the clinical significance of serrated polyps...serrated polyps are defi ned as epithelial lesions,...

© 2011 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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CLINICAL AND SYSTEMATIC REVIEWS

INTRODUCTION Th e serrated pathway to adenocarcinoma represents a major chal-

lenge to colorectal cancer (CRC) prevention eff orts. Although

screening and surveillance colonoscopy have been shown to

signifi cantly reduce CRC incidence and mortality, this eff ect

appears to be limited mainly to cancers in the distal colon and

rectum ( 1 – 4 ), the majority of which arise via the conventional

adenoma – carcinoma sequence. Prevention of proximal CRCs has

proven more diffi cult, and “ interval cancers ” following a negative

or “ clearing ” colonoscopy continue to contribute importantly to

the overall CRC burden. Th ere is a growing body of evidence that

some of these cancers arise via the serrated polyp pathway, and

there are many features that distinguish these groups of cancers

and their precursors from conventional CRCs. In major con-

trast to the adenoma – carcinoma sequence, the serrated pathway

implicates hyperplastic polyps (HPs) as potential precursors to

CRC, which contradicts what generations of endoscopists and

pathologists have been trained to believe ( 5 – 9 ). Molecular genet-

ics combined with histological and clinical studies have provided

ample evidence, however, that variants of HPs carry the genetic

“ signatures ” of certain types of CRC, particularly cancers with

high levels of microsatellite instability (MSI-H) ( 10 – 14 ). In addi-

tion to their morphological and molecular diff erences from con-

ventional CRC, these serrated pathway cancers also have distinct

clinical and demographic characteristics: they are more likely

to be found in females, located in the proximal colon, and are

incident in the mid- to late-70s, a decade later than CRC overall.

Th ese characteristics may be linked to the proposed underlying

molecular basis for these cancers, a phenomenon called CpG

island methylation, a progressive epigenetic process whereby the

CpG-rich promoter regions of mutator and suppressor genes

become inactivated ( 15 ). Th is phenomenon fi nds its greatest

expression in proximally located HP-type precursors that typi-

cally exhibit BRAF mutation ( 16 ), and this susceptibility may also

be related to gender and older age ( 11 ). Th ese serrated polyps

are typically fl at or sessile lesions and may be readily overlooked

unless specifi cally sought out by the endoscopist.

Recognizing that our understanding of this topic is still evolv-

ing and that there are many uncertainties that remain, this arti-

cle will attempt to build upon our previous review on this topic

( 7 ), with an emphasis on the most clinically important subtypes

of serrated polyps, and the impact that these lesions may have on

the overall CRC burden. Th e review will also address management

and surveillance recommendations and suggest potential changes

to our current CRC prevention practices. Readers are encouraged

to review Table 1 , which provides the defi nitions of key molecu-

lar genetic terms that are central to the discussion of the serrated

pathway.

CLASSIFICATION OF SERRATED POLYPS Serrated polyps are defi ned as epithelial lesions, which demon-

strate a “ saw-toothed ” or serrated appearance on histologic sec-

tion due to infolding of crypt epithelium. Th ey comprise typical

HPs (of which there are at least two main subtypes), atypical HP

variants called sessile serrated adenomas (SSAs), and dysplastic

serrated polyps, previously known generically as serrated adeno-

mas (SAs). Table 2 shows a proposed classifi cation scheme, which

groups serrated polyps into two main categories based on the

presence or absence of dysplasia.

The Clinical Signifi cance of Serrated Polyps Christopher S. Huang , MD 1 , Francis A. Farraye , MD , MSc 1 , Shi Yang , MD 2 and Michael J. O ’ Brien , MD , MPH 2

Colorectal cancer (CRC) is a heterogeneous disorder than arises via multiple distinct pathways, such as the serrated pathway, in which serrated polyps (including variants of hyperplastic polyps) are the precursor lesions. Approximately 15 – 20 % of all CRCs arise via the serrated pathway, and these serrated carcinomas are clinically, morphologically, and molecularly distinct from conventional CRCs. The prevention of serrated carcinomas represents an important clinical challenge. Gastroenterologists need to recognize and remove potential precursor lesions and implement a post-polypectomy surveillance program when appropriate. This article focuses on the characteristics and signifi cance of clinically relevant serrated polyps and addresses implications for CRC prevention practices.

Am J Gastroenterol 2011; 106:229–240; doi: 10.1038/ajg.2010.429; published online 2 November 2010

1 Department of Medicine, Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine , Boston , Massachusetts , USA ; 2 Department of Pathology and Laboratory Medicine, Boston Medical Center, Boston University School of Medicine , Boston , Massachusetts , USA . Correspondence: Christopher S. Huang, MD , Department of Internal Medicine, Section of Gastroenterology , Boston Medical Center, Boston University School of Medicine , 85 East Concord Street , # 7714, Boston , Massachusetts 02118 , USA . E-mail: [email protected] Received 4 June 2010; accepted 6 October 2010

CME

The American Journal of GASTROENTEROLOGY VOLUME 106 | FEBRUARY 2011 www.amjgastro.com

230 Huang et al. R

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Table 2 . Classifi cation of serrated polyps

Non-dysplastic Dysplastic

Hyperplastic polyps Sessile serrated adenoma, dysplastic (SSAD)

Goblet cell serrated polyp (GCSP)

Traditional serrated adenoma (TSA)

Microvesicular serrated polyp (MVSP)

Sessile serrated adenoma (SSA, also known as sessile serrated polyp, sessile serrated lesion and serrated polyp with abnormal proliferation)

A persistent area of contention with respect to the nomencla-

ture of these polyps has been use of the term SSA, in that by con-

vention colorectal adenomas are dysplastic, whereas SSAs lack

cytological dysplasia, although compared with HPs they mani-

fest both disordered proliferation and disordered crypt archi-

tecture ( 17 ). Th e most recent edition of a major gastrointestinal

pathology reference textbook opts for the term sessile serrated

polyp ( 18 ), and recent consensus European publications have

used the term sessile serrated lesion in preference to SSA ( 19 ).

