Clinical Gastroenterology and Hepatology 2020;18:777–779
HERE AND NOW: CLINICAL PRACTICE
Serrated Polyposis Syndrome
Gautam Mankaney,*,‡ Carol Rouphael,* and Carol A. Burke*,‡,§
*Department of Gastroenterology, Hepatology, and Nutrition, ‡Sanford R. Weiss, MD, Center for Hereditary Colorectal
Neoplasia, and §Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio
olorectal serrated polyps (SPs) are a pathologi-
C cally diverse group of lesions that include hyper-
plastic polyps (HPs), traditional serrated adenomas
(TSAs), and sessile serrated polyps (SSPs). Although the
majority of sporadic colorectal cancers (CRCs) arise from
adenomatous polyps, SSPs are believed to be the pre-
cursor in up to 30% of cases. Serrated polyposis syn-
drome (SPS), formerly called hyperplastic polyposis
syndrome, is the most common, yet underdiagnosed,
colorectal polyposis syndrome characterized by an
accumulation of SPs and adenomas and associated with
an increased risk of both prevalent and incident CRC.
Tracking lifetime cumulative features of SPs and endo-
scopic clearance of adenomas and SPs are the mainstays
of management. Colorectal surgery is used in cases
where endoscopic control is not feasible and for the
treatment of CRC.
Description
The diagnosis of SPS is based on the cumulative
lifetime number of HPs, TSAs, and SSPs in a patient who
meets 1 of the 2 following World Health Organization
(WHO) criteria including (1) 5 SPs proximal to
rectum, all being 5 mm in size, including 2 that are
10 mm; or (2) >20 SPs of any size distributed
throughout the colon, with 5 being proximal to the
rectum (Figure 1).1 Those criteria are the recently
published 2019 WHO criteria. The previous WHO
criteria for the diagnosis of SPS were revised to include
patients with distal serrated polyps in the rectosigmoid
colon. In addition, the previous criterion of having 1
SPs proximal to the sigmoid colon with family history of
SPS was dropped.2 This alteration is likely due to data
demonstrating the heterogeneous risk of CRC in pa-
tients with 1 SPs proximal to the sigmoid colon with
family history of SPS, and the fact that nearly 50% of
CRCs in SPS occur in the rectosigmoid colon.3 SPS was
once thought to be a rare polyposis condition; however,
it is more likely under-recognized and not diagnosed
because of the need to keep track of the cumulative
number of SPs in a patient. One study of 529 patients
referred to an expert center for removal of polyps
>20 mm in size observed that 4% of patients met the
Charles J. Kahi, Section Editor
WHO criteria, nearly half at the index examination and
the other half during surveillance. Only 1 patient was
suspected to have SPS by the referring physician, and
50% were diagnosed by the consultant endoscopist.3
These authors cited that the failure to detect SPS was
attributed to the lack of systematic tracking of polyps
and application of WHO criteria. In fact, international
data on CRC screening populations have documented
that SPS is the most common polyposis syndrome, with
an occurrence of 1 in 127 to 1 in 242 patients under-
going colonoscopy.4,5 Awareness of the clinical signifi-
cance of SSPs, creation of international standards for
performance of quality colonoscopy, and use of high-
definition, enhanced imaging colonoscopy have likely
contributed to an increase in the detection rate of all
colorectal lesions including SPs, which contribute to
enhancing the diagnosis of SPS.
The etiology of SPS is unknown, and the syndrome
likely represents a spectrum of disease modified by ge-
netic and environmental factors. Evidence suggests a
familial association is seen; however, investigation into a
monoallelic cause of SPS has not identified a common
cause. Pathogenic germline variants in the tumor sup-
pressor gene RNF43 have been detected in SPS, but in the
2 largest series of patients studied the mutation occurred
in less than 2% of 170 individuals tested.6 Commercial
germline testing for RNF43 is currently available on a
pan-cancer gene panel through at least 1 commercial
laboratory in the United States. We will learn more about
the role of RNF43 in SPS and other cancers as more pa-
tients undergo panel tests that include RNF43. Some
evidence exists that CpG island methylation is an
important pathway involved in SPS. The high proportion
of BRAF or KRAS mutations detected in the SPs from
patients with SPS compared with patients with sporadic
Abbreviations used in this paper: CI, confidence interval; CRC, colorectal
cancer; FDR, first-degree relative; HP, hyperplastic polyp; OR, odds ratio;
SIR, standardized incidence ratio; SP, serrated polyp; SPS, serrated pol-
yposis syndrome; SSP, sessile serrated polyp; TSA, traditional serrated
adenoma; WHO, World Health Organization.
Most current article
© 2020 by the AGA Institute
1542-3565/$36.00
https://doi.org/10.1016/j.cgh.2019.09.006
778 Mankaney et al Clinical Gastroenterology and Hepatology Vol. 18, No. 4

Figure 1. Diagnosis and

management algorithm for
SPS. CRC, colorectal
cancer; HP, hyperplastic
polyp; SPS, serrated pol-
yposis syndrome; SSP,
sessile serrated polyp;
TSA, traditional serrated
adenoma; WHO, World
Health Organization.

SPs has been suggested as a potential molecular marker colonoscopy with polypectomy and close polypectomy
of SPS. The sensitivity and specificity of somatic BRAF or surveillance to decrease incident CRC (Figures 1 and 2),
KRAS mutation frequency for the diagnosis of SPS have which may arise from 1 of 2 molecular mechanisms
not been assessed in a prospective study and may be (the adenoma-carcinoma and serrated polyp–carcinoma
impractical and cost prohibitive. We and other centers pathway). Colorectal surgery is reserved as the primary
have noted an association between SPS and lymphoma. management for individuals with CRC or an endoscopi-
In a recent case-control trial, 6% of 101 survivors of cally unmanageable polyp burden. Colonoscopy should
Hodgkin lymphoma treated with abdominal radiotherapy be done in 2 phases, clearance and then surveillance.
and/or chemotherapy with alkylating agents were diag- Guidelines recommend that colonoscopy be done until
nosed with SPS on surveillance colonoscopy versus none clearance of all polyps 3–5 mm is attained (Figure 2).
of the 1426 general population patients undergoing
screening colonoscopy.7 The impact of chemotherapy or
radiotherapy on inducing methylation or other effects on
the SPS pathway is not known.
The risk of advanced conventional and serrated
neoplasia in SPS is high. In a recent multicenter Euro-
pean cohort study, CRC occurred in 127 of 434 patients
(29.3%) at a median age of 61 years. Approximately half
of the cases were detected before the diagnosis of SPS
and the other half at the time of SPS diagnosis.3 In the
study, a median of 29 SPs were detected on baseline
colonoscopy, and 76% of SPS patients had an SP 10
mm. Adenomas were observed in 75% of patients and
advanced adenomas in 35%. The independent risk fac-
tors for CRC included having at least 1 advanced ade-
noma (odds ratio [OR], 2.46; 95% confidence interval
[CI], 1.59–3.80), 1 or more SPs with dysplasia (OR, 2.34;
95% CI, 1.48–3.70), and patients who met criterion 1 Figure 2. Endoscopic images obtained during clearance
plus 3 of the older WHO criteria for SPS diagnosis (OR, phase in a patient who met World Health Organization SPS
criterion 3 (now criterion 2 in revised 2019 WHO criteria).
1.62; 95% CI, 1.05–2.49). More than 50 SSPs, ranging from 2 to 50 mm, have been
The cornerstones of management of patients with SPS removed from patient to date. SPS, serrated polyposis syn-
and an endoscopically manageable polyp burden are drome; SSP, sessile serrated polyp.
April 2020
The interval between clearance colonoscopy is not
defined but probably should be based on the size, his-
tory, and number of polyps at 3–6 months. Surveillance
colonoscopy after clearance of all 3- to 5-mm polyps is
recommended at 1- to 3-year intervals to decrease the
risk of incident cancer. CRC occurring after polyp clear-
ance has ranged widely. Recent studies demonstrate
incident CRC in 0%–3% of patients undergoing surveil-
lance colonoscopy at 1- to 2-year intervals and follow-up
times ranging from 3 to 5 years. Only 2 patients devel-
oped CRC in a prospective European trial of 271 patients
with SPS followed for a median 3.6 years after
completing clearance colonoscopy for a cumulative 5-
year incidence of 1.3%.8 The 5-year incidence of
advanced neoplasia was 44%. In the trial, patients with
more than 5 polyps, an advanced serrated or adenoma-
tous polyp, or who required surgery were recommended
a 1-year surveillance interval versus 2 years in patients
without those features. Advanced neoplasia after a 2-
year recommendation was not significantly different
than after a 1-year recommendation, 15.6% versus
24.4%, respectively.
CRC is commonly reported in the first-degree rela-
tives (FDRs) of patients with SPS. A provocative study
from Spain compared the prevalence and standardized
incidence ratio (SIR) of CRC in FDRs of patients with SPS
and patients who did not meet the WHO criteria for SPS
but had more than 10 polyps, at least 50% of which were
serrated.9 No difference in CRC in FDRs was observed
between the cohorts, reported at 12.2% (SIR, 3.28; 95%
CI, 2.16–4.77) and 10.4% (SIR, 2.79; 95% CI, 2.10–3.63),
respectively. Guidelines suggest FDRs of patients with
SPS undergo colonoscopy every 5 years at earliest of the
following: age 40, the same age as youngest diagnosis of
SPS in the family, or 10 years younger than earliest CRC
complicating SPS.10 The evidence to support this and
other recommendations regarding clearance and sur-
veillance is modest at best.
Future Studies
Further work regarding ways to increase the diag-
nosis of SPS such as automated tools for systematic
tracking of serrated polyps in the electronic medical
record and improve the endoscopic detection and
resection of lesions is necessary. Patients with SPS and
their FDRs are at increased risk of CRC, but the rate of
incident CRC in SPS patients after clearance is lower than
previously thought. Clinicians should regard patients
with a history of lymphoma, particularly those exposed
to abdominal radiotherapy and/or the use of alkylating
chemotherapy, as a high-risk group to develop SPS (and
advanced neoplasia) and consider offering heightened
SPS 779
screening and surveillance. The optimal interval for
surveillance in SPS remains to be defined, yet emerging
data suggest specific features of neoplasia may help
stratify individuals who need a 1 versus a 2 or more year
follow-up interval. No data exist regarding the utility of
chemoprevention or biomarkers for the diagnosis of SPS,
and these are areas that should be explored. The CRC-
specific and all-cause mortality benefit of endoscopic
surveillance and surgery has yet to be established.
Finally, the phenotypic expression of patients with and
without an RNF43 mutation is unknown but will be
clarified with the ongoing use of pan-cancer gene panels.
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Accessed November 4, 2019.
Reprint requests
Address requests for reprints to: Gautam Mankaney, MD, 9500 Euclid Avenue/
A30, Cleveland, Ohio 44195. e-mail: mankang@ccf.org; fax: (216) 444-6305.
Conflicts of interest
The authors disclose no conflicts.