Abstract
Our understanding of serrated colorectal polyps has increased dramatically over the past two decades and has led to a modern classification scheme for these lesions. Sessile serrated polyps with dysplasia represent the most clinically significant serrated polyp; however, the morphologic heterogeneity of dysplasia in sessile serrated polyps has only recently been recognized and correlated with MLH1 immunohistochemistry. Detailed morphologic analysis of traditional serrated adenomas has led to the recognition of flat and early forms of this polyp. Robust data on the risk of metachronous lesions in patients with serrated polyps are also beginning to emerge. This review will summarize our current understanding of serrated polyps and associated carcinomas with a focus on diagnostic criteria, morphologic heterogeneity, molecular findings, and natural history. Controversial issues in the diagnosis and classification of these polyps are also discussed.
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Introduction
Detection and removal of premalignant lesions is the guiding principle of colorectal carcinoma screening programs. Both colonoscopic surveillance and/or stool-based tests are utilized in most counties but only colonoscopy allows for resection of precursor lesions. Colonoscopy also allows for identification of patients at higher risk for developing metachronous lesions based on pathologic review of polypectomy specimens. While the conventional adenoma has long been recognized as a precursor to colorectal carcinoma and served as the primary driver of post-polypectomy surveillance guidelines, work over the past few decades has identified and characterized other precursor lesions. It is now recognized that up to at least 20% of colorectal carcinomas arise not through conventional adenomas but rather through serrated polyps [1, 2].
Serrated polyps range in morphology from polyps with only superficial serrations to those with exaggerated serrated architecture and overt dysplasia. These polyps are also molecularly heterogenous and can give rise to carcinomas with divergent clinical outcomes. This review will summarize the classification and molecular characterization of serrated polyps. Key morphologic features that are necessary for proper classification will be presented and unusual serrated lesions that do not fit neatly into a specific category will be discussed. The emerging data on the natural history of serrated precursors will be emphasized in addition to the features that should guide future colonoscopy surveillance intervals. Finally, an update on serrated polyposis, as well as colorectal carcinomas arising from serrated precursors will be provided.
Classification and terminology
Table 1 provides a classification scheme of serrated colorectal polyps along with key morphologic and molecular features. Two types of hyperplastic polyp are recognized morphologically; however, it is not yet necessary to distinguish between these two variants in clinical practice. Rather, it is important to recognize the subtler features of the goblet cell variant of hyperplastic polyp (goblet cell hyperplastic polyp) in order to distinguish this from normal mucosa and to separate it from other types of serrated polyps. The much more common microvesicular variant of hyperplastic polyp has been referred to as mucosal hyperplasia and metaplastic polyp in the older literature; however, those terms are no longer recommended.
Snover and colleagues first recognized an unusual serrated polyp that tended to occur in patients with so-called “hyperplastic polyposis syndrome” [3]. In 2003, Torlakovic et al. provided the first description of similar unusual serrated polyps in patients without any known polyposis syndrome and termed them serrated polyps with abnormal proliferation [4]. Since 2003, this polyp has been known by many names including sessile serrated adenoma, sessile serrated polyp, sessile serrated adenoma/polyp, and more recently sessile serrated lesion [5]. The argument for including adenoma in the name was to emphasize that these lesions are precursors to colorectal carcinoma; however, as these polyps lack adenomatous epithelium, the use of the word “adenoma” in the name has drawn criticism. To avoid confusion with truly adenomatous polyps, recent consensus guidelines have recommended against sessile serrated adenoma [6]. It is likely that sessile serrated polyp (and sessile serrated adenoma) will continue to be used, at least in the United States, while sessile serrated lesion gains wider acceptance elsewhere. Both sessile serrated polyp and sessile serrated lesion are appropriate terms as long as it is recognized by clinicians that they are two names for the same polyp. For simplicity, sessile serrated polyp will be used throughout this review. If dysplasia is present within sessile serrated polyp then simply making the diagnosis of sessile serrated polyp with dysplasia is appropriate rather than qualifying the dysplasia as “cytologic” as is necessary when using the term sessile serrated adenoma.
Traditional serrated adenoma is the recognized term used to describe the “serrated adenoma” reported by Longacre and Fenoglio-Preiser in 1990 [7]. As sessile serrated adenoma will progressively become abandoned and replaced by sessile serrated polyp or sessile serrated lesion, adenoma will only be used for serrated polyps falling into the category of the currently named traditional serrated adenoma. Thus, serrated adenoma may therefore be a preferred and more simple term to use in the future. These lesions have distinctive morphologic features as described below, and we have only recently appreciated the diversity of molecular and morphologic alterations that can occur in a traditional serrated adenoma. Finally, over the past few years we have begun to recognize new and unusual dysplastic serrated polyps that do not qualify as typical traditional serrated adenoma or sessile serrated polyp with dysplasia. Forcing these polyps into a specific diagnostic category is premature and for this reason a serrated adenoma-unclassified category will be proposed by the World Health Organization committee for the 5th edition of the Classification of Tumors of the Digestive System (personal communication).
Pathologic features of serrated polyps
Hyperplastic polyps
Microvesicular hyperplastic polyps are sessile polyps that predominately occur in the distal large bowel. Endoscopically they are small or diminutive polyps that can be recognized by a stellate pit pattern as described by Kudo et al. [8]. Histologically, they are composed of serrated epithelium with funnel-shaped, evenly spaced crypts. The proliferative zones are confined to crypt bases imparting a hyperchromatic appearance along with increased mitotic figures. The cells lining the crypts are composed of variable numbers of goblet cells and cells with abundant fine apical vacuoles with microvesicular mucin (Fig. 1). In most cases, the microvesicular cells predominate. The nuclei of the surface epithelium are small, round to oval, and basally located. The serrations are limited to the upper two-thirds of the crypt without deep crypt serrations or abnormal basilar crypt architecture [4]. In cross section, the serrated crypts of microvesicular hyperplastic polyps have a uniform stellate appearance. Based on these diagnostic criteria of microvesicular hyperplastic polyp, it is clear that a diagnosis requires specimens that are well-oriented as microvesicular hyperplastic polyp is defined, in part, by the absence of the abnormal crypt architecture that is seen in sessile serrated polyp [4, 9, 10]. Deeper levels may help in the setting of poorly oriented specimens. In the initial study by Torlakovic et al. [4], a mucin poor variant of hyperplastic polyp was described; however, this mucin poor variant likely represents an inflamed and mucin-depleted microvesicular hyperplastic polyp rather than a distinct subtype of hyperplastic polyp.
