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Longacre and Fenoglia-Preiser added the term ‘serrated adenoma’ to the medical lexicon just over two decades ago.1 When they re-evaluated so-called mixed hyperplastic adenomatous polyps, they noticed important histopathological differences with the common hyperplastic polyp, and coined the term ‘serrated adenoma’.1 Torlakovic and Snover further refined this observation in 1996 under the appellation, ‘serrated adenomatous polyposis’, in describing a hereditary or familial hyperplastic polyposis condition that predisposes to adenocarcinoma.2 As a result of this observation, a constellation of clinicopathological features emerged that define a new category of polyp, and in the last 6 or 7 years, the term ‘sessile serrated polyp or adenoma’ has appeared more frequently in the pathology and clinical literature. Despite this, there is still a degree of uncertainty surrounding the terminology, diagnostic criteria and importantly, the management implications. There is now no doubt that ‘sessile serrated polyp or adenoma’ is a premalignant lesion and, as such, it is incumbent on pathologists to be aware of and diagnose this lesion.
For the purposes of this brief overview, we intend to highlight the role of the pathologist in making the diagnosis and some of the confusing issues related to diagnosis, the state of play with regard to the molecular pathogenesis of these lesions and the clinical ramifications once a diagnosis of sessile serrated polyp/adenoma is made.
There are several recent publications that detail the diagnostic features, and it is not the intention of this overview to cover those aspects. We wish to highlight some areas that are unclear or may cause confusion. A recent publication by an expert panel has recommended that even ‘a single unequivocal architecturally distorted, dilated, and/or horizontally branched crypt, particularly if it is associated with inverted maturation, is sufficient for a diagnosis of SSA/P’.3 Suffice to say, that sessile serrated polyps/adenoma are recognised by their unique architecture and awareness that not all serrated polypoid lesions are common garden hyperplastic polyps, especially if large, multiple and right-sided.
Although first labelled sessile serrated adenomas (SSAs), potential confusion with conventional adenomas and their inherent dysplasia has arisen. It is clear that the majority of these lesions lack ‘adenomatous dysplasia’, and the preferable term in the absence of dysplasia is ‘sessile serrated polyp’. However, ‘SSA’ appears to be used by many as synonymous with sessile serrated polyp to connote a lesion that does not have any adenomatous dysplasia. It does make nomenclatural sense to use polyp when there is no dysplasia, and adenoma when there is dysplasia. Until there is consensus, sessile serrated polyp and adenoma (SSP/A) are regarded as synonymous at the moment.
The term ‘serrated dysplasia’ has been used in some of the earlier publications. This is not a conventional adenomatous type of dysplasia characterised by elongated, pencillate, pseudostratified, hyperchromatic nuclei with mitoses. Rather, the nuclear changes are a reflection of a ‘dysmaturation’ or altered maturation. These nuclei are round to oval, basally located, have more vesicular chromatin and sometimes, prominent nucleoli.
A proportion of sessile serrated polyps/adenoma will harbour conventional, adenomatous dysplasia as seen in conventional adenomas of the gastrointestinal tract. This may be low-grade or high-grade dysplasia. It is often separate from the non-dysplastic serrated glands and would previously have been called, ‘mixed hyperplastic adenomatous polyps’. A sessile serrated polyp with adenomatous dysplasia implies that this polyp is well into the serrated carcinogenic pathway (see below). In view of this, it would make sense to separate sessile serrated lesions into: sessile serrated polyps (no adenomatous dysplasia) and SSA (with low-grade or high-grade adenomatous-type dysplasia).
There is an undoubted bias for the right colon extending distally to the splenic flexure. The preponderance of SSP/A occurs in the caecum, ascending colon and up to the mid-transverse colon. However, bona fide cases have been described in the left colon as well. The reason for the right-sided predilection is not yet known, but it is attractive to think that the microenvironment in the right colon is more permissive for the molecular events to occur in than the left colon.
The importance of location cannot be underscored, and there are some who call all serrated polyps SSP/A if they occur in the right colon. There is no clinically proven evidence that is the correct approach, but a serrated lesion in the right colon should be looked at very carefully and extra sections cut to see if the diagnostic features of SSP/A are evident.
While more common in middle aged and elderly females, SSP/A also occur in males.
This is not a diagnostic criterion, but SSP/A over 10 mm are likely to show all the diagnostic features. A ‘hyperplastic’ polyp over 10 mm and more should heighten awareness that this could be a SSP/A, especially if in the right colon. SSP/A range in size, and early and/or small lesions are difficult to diagnose.
Do simple sporadic hyperplastic polyps exist in the right colon?
Almost certainly, yes! If in a properly oriented biopsy the diagnostic architectural features of SSP/A are lacking, then the lesion is a hyperplastic polyp. If small (<3 mm) and solitary, then it is almost certainly a hyperplastic polyp.
The suboptimal right colon biopsy
Besides being aware that SSP/A exists especially in the right colon, sometimes the diagnostic architectural features are simply not evident. There are several reasons for this, but perhaps the most common is due to oblique/suboptimal sectioning of a superficial biopsy. If even after resorting to deeper sections, a diagnosis of SSP/A cannot be sustained, or if the architectural complexity even in the tangentially sectioned biopsy raises the suspicion of SSP/A, then a suitable comment reflecting this should be made. Clinicopathological correlation is extremely important in this scenario.
Three main mechanistic pathways have arisen from the phenotypic and molecular characterisation of colorectal cancer: Chromosomal instability, defective mismatch repair leading to microsatellite instability (MSI) and the hypermethylation and transcriptional silencing of genes leading to the CpG island methylator phenotype (CIMP). Although there can be considerable overlap between these pathways within an individual tumour, this molecular classification can help to distinguish important clinical characteristics such as patient demographics, tumour distribution, response to therapy and prognosis. Furthermore, this molecular characterisation can also be applied to benign precursor lesions, and this has led to the recent reappraisal of the malignant potential of proximal hyperplastic polyps and the emerging significance of the serrated neoplastic pathway leading to CIMP+ carcinomas.4
Serrated carcinogenesis pathway
By comparison with conventional adenomas, little is known about the molecular pathogenesis of the serrated pathway. The association of an increasing (epi)genetic mutation burden in different histological subtypes of proximal colonic benign serrated lesions has led to the proposal of a hyperplastic—serrated adenoma (SSA)—serrated adenoma with dysplasia—carcinoma sequence.4 Histologically, serrated polyps are divided into sessile serrated or traditional serrated lesions, and this morphological distinction correlates with the predominance of B-type Raf (BRAF) or Kirsten rat sarcoma (KRAS) activating mutations as the earliest apparent genetic events. Mutation of BRAF is strongly correlated with the CIMP5 and both these genetic and epigenetic events have been reported at the earliest stages of colorectal carcinogenesis: aberrant hypermethylation in the normal mucosa of hyperplastic polyposis patients6 and BRAF mutations in sporadic hyperplastic aberrant crypt foci.7 However, it is unclear whether, or which one of these events predisposes to the other.8
The characteristic serrated phenotype is the consequence of abnormal cellular proliferation driven by the constitutive activation of the MAPK pathway by mutually exclusive BRAF or KRAS mutations in humans, or by activation of epidermal growth factor signalling in a recent mouse model.9 Activation of the MAPK pathway induces an initial proliferation burst followed by activation of oncogene-induced senescence pathways (OIS).10 OIS results in telomere-independent cell-cycle arrest, and is dependent on tumour suppressors, such as the p16INK4a-Rb and p53-p21Waf1 pathways.10 Analogous to melanocytic naevi in the skin, it has been proposed that small, non-progressive colonic hyperplastic polyps consist of oncogene-initiated cells held in check by these activated senescence pathways,11 thus, escape from OIS is necessary for hyperplastic/serrated lesions to progress. Hypermethylation and selective inactivation of key senescence-related genes, such as p16INK4a and IGFBP7,8 occur early in the serrated carcinogenesis pathway, suggesting a synergistic link between aberrant methylation (CIMP) and the progression of cells with oncogene activation of the MAPK pathway. Why OIS subversion and lesion progression occur preferentially in the proximal colon is an unanswered research question, but plausibly could be a consequence of colonic regional variation in epithelial methylation,12 the microbiome and luminal microenvironment,13 or morphogen balance.14
SSAs can give rise to both microsatellite unstable (MSI) or microsatellite stable (MSS) tumours, and this depends on the pathways transcriptionally silenced as the lesions advance and develop cellular atypia. Epigenetic silencing of mismatch repair genes, such as MLH1, can lead to widespread persistence of DNA slippage events, genetically inactivating genes with dinucleotide repeats such as TGFBR2. The sequence of events leading to MSS cancers is less well defined, but these lesions have a higher frequency of p53 mutations and commonly have dysregulated Wnt signalling15 through (epi)genetic inactivation of Wnt antagonists (such as the SFRPs), or transcription factors (such as Cdx1).16 Given the similarity between the pathways disrupted in the late stages of the serrated pathway and the conventional adenoma-carcinoma sequence, it is unsurprising that areas of dysplasia in SSAs may develop a phenotype similar to that seen in tubulovillous adenomas.