In this review, we are not presuming to adjudicate the matter

but use the term SSA in deference, at this point, to its growing

acceptance in clinical practice and its more widespread use in

the literature.

Hyperplastic polyps Typical HPs, as a group, are highly prevalent, diminutive sessile

polyps that are most commonly located in the distal colon and

rectum ( 20 – 25 ). Endoscopically, HPs are usually readily iden-

tifi able by their smooth, symmetrical, pale appearance, as well

as their tendency to fl atten when the colon is insuffl ated with

air ( 26,27 ). Image-enhanced endoscopy techniques reveal that

HPs exhibit two distinct surface patterns: one shows large and

regular stellate pit openings; the second shows enlarged round

crypts with an expanded (relative to normal) pericryptal zone.

Th ese two surface patterns correspond to the two histological

subtypes ( Figure 1 ): microvesicular serrated polyps (MVSPs)

and goblet cell serrated polyps (GCSPs) ( 17 ). Not surprisingly,

these two distinct HP phenotypes also diff er in their molecu-

lar profi les. MVSPs frequently have the same molecular genetic

abnormalities found in more advanced serrated lesions (SSAs),

namely BRAF V600E mutation ( BRAF -mut) and an increased level

of susceptibility to aberrant methylation at promoter regions

(CpG island methylation phenotype (CIMP)) ( 8,11,12,28 ). It

would appear, therefore, that MVSPs may progress to SSAs,

particularly when located in the proximal colon. Th e GCSP

variant, in contrast, is likely to have a KRAS mutation ( KRAS -

mut), a molecular genetic change that is mutually exclusive

with BRAF- mut and infrequently found in SSAs ( 28 ). Whether

GCSPs progress to more advanced lesions is not known with

certainty, but there is some evidence that large GCSPs mimic

SSAs and are potentially the precursors of KRAS- mut dysplas-

tic serrated polyps ( 29 ). At this time, classifying HPs as either

MVSPs or GCSPs is of no clinical importance, except perhaps in

Table 1 . Defi nition of key molecular genetic terms pertinent to the serrated pathway

BRAF-mut A mutation of the BRAF oncogene at the V600E locus results in its activation and consequent persistent signaling of an intracel-lular growth control pathway called mitogen-activated protein kinase (MAPK). This mutation has high sensitivity and specifi city for the serrated polyp pathway and is found in most MVSPs, SSAs, and sporadic CIMP-H CRC, and rarely, if ever, in the conventional adenoma – carcinoma sequence.

CpG island methylation Dense clusters of cytosine nucleotides followed by a guanine nucleotide, referred to as CpG islands , occur selectively in the promotor (transcription control) regions of many genes, including growth suppressor and DNA repair genes. CpG island methylation refers to the addition of methyl groups to cytosine in such locations, where it can cause silencing of the genes and lead to neoplastic growth. Gene panel assays have been developed that reliably identify CRCs that have high levels of CpG island methylation ( CIMP-high ); these cancers are very strongly associated with BRAF mutation, both with and without MSI. A lower level of aberrant gene methylation, best revealed by alternative assay panels, is referred to as CIMP-low . This pattern appears to be associated with KRAS-mut carcinomas, both serrated and conventional.

Epigenetic Methylation of cytosine in the CpG island regions of DNA is a molecular change that is transmissible to cell progeny, but it does not alter the nucleotide sequence of the DNA and thus is referred to as epigenetic as distinct from a genetic change.

KRAS-mut KRAS is an oncogene that, when activated, signals in tandem with BRAF in the MAPK cell signaling pathway. Activating mutations of KRAS (usually at codon 12 or 13) are prevalent in tubulovillous and villous adenomas of the conventional adenoma – carcinoma sequence. They are also frequently found in serrated polyps, including the hyperplastic polyp subtype GCSP and dysplastic serrated polyps that have a traditional serrated adenoma phenotype.

Microsatellite instability Microsatellites are repeat nucleotide sequences of variable length that are distributed throughout the genome including the coding regions of many growth control genes. During cell replication, errors in copying these sequences are prevented by a series of DNA repair proteins produced by the mismatch repair genes . Inactivation of both alleles of one of these genes results in myriad muta-tions in microsatellites, a status referred to as microsatellite instability . This can be found in about 15 % of all colorectal cancers. Inactivation of the mismatch repair gene hMLH1 , as a result of CPG island methylation of its promoter region, accounts for ~ 75 % of MSI CRC and most of the remainder are associated with the inherited mutations of Lynch syndrome (hereditary non-polyposis colon cancer syndrome).

CIMP, CpG island methylation phenotype; CRC, colorectal cancer; MSI, microsatellite instability; MVSPs, microvesicular serrated polyps; SSA, sessile serrated adenoma.


231 Serrated Polyps Review

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island methylation (CIMP-H) ( 12,35,37 ). Th e large columnar

vacuolated cells of the upper crypts of the MVSP and SSA are a

manifestation of cell senescence. Th is cellular change is thought

to be an adaptive response to oncogenic signaling from the

mutated BRAF gene ( 38 ). Senescent cells have switched off cell

division, and it is hypothesized that induction of cell senescence

accounts for HPs being at very low risk for further neoplastic

progression. SSAs on the other hand can progress to dysplasia

and malignancy, and this propensity has been linked to short

circuiting of the senescence response in the crypt cells by CpG

island methylation-induced inactivation of growth control

genes ( 11,12,39,40 ).