Goblet cell hyperplastic polyps were also described by Torlakovic et al. and further refined by O’Brien et al. [4, 11]. They are often overlooked because of small size, and their morphological alterations are often so subtle that they are easily mistaken as surface hyperplastic change by pathologists [12]. The majority of the cells of the surface and crypt epithelium are goblet cells with small, uniform basal nuclei (Fig. 1). In goblet cell hyperplastic polyps, the crypts are taller and wider than in normal mucosa, and show occasional branching or tortuosity that should not be mistaken as sessile serrated polyp. Instead of being obviously serrated, the epithelium shows tufting that is confined to the surface epithelium and crypt orifices. The cross sections of crypt lumen are not stellate but round [13, 14].
Sessile serrated polyp
Sessile serrated polyp can be difficult to identify at colonoscopy; however, awareness and specific training can improve detection. They appear as ill-defined, sessile, and pale lesions with an irregular shape and “cloud-like” surface [13, 14]. There is often adherent mucin over the surface and a rim of bubbles or fecal debris can sometimes collect at the periphery (Fig. 2) [15]. The Kudo pit pattern is II (stellate) in most cases and the Paris classification is predominately 0-IIa (superficial elevated lesions) [8, 16]. Using the Narrow-band imaging International Colorectal Endoscopic classification, they are type 1 [17].
Sessile serrated polyp harbor a range of abnormal histological features that are mostly generated by aberrant proliferation centers [4, 18]. Unlike microvesicular hyperplastic polyps, sessile serrated polyps have foci of proliferation both in the crypt bases and at irregular points along the crypt lumen. Epithelial cells then spread both luminally and basally from these proliferation centers, which is in contrast to the orderly luminal migration of epithelial cells in normal crypts and in hyperplastic polyps. This loss of orderly migration, in turn gives rise to the characteristic histological features of sessile serrated polyp, which include at least one of the following: asymmetric dilatation, horizontal growth of crypts along the muscularis mucosae, and exaggerated serrations that extend deep into the crypt accompanied by basilar crypt dilatation (Fig. 2). The majority of crypts in sessile serrated polyp, however, do not show the typical architectural distortion. One unequivocal sessile serrated polyp-type crypt is now advocated to be sufficient for the diagnosis of sessile serrated polyp. Symmetrical dilatation of crypt bases without other architectural abnormalities is considered by some not sufficient for the diagnosis of sessile serrated polyp; it can be seen in some goblet cell hyperplastic polyps and other polyps with superimposed prolapse changes. While the distribution in the large intestine and the average size are different between hyperplastic polyp and sessile serrated polyp, the histological diagnosis should be primarily based on morphologic criteria (see discussion below).
Architectural abnormalities are best appreciated at low power. They include aberrant crypt growth along the muscularis mucosae as L-shaped or inverted T-shaped crypts or as crypts with prominent asymmetric dilation of the basal aspect [4, 9]. Exaggerated serration manifests as piled up and serrated tufts of epithelium at irregular intervals along the crypt, with more basal serrations having more significance when separating from a hyperplastic polyp. At higher power the cytology is bland. Goblet cell and microvesicular mucin are common and mucin containing cells tend to out-number enterocytes. Some degree of neuroendocrine cell hyperplasia is usually present. An unusual lamina propria stromal proliferation has also been associated with sessile serrated polyp (as well as microvesicular hyperplastic polyp). Morphologically and immunohistochemically these stromal cells resemble perineurial cells and likely represent a reactive proliferation induced by the serrated epithelium [19,20,21].
Immunohistochemical stains are not required for the diagnosis of an sessile serrated polyp but are often used for research purposes. A Ki67 stain will show an expanded basal proliferative compartment (similar to a hyperplastic polyp) but also with irregular foci of proliferation along the sides of the crypt (corresponding to the aberrant proliferation centers) [22]. CK20 shows luminal staining. Mucin stains can be slightly variable. MUC2 is uniformly positive and MUC5AC is positive in the majority. Scattered MUC6 staining is a frequent finding [23, 24]. There has been recent interest in Annexin A10 as a marker of sessile serrated polyp [25, 26]. This stain is more likely to be positive in sessile serrated polyps than microvesicular hyperplastic polyps, however, interpretation is most unreliable in the most equivocal lesions, which has been an obstacle to widespread adoption. Markers of more advanced molecular alterations are not seen (e.g., no loss of MLH1 expression, no over-expression or complete loss of p53 and no over-expression or complete loss of p16).
Sessile serrated polyp with dysplasia
Sessile serrated polyp with dysplasia is the most advanced subtype of serrated polyp and the most clinically relevant lesion. When sessile serrated polyps progress to malignancy, a critical transient step of dysplasia occurs. Sessile serrated polyps with dysplasia are rare, representing 2–5% of all sessile serrated polyps and <0.5% of all colorectal polyps [27,28,29]. In the first descriptions of sessile serrated polyp with dysplasia, Goldstein and Sheridan et al. reported rare cases of small serrated polyps ‘caught in the act’ of malignant transformation, showing high grade dysplasia and frequent loss of MLH1 expression [30, 31]. These early observations already pointed out the rapid malignant transformation of these lesions. Data from a recent large series demonstrates that sessile serrated polyps had a mean dwell time of 17 years before progressing into sessile serrated polyps with dysplasia. However, there was no difference in the mean age of patients with sessile serrated polyps with dysplasia and patients with sessile serrated polyps with carcinoma, supporting the concept of rapid malignant transformation and probably explaining why these lesions are rarely encountered endoscopically [27]. In the past, sessile serrated polyps with dysplasia were often reported as mixed polyps with a serrated component and a tubular adenoma component. We now know that both components share the same BRAF V600E mutation and therefore represent two stages of a single lesion with molecular abnormalities different from that of conventional adenomas.
Like sessile serrated polyps, sessile serrated polyps with dysplasia are more frequently diagnosed in the proximal colon (cecum and ascending colon) with female predominance [29]. Increasing age and increasing lesion size are associated with the development of dysplasia in sessile serrated polyps. However, while dysplasia has been reported in upto 32% of sessile serrated polyps >20 mm [32], it can be present in small sessile serrated polyps, sometimes measuring <5 mm [27, 33]. From a series of 266 cases, the median size of sessile serrated polyps with dysplasia was 12 mm, with 40% of lesions measuring <10 mm [28].
Some sessile serrated polyps with dysplasia are protuberant polyps with a distinctive endoscopic appearance that can resemble conventional adenomas; other cases present as flat or depressed lesions (Fig. 3). The histologic diagnosis of sessile serrated polyp with dysplasia requires an abrupt transition from an sessile serrated polyp to an area exhibiting increased complexity in crypt architecture, associated with various forms of cytologic atypia. One should exercise caution when considering a diagnosis of sessile serrated polyp with dysplasia when the dysplastic fragments do not contain adjacent non-dysplastic sessile serrated polyp as this may represent a separate conventional adenoma. MLH1 immunohistochemistry, as described below, may be helpful in this setting. Two dysplastic patterns were initially described in the 4th edition of the World Health Organization classification: the adenomatous/intestinal type, loosely resembling dysplasia of conventional adenoma and the serrated type, with cuboidal cells, eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli [34]. More recently, additional patterns of dysplasia have been reported, making sessile serrated polyp with dysplasia a more heterogeneous lesion than initially recognized [28].
Architectural changes include crowding of crypts separated by reduced amount of lamina propria, increased complexity in crypt branching, crypt elongation, cribriforming, and villous architecture (Fig. 3). The degree of crypt serration is usually different from the adjacent sessile serrated polyp, either increased or reduced. Cytologic atypia varies from subtle hypermucinous changes to overt dysplastic changes. The mucin content of dysplastic cells is almost always different from that seen in the adjacent sessile serrated polyp. Dysplastic cells tend to have a more homogeneous mucin appearance, from complete lack of mucin to hypermucinous phenotype. Goblet cells are often less prominent than in the adjacent sessile serrated polyp. Gastric-type apical mucin vacuoles are sometimes present.
The morphologic variety of sessile serrated polyps with dysplasia has been reported by Liu et al. [28]. They described four patterns of dysplasia including three specific types (serrated, adenomatous, and minimal deviation) and one not otherwise specified group to include all of the cases not falling into one of the other categories. Like most histologic classifications, the not otherwise specified group is the prototypic and most common pattern and encompasses the majority of cases that would be considered adenomatous dysplasia in the 4th the edition of the World Health Organization classification. These polyps show a variety of architectural and cytologic abnormalities that while clearly dysplastic, do not fall neatly into any of the specific types described below. In contrast to true adenomatous dysplasia these polyps usually show atypia across the full depth of the mucosa, often have variable patterns in the one polyp and do not have the typical basophilic appearance of conventional adenomas. The vast majority of these cases are MLH1 deficient. In contrast, the polyps with truly adenomatous dysplasia are rare and almost always MLH1 proficient leading the authors to propose that these may in fact represent collision lesions rather than a true sessile serrated polyp with dysplasia [35]. Serrated dysplasia—the same as the World Health Organization description in its 4th edition—has tightly packed glands composed of cells with large nuclei, prominent nucleoli, and brightly eosinophilic cytoplasm. The dysplasia covers the full depth of the mucosa, and mitoses are frequent and often atypical. MLH1 expression is retained in most cases. Lastly, minimal deviation dysplasia with subtle but noticeable architectural and cytologic changes is described (Fig. 4). While it is helpful diagnostically, in practice it is not entirely necessary to subtype dysplasia in sessile serrated polyp, rather it is important to recognize the morphologic heterogeneity of these lesions and to be aware of the MLH1 expression in each morphologic subgroup (Table 2).
The chance of diagnosing minimal deviation dysplasia is higher in female patients >60 years, with history of advanced serrated polyps or sporadic MLH1-deficient colorectal carcinoma. To become familiar with the minimal deviation dysplasia pattern, staining obvious sessile serrated polyps with dysplasia with MLH1 may be useful. Not infrequently, areas of MLH1 loss are identified outside the obvious dysplastic component, in what looked like otherwise ordinary sessile serrated polyp fragments. Reviewing these areas in hindsight will help pathologists to recognize the subtle morphologic patterns associated with MLH1 loss. When changes suspicious for minimal deviation dysplasia are found in an sessile serrated polyp, we recommend a low threshold for ordering an MLH1 immunostain to gain familiarity with the minimal deviation pattern and to further refine diagnostic criteria. We currently recommend that the loss of MLH1 expression is required for the diagnosis of sessile serrated polyp with minimal deviation dysplasia. Further studies are needed to assess the reproducibility of the diagnosis and whether minimal deviation dysplasia can be diagnosed when MLH1 is retained.
Importantly, incidental loss of MLH1 expression restricted to the base of one or a few histologically unremarkable serrated colonic crypts should not be regarded as sessile serrated polyp with dysplasia. In sessile serrated polyps with minimal deviation dysplasia, loss of MLH1 expression involves the full length of multiple adjacent crypts that always show some abnormalities on the H&E-stained sections.
Traditional serrated adenoma
The traditional serrated adenoma is a relatively rare serrated polyp at risk of progression to malignancy. First reported as ‘serrated adenoma’ in 1990 by Longacre and Fenoglio–Preiser [7], traditional serrated adenoma is characterized by 3 histologic features: typical eosinophilic cells with bland elongated nuclei, slit-like serration, and ectopic crypt foci (also called ectopic crypt formations). None of these features is on its own specific of traditional serrated adenoma and can be encountered in other subtypes of colonic polyps.
Traditional serrated adenoma is much less common than sessile serrated polyp, representing up to 2% of all colorectal polyps from various series depending on diagnostic criteria [36]. The prevalence of traditional serrated adenoma is probably an underestimate as advanced traditional serrated adenoma may resemble conventional adenoma, and flat traditional serrated adenoma is often reported as sessile serrated polyp with dysplasia. Both males and females are equally affected, usually in the sixth or seventh decade [37,38,39,40,41,42]. The prototypical traditional serrated adenoma is a large protuberant polyp in the distal colon or rectum with villiform architecture, uniform cytology, slit-like serration, and ectopic crypt foci (Fig. 5). The characteristic traditional serrated adenoma cells have abundant and intensely eosinophilic cytoplasm, bland oval palisaded nuclei without mitotic activity or Ki-67 positivity by immunohistochemistry [37, 41, 43]. It is unclear what proportion of the polyp needs to have the traditional serrated adenoma cytology for the diagnosis. If the other two histological features of traditional serrated adenoma are present, focal traditional serrated adenoma cytology may be sufficient for the diagnosis. Some traditional serrated adenomas with typical slit-like serration and at least focal ectopic crypt foci may have a predominance of goblet cells (mucin rich variant) [44, 45]. Another confusing point is the presence of superimposed intestinal dysplasia that can arise in an advanced traditional serrated adenoma, completely replacing the original epithelial lining and mimicking a tubulovillous adenoma (see discussion below).
The second and probably most typical feature of traditional serrated adenoma is the distinctive type of serration (slit-like serration), reminiscent of the narrow slits in the normal small intestinal mucosa [36, 37]. (Fig. 5). The association of both the traditional serrated adenoma cytology and slit-like serrations makes the diagnosis of traditional serrated adenoma straightforward.
Ectopic crypt foci are small buds of epithelial cells resembling the bases of normal crypts, not anchored to the muscularis mucosae, and found along the villous projections of the polyp (Fig. 5) [22]. When multiple, they may be misinterpreted as superimposed dysplasia on cross section. Rather than specific of traditional serrated adenoma, ectopic crypt foci may represent small proliferation zones in polyps with villiform growth pattern, including some tubulovillous adenomas [46, 47]. Moreover, flat traditional serrated adenomas may lack ectopic crypt foci. Ectopic crypt foci are therefore not an absolute prerequisite for the diagnosis of traditional serrated adenoma.
In up to 50% of traditional serrated adenomas, an adjacent polyp is identified which may represent a precursor lesion [37, 39, 40, 48]. (Fig. 5) The fact that traditional serrated adenoma may represent adenomatous transformation in a hyperplastic polyp was alluded to in the seminal paper by Longacre et al. [7] and was preceded by a similar suggestion in 1970 by Goldman et al. [49]. Proximal flat traditional serrated adenomas are more likely to harbor a BRAF mutation and to have an adjacent microvesicular hyperplastic polyp or a sessile serrated polyp. Distal traditional serrated adenomas are often KRAS-mutated and may have a ‘shoulder’ area of flat traditional serrated adenoma at the edge of a large protuberant lesion. A goblet cell hyperplastic polyp can also sometimes be found, suggesting that some KRAS-mutated traditional serrated adenomas may arise from a goblet cell hyperplastic polyp. In a recent study, small (<10 mm) polyps resembling the shoulder area seen in large protuberant traditional serrated adenomas were shown to be the early forms of traditional serrated adenoma [50]. Like larger traditional serrated adenomas, these small lesions are characterized by at least 2 of the features of traditional serrated adenoma: slit-like serrations, typical cytology, and ectopic crypt foci.
Despite being a polyp with malignant potential, ordinary traditional serrated adenomas do not have the cytological characteristics of the usual type of dysplasia as seen in the colon. However, overt dysplasia develops when traditional serrated adenomas progress to advanced lesions. This superimposed dysplasia can be either of intestinal type resembling dysplasia seen in conventional adenoma or of serrated type as seen in sessile serrated polyp progressing to serrated type dysplasia [37, 39,40,41, 43]. (Fig. 6) There are currently no specific surveillance guidelines when superimposed dysplasia is diagnosed in a traditional serrated adenoma. We recommend that high grade intestinal dysplasia and serrated dysplasia should be reported as this heralds an advanced stage of the lesion.
Serrated adenoma-unclassified
It has become clear over the past few years that some dysplastic serrated polyps do not fit neatly into traditional serrated adenoma or sessile serrated polyp with dysplasia or conventional adenoma. In particular, some adenomas that lack the cytologic features of traditional serrated adenoma can demonstrate serrated morphology. These have been termed serrated tubulovillous adenomas by some authors (Fig. 7) [45, 46]. These polyps demonstrate molecular features intermediate between traditional serrated adenoma and conventional tubulovillous adenoma. Other polyps may consist predominately of conventional tubulovillous adenoma with only focal features suggestive but not entirely diagnostic of a traditional serrated adenoma. Some of these polyps may represent traditional serrated adenomas overgrown by conventional dysplasia, but uncertainty exists as to the diagnosis. In one study, re-review of 180 distal villous and tubulovillous adenomas resulted in re-classification of 20 polyps as traditional serrated adenoma indicating histologic overlap between these polyp types [47, 48]. Finally, sessile serrated polyps with small areas of eosinophilic cells can be confusing to classify. These sessile serrated polyps have been regarded as having either low-grade serrated dysplasia, features of traditional serrated adenoma, or “enteric metaplasia” (see discussion below) by various authors. Given the uncertainties in the classification of these serrated polyps, the term “serrated adenoma, unclassified” is proposed. In our opinion this term should be used sparingly.
Differential diagnosis and controversial issues
Sessile serrated polyp versus hyperplastic polyp
The major differential diagnosis of sessile serrated polyp is with a microvesicular hyperplastic polyp and this distinction continues to be problematic [51,52,53]. This is true not only in the community setting but even among subspecialized pathologists with an interest in serrated polyps. In a recent population-based study from Denmark, nearly 25% of all serrated polyps were excluded from the study because they could not be classified into hyperplastic polyp or sessile serrated polyp with certainty by four expert gastrointestinal pathologists [54]. The current recommendations suggest that a polyp with one classical sessile serrated polyp-type crypt is sufficient to render the diagnosis of a sessile serrated polyp over a microvesicular hyperplastic polyp [9, 10]. It should be emphasized that when making the assessment on a single crypt, the changes should be overt and the polyp free of prolapse effect which can induce spurious crypt architectural abnormalities (Fig. 8) [55, 56]. In equivocal cases deeper levels can often be informative as more classical sessile serrated polyp-type architectural changes may become apparent.
It is important to emphasize that the size, location, number, and endoscopic appearance are not part of the pathological diagnosis of a hyperplastic polyp or a sessile serrated polyp. Using these parameters can hamper future efforts to refine the risk profile of patients with serrated polyps, especially in scenarios such as small proximal hyperplastic polyps or large distal hyperplastic polyps. Only a proper morphologic classification of serrated polyps that is reproducible amongst practicing pathologists will allow further refinement of the risk of metachronous neoplasia in these patients. Results from such analyses can then be used to modify the diagnostic criteria if necessary.
From a practical perspective, it is exceedingly rare to encounter a microvesicular hyperplastic polyp >10 mm and such polyps should be considered advanced serrated polyps for the purposes of deciding subsequent surveillance intervals and ensuring complete resection. The main dilemma occurs when encountering small or dimunitive proximal serrated polyps that morphologically are best classified as microvesicular hyperplastic polyp (Fig. 8). Furthermore, goblet cell hyperplastic polyps are frequently seen in the proximal colon. There has been a tendency to consider all proximal serrated polyps as sessile serrated polyp, despite the lack of diagnostic features, due to the presumption that hyperplastic polyps do not exist in the proximal colon. Such a strategy will lead to increased frequency of colonoscopy for these patients and an increased burden on already busy surveillance programs. In rare cases of polyps with marginal histological features, size and location can be used to tip the diagnosis one way or another. In general, we try to avoid using diagnoses such as indeterminate serrated polyp, as they are unhelpful to the clinician. In our experience such a diagnosis is almost always managed as per a sessile serrated polyp.
Significance of eosinophilic cells in various serrated polyps
One of the most controversial points in serrated polyp diagnosis is the significance of traditional serrated adenoma-type cells in various colonic lesions. The appearance is reminiscent of absorptive cells in the normal small bowel with narrow slits along the epithelium and a brush border on the apical surface [57]. For these reasons, this phenotype has been called by some authors enteric metaplasia, which have characteristics of senescent cells rather than dysplastic cells [34]. However, others consider that the presence of this cell type in a serrated polyp represents a form of serrated dysplasia and should be reported as sessile serrated polyp with traditional serrated adenoma-like dysplasia or low-grade serrated dysplasia. The different opinions add to the confusion in the differential diagnosis between traditional serrated adenoma and sessile serrated polyp with dysplasia. We recommend that the term ‘serrated dysplasia’ should only be used for the “high-grade” dysplastic changes as described above, which are similar to the cytological features of serrated adenocarcinomas of the colon [58]. We believe the traditional serrated adenoma-type cytology should not be classified as serrated dysplasia and, if present in a sessile serrated polyp, should not be interpreted as a sessile serrated polyp with (serrated) dysplasia. Further studies are needed to investigate whether sessile serrated polyp with traditional serrated adenoma-like cytology (or flat traditional serrated adenoma arising from a sessile serrated polyp) have molecular features of traditional serrated adenoma supporting the hypothesis that these lesions are a form of traditional serrated adenoma or whether they represent a subtype of advanced sessile serrated polyp.
Inflammatory pseudopolyps and mucosal prolapse of the large intestine are common non-neoplastic lesions that can exhibit the same eosinophilic cell changes as seen in traditional serrated adenoma (Fig. 9) (and also display some serration mimicking a sessile serrated polyp or a traditional serrated adenoma). The differential diagnosis between a traditional serrated adenoma with prolapse changes and an inflammatory pseudopolyp with prominent serration and traditional serrated adenoma-type cytology can occasionally be challenging. In the latter, the inflammation in the lamina propria is usually more marked and crypts show more obvious architectural distortion.
As mentioned, in some sessile serrated polyps, patches of eosinophilic cell changes (focal enteric metaplasia) can be present involving only parts of the superficial aspect of crypts that otherwise show a typical sessile serrated polyp morphology (Fig. 9). This most likely represents a reactive change in an ordinary sessile serrated polyp. The difficulty arises with the differential diagnosis of flat traditional serrated adenoma. Compared with sessile serrated polyps showing focal enteric metaplasia, flat traditional serrated adenomas demonstrate a traditional serrated adenoma-type cytology covering the entire luminal aspect of the lesion and often extending toward the crypt bases. Another histologic feature of traditional serrated adenoma needs to be present. In flat traditional serrated adenoma, slit-like serration is most commonly seen. Ectopic crypt foci are rarely present in flat traditional serrated adenomas while it is a feature of protuberant traditional serrated adenomas. While this approach can resolve the diagnostic dilemma for most lesions, some still defy proper categorization. As mentioned, a diagnosis of serrated adenoma-unclassified can be appropriate in this setting.
Grading dysplasia in sessile serrated polyps
Throughout the gastrointestinal tract, dysplasia is graded using a two-tiered system. However, grading dysplasia in sessile serrated polyp is not recommended for multiple reasons. First, cytoarchitectural features used to grade dysplasia may not be applicable to dysplastic sessile serrated polyps given the wide morphologic heterogeneity. Furthermore, there has not been a study measuring the inter-observer agreement in the grading of dysplasia in sessile serrated polyp. More importantly, MLH1 loss is seen in dysplastic areas that are histologically quite bland. Loss of MLH1 expression in a dysplastic area indicates a lesion that has acquired a microsatellite instability phenotype and is at high-risk of rapid progression to invasive carcinoma. Given that MLH1 loss does not reliably correlate with traditional grades of dysplasia, grading does not adequately reflect the malignant potential of these lesions.
Advances in the molecular pathology of the serrated neoplasia pathway
The serrated neoplasia pathway, like most neoplastic pathways, is complex. The hallmarks are MAP kinase pathway activation (especially by BRAF mutation) and the CpG island methylator phenotype. These changes tend to occur early in polyp development. From a conceptual viewpoint, serrated lesions can be broadly divided into early, advanced and malignant. Early polyps include microvesicular hyperplastic polyp, goblet cell hyperplastic polyp, sessile serrated polyp and potentially (depending on individual preference) traditional serrated adenoma. Advanced polyps then include sessile serrated polyp with dysplasia and traditional serrated adenoma with high grade dysplasia. These culminate in serrated pathway carcinomas. The natural history of serrated pathway carcinomas is remarkably variable depending on the molecular events that have resulted in malignant transformation. Figure 10 is a schematic of the major routes to serrated carcinoma arising from serrated polyps.
Early serrated polyps
Microvesicular hyperplastic polyp and sessile serrated polyp have overlapping molecular alterations. Most microvesicular hyperplastic polyps and sessile serrated polyps harbor an activating BRAF mutation [59, 60]. In contrast relatively few microvesicular hyperplastic polyps are CpG island methylator phenotype-high (10%) versus 40–50% of sessile serrated polyps [59, 60]. Currently there is no reliable molecular marker that can distinguish these lesions and despite the imperfections discussed above, histology is currently considered the gold standard. Whether sessile serrated polyps arise de novo or from microvesicular hyperplastic polyps still remains a matter of debate, but if a microvesicular hyperplastic polyp does transition to a sessile serrated polyp, the driver(s) of this change are not clear. The molecular changes that occur in goblet cell hyperplastic polyps are less well described but KRAS mutations have been observed. Furthermore, a recent study has suggested that goblet cell content in non-dysplastic serrated polyps is predictive of KRAS alterations [61].
Whether the traditional serrated adenoma should be included in the non-dysplastic group is unsettled. Most authors would consider these lesions to have low grade dysplasia. However, the cytology is bland and proliferation is limited [37]. Regardless, traditional serrated adenomas appear to have more molecular alterations at this initial stage than either microvesicular hyperplastic polyps or sessile serrated polyps. The majority show MAP kinase activation with around 50% having a BRAF mutation and 30% a KRAS mutation [37, 38, 43]. CpG island methylator phenotype-high is common in the BRAF mutated polyps but is less frequent in the KRAS mutated cases [37]. While many of the BRAF mutated traditional serrated adenomas arise from sessile serrated polyps and microvesicular hyperplastic polyps, the origins of the KRAS mutated cases are more obscure; however, two recent publications suggest they may arise de novo or from a similar appearing precursor [50, 62]. Additional mutations in traditional serrated adenomas without overt dysplasia have recently been demonstrated in several excellent publications from Japan by Sekine and co-authors [63, 64]. They have shown that KRAS mutated traditional serrated adenomas have fairly frequent RSPO fusion transcripts and that BRAF mutated traditional serrated adenomas have quite frequent RNF43 mutations. In addition, the authors have demonstrated that these molecular alterations tend to occur at the transition from precursor polyp (e.g., microvesicular hyperplastic polyp or sessile serrated polyp) to traditional serrated adenoma [65].
Advanced serrated polyps
The two categories of advanced serrated polyp are the sessile serrated polyp with dysplasia and traditional serrated adenoma with superimposed dysplasia. Both are recognized by a transition to overt dysplasia in a discrete area of the polyp. The sessile serrated polyp with dysplasia is the most intensively studied of the two groups. Methylation induced silencing of the MLH1 gene is the most recognized molecular event occurring in these lesions. The frequency of this occurrence is quite variable in the literature, ranging from 15–73% [30, 66]. In our opinion, the lower values reflect inclusion of sessile serrated polyps with enteric metaplasia or early and flat traditional serrated adenoma within the sessile serrated polyp with the dysplasia group. These early and flat traditional serrated adenomas are often recorded as so-called low-grade serrated dysplasia. We do not consider these polyps to represent true sessile serrated polyp with dysplasia and in a recent publication where these cases were not included, 73% of cases were mismatch repair deficient [27]. This value is more reflective of the mismatch repair status in BRAF mutated carcinomas, where the majority are also mismatch repair deficient. Other molecular events are also critical to the progression from sessile serrated polyp to carcinoma. Several studies have demonstrated silencing of the critical tumor suppressor genes p16 and TP53 mutation in a significant minority of cases [27, 67, 68]. WNT pathway activation is also frequent, however in contrast to the chromosomal instability pathway, WNT pathway activation tends to occur later in serrated polyps. In addition, APC mutation is less common in the serrated pathway [69]. Instead methylation induced silencing of WNT antagonists such as the SFRP genes, AXIN2 and MCC all play a role [70].
By contrast there is effectively never loss of MLH1 expression in the transition of traditional serrated adenoma to high grade dysplasia [43]. As discussed above, RNF43 mutation and RSPO fusions are common early events in traditional serrated adenomas. Similar to the sessile serrated polyp with dysplasia, loss of p16 expression and TP53 mutation are relatively common at the transition to high-grade dysplasia [37].
Risk of metachronous and synchronous neoplasia in patients with serrated polyps
The original description of sessile serrated polyp as a histological entity was not based on any longitudinal outcome data. Subsequent studies to determine the surveillance implications of a diagnosis of sessile serrated polyp have been hampered by diagnostic variability. Consequently, current guidelines for surveillance in patients with serrated polyps contain recommendations based on limited data [10, 71]. The distinction of hyperplastic polyp from sessile serrated polyp continues to be problematic and confounds longitudinal studies attempting to assess neoplastic risk based on histologic subtype of serrated polyp [51,52,53]. Concurrent conventional adenomas in patients with serrated polyps are confounding factors that must be adjusted for in outcome studies but this is often not feasible outside the setting of a large multi-institutional or population-based study. In a study of US male veterans, patients with proximal serrated polyps (hyperplastic polyp and sessile serrated polyp combined) were twice as likely to have concurrent conventional advanced or multiple (≥3) adenomas and those with large (≥10 mm) serrated polyps were over three times as likely to have concurrent advanced adenomas [72]. This association has been confirmed in several studies and holds true even when the serrated polyps are sub-classified into hyperplastic polyp or sessile serrated polyp [73]. In fact, presence of a synchronous advanced adenoma makes it more than twice as likely that a hyperplastic polyp from the pre-sessile serrated polyp era will be re-classified as a sessile serrated polyp upon review [74]. Moreover, multiple polyps occur over time in patients undergoing surveillance colonoscopy. It is difficult to ascribe the subsequent cancer risk to a particular histologic type of precursor lesion in such patients unless the study sample size permits an adequate regression analysis. Certain polyp characteristics may alter the subsequent risk of colorectal carcinoma. Patients with large polyps are more likely to undergo a careful and thorough examination leading to “detection bias” where other concurrent polyps are more likely to be detected and removed during the procedure. This lowers the risk of subsequent colorectal carcinoma in these patients even though they may harbor precursor lesions at significant risk of malignant transformation. Similarly, patients with advanced and/or multiple conventional adenomas undergo close surveillance and metachronous risk of colorectal carcinoma in these patients may appear spuriously lower compared to low-risk patient groups that undergo surveillance at longer intervals. Colorectal carcinoma is not commonly detected in patients undergoing surveillance colonoscopy and markers of high risk, such as advanced adenomas or large serrated polyps, are often used as surrogate outcomes of interest in longitudinal outcomes studies. While these markers are indirectly helpful in determining appropriate surveillance intervals they do not represent the true outcome of interest in patients undergoing surveillance colonoscopy, which is reduction in mortality from colorectal carcinoma.
Despite the above limitations several conclusions can be drawn based on published literature summarized in Table 3. Serrated polyps without dysplasia are indeed a risk factor for colorectal carcinoma in the long term but the short-term risk of malignancy, at least in patients under surveillance, appears to be low. In a retrospective study from a period when sessile serrated polyps were all diagnosed as hyperplastic polyp, 23 large (≥10 mm) “hyperplastic polyp” left in-situ did not progress to cancer over a median follow up of 11 years which argues against a fast progression to cancer [75]. Similarly, in the study by Lu et al. on patients with sessile serrated polyp, the reported risk of incident colorectal carcinoma was much higher (12.5%) than other studies, but even they reported a median interval of 8.3 years between the detection of sessile serrated polyp and the eventual diagnosis of colorectal carcinoma [76]. There have also been suggestions that serrated polyps may play a larger than expected role in the development of interval colon cancers [77]. However, interval colorectal carcinomas are more common in the proximal colon where mismatch repair deficient tumors are more prevalent. Once location is matched between sporadic interval and non-interval colon cancers, the genetic landscape of both groups of tumors appears to be quite similar [78]. This suggests that interval colon cancers are more likely to arise from missed lesions or incompletely excised precursors rather than a distinct pathogenetic pathway. This conclusion is also supported by the prospective CARE (completeness of adenoma resection) study that showed an overall incomplete polyp excision rate of 10%. The incomplete resection rate increased to 17% for large (10–20 mm) polyps, 31% overall for sessile serrated polyp and nearly 50% for sessile serrated polyp larger than 10 mm [79]. The prevalence of missed lesions on colonoscopy has been estimated to range from 2–13% [80, 81] but a recent meta-analysis of over 15,000 tandem colonoscopies estimated the average miss rates to be 26% for adenomas, 9% for advanced adenomas and 27% for serrated polyps [82].
There is little evidence at this time to suggest that histologic subtype of serrated polyp carries a predictive value for metachronous advanced outcomes independent of polyp size, location and number although multiple studies using centralized pathologic review with updated diagnostic criteria have yet to be performed. Polyp size and location do appear to be important predictors of risk for both concurrent and subsequent advanced neoplasia and cancer. As mentioned above, cross-sectional studies have shown that sessile serrated polyp and large hyperplastic polyp are associated with synchronous multiple adenomas and advanced adenomas and with additional synchronous large sessile serrated polyp [72, 83,84,85]. A higher prevalence of synchronous advanced adenomas occurs in patients with large and proximal serrated polyps [83, 86] and large distal serrated polyps are reported to be four times more likely to be associated with proximal adenocarcinoma [86] emphasizing the importance of polyp size in serrated polyp risk stratification. A recent nationwide multi-institutional study evaluated outcomes in patients with multiple (>50% of total) serrated polyps who did not meet the criteria for serrated polyposis. The incident risk of colorectal carcinoma in these patients, and their first-degree relatives, was similar to confirmed serrated polyposis patients, suggesting an increased cancer risk with increasing cumulative number of serrated polyps [87].
There also seems to be emerging consensus that patients with high risk conventional adenomas (≥3 in number, ≥10 mm in size, or those with a villous component or high-grade dysplasia) and/or large serrated polyps can be binned into three distinct risk groups. Patients with only high-risk conventional adenomas at baseline are more likely to develop subsequent high-risk adenomas on surveillance but not large serrated polyps [54, 88, 89]. Conversely, patients with large (≥10 mm) serrated polyps or those with sessile serrated polyp histology, are more likely to develop large serrated polyps on surveillance but not high-risk conventional adenomas [88, 89]. This finding is similar to that reported in prior literature where index hyperplastic polyps were reported to be predictive of subsequent hyperplastic polyps but not conventional adenomas [90,91,92]. Interestingly, the highest risk for metachronous high-risk conventional adenomas seems to be in patients who harbor both high-risk conventional adenomas and large serrated polyps at baseline colonoscopy [72, 89, 93]. This last group of patients seem to possess a background colonic mucosa prone to development of neoplastic polyps along multiple pathways and are likely to benefit the most from close surveillance. This finding in the sporadic setting is analogous to patients with serrated polyposis in whom the risk of colorectal carcinoma is not only associated with the type or number of serrated polyp but also the presence of concurrent conventional adenomas [94,95,96]. Similarly, there is some data to suggest that the metachronous risk of advanced neoplasia in patients with low-risk adenomas and sessile serrated polyp is similar to high-risk adenoma patients without any sessile serrated polyp [97]. Patients with a diagnosis of sessile serrated polyp may have a higher risk for metachronous large serrated polyps compared to patients with large or proximal hyperplastic polyps (unpublished data). While this may reflect a true biological difference between hyperplastic polyp and sessile serrated polyp, this may also be due to sessile serrated polyp being more likely to be missed or incompletely excised on index examination and thus more likely to develop large metachronous lesions.
Finally, the surveillance implications of a diagnosis of traditional serrated adenoma also remain unclear given its infrequent occurrence independent of other concurrent polyps. An additional complication in recent years has been an increasing trend to diagnose traditional serrated adenoma as sessile serrated polyp with dysplasia when they occur in a background of sessile serrated polyp or hyperplastic polyp, a practice we discourage. Prior studies suggesting a high risk of concurrent colorectal carcinoma and metachronous adenomas in patients with baseline traditional serrated adenoma were limited by small number of patients [91, 98]. More recently, in a relatively large study of Korean patients with traditional serrated adenomas, the risk of metachronous serrated polyps, conventional adenomas, as well as high-risk adenomas was higher than a control population with only baseline conventional adenomas [99]. A recent population-based study from Denmark also showed patients with traditional serrated adenoma to be nearly five times more likely to develop colorectal carcinoma on follow up [54]. However, this study included incident inflammatory bowel disease-dysplasia patients, was from a time when routine screening colonoscopy was not being performed in Denmark, and despite the large sample size only 31 cases and controls had a prior traditional serrated adenoma.
In summary, current evidence suggests that managing large serrated polyps similar to low-risk adenomas is adequate since the risk of cancer in the short term is low. Close surveillance should be restricted to patients with concurrent advanced adenomas and large serrated polyps. Awareness of flat serrated precursor lesions in the right colon will hopefully lead to greater emphasis on detection and complete excision of these lesions and reduce the metachronous risk of colorectal carcinoma in these patients in the future.
Serrated polyposis
Serrated polyposis is a rare condition of largely unknown etiology characterized by the development of multiple serrated polyps in the large bowel. The upper gastrointestinal tract and the small bowel are not affected [100]. Patients do not have any extracolonic manifestation.
A familial component is well documented. About a third of serrated polyposis patients have at least one first-degree relative with colorectal carcinoma and 5% have a first-degree relative with serrated polyposis [95, 96]. However, no high-penetrance causative gene has been identified. Approximately 2% of affected patients have a pathogenic germline variant in RNF43, a gene involved in the WNT signaling pathway [101,102,103,104].
Both genders are equally affected with most patients diagnosed in their 5th or 6th decade [95, 96, 100, 105]. However, serrated polyposis may be identified in younger adults. Because serrated polyps are less likely to bleed than conventional adenomas, screening fecal blood tests do not often lead to the diagnosis unless conventional adenomas or advanced neoplasia are present.
The diagnostic criteria have been recently revised to include patients who present with a predominantly distal polyposis phenotype (including the sigmoid colon and the rectum) [106]. In addition, the previous criterion 2 (any number of serrated polyp proximal to the sigmoid colon in an individual who had a first degree relative with serrated polyposis) has been discarded.
The updated criteria for the diagnosis are:
Criterion 1: At least 5 serrated polyps proximal to the rectum all ≥5 mm, with at least two ≥10 mm.
Criterion 2: More than 20 serrated polyps of any size but distributed throughout the large bowel, with at least 5 proximal to the rectum.
Any histologic subtype of serrated polyp is included in the final count. The diagnosis may require more than one colonoscopy and the polyp count is cumulative over time.
Importantly, the phenotype is highly heterogeneous from patients with low polyp burden to patients with large numbers of polyps fulfilling both criteria and difficult to manage by colonoscopy. Data from two large European studies showed that 25% of patients meet only criterion 1 (type 1 phenotype), 45% meet only criterion 2 (type 2 phenotype) and the remaining 30% have both phenotypes [95, 96].
Patients with serrated polyposis have an increased risk of colorectal carcinoma compared to the general population. Results from two large retrospective studies showed that colorectal carcinoma was diagnosed in 16% and 29% of patients [95, 96]. In most cases, the diagnosis of cancer was made before or at the time of serrated polyposis diagnosis. Risk factors associated with colorectal carcinoma were (1) the fulfillment of both clinical criteria; (2) more than 2 sessile serrated polyps proximal to the splenic flexure; (3) presence of at least one serrated polyp with dysplasia; (4) presence of and at least one advanced conventional adenoma. Interestingly, nearly half of cancers were located in the rectosigmoid, indicating that distal polyps are at risk of progression and should be included in the diagnostic criteria.
The molecular characterization of 45 serrated polyposis-associated colorectal carcinomas showed that 46% harbored a BRAF mutation, while KRAS mutation was rare (<5%). MLH1 loss of expression was identified in 38% of cases [107]. This suggests that not all cancers develop from serrated polyps and that at least half may follow the conventional adenoma-carcinoma pathway.
The diagnosis of serrated polyposis is frequently missed [108, 109]. It is important for pathologists to know the clinical criteria and make the diagnosis when all information on polyp number and polyp size is available but may be challenging when cumulative counts meet the criteria but data from prior colonoscopies is not available. When a patient has multiple serrated polyps but the exact location, size and number are not clear, the pathologist should still raise the possibility of serrated polyposis to prompt the clinician to consider the diagnosis. Current surveillance guidelines recommend referral to genetic counseling and monitoring in tertiary centers [6, 10]. The aims are to exclude rare known genetic syndromes that may present with a serrated polyposis phenotype (MUTYH-associated polyposis, hereditary mixed polyposis syndrome and PTEN-hamartoma tumor syndrome), clear the entire large bowel from polyps >3–5 mm in size, and undergo yearly colonoscopy surveillance to prevent colorectal carcinoma. If the polyp burden cannot be controlled by serial colonoscopies or if an advanced lesion is diagnosed, the patient should be considered for surgery [6, 110]. Screening colonoscopy is recommended for first-degree relatives who have 5 times the incidence of colorectal carcinoma compared with the general population [105, 111].
Serrated pathway associated carcinomas
The end point of these pathways is the development of invasive malignancy (Fig. 11). Broadly, three major molecular subtypes of colorectal carcinoma can arise from the serrated pathway including (1) BRAF mutated, mismatch repair deficient; (2) BRAF mutated, mismatch repair proficient; and (3) KRAS mutated, mismatch repair proficient (Table 4) [112]. Serrated adenocarcinoma is a morphologic variant recognized by the World Health Organization characterized by epithelial serrations, eosinophilic cytoplasm, vesicular nuclei, absence of necrosis, and a mucinous or trabecular growth pattern. While this variant can be reliably recognized histologically and likely arise from malignant transformation of some sessile serrated polyps and traditional serrated adenomas, most carcinomas arising from serrated precursors do not have a serrated adenocarcinoma morphology [58, 113].
BRAF mutated, mismatch repair deficient cancers have a favorable prognosis and arise from sessile serrated polyp with dysplasia that demonstrate loss of MLH1 (and PMS2) expression [2, 114]. These tumors display classic features of mismatch repair deficient colon cancers including medullary growth pattern, tumor infiltrating lymphocytes, mucinous differentiation, and/or Crohn’s like peritumoral reaction. The presence of a BRAF mutation and hypermethylation distinguishes these tumors from Lynch syndrome associated cancers. Mismatch repair deficient colon cancers demonstrate a high tumor mutational burden and are amenable to treatment with immune checkpoint inhibitors.
BRAF mutated mismatch repair proficient cancers have a dismal prognosis and likely arise from the ~25% of sessile serrated polyp with dysplasia that demonstrate retained MLH1 expression and/or BRAF mutated traditional serrated adenomas [115,116,117,118,119]. These tumors often present at an advanced stage and may demonstrate an aberrant immunophenotype with reduced CDX2 and cytokeratin 20 expression and increased cytokeratin 7 expression [118]. Histologically they may demonstrate partial mucinous differentiation or neuroendocrine differentiation and often have high-grade tumor budding, perineural invasion, and extensive lymphovascular invasion [117].
KRAS mutated mismatch repair proficient tumors are common and the vast majority likely arise through conventional adenomas without evidence of CpG hypermethylation [2, 114]. A small subset of these tumors, however, likely arise through KRAS mutated traditional serrated adenomas and demonstrate low levels of CpG island methylation [120]. Separating the subset of mismatch repair proficient KRAS mutated tumors that arise from traditional serrated adenomas and from conventional adenomas is difficult and studies comparing the two have yet to be performed. It is interesting to note that methylation array studies on colorectal carcinoma have shown not just two but four distinct clusters [121]. It is remains to be seen whether KRAS mutated mismatch repair proficient tumors arising from traditional serrated adenomas and conventional adenomas can be separated by virtue of their methylation signatures.
A small but significant percentage of the colorectal carcinomas arising from a serrated precursor have an unusual molecular phenotype. In particular, a ~25% of mismatch repair deficient cancers lack BRAF mutations but will demonstrate CpG island methylator phenotype-high with hypermethylation of MLH1 [122,123,124]. The BRAF wild-type mismatch repair deficient tumors may arise through the small percentage of sessile serrated polyp that lack BRAF mutations. These tumors behave similarly to BRAF mutated mismatch repair deficient tumors. However, upto 30% of these BRAF wild-type mismatch repair deficient cancers harbor KRAS mutations [125]. The origin of the rare KRAS-mutