Serrated Colorectal Polyps: New Challenges to Old Dogma
Kenneth P. Batts
Abbott Northwestern Hospital
Serrated Colorectal Polyps: New Challenges to Old Dogma
Overview of Known Colorectal Cancer Pathways
Traditionally, the two
main categories of colorectal epithelial polyps have been adenomatous and hyperplastic polyps (HPPs). It
has long been recognized that adenomatous polyps are premalignant lesions, and indeed the discovery of
the molecular basis of the now famous adenoma-carcinoma sequence is one of the scientific triumphs of the
past quarter century . This pathway is most often seen in sporadic colorectal cancers but
also characterizes familial adenomatous polyposis and is thus called the "adenomatous polyposis coli" or
"APC" pathway. Subsequently, another molecular pathway to colorectal cancer, the DNA mismatch repair
pathway, has also been described.  Like the APC pathway, this can be seen in either sporadic
colorectal adenocarcinomas or an inherited condition called "hereditary non-polyposis colon cancer"
(HNPCC). The key elements of this pathway are dysfunctional mismatch repair enzymes  and
subsequent accumulation of mutations, some of which may involve key oncogenes.
"Hyperplastic Polyps" and Cancer
Morphologic Evidence Linking "Hyperplastic Polyps" and Cancer
regarded as benign and metaplastic, there is now considerable and compelling evidence implicating at
least a subset of what have traditionally been called HPPs in the development of a subset of colorectal
carcinomas and a number of colorfully titled commentaries and editorials supporting this have been
Morphologic evidence for this has come from a variety of directions.
There have been scattered reports and small series of adenocarcinomas being associated with "giant" or
"large" hyperplastic polyps (usually defined as > 1cm).
Presence of multiple "HPPs" in
the form of hyperplastic polyposis  (also known as "giant" hyperplastic polyposis 
or "serrated adenomatous polyposis"),  is clearly associated with the development of
adenocarcinoma. Short of overt hyperplastic polyposis, polyps traditionally called hyperplastic polyps
seem to be a fertile soil for a subset of colorectal cancers given the observation that in patients with
microsatellite unstable (MSI) colorectal cancers there is an increase in serrated polyps (HPPs and
serrated adenomas) but not in adenomas in the background mucosa .  A large series of more
than 90 MSI colorectal cancers in which HPPs had been had been diagnosed near the site of the colorectal
cancer at earlier examination further implicates HPPs in a subset of colorectal carcinoma. 
Serrated polyps have been noted adjacent to 5.8% of colorectal cancers in one study. 
Molecular Evidence for the "Serrated Pathway" of Colorectal Cancer
Triggered by the morphologic observations, molecular studies now provide convincing evidence for a
pathway from HPPs (or HPP-like polyps) to colorectal carcinoma. This is being described as the
"serrated" pathway to colorectal cancer.
Our understanding of this pathway is still
evolving and details are discussed in a number of recent articles.
Early steps appear to involve decreased cell death (apoptosis) in serrated polyps leading to prolonged
cell life, an increased concentration of epithelial cells resulting in a serrated
appearance,  and a presumed susceptibility to DNA methylation. Foci rich in
cytosine-guanine bases are particularly susceptible to methylation (CpG island methylator phenotype or
CIMP for short). This may result in methylation-induced transcriptional silencing of the promoters for
tumor suppressor genes. Hypermethylation is observed in 20-40% of colon cancers, and in about one third
of these hypermethylation induced inactivation of the DNA mismatch repair gene hMLH1has occurred with
resulting accumulation of DNA microsatellite repeat sequences of DNA of either low (MSI-L) or high
(MSI-H) degrees (ie "microsatellite instability"). [38 ]Of interest, among the mutated genes
there is evidence that the serrated pathway involving SAs is associated with BRAF mutations whereas the
pathway through MHAPs may involve Kras mutations. 
Implications for the Diagnostic Surgical Pathologist
While the concept
of a "serrated pathway" to colorectal neoplasia is very exciting from a scientific sense, from a
practical perspective it raises many as-yet unanswered issues. The challenges in this area may not be
readily apparent when reading literature on this topic and fall into the categories of terminology,
morphologic reproducibility, conceptual framework, and treatment levels.