Endoscopically, SSAs are usually larger than 5 mm, fl at, sessile

or superfi cially elevated in morphology, malleable, and frequently

covered by a thin layer of yellowish mucus ( 19,41 – 44 ). Th ey tend

to be larger than typical HPs and are more commonly located in

the proximal colon ( 17,33,35 ). Th eir surface is generally smooth

or granular, and they oft en have poorly defi ned, irregular bor-

ders, at times resembling a prominent fold of redundant mucosa

( Figure 3 ). Th ese endoscopic characteristics may make SSAs dif-

fi cult to detect and resect in entirety. Th e use of image-enhanced

the context of evaluating patients with multiple serrated polyps.

Th e same cannot be said, however, of distinguishing these HPs

from SSAs, which although non-dysplastic are of paramount

clinical interest.

Sessile serrated adenoma Th e prevalence, characteristics, and signifi cance of SSAs as spo-

radic lesions were not widely appreciated until 2003, when their

histologic features were formally analyzed ( 17 ), and they were

specifi cally identifi ed as the probable precursors to MSI-H can-

cers ( 30 ). Th ere is now emerging scientifi c consensus that the

SSA is the precursor whose detection is at the root of preventing

serrated pathway cancers.

Epidemiology Based on recent studies, SSAs are present in 1 – 4 % of the gen-

eral population ( 31,32 ), and represent approximately 1 – 9 % of all

polyps ( 31,33 – 35 ). Th e median age of patients with SSAs in one

large cross-sectional analysis of resected polyps was approxi-

mately 61 years ( 36 ), and there is a trend toward a female gender

bias ( 35 ).

Characteristics SSAs are the likely successor lesions of pre-existing MVSPs and

hyperplastic aberrant crypt foci, although some have argued

that they manifest their characteristic abnormal growth patterns

ab initio ( 35 ). Histologically, SSAs are distinguished from typi-

cal HPs by the presence of crypt architectural alterations that

refl ect disordered growth, or dysmaturation ( Figure 2 ) ( 17,30 ).

Th e most characteristic and recognizable of these include the

presence of inverted T- or L-shaped crypt bases. Other features

include dilated crypts and serration extending into the lower

third of the crypt. Focal nuclear stratifi cation, mild nuclear aty-

pia, or dystrophic goblet cells may be seen in the crypt bases, but

overt cytologic dysplasia, as has been emphasized, is not a feature

of SSAs ( 17 ).

SSAs have two defi ning molecular genetic characteristics

that indicate their relationship to MVSPs as well as to spo-

radic MSI-H CRCs, namely, BRAF -mut and high levels of CpG

Figure 1 . Histologic features of the two major subtypes of typical hyperplastic polyps. Goblet cell serrated polyps ( a ) have enlarged crypts with an abun-dance of mature goblet cells in the upper crypts, prominent tufting of the surface epithelium and inconspicuous serration. Microvesicular serrated polyps ( b ) are characterized by elongated funnel-shaped crypts with orderly maturation from crypt base to surface. The cells of the upper crypt show small cytoplasmic vacuoles (microvesicular); serration is present in the upper and mid crypt.

Figure 2 . Histologic features of sessile serrated adenomas. This hyperplastic polyp (HP) variant resembles microvesicular serrated polyps (MVSPs) in its upper part but the lower crypts show architectural disorder with the formation of irregular crypt bases with inverted T or L shapes (arrow). Other typical features represented here are dilated and serrated crypt bases.


232 Huang et al. R

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endoscopy techniques such as high-resolution / magnifi cation

chromoendoscopy and narrow-band imaging reveals that the

majority of SSAs have a type II (stellate / asteroid) pit pattern and

weak or normal vascular pattern intensity ( 45 ).

Clinical signifi cance Th e signifi cance of SSAs lies in their malignant potential. Th e

SSA was fi rst specifi cally identifi ed as the potential precursor to

CRC in a histologic analysis of a series of patients with hyper-

plastic polyposis ( 46 ). Subsequent studies identifi ed links between

proximal serrated polyps (originally diagnosed as HPs) and the

development of MSI-H CRCs ( 30,47 ). Although SSAs are at the

outset non-dysplastic, dysplasia can and does arise within SSAs,

giving rise to dysplastic serrated polyps. Th ere is some evidence

that aberrant Wnt signaling leading to β -catenin translocation to

the nucleus, by mechanisms diff erent from those in conventional

adenomas, may drive this transition ( 48 ). Yachida et al. ( 49 ) have

recently reported abnormal nuclear labeling of β -catenin in 29 %

of SSAs lacking dysplasia compared with 100 % of SSAs with dys-

plasia. Whatever the underlying mechanism, that development

of dysplasia is a necessary step for progression to malignancy is

supported by several histological studies that have demonstrated

a transitional zone of dysplasia, oft en showing a conventional

tubular or tubulovillous appearance, intervening between charac-

teristic SSA and invasive carcinoma in early serrated carcinomas

(12,50 – 52). Development of dysplasia can sometimes be appreci-

ated at endoscopy with the emergence of a mixture of type IIIL or

IV pit patterns within the SSA ( 19,43 – 45 ). An estimate of the risk

for progression of SSA is provided by a recent study, which found

that among 2,139 patients with at least one SSA, 12, 2, and 1 % of

patients harbored SSAs with low-grade dysplasia, high-grade dys-

plasia, and adenocarcinoma, respectively ( 36 ). Th erefore, there is

cogent morphological as well as molecular genetic evidence link-

ing SSAs to dysplasia and CRC, mandating that gastroenterolo-

gists recognize and manage these lesions appropriately.

Dysplastic serrated polyps Dysplastic serrated polyps, also known generically as SAs, are

defi ned as polyps that share two histological features: (i) a ser-

rated gland component and (ii) the presence of cytologic dys-

plasia. Th e current convention appears to be to further divide

dysplastic serrated polyps into two main categories: (i) SSA with

dysplasia (SSAD), which exhibits SSA morphologic characteris-

tics (e.g., inverted T- and L-shaped crypt bases, crypt branching

and dilatation, presence of mature goblet cells in the crypt bases)

or shows SSA contiguous to an area of serrated or conventional

dysplasia ( Figure 4 ) and (ii) traditional serrated adenoma (TSA),

which lacks SSA patterns and more closely resembles conven-

tional adenoma ( Figure 5 ) ( 53 ). Features more frequently associ-

ated with TSAs than with SSADs include distal location, polypoid

as distinct from sessile growth pattern, tubulovillous architecture,

and marked cytoplasmic eosinophilia ( 33,43,44,54 – 58 ). Recently,

Torlakovic et al. ( 54 ) have proposed that ectopic crypt formation

is the essential histological feature that distinguishes TSAs from

Figure 3 . Endoscopic features of sessile serrated adenomas. These lesions are frequently subtle and fl at, and may resemble a redundant mucosal fold ( a ) with an adherent layer of mucus on the surface ( b ). They typically have a smooth surface seen on white light endoscopy ( c ) and a weak / normal vascular pattern intensity seen using narrow-band imaging ( d ).



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called these polyps “ fusion pathway polyps, ” the term referring to

their combination of serrated pathway features such as CpG island

methylation and characteristics of the conventional pathway (ade-

noma – carcinoma sequence) such as chromosomal deletions and

p53 mutation. Th e most prudent approach to dysplastic serrated

polyps, whether SSAD or TSA, may be to implement a surveillance

program similar to that for advanced conventional adenomas once

the polyp has been judged, with a high level of confi dence, to have

completely removed.

THE CLINICAL SIGNIFICANCE OF END POINT CARCINOMAS OF THE SERRATED PATHWAY Although most cases of CRC arise via the conventional adenoma –

carcinoma sequence ( 63 ), it has become evident that several alterna-

tive pathways exist, culminating in end point cancers with specifi c

genetic signatures and distinctive clinical and morphological profi les

( 10 ). It is estimated that up to 20 % of all CRCs originate from ser-

rated polyps ( 10 ), amounting to nearly 30,000 cases annually based

on 2009 statistics ( 64 ). Recognition of the heterogeneity of serrated

polyps and end point serrated cancers has led to the hypothesis

that there are two parallel serrated pathways: one characterized by

BRAF -mut and the other by KRAS -mut ( Figure 6 ) ( 8,9,12,28,62 ).

Th e predominant, BRAF -mut serrated pathway culminates in

end point cancers which demonstrate high levels of CpG island

methylation (CIMP-H). Th ey include the majority of sporadic

(non-syndromic) MSI-H CRCs and represent ~ 12 – 15 % of all

CRCs. Epigenetic silencing of the DNA mismatch repair gene

hMLH1 by promoter methylation is a key event in this arm, leading

to MSI-H which is thought to drive progression from low-grade

dysplasia, to high-grade dysplasia, and ultimately to invasive cancer

( 12 ). A proportion of BRAF -mut, CIMP-H cancers are micro satellite

stable (MSS) and frequently have a p53 mutation, and, perhaps for

this reason, tend to exhibit more aggressive clinical behavior and

poorer prognosis than their MSI counterparts ( 65 ).

Distinguishing clinical features of all CIMP-H CRCs include

their over-representation in women and predilection for location in

the proximal colon. Morphologically, they frequently demonstrate

glandular serration, mucinous diff erentiation, poorly diff erentiated

glands or none (as in undiff erentiated or medullary carcinoma),

SSAs. Th is term refers to new crypt formation in which orienta-

tion of the crypt base to the muscularis mucosae is lost, in contrast

to SSAs in which anchorage of new crypts to muscularis mucosae

is generally maintained. On a molecular genetic level, the majority

of SSADs are BRAF -mut; TSAs are frequently KRAS -mut ( 49 ) but

are also found in a proportion of cases to be both KRAS wild type

and BRAF wild type, and in some cases to be BRAF -mut, defying

histological predictors ( 59 ). So-called mixed polyps can be incor-

porated within the SSAD and TSA categories. Other types of dys-

plastic serrated polyps that have been proposed, that are beyond

the scope of this discussion, include conventional adenoma with

serrated architecture, which refers to a conventional adenoma

with focal and ill-defi ned serrated features ( 60 ).

Dysplastic serrated polyps as a group are much less common

than conventional adenomas or HPs, representing only 0.6 % of

over 18,000 polyps analyzed in the original report by Longacre

and Fenoglio-Preiser ( 61 ). Data from more recent studies demon-

strate that TSAs and SSADs may each represent 1 – 2 % of all polyps

( 31,33,35,62 ).

Some authorities have expressed the view that SSADs are at

greater risk of progressing to CRC than TSAs ( 54 ), warranting

more aggressive surveillance. However, a recent Korean study

has reported a high frequency of high-grade dysplasia or intra-

mucosal carcinoma in KRAS- mut TSAs ( 59 ). Jass et al. ( 62 ) have

Figure 4 . Endoscopic appearance and histology of a sessile serrated adenoma with dysplasia. Endoscopically ( a ), the polyp has a sessile, lobulated appearance. Histology ( b ) demonstrates a protruding nodule of adenomatous low- and high-grade dysplasia (black arrow) arising within a non-dysplastic sessile serrated adenoma (SSA) on the left of the image, identifi ed by serration and marked irregularity of the crypt architecture.

Figure 5 . Histologic features of a traditional serrated adenoma. This example, which has a KRAS mutation and is microsatellite stable (MSS), shows cytoplasmic eosinophilia, an exophytic tubulovillous architecture, and prominence of ectopic crypt formation (arrows).


234 Huang et al. R

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Distalpredominance

MSI-L/MSS

Chromosomalinstability

Serratedcarcinoma

SSA+HGDSSA+DSessileserratedadenoma

Serratedadenoma

SA+HGD

CpG island methylation

CpG island methylation

?Precursor

lesion

Serratedcarcinoma

(TSA)

HP - MVSPsubtype

ACF-H

ACF-H

KRAS mutation

BRAF mutation

Normal

Microsatellite instability

Chromosomal instability

Proximalpredominance

MSI-H

Loss of hMLH1

Figure 6 . Schematic illustration of the postulated serrated pathways to colorectal cancer. ACF-H, aberrant crypt foci-hyperplastic type; HP-MVSP, hyper-plastic polyp, microvesicular serrated polyp subtype; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable; SA + HGD, serrated adenoma with high-grade dysplasia; SSA + D, sessile serrated adenoma with dysplasia; SSA + HGD, sessile serrated adenoma with high-grade dysplasia; TSA, traditional serrated adenoma.

increased intratumoral lymphocytes, and Crohn ’ s-like nodular

peritumoral lymphocytic infi ltrates ( 66 – 68 ).

Th e KRAS -mut arm of the serrated polyp pathway culminates

in end point carcinomas that demonstrate lower levels of CIMP

(CIMP-L). Th e measurement and signifi cance of low levels of

CpG island methylation is controversial ( 14 ). In contrast to the

BRAF -mut arm, hMLH1 is not inactivated in these cancers and

they are invariably MSS. Mutation of suppressor genes and p53,

rather than aberrant methylation, appears to be the main driving

force for their evolution. Some authors have suggested that KRAS-

mut serrated cancers account for ~ 5 % of all CRC ( 10 ), but it is dif-

fi cult to make a precise estimate because KRAS , unlike BRAF , is

also found in up to 50 % of conventional CRCs. Perhaps, the best

current evidence that these cancers represent a distinct entity is

the fi nding of KRAS -mut dysplastic serrated polyps in continuity

with high-grade dysplasia and or early invasive carcinoma, a fi nd-

ing most frequently encountered in the distal colon.

The problem of right-sided and interval cancers Recent studies have demonstrated that the age-adjusted incidence

and mortality rates from right-sided CRCs have not decreased in

recent years despite the more widespread use of screening colon-

oscopy ( 1,4 ). Possible explanations for this phenomenon include

missed lesions in the proximal colon due to incomplete examina-

tion, suboptimal bowel preparation, incomplete polyp removal, or

unrecognized abnormalities (e.g., SSAs), as well as diff ering biologic

behaviors of proximal vs. distal precursor lesions. Although this

hypothesis has not been directly studied, serrated pathway cancers

are likely a major contributor to the rising ratio of proximal-to-distal

CRCs ( 69 ). A recent population-based study found that right-sided

CRCs were signifi cantly associated with female gender and advanc-

ing age ( 70 ), features that are disproportionately represented among

patients with MSI-H CRCs arising via the serrated pathway.

Interval cancers, typically defi ned as cancers that are diag-

nosed within 5 years of a complete / clearing colonoscopy, repre-

sent ~ 2 – 6 % of all CRCs ( 71 – 74 ). Several studies have shown that

interval cancers, compared with non-interval cancers, are much

more likely to occur in the proximal colon, demonstrate CIMP and

MSI-H ( 71,73,75,76 ), features that are suggestive of a BRAF -mut

serrated origin. It is therefore plausible that a signifi cant propor-

tion of interval cancers arise from prevalent SSAs that go unrec-

ognized or are incompletely resected, which ultimately transform

into invasive cancers.

Risk and rate of progression to malignancy Although the malignant progression of serrated polyps has been

clearly documented, the natural history and rate of progression

of serrated polyps are less well established. Th ere has been a



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the predominant type of polyp is constant ( 88 ). A recent study by

Pai et al. ( 89 ) reported that the fi nding of one SSA was frequently

associated with synchronous serrated polyps in non-syndromic

patients, suggesting a strong fi eld phenomenon predisposing

patients to multiple serrated polyps. Th is group has also reported

that patients with SSAs frequently are found to have histologi-

cally distinctive conventional adenomas that exhibit low levels of

CIMP ( 60 ).

More recently, several studies have highlighted the association

between serrated polyps and conventional adenomas and advanced

colorectal neoplasia ( 90 – 93 ). In a study of 4,714 asymptomatic

subjects undergoing screening colonoscopy, Li et al. ( 92 ) found

that large serrated polyps ( ≥ 1 cm) were strongly and independ-

ently associated with synchronous advanced neoplasia defi ned as

invasive carcinoma, tubular adenoma ≥ 1 cm, or adenoma with any

villous histology or high-grade dysplasia. Nearly 25 % of subjects

with large serrated polyps had synchronous advanced colorectal

neoplasia, compared with ~ 10 % of subjects without large ser-

rated polyps. Th is association between large serrated polyps and

advanced colorectal neoplasia, particularly CRC, was confi rmed in

a large, multi-center observational study of over 10,000 subjects

who underwent fi rst-time colonoscopy for a variety of indications

( 91 ). CRC was present in 708 subjects (6.9 % ), and on multivariate

analysis, the presence of large serrated polyps was the strongest

risk factor for CRC, particularly for proximal CRCs. Finally, Sch-

reiner et al. ( 93 ) have also demonstrated the signifi cant associa-

tion between proximal or large non-dysplastic serrated polyps and

the presence of synchronous advanced neoplasia. Furthermore,

they found that individuals with proximal non-dysplastic serrated

polyps at baseline were at increased risk of having three or more

synchronous small tubular adenomas at baseline, as well as any

non-advanced adenomas detected during surveillance colono-

scopy. Altogether, the weight of the available evidence suggests

that large serrated polyps should be considered a marker for syn-

chronous advanced colorectal neoplasia, including CRC, and that

certain serrated polyps (proximal or dysplastic) increase the risk

of metachronous serrated and / or conventional adenomas.

Risk factors for serrated neoplasia Few epidemiologic studies have specifi c investigated risk fac-

tors for serrated polyps. Serrated polyps tend to be less common

in African Americans and Hispanics compared to Caucasians

( 22,94 ). Studies on various dietary and lifestyle factors have not

revealed consistent eff ects on the risk of serrated polyps, and a

recent study suggested that the risk profi le for distal serrated pol-

yps actually diff ers from that of proximal serrated polyps ( 94 ).

Th is study found that obesity, cigarette smoking, dietary fat,

total energy intake, and red meat intake were associated with

an increased risk of distal (but not proximal) serrated polyps. In

contrast, others have demonstrated an increased risk of right-

sided serrated polyps associated with smoking ( 93 ). Cigarette

smoking is a known risk factor for serrated polyps and is also

associated with MSI in sporadic CRCs ( 22,95 – 97 ). Furthermore,

smoking has also been shown to be associated with an increased

risk of CRCs with BRAF -mut and / or CIMP ( 98 ), features that

concern that BRAF -mut dysplastic serrated polyps will progress

rapidly to carcinoma upon the acquisition of MSI-H status, akin

to the behavior of adenomas in the hereditary non-polyposis

colon cancer syndrome. In the original report on SAs, 37 % had

foci of “ signifi cant dysplasia ” and 11 % contained intramucosal

carcinoma ( 61 ). Subsequent studies have reported a 3 – 16 %

prevalence rate of high-grade dysplasia or intramucosal carci-

noma in SAs ( 56,58,77 – 81 ). As mentioned above, a recent study

on patients with SSAs reported prevalence rates of 12 and 2 %

for low-grade dysplasia and high-grade dysplasia, respectively

( 36 ). It has been estimated that ~ 6 % of SSAs develop into MSI-

H CRCs, based on the assumptions that the prevalence rate of

SSAs is 12 % ( 82 ), and the expected lifetime risk of MSI-H CRCs

is 0.75 % ( 83 ).

Th e rate at which serrated polyps progress to CRC is uncertain

and likely is variable, depending on if, or when, MSI-H status is

acquired. Th e observation that serrated cancers are more prevalent

than dysplastic serrated polyps would suggest rapid transformation

to CRC ( 9,33,52,84 ). Clearly, the possibility of rapid transforma-

tion exists, as evidenced in a recent case report describing progres-

sion from SSA to early carcinoma within 8 months ( 85 ). However,

not all the available data suggest a frequent or rapid progression to

CRC down the serrated pathway. One large cross-sectional analy-

sis reported that the median age of patients with SSAs, SSADs, and

SSAs with carcinoma were 61, 66, and 76 years, respectively, sug-

gesting a progression that occurs over a period of 15 years ( 36 ). In

addition, data from one of the fi rst studies to specifi cally identify

SSAs as the precursors to MSI-H cancer suggested a slow progres-

sion, with an interval between the CRC and the SSAs that preceded

them of over 3 years in 90 % of cases, and over 6 years in 55 % ( 30 ).

Furthermore, several studies have shown that the malignant poten-

tial of dysplastic serrated polyps is similar to, if not lower than that

of conventional adenomas ( 77,81,86,87 ). Th erefore, at this time, no

fi rm conclusions regarding the true frequency and rate of progres-

sion from SSA or dysplastic serrated polyp to CRC can be drawn.

Th is uncertainty notwithstanding, the malignant potential of these

lesions is beyond doubt, and they represent the precursors to an

important proportion of the overall CRC burden. As such, these

lesions should be regarded as important targets of our CRC pre-

vention strategies.

Risk of metachronous and synchronous neoplasia in patients with serrated polyps Th ere are limited data on the risk of metachronous and synchro-

nous neoplasia in patients with clinically important serrated

polyps, specifi cally dysplastic serrated polyps and SSAs. In a ret-

rospective study of 239 subjects with HPs, SAs or conventional

adenomas at index examination, metachronous serrated CRC was

diagnosed aft er a mean of 14 years in 5 % of patients with SAs

removed during index examination ( 88 ). Th is study also found

that the presence of SA on index examination predicted the pres-

ence of metachronous SAs, but not conventional adenomas: in

patients with index SAs, 75 % of metachronous polyps were SAs,

whereas only 6 % were conventional adenomas, suggesting that

the eff ect of genetic and environmental factors in determining


236 Huang et al. R

EV

IEW

are characteristic of proximally located serrated polyps. Female

gender, multiplicity of serrated polyps, larger polyp size, and

polyp location in the proximal colon have also been identifi ed as

risk factors for SSAs as well as CIMP and BRAF -mutated CRCs

( 35,99,100 ). Higher BMI is associated with an increased risk of

large serrated polyps ( 92 ), and as mentioned above, may have a

particular infl uence on the risk of serrated polyps in the left colon

( 94 ). Finally, a family history of CRC or polyps may increase the

risk of SSAs and right-sided serrated polyps ( 35,93,94 ).

Hyperplastic polyposis syndrome: a precancerous condition Hyperplastic polyposis syndrome is an uncommon and hetero-

geneous condition characterized by the presence of multiple

and / or large serrated polyps. Following its description as a con-

dition with little or no malignant potential by Williams et al.

( 101 ) in 1980, several reports of CRC arising in patients with

this syndrome have been published, providing some of the earli-

est evidence of a link between serrated polyps and CRC ( 102 –

108 ). Although the true risk of CRC in hyperplastic polyposis is

not known, based on available data from case reports and case

series, the incidence of CRC appears to range from 40 to 50 %

( 109 – 111 ).

Th e World Health Organization has established the follow-

ing criteria for the diagnosis of hyperplastic polyposis ( 112 ): (i)

at least fi ve HPs located proximal to the sigmoid colon, two of

which are larger than 10 mm in diameter; (ii) any number of HPs

located proximal to the sigmoid colon in an individual who has

a fi rst-degree relative with hyperplastic polyposis; or (iii) > 30

HPs of any size, distributed throughout the colon. Appreciated

to be a genetically and phenotypically heterogeneous condition,

it has been proposed that there are two distinct types of hyper-

plastic polyposis ( 113,114 ): type I hyperplastic polyposis (ser-

rated adenomatous polyposis) is characterized by multiple (fi ve

or more), large, proximally located SSAs (coexisting with TSAs,

mixed polyps, and conventional adenomas) and is associated

with a signifi cant risk for CRC ( 46 ). In this syndrome, there is

a high frequency of concordant BRAF- mut and CIMP-H in ser-

rated lesions, and aberrant methylation can be demonstrated even

in normal mucosa, suggesting a fi eld defect in epigenetic regula-

tion ( 115 ). Type II hyperplastic polyposis, a more heterogeneous

condition, is characterized by numerous ( ≥ 30), small HPs dis-

tributed throughout the colon, and is believed to have a signifi -

cantly weaker association with CRC ( 101,116 ). Further studies are

needed to validate the distinction between the proposed types of

hyperplastic polyposis syndrome, characterize their clinical and

molecular features and natural history, and determine appropriate

clinical management.

Only 50 % of patients with hyperplastic polyposis have a fam-

ily history of colon cancer and the syndrome has no proven

hereditary basis, but there is substantial evidence in support of

a genetic etiology. Th is evidence includes examples of familial

hyperplastic polyposis, early age of onset, polyp multiplicity,

high level of risk for CRC, and ethnic associations in population

studies ( 115,117 ). Young and Jass ( 115 ) proposed that a fi eld

susceptibility to CpG island methylation is the most likely basis

for the genetic predisposition in type I hyperplastic polyposis.

Hyperplastic polyposis with multiple KRAS -mut serrated polyps

has also been described in association with bi-allelic germline

mutations of MUTYH ( 29 ).

IMPLICATIONS FOR CRC PREVENTION PRACTICES Th ere are currently no formal guidelines on the management

of serrated polyps other than small rectal HPs, which can be

regarded as inconsequential and do not require complete resec-

tion or surveillance. Th e most recent consensus statement by the

United States Multi-Society Task Force on CRC, American Can-

cer Society, and American College of Radiology addressed the

issue of SAs and SSAs, but concluded that there was insuffi cient

data to formulate surveillance guidelines for these lesions ( 118 ).

Th erefore, the recommendations presented in this article are

based on expert opinion, shaped by current knowledge regarding

the malignant potential of these serrated polyps.

Recognition and resection of serrated lesions In order to prevent serrated pathway cancers, the precursor

lesions need to be recognized and resected in their entirety. Given

what we know about the gross morphology of SSAs as well as their

predilection for the proximal colon, colonoscopy is the preferred

method for detecting these lesions ( 83 ). Endoscopists need to

be particularly aware of the subtle appearance of SSAs, and rec-

ognize clues such as an adherent mucus coating. A recent study

performed at our institution found that there is signifi cant varia-

tion in detection rates of patients with SSAs among experienced

gastroenterologists using white light endoscopy, ranging from

0 to 2.2 % ( 119 ). Image-enhanced endoscopy techniques such

as chromoendoscopy may improve detection of serrated polyps

( 35,43,120 – 122 ), but they are not yet recommended for routine

use in screening procedures ( 123 ). Chromoendoscopy using a

contrast dye, either sprayed on the surface or injected submucos-

ally, may also facilitate complete resection of sessile lesions by

delineating the margins of the polyp ( Figure 7 ).

Th e techniques used to resect serrated polyps are the same as

those used for conventional adenomas, and can be selected accord-

ing to the size, location, and gross morphology of the polyp. Cold

snare polypectomy can be safely performed for diminutive ses-

sile polyps ( 124 – 126 ) and avoids the potential for cautery arti-

fact interfering with histologic examination of the specimen.

In the authors ’ experience, inject-and-cut endoscopic mucosal

resection is the preferred technique ( 127,128 ) for resecting large,

sessile / superfi cially elevated, or poorly defi ned serrated lesions.

Follow-up examination in 3 months and then in 1 year should be

performed in these circumstances to examine the polypectomy site

and ensure a “ clean colon ” before entering the patient into a long-

term surveillance program.

Post-polypectomy surveillance Although surveillance following removal of isolated typical HPs is

not necessary, surveillance aft er resection of SSAs and dysplastic

serrated polyps is recommended ( Table 3 ). Polyps diagnosed as



RE

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Th e optimal surveillance interval aft er resection of these serrated

lesions is unknown, given uncertainty regarding their natural history

and risk of recurrent / metachronous neoplasia. Until further data are

available, it would be reasonable to follow SSAs without cytologic

dysplasia as per the current surveillance guidelines for conventional

adenomas, stratifi ed according to polyp size and number ( 8,83 ).

Dysplastic serrated polyps, both SSADs and TSAs, may warrant

more intensive surveillance, similar to that performed for advanced

conventional adenomas. Accordingly, surveillance colonoscopy in 3

years would be reasonable aft er ensuring complete resection. Finally,

the presence of multiple (5 + ), large ( > 1 cm), proximally located

serrated polyps may be a manifestation of type I hyperplastic poly-

posis syndrome ( 114 ). Although data on screening and surveillance

in this condition are severely lacking, given its frequent association

with CRC, we would recommend colono scopy every 1 – 3 years with

resection of all lesions larger than 5 mm ( 83,116 ). Colectomy may

be justifi ed in patients with an extremely high polyp burden, con-

comitant dysplastic serrated polyps, or multiple advanced adeno-

mas. Colonoscopic screening of fi rst-degree relatives should be

considered starting at age 40 years, or 10 years earlier than the earli-

est age at diagnosis in the family ( 131 ).

SUMMARY CRC is a heterogeneous disorder that arises via multiple distinct

pathways. In one such pathway, serrated polyps, including variants

HPs may also warrant surveillance if there are attendant risk factors

such as multiplicity, large size, proximal location, or family history

of CRC. Gastroenterologists should appreciate that accurate and

reproducible categorization of serrated polyps by pathologists can

be challenging in clinical practice ( 34,53,54,119,129,130 ). As the

distinction between HP and SSA represents a continuum of his-

tological abnormality without sharp boundaries, particularly in

smaller “ early ” SSAs ( 130 ), gastroenterologists need to be aware of

the possibility of misclassifi cation, and take into account clinical

and endoscopic factors when deciding how to manage a particular

patient diagnosed with a “ HP. ”

Figure 7 . Endoscopic appearance of a large sessile serrated adenoma and the use of chromoendoscopy to facilitate polyp delineation and resection. ( a ) This lesion, which demonstrates the characteristic mucus covering and smooth surface, was initially biopsied but not resected by the referring gastroen-terologist, and the adjacent mucosa was tattooed. ( b ) Follow-up examination revealed this to be a large lesion with a redundant, fold-like morphology and poorly defi ned margins. ( c ) Chromoendoscopy using topical application of 0.2 % indigo carmine clearly delineated the margins of the polyp. ( d ) Submucosal injection of 0.2 % indigo carmine further highlighted the extent of the polyp and simultaneously provided a cushion for endoscopic mucosal resection.

Table 3 . Surveillance recommendations after resection of serrated polyps

Category Recommended surveillance interval

Typical hyperplastic polyp No surveillance recommended, unless multiple, large and proximally located

Sessile serrated adenoma (non-dysplastic)

5 Years if < 3 lesions, all < 1 cm size; 3 Years if ≥ 3 lesions, or any ≥ 1 cm size

Sessile serrated adenoma with dysplasia (SSAD) Traditional serrated adenoma (TSA)

3 Years, after ensuring complete resection (see text)

Suspected type I hyperplastic polyposis (serrated adenomatous polyposis)

1 – 3 Years, with resection of polyps > 5 mm


238 Huang et al. R

EV

IEW

of HPs, are the precursor lesions. Approximately 15 – 20 % of all

CRCs arise via this serrated pathway; most are proximally located

and are characterized by a molecular genetic profi le of BRAF -mut

and CIMP-H. Serrated polyps that are KRAS -mut also contribute

to serrated pathway carcinomas and these, in contrast, are gener-

ally distally located, CIMP-L and MSS. Th ere is growing evidence

that end point cancers of the serrated pathway, particularly when

proximally located, are major contributors to occurrences of

“ interval cancer ” following negative colonoscopy. Gastroenterolo-

gists need to be able to recognize and remove potential precursor

lesions and implement a post-polypectomy surveillance program

in order to prevent these cancers. Further investigation is needed

to improve our ability to detect important serrated polyps, clarify

their natural history, and determine their optimal management.

ACKNOWLEDGMENTS We thank John O ’ Hara for his assistance in preparing the histology

images used in this article.

CONFLICT OF INTEREST Guarantor of the article : Christopher S. Huang, MD.

Specifi c author contributions: Draft ed and revised the manuscript

and approved the fi nal version: Christopher S. Huang; initiated

the plan to write this article, edited the manuscript, and approved

the fi nal version: Francis A. Farraye; edited the manuscript and

approved the fi nal version: Shi Yang; provided his expertise on the

molecular genetic and pathology aspects of the topic, helped draft

and revise the manuscript, and approved the fi nal version:

Michael J. O ’ Brien.

Financial support : None.

Potential competing interests : None.

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the clinical significance of serrated polyps...serrated polyps are defi ned as epithelial lesions,...

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