Serrated polyps and colorectal cancer: new pathway to malignancy.

Abstract

Until recently, two major forms of colorectal epithelial polyp were recognized: the adenoma and the hyperplastic polyp. Adenomas were perceived to represent the precursor to colorectal cancer, whereas hyperplastic polyps were viewed as innocuous lesions with no potential for progression to malignancy. We now recognize, however, that the lesions formerly classified as hyperplastic actually represent a heterogeneous group of polyps, some of which have a significant risk for neoplastic transformation. These serrated polyps include not only hyperplastic polyps but also traditional serrated adenomas and sessile serrated adenomas. These polyps demonstrate characteristic molecular alterations not commonly seen in colorectal adenomas, and they probably progress to colorectal cancer by means of a new pathway: the serrated neoplasia pathway. The morphologic features of serrated colorectal lesions, the molecular alterations that characterize them, and their role in colorectal cancer development are discussed herein.

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Serrated Polyps
and Colorectal Cancer:
New Pathway to Malignancy
Amy E. Noffsinger
Department of Pathology, The University of Chicago, Chicago, Illinois 60637;
email: Amy.Noffsinger@uchospitals.edu
Annu. Rev. Pathol. Mech. Dis. 2009. 4:343–64
First published online as a Review in Advance on
November 17, 2008
The Annual Review of Pathology: Mechanisms of
Disease is online at pathmechdis.annualreviews.org
This article’s doi:
10.1146/annurev.pathol.4.110807.092317
Copyright c ? 2009 by Annual Reviews.
All rights reserved
1553-4006/09/0228-0343$20.00
Key Words
adenoma, colon carcinoma, hyperplastic polyp, microsatellite
instability, CpG island methylator phenotype
Abstract
Until recently, two major forms of colorectal epithelial polyp were rec-
ognized: the adenoma and the hyperplastic polyp. Adenomas were per-
ceived to represent the precursor to colorectal cancer, whereas hyper-
plastic polyps were viewed as innocuous lesions with no potential for
progressiontomalignancy.Wenowrecognize,however,thatthelesions
formerly classified as hyperplastic actually represent a heterogeneous
group of polyps, some of which have a significant risk for neoplastic
transformation. These serrated polyps include not only hyperplastic
polyps but also traditional serrated adenomas and sessile serrated ade-
nomas. These polyps demonstrate characteristic molecular alterations
notcommonlyseenincolorectaladenomas,andtheyprobablyprogress
to colorectal cancer by means of a new pathway: the serrated neoplasia
pathway. The morphologic features of serrated colorectal lesions, the
molecularalterationsthatcharacterizethem,andtheirroleincolorectal
cancer development are discussed herein.
343
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APC: adenomatous
polyposis coli
HNPCC: hereditary
nonpolyposis
colorectal cancer
syndrome
MSI: microsatellite
instability
INTRODUCTION
Before 1990, two major forms of colorectal ep-
ithelial polyp were recognized: the adenoma
and the hyperplastic polyp. Adenomatous
polyps have long been known to represent neo-
plastic, precursor lesions for colorectal adeno-
carcinoma. Hyperplastic polyps, on the other
hand, were for the most part regarded as in-
nocuous lesions that, although often observed
in colons of patients with colorectal cancer,
were thought to have no malignant potential of
their own. There were early reports of hyper-
plastic polyps adjacent to a significant percent-
age of adenomas in the literature (1), and it was
knownthathyperplasticpolypswerefoundwith
a higher frequency in populations with a higher
risk of developing colorectal cancers (2). Nev-
ertheless,despitethesedatahyperplasticpolyps
were dismissed by most investigators as non-
neoplastic “bystander” lesions.
Theroleoftheadenomaincolorectalcancer
development was clearly established when Vo-
gelstein and colleagues (3) published their sem-
inal paper demonstrating that a stepwise accu-
mulation of molecular alterations accompanies
the adenoma-carcinoma sequence in the colon.
This stepwise accumulation of genetic alter-
ations occurs concomitantly with a stepwise
change in morphology: It begins with the for-
mation of a small adenomatous polyp, followed
by formation of a larger polyp with dysplasia,
which ultimately leads to the development of
invasive carcinoma. The earliest molecular ab-
normality in this pathway is mutation in APC, a
component of the Wnt signaling pathway and
the gene known to be involved in the heredi-
tary condition familial adenomatous polyposis
coli (APC). APC mutation is followed by ac-
quisition of mutations in KRAS and P53 in in-
creasingly large adenomas and invasive cancer
(3). The adenoma-carcinoma molecular path-
way applies predominantly to sporadic colorec-
talcancers,butitalsocharacterizesfamilialade-
nomatous polyposis and is thus often known as
the APC pathway. Alternatively, this pathway
may be referred to as the chromosomal insta-
bilitypathwaybecausecolorectaltumorsarising
bythispathwayarecharacterizedbygrosschro-
mosomal abnormalities including deletions, in-
sertions, and loss of heterozygosity.
Subsequently, another molecular pathway
leading from adenomatous polyps to colorec-
tal cancer, the DNA mismatch repair path-
way, was also described (4). The mismatch re-
pair pathway is involved in colorectal cancers
arising in association with the inherited con-
dition hereditary nonpolyposis colon cancer
(HNPCC), also known as Lynch syndrome.
The key elements of this pathway are dysfunc-
tionsofDNAmismatchrepairenzymes(5)that
result from germline mutation in one of sev-
eral DNA mismatch repair genes, most com-
monly MLH1 or MSH2. The loss of DNA mis-
match repair function results in accumulation
of mutations in microsatellite regions of the
genome (6). The result is the development of
microsatellite instability (MSI) in the tumors
derived through this genetic pathway.
Microsatellites are short repetitive se-
quences of DNA that appear throughout the
genome. They are usually located in nonen-
coding regions, but they sometimes also lie in
coding regions of genes involved in control
of cell proliferation or apoptosis. Colorectal
and other cancers from patients with HNPCC
are characterized by alterations in genes con-
taining such microsatellite repeat sequences.
Thesegenesincludethoseencodingtransform-
ing growth factor beta receptor II, insulin-like
growth factor receptor 2, and Bax (7–9), among
others. Tumors arising via the mismatch repair
pathway characteristically have a diploid DNA
content and fail to show evidence of chromoso-
mal losses or gains, as occurs in cancers aris-
ing via the chromosomal instability pathway
(10, 11).
Abnormalities in mismatch repair are also
identifiable in approximately 15% of sporadic
colorectal adenocarcinomas, but the underly-
ing mechanism by which these tumors de-
velop appears to be different from that of the
inherited mismatch repair–deficient tumors.
Studies show that sporadic adenomas rarely
demonstrate high levels of MSI (MSI-H), and
those that are MSI positive are almost always
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associated with HNPCC. It has been argued
that in contrast to adenomas in patients with
HNPCC, MSI is a late occurrence in polyps
precedingMSI-positivesporadiccoloncancers.
However, other early changes that are charac-
teristic of early adenomatous polyps (such as
APClossorKRASmutations)areunusualinthe
sporadicmicrosatellite-unstablecolorectalcan-
cers (12–14). In addition, alterations in other
componentsoftheWntsignalingpathwaysuch
as β-catenin (13, 15) do not appear to play a
role in these cancers, but other Wnt signal-
ing components such as AXIN2 (16) and TCF4
(17) may be altered in sporadic MSI-H cancers.
Thesealterations,however,donotseemtorep-
resent surrogate markers for APC inactivation
because they occur following the acquisition
of MSI rather than early in tumor develop-
ment. These findings suggest that nonhered-
itary MSI-positive colorectal cancers arise by
different mechanisms than the MSI-high can-
cers that characterize HNPCC.
Evidence that adenomas might not repre-
sent the only colorectal cancer precursor also
began to emerge around 1990. In that year,
Longacre & Fenoglio-Preiser (18) studied a
groupofpolypsthatdemonstratedmixedhisto-
logic features of both hyperplastic and adeno-
matous polyps. These lesions were perceived
to represent not a mixed tumor with two sepa-
rateserratedandadenomatouscomponentsbut
asingleentityinwhichtheglandshadaserrated
architecture, and the cells lining these glands
showed nuclear features reminiscent of ade-
noma. These lesions were termed serrated ade-
nomas, but the authors (18) believed that they
represented a variant of villous or tubulovillous
adenoma, rather than a lesion related to hyper-
plastic polyps.
Various reports and small series of colorec-
tal adenocarcinomas associated with giant hy-
perplastic polyps (usually defined as >1 cm),
however, suggested that at least some hyper-
plasticpolypsmayhavemalignantpotential(19,
20). Adenocarcinomas were also reported to
arise in mixed hyperplastic and adenomatous
polyps (21). In addition, the presence of mul-
MSI-H: high-level
microsatellite
instability
tiple hyperplastic polyps in the form of hyper-
plastic polyposis (22–24) was clearly associated
with the development of colorectal adenocar-
cinoma. In some nonpolyposis patients with
microsatellite-unstable colorectal cancers, an
increased incidence of both hyperplastic polyps
and serrated adenomas was observed (25, 26).
A large series of more than 90 microsatellite-
unstablecolorectalcancers,inwhichhyperplas-
tic polyps had been diagnosed near the site of
thecolorectalcanceratearlierexamination,fur-
ther implicated hyperplastic polyps in at least
a subset of colorectal carcinomas (27). These
findings suggested that an alternate serrated
pathway to colorectal carcinoma might exist.
The idea that the lesions previously cate-
gorized as hyperplastic polyps probably repre-
sented several different entities emerged with
the work of Torlakovic & Snover (24). These
authors showed that the polyps arising in pa-
tientswithhyperplasticpolyposisdemonstrated
morphologic features different from those of
small sporadic hyperplastic polyps and that
these features could reliably be used to differ-
entiate between the potentially precancerous
polyps of hyperplastic polyposis and those that
did not seem to pose a risk for progression to
colorectal cancer. In 2003, the same authors re-
ported a study of sporadic serrated lesions and
demonstrated the existence of several discrete
types of serrated polyps, which could generally
be divided into polyps with abnormal prolif-
eration, termed sessile serrated adenomas, and
those with normal proliferation, termed hyper-
plastic polyps (28).
MORPHOLOGIC FEATURES AND
CLASSIFICATION OF SERRATED
COLON POLYPS
The studies described above have made clear
that serrated polyps represent not only innocu-
ous hyperplastic polyps but a heterogeneous
group of lesions, some of which are likely asso-
ciated with a significant cancer risk. The classi-
fication of serrated colorectal polyps is summa-
rized in Table 1.
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Table 1
colorectum
Hyperplastic polyps
Goblet cell–rich variant
Microvesicular variant
Mucin-poor variant
Sessile serrated polyp (sessile serrated adenoma)
Serrated adenoma
Traditional adenoma with serration
Mixed polyps
Hyperplastic polyp with traditional adenoma
Hyperplastic polyp with serrated adenoma
Hyperplastic polyposis
Serrated carcinoma
Classification of serrated lesions of the
HYPERPLASTIC POLYPS
True hyperplastic polyps are most frequently
found in the left colon and rectum (29). They
constitute 80–90% of all serrated polyps and
usuallyrepresentinnocuouslesions(18,28,30).
Generally, they are small, slightly raised lesions
measuring less than 5 mm in greatest dimen-
sion. The colonic glands appear serrated, but
the serrated change is limited to the upper one-
half to one-third of the crypt (Figure 1). The
degree of serration varies from lesion to le-
sion. The deeper crypts often show expansion
of the proliferative zone but do not appear di-
lated; they appear straight and tubular, similar
tothoseseeninnormalcoloniccrypts.Thecol-
lagentableunderlyingthesurfaceepitheliumof
hyperplastic polyps is usually thickened.
Conventional hyperplastic polyps demon-
strate an expanded (yet symmetrical) prolifer-
ation zone, as illustrated by Ki-67 (MIB-1) im-
munostains (31). In addition, cytokeratin 20
staining is retained in the upper portion of the
colonic crypt in a pattern similar to that seen in
normal colonic mucosa (31).
Subclassification of hyperplastic polyps into
microvesicular, goblet cell–rich, and mucin-
poor variants based on the mucin content of
the epithelial cells (28) probably has little clini-
calutility,butitdoeshaveinterestingmolecular
ab
c
Figure 1
Hyperplastic polyp.
(a) True hyperplastic
polyps comprise
glands with serrations
limited to the upper
one-half of the crypt.
The crypt bases are
similar in diameter and
shape to those of
normal colon. (b) The
microvesicular variant
of hyperplastic polyp
contains crypts lined
by cells with cytoplasm
that appears bubbly.
Scattered goblet cells
are also present.
(c) The goblet cell–rich
variant of hyperplastic
polyp contains
abundant goblet cells,
but no microvesicular
cells are present.
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Page 5

biologic correlates (see “Molecular Biologic
Changes,” below). The microvesicular vari-
ant of hyperplastic polyp is the most com-
mon, and it represents the typical hyperplastic
polyp found in the distal colon. It is charac-
terized by vesicular mucin–containing epithe-
lialcellsandnumerousgobletcellabnormalities
(Figure 1). Overall, the number of goblet cells
isdecreasedcomparedwithnormalcolonicmu-
cosa. Microvesicular hyperplastic polyps have a
large proliferative compartment that may make
up as much as one-half of the crypt. Nuclear
atypia is variable and in rare cases can be se-
vere.Nuclearstratificationmaybeseen.Thick-
ening of the basement membrane is usually
present,atleastfocally,andfibersofthemuscu-
laris mucosae often extend upward between the
glands.
Goblet cell–rich hyperplastic polyps com-
monly show less serration of the crypts than
dootherhyperplasticpolypvariants(Figure1).
Serration in this group of polyps may be lim-
ited to the superficial one-third of the mucosa,
or even to its surface. As the name implies, the
mucin in this type of polyp is strictly of gob-
let cell type. There is minimal nuclear atypia
or stratification. The basement membrane is
thickened in nearly all polyps of this type.
Mucin-poorhyperplasticpolypsaretheleast
common variant. Goblet cells are decreased or
absent in this type of polyp, and there may be
prominent nuclear atypia. These lesions typi-
cally contain an associated hyperplasia of clear
neuroendocrine cells.
TRADITIONAL SERRATED
ADENOMA
As described above, the term serrated adenoma
was first applied in 1990 to a subset of polyps
that had both a serrated hyperplastic-like ar-
chitecture and adenomatous changes or dys-
plasia (18). In the original report (18), serrated
adenomas represented less than 1% of colorec-
tal polyps. However, more recent studies have
demonstratedahigherincidence.Inarecentre-
view from Finland, 15.9% of colorectal polyps
werediagnosedasserratedadenoma(32).Other
studies have shown that traditional serrated
adenomas are identified in up to 7% of colono-
scopies, with most polyps (54%) occurring in
theleftcolon(18,33).Thesepolypsoftenhavea
pedunculated or broad-based polypoid pattern
of growth, with a cerebriform or petal-like en-
doscopic appearance (34–36). Smaller polyps,
however, are endoscopically indistinguishable
from hyperplastic polyps (33).
Traditional serrated adenomas, as defined
by Longacre & Fenoglio-Preiser (18), are
distinguishable from sessile serrated adenomas
in that they contain a uniform population of
abnormal epithelial cells. The epithelial cells
in a traditional serrated adenoma are tall,
columnar cells with eosinophilic cytoplasm and
a centrally placed, elongated, hyperchromatic
nucleus (Figure 2). A degree of nuclear
pseudostratification may be present, but not
to the same extent as in a typical tubular or
villous adenoma. There are also architectural
differences, which differentiate the two types
of polyp. Traditional serrated adenomas tend
to be pedunculated and often have a villiform
appearance, but they may also be flat or slightly
raised (29). However, traditional serrated
adenomasusuallyhave
crypts, in which the normal relationship of the
crypts with the adjacent muscularis mucosae
is not preserved (29). Ectopic crypts appear
shortened and do not contact the muscularis
mucosae, as do normal colonic crypts. In
addition, Ki-67 immunostains demonstrate
localization of the proliferative compartment
of the mucosa to these ectopic crypts. For the
most part, cytokeratin 20 staining is limited to
thesurfaceepitheliuminthistypeofpolyp(29).
Longacre & Fenoglio-Preiser (18) distin-
guished serrated adenomas from mixed polyps,
whichhadbeenconsideredachancecollisionof
two independent polyps, one hyperplastic and
theotheradenomatous.However,serratedade-
nomas may themselves be mixed and can in-
clude components resembling sessile serrated
adenoma, classical hyperplastic polyp, or ade-
noma. Some serrated adenomas show high-
grade dysplastic changes or intramucosal car-
cinoma (Figure 2).
so-called ectopic
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