Early History of the "Serrated Adenoma"
The common morphologic thread in
the "serrated pathway" is the name giving feature of epithelial serrations. Traditionally, serrated
epithelial neoplasms without dysplasia were termed HPPs, but the term "serrated adenoma" (SA) was applied
in 1990 to a subset of polyps that had admixed features of a serrated HPP-like architecture but also
dysplasia.  Thus, in most practices, through the 1990's serrated polyps were classified as
either HPPs, SA's, or mixed HPP/adenomas (MHAPs), the latter being polyps with admixed HPP and
adenomatous areas. In most practices, SA's have been rare, reflecting the incidence of <1% noted in
the original SA article  and in other large series.
management purposes, SA's have been largely regarded as equivalent to adenomas, as reflected in major
textbooks.  We suspect that in many daily practices, SAs may have been underestimated and
many called villous adenomas since the absence of a known significance for the serrated morphology would
lead one to perhaps not spend too much time worrying about whether a dysplastic polyp demonstrated
serrations or not.
The Birth of the "Sessile Serrated Adenoma" (aka "Sessile Serrated
There is a movement to potentially expand the category of "SA", largely by including a
subset of what have usually been called "HPPs". Torlakovic and Snover recognized in 1996 that the "HPPs"
in HPPosis were morphologically different from traditional HPPs and proposed the term "serrated
adenomatous polyposis" for this syndrome.  Their morphologic criteria are summarized in
Table 1, major components being a tendency for an atypical architecture (sessile growth, dilated and
often laterally branching crypts, and sometimes exaggerated serrations) and abnormal maturation (rounded
hyperchromatic nuclei with nucleoli and mitotic figures extending into mid and upper crypts).
Table 1. Major Morphologic Features of Sessile Serrated Polyps
|Abnormal Proliferation / Dysmaturation |
Nuclear atypia in mid/upper crypts 
Oval nuclei in middle crypts 
Prominent nucleoli in middle/superficial crypts 
Dystrophic goblet cells 
Irregular distribution of goblet cells 
Mitoses in mid/upper crypts 
Basal crypt dilatation
Horizontal orientation of deep crypts
Inverted crypts 
Lack of thickened basement membrane 
Focal loss of hMLH1 positivity
polyps are not confined to HPPosis, however. Goldstein et al noted that all of the "HPP-like" polyps
antedating MSI-H cancers have the same morphologic characteristics as the polyps in
HPPosis  and my personal experiences support this.  I suspect many of the
"giant" HPPs in the literature and perhaps many of the "HPPs" with unusual molecular characteristics may
also fit into this category. These polyps have a tendency to be right sided, large, sessile, and
endoscopically poorly circumscribed, sometimes mimicking enlarged folds.
The term "serrated adenomatous polyposis" was initially largely ignored, probably due to the fact that
most of these polyps did not appear to have the obvious sharply demarcated surface dysplasia that
comfortably identifies adenomatous polyps of the colon. In fact this apparent expanding of the SA
category was probably justifiable as the original SA article by Longacre contains polyps that do fit the
description by Torlakovic and about one third of the original Longacre SA series had originally been
called HPPs, implying that the "dysplasia" may not have been obvious.
I believe the polyp described by Torlakovic is real, but it is very difficult to decipher the
literature on this polyp since it hides under a plethora of names: HPPs, "giant" or "large" HPPs, SA's,
sessile SA's,  HPP-like polyps,  inverted HPPs,
polyps with epithelial serrated proliferation" , sessile serrated polyps,
and likely still others. It is patently clear that this polyp needs a single name in order to
better identify and study it as a discrete entity and to devise treatment guidelines. The term currently
used in the Twin Cities is "sessile SA", taken from the work of local investigators Emina Torlakovic and
and endorsed by Goldstein.  I believe "SSA" is a reasonable
name and use it in my daily practice because of local precedence. I will admit, however, that my
personal preference is the name "sessile serrated polyp" (SSP)
because it: a) reflects
that these lesions lack the traditional-type dysplasia that we see in other "adenomas" of the colon, and
b)the word "adenoma" may prompt clinicians into doing segmental resection for endoscopically unresectable
polyps when we don't know at the current time whether this is always appropriate. Regardless of the
term you use, it is important that your constituent clinicians understand the biologic nature of the
polyp you are diagnosing. Only time will determine what term is ultimately favored by the medical
community at large.
