
reasonable if the polyp count is low.
280
PolyPosis syndr
omes
PTEN Tumor Hamartoma Syndrome
PTEN i
s a critical growth-regulating gene that codes for a phosphatase with functions in the cytoplasm and nucleus. In the nucleus, it
predominantly signals down the mitogen-activated protein kinase
pathway, leading to cell cycle arrest. In the cytoplasm, its main role
is in the AKT pathway to elicit apoptosis. Germline mutations produce syndromes characterized by craniofacial anomalies and benign
and malignant tumors. Four syndromes are associated with germline
PTEN mutations; all are rare. e most common is Cowden syndrome, which is characterized by multiple benign skin lesions, typically trichilemmomas and papillary papillomas, and macrocephaly.
Colonoscopy and EGD oen reveal multiple polyps of unusual histology (bromas, ganglioneuromas, neuromas, and lipomas). Diagnostic criteria for Cowden syndrome have been published (see the
suggested reading list), and if the syndrome is suspected, testing for
a germline mutation of PTEN should be sought. Cowden syndrome
is associated with an increased risk of breast, thyroid, endometrial,
renal, and colorectal cancer, and thus a program of surveillance of
these organs is recommended. Sometimes a prophylactic colectomy
is necessary if cancer is already present or if the polyps cannot be
controlled endoscopically.
Bannayan Ruvalcaba Riley syndrome (BRRS), Proteus syndrome,
and Proteus-like syndrome are also associated with germline mutations of PTEN. ese syndromes are very uncommon and are treated
similarly to Cowden syndrome. BRRS is characterized by developmental delay and mental deciency, macrocephaly, intestinal polyposis, lipomas, and pigmented macules of the glans penis. e risk of
colorectal cancer associated with BRRS is thought to be similar to
that in Cowden syndrome.
Proteus syndrome has a highly variable presentation involving
congenital malformations and overgrowth of multiple tissues.
ermline mutation upstream of GREM1 can be sought. is mutation
g
(a duplication) causes expression of GREM1 in the colorectal epithelium and is associated with hereditary mixed polyposis syndrome.
e syndrome has been described in Ashkenazi Jewish families, and
management consists of surveillance, colonoscopic polypectomy, and
colectomy for cancers and uncontrollable polyps.
u
S
B
Church JM. Polymerase proofreading-associated polyposis: a new, dominant-
Church JM, Heald B, Burke C, Kalady M. Understanding MYH-associated
Dunlop MG. British Society for Gastroenterology; Association of Coloproc-
Hegde M, Ferber M, Mao R, etal. Working Group of the American College of
Pilarski R, Burt R, Kohlman W, et al. Cowden syndrome and the PTEN
Vasen HF, Möslein G, Alonso A, etal. Guidelines for the clinical management
S t
g g e
eggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: a sys-
tematic review and recommendations for management. Gut. 2010;59(7):
975–986.
ly inherited syndrome of hereditary colorectal cancer predisposition. Dis
Colon Rectum. 2014;57(3):396–397.
neoplasia. Dis Colon Rectum. 2012;55(3):359–362.
tology for Great Britain and Ireland. Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers syndrome. Gut.
2002;51(suppl 5):V21–V27.
Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance
Committee. ACMG technical standards and guidelines for genetic testing
for inherited colorectal cancer (Lynch syndrome, familial adenomatous
polyposis, and MYH-associated polyposis). Genet Med. 2014;16(1):101–
116.
hamartoma tumor syndrome: systematic review and revised diagnostic
criteria. J Natl Cancer Inst. 2013;105(21):1607–1616.
of familial adenomatous polyposis (FAP). Gut. 2008;57(5):704–713.
e d
R
e
a d i n g
HEREDIT
ARY MIXED POLYPOSIS
SYNDROME
e presence of colorectal adenomas, serrated polyps, and hamar-
tomas (juvenile) polyps raises the possibility of hereditary mixed
polyposis syndrome. When the family history pattern is dominant, a