Missed lesions and/or accelerated carcinogenesis
Recent population-based trials of endoscopic polypectomy have been shown to reduce distal colorectal cancer and mortality,17 however, epidemiological studies suggest that colonoscopy appears to have minimal or no protective effect on proximal cancers, a surprising and concerning finding.18 Furthermore, analysis of tumours arising between colonoscopic examinations in screening populations (interval tumours), has shown a disproportionately high frequency of both MSI and CIMP lesions.19 ,20 SSAs are notoriously difficult to detect with white light endoscopy. The subtle endoscopic signs are of a flat area of thickened mucosa often draped over a fold, which may be indistinct from surrounding normal mucosa once the characteristic mucus cap has been washed off. The variability of detection rates among endoscopists suggests that the endoscopic identification of sessile serrated lesions is operator-dependent, and that they are significantly underdiagnosed clinically.21 Serrated adenoma prevalence data suggest that these lesions may progress indolently initially, being present for many years without change.22 However, once sufficient (epi)genetic mutations have accumulated to initiate cellular atypia, progression to cancer is accelerated and occurs at a much higher frequency than in equivalent-sized conventional adenomas.23 In MSI lesions, this is likely to be a consequence of the development of a mutator phenotype analogous to that seen in Lynch syndrome.24
Clinical implications and recommendations
The evolving molecular evidence strongly linking SSA/Ps to colorectal cancer means that serrated lesions, particularly in the proximal colon, have become a new target lesion for colonoscopists. Detection rates vary considerably, between 1% and 18% in one study.25 The level of serrated lesion detection which prevents interval cancer is unclear. For adenomas, detection rates of above 20% in screening populations appear to lead to very low rates of interval cancers.26 Adenoma and serrated lesion detection rates are correlated. Extrapolation of proposed adenoma detection rates in US guidelines (25% for men, 15% for women) produce an equivalent proximal serrated lesion detection rate of 5% for men and women.25 This might be a reasonable benchmark to aim for, pending more data. Serrated lesions also appear to be more likely than other polyps to be incompletely resected, which again may lead to interval cancer, so extra care needs to be taken to resect comprehensively.27
It seems likely that like adenomas, large or multiple serrated lesions are likely to be biomarkers for future colorectal neoplasia, although definitive data is lacking. Schreiner and colleagues noted in a reanalysis of data from an era where the significance of serrated lesions was not appreciated, that a proximal serrated lesion, either alone or in combination with advanced adenomatous dysplasia predicted future dysplasia within 5 years.28 This, in combination with molecular data, has lead to new US 2012 polyp follow-up guidelines advocating shorter surveillance intervals for patients with serrated lesions.29 A 3-year surveillance is recommended for SSPs ≥10 mm, or SSPs with adenomatous dysplasia, and 5 years for SSPs <10 mm. Follow-up for serrated polyps is recommended to be as for low-risk adenomas, that is, 5–10 years. Multiplicity of serrated lesions is not considered; however, if serrated polyposis is detected, surveillance is recommended yearly.
This approach requires pathologists to be able to accurately and reproducibly diagnose and differentiate hyperplastic (serrated) polyps, SSAs/polyps and SSAs/polyps with dysplasia. This can be challenging, as described above. Failure to correctly classify will lead to an incorrect surveillance interval being assigned, too long risking interval cancer, too short using up scare surveillance resource and exposing patients to the risks of unnecessary colonoscopy. Therefore, the proposal above, to classify all proximal serrated polyps as SSA/Ps would lead to overuse of surveillance, with no high-quality data yet suggesting surveillance for serrated polyps offers clinical benefit. Given the difficultly in pathological interpretation, biopsy specimens should be avoided where possible, and lesions should be comprehensively resected, ideally en bloc below 10 mm, to allow for comprehensive pathological assessment. For larger lesions in the right colon this may require referral to specialist endoscopists.
With regard to serrated polyps, we recommend that colonoscopic surveillance be undertaken as per the flow chart in figure 1, and in addition
Numbers of serrated lesions and adenomas should be additive. Therefore, for instance, two adenomas <10 mm in size plus one proximal SSA/P <10 mm would lead to a 3-yearly surveillance.
Distal small and diminutive hyperplastic polyps do not confer increased risk, unless >20 in whole colon, and should not contribute to surveillance intervals.
If the pathologist is unable to make a reasonable assessment based on the material presented, for instance, superficial biopsy, then all proximal serrated polyps should be considered SSA/Ps.
Piecemeal endoscopic resection of serrated polyps should lead to a site check at 2–6 months.
If a large proximal serrated polyp, or multiple serrated polyps are detected, consideration should be given to enhancing detection of serrated lesions with advanced endoscopic techniques such as chromoendoscopy32 or Narrow Band Imaging,33 to try to detect unrecognised cases of serrated polyposis.
These recommendations are pragmatic and based on the limited available evidence, and aim for simplicity and ability to be integrated with current adenoma follow-up guidance. They will need to be updated as further data becomes available.
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Contributors All authors contributed equally to the planning, conduct, and reporting of the work described in the article. RC is responsible for the overall content as guarantor.
Competing interests None.
Provenance and peer review Not commissioned; internally peer reviewed.
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