The trust placed in a pathologist's diagnosis will be diminished if it becomes apparent that a given
lesion cannot be reliably placed into the same diagnostic category by the pathology community. This is
of considerable relevance to this issue since hyperplastic polyps are so common and both
Torlakovic  and Goldstein  noted that while SSPs (their "SSAs") tend to be larger
than HPPs and are more often right sided, about 15-20% of smaller, left-sided "HPPs" have the morphologic
features of SSPs. These are almost surely nearly always regarded as HPPs in daily practice today.
It is not too difficult to identify large SSAs, but I have less confidence in my ability to diagnose
the potential 15-20% of smaller serrated polyps that may be SSAs. Lack of data on reproducibility makes
the transfer of the concept of SSA to clinical practice fraught with uncertainty, particularly since in
the pre-SSA era one study of community-based pathologists showed that HPPs were recognized accurately
only 75% of the time. 
Conceptual Issues – Understanding the Disease
What Lesions Participate in the Serrated Pathway?
between the components of the serrated polyp family [HPPs, "SSPs", MHAPs and SAs] is not entirely clear
but some fairly strong inferences can be made at this time:
Can we call the atypia in SSAs "dysplasia"?
- Molecular and immunohistochemical data fairly convincingly places traditional SAs in the serrated
family of polyps (with HPP and SSP) rather than the traditional adenoma family. Similar to HPPs and
unlike adenomas, SAs tend to demonstrate a gastric-type mucin profile.
a mouse model exists for a serrated adenoma/mixed polyp pathway  and in humans a propensity
for microsatellite instability links SAs more closely with HPPs than traditional adenomas. 
- The majority of mixed polyps with serrated and traditional adenoma-like components (MHAPs) seem to
be examples of serrated polyps developing dysplasia as a precursor to malignancy based on molecular
and anecdotal experience.
- The SSP → either SA or MHAP → carcinoma sequence seems likely, however it is not
entirely clear whether the HPP is the precursor to the SSP (as seems to be most commonly assumed by most
authors) or whether HPPs and SSPs are morphologically similar cousins.  Obviously
addressing this issue is complicated by the frequent difficulties in reliably distinguishing HPPs from
SSPs and the difficulty in interpreting existing literature due to mixed terminologies and definitions.
The answer is not currently known.
- There is emerging evidence that the carcinomas arising from the serrated pathway have some
characteristic morphologic features - serrated architecture, eosinophilic epithelium and abundant
mucus.  These features probably serve as markers for tumors arising via the serrated
pathway. The term "serrated adenocarcinoma" is being used to describe these tumors.
Classical teaching reading
adenomas of the colon requires the presence of at least surface dysplasia with variable extension into
crypts and a sharp demarcation from adjacent non-dysplastic epithelium. In contrast, many of the lesions
being called "SAs" in the literature (the SSA in our parlance) appear to demonstrate only a bottom-up
form of atypia  that some regard as an alternative, early form of dysplasia. 
While this may well turn out to be the case, the bottom-up rather than top-down appearance and the
typical lack of a sharp clonal-type demarcation for the atypia in these lesions helps make this putative
form of dysplasia very difficult to identify with certainty in daily practice. Whether or not this
should process should be equated with adenomatous-type dysplasia remains unclear and I prefer not to
refer to the bottom-up abnormal maturation as overt "dysplasia" at present – perhaps this process needs
its own name.
Treatment Issues – Taking these Concepts from Bench to
The key practical, translational issue is how to manage patients with the various serrated polyps, the
main clinical decisions being what to do with incompletely excised polyps, whether to do pan-colonoscopy
when index lesions are identified on procotoscopy or sigmoidoscopy, and whether long-term endoscopic
surveillance is needed (and if so, the frequency of such). Currently, straightforward guidelines exist
for the management of adenomatous polyps  but guidelines for the serrated family of polyps are
lacking and sorely needed.
There is no doubt about the existence of a serrated pathway of colorectal cancer, but there is little
information to date about how to transfer this information to clinical practice. There is considerable
evidence that a largely unrecognized HPP-like polyp with subtle morphologic features that distinguish it
from usual HPPs is an important early step in the serrated pathway – this polyp is termed "sessile
serrated adenoma" locally. This polyp tends to often be large, sessile, and right sided and can progress
to cancer by way of either transition to overt dysplasia (MHAP) or "traditional" serrated adenoma. Data
are still lacking on the natural history of these lesions and there are no published guidelines for the
optimal treatment of these lesions.
- Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial colorectal cancer. Science. 1993 May 7;260(5109):812-6.
- Azimuddin K, Stasik JJ, Khubchandani IT, et al. Hyperplastic polyps: "more than meets the eye"? Report of sixteen cases. Dis Colon Rectum. 2000 Sep;43(9):1309-13.
- Bariol, Hawkins NJ, Turner JJ, et al. Histopathological and clinical evaluation of serrated adenomas of the colon and rectum. Mod Pathol. 2003 May;16(5):417-23.
- Batts KP, Burgart LJ, Goldblum JR, et al. Sessile Serrated Polyp: A Multi-Institutional Incidence Study (abstract). Modern Pathology 2002; 15(1):113A.
- Biemer-Huttmann A-E, Walsh MD, McGuckin MA, et al. Immunohistochemical staining patterns of MUC1, MUC2, MUC4, and MUC5AC mucins in hyperplastic polyps, serrated adenomas, and traditional adenomas of the colorectum. J Histochem Cytochem. 1999 Aug;47(8):1039-48
- Bond JH. Polyp guideline: diagnosis, treatment, and surveillance for patients with colorectal polyps. Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol. 2000 Nov;95(11):3053-63.
- Chan AO, Issa JP, Morris JS, et al. Concordant CpG island methylation in hyperplastic polyposis. Am J Pathol. 2002 Feb;160(2):529-36.
- Chan TL, Zhao W, Leung SY, et al. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 2003 Aug 15;63(16):4878-81.
- Fenoglio-Preiser CF. Gastrointestinal Pathology – An Atlas and Text, 2nd edition. Fenoglio-Preiser CF, Noffsinger AE, Stemmerman GN, Lantz PE, Listrom MB, Rilke FO, eds., Lippincott-Raven, 1998.
- Goldstein NS, Bhanot P, Odish E, et al. Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas. Am J Clin Pathol. 2003 Jun;119(6):778-96.
- Hamatani S, Wada R, Tsujimoto S, et al. Histomorphometric characteristics and cellular kinetics of colorectal polyps with epithelial serrated proliferation adjacent to carcinoma. Oncol Rep. 2001 Jan-Feb;8(1):49-55.
- Hamilton SR. Origin of colorectal cancers in hyperplastic polyps and serrated adenomas: another truism bites the dust. J Natl Cancer Inst. 2001 Sep 5;93(17):1282-3.
- Hawkins NJ, Bariol C, Ward RL. The serrated neoplasia pathway. Pathology. 2002 Dec;34(6):548-55.
- Hawkins NJ, Ward RL. Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas. J Natl Cancer Inst. 2001 Sep 5;93(17):1307-13.
- Hohenstein P, Molenaar L, Elsinga J, et al. Serrated adenomas and mixed polyposis caused by a splice acceptor deletion in the mouse Smad4 gene. Genes Chromosomes Cancer. 2003 Mar;36(3):273-82.
- Iino H, Jass JR, Simms LA, et al. DNA microsatellite instability in hyperplastic polyps, serrated adenomas, and mixed polyps: a mild mutator pathway for colorectal cancer? J Clin Pathol. 1999 Jan;52(1):5-9.
- Iwabuchi M, Sasano H, Hiwatashi N, et al. Serrated Adenoma: A Clinicopathological, DNA Ploidy, and Immunohistochemical Study. Anticancer Research 2000;20:1141-1148, 2000
- Jass JR. Hyperplastic polyps of the colorectum – innocent or guilty? Dis Colon Rectum 2001;44(2):163-166.
- Jass JR. Hyperplastic-like polyps as precursors of microsatellite-unstable colorectal cancer.Am J Clin Pathol. 2003 Jun;119(6):773-5.
- Jass JR. Serrated adenoma of the colorectum. A lesion with teeth. Am J Path 2003;162(3):705-708.
- Jass JR, Iino H, Ruszkiewicz A, et al. Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum. Gut. 2000 Jul;47(1):43-9.
- Jass JR, Whitehall VL, Young J, et al. Emerging concepts in colorectal neoplasia. Gastroenterology. 2002 Sep;123(3):862-76.
- Jass JR. Serrated route to colorectal cancer: back street or super highway? J Pathol. 2001 Mar;193(3):283-5.
- Jeevaratnam P, Cottier DS, Browett PJ, et al. Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol. 1996 May;179(1):20-5.
- Koike M, Inada K, Nakanishi H, et al. Cellular differentiation status of epithelial polyps of the colorectum: the gastric foveolar cell-type in hyperplastic polyps. Histopathology. 2003 Apr;42(4):357-64.
- Longacre TA, Fenoglio-Preiser CF. Mixed hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal neoplasia. Am J Surg Pathol. 1990 Jun;14(6):524-37.
- Makinen MJ, George SMC, Jenvall P, et al. Colorectal carcinoma associated with serrated adenoma--prevalence, histological features, and prognosis. J Pathol. 2001 Mar;193(3):286-94.
- Park SJ, Rashid A, Lee JH, et al. Frequent CpG island methylation in serrated adenomas of the colorectum. Am J Pathol. 2003 Mar;162(3):815-22.
- Renaut AJ, Douglas PR, Newstead GL. Hyperplastic polyposis of the colon and rectum. Colorectal Dis. 2002 May;4(3):213-215.
- Rex DK, Alikhan M, Cummings O, Ulbright TM. Accuracy of pathologic interpretation of colorectal polyps by general pathologists in community practice. Gastrointest Endosc. 1999 Oct;50(4):468-74.
- Rubio CA. Colorectal Adenomas: Time for Reappraisal. Pathology Res Pract 2002;198:615-620.
- Shepherd NA. Inverted hyperplastic polyposis of the colon. J Clin Pathol. 1993 Jan;46(1):56-60.
- Sobin LH. Inverted hyperplastic polyps of the colon. Am J Surg Pathol. 1985 Apr;9(4):265-72.
- Tateyama H, Wenxin L, Takahashi E, et al. Apoptosis index and apoptosis-related antigen expression in serrated adenoma of the colorectum: the saw-toothed structure may be related to inhibition of apoptosis. Am J Surg Pathol. 2002 Feb;26(2):249-56.
- Thibodeau SN, French AJ, Roche PC, et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res. 1996 Nov 1;56(21):4836-40.
- Torlakovic E, Skovland E, Snover DC, et al. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol. 2003 Jan;27(1):65-81.
- Torlakovic E, Snover DC. Serrated adenomatous polyposis in humans. Gastroenterology. 1996 Mar;110(3):748-55.
- VanRijnsoever M, Elsaleh H, Joseph D, McCaul K, Iacopetta B. CpG Island Methylator Phenotype is an Independent Precitor of Survival Benefit from 5-Fluorouracil in Stage III Colorectal Cancer. Clin Cancer Res 2003;9:2898-2903.
- Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colo-rectal tumor development. N Engl J Med 1988;319:525-532.
- Wang L, Cunningham JM, Winters JL, et al. BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res. 2003 Sep 1;63(17):5209-12.
- Warner AS, Glick ME, Fogt F. Multiple large hyperplastic polyps of the colon coincident with adenocarcinoma. Am J Gastroenterol. 1994 Jan;89(1):123-5.
- Williams GT. Metaplastic (hyperplastic) polyps of the large bowel: benign neoplasms after all? Gut. 1997 May;40(5):691-2.
- Yao T, Kouzuki T, Kajiwara M, et al. 'Serrated' adenoma of the colorectum, with reference to its gastric differentiation and its malignant potential. J Pathol. 1999 Apr;187(5):511-7.
- Yao T, Nishayama K, Oya M, et al, Multiple 'serrated adenocarcinomas' of the colon with a cell lineage common to metaplastic polyp and serrated adenoma. Case report of a new subtype of colonic adenocarcinoma with gastric differentiation. J Pathol. 2000 Mar;190(4):444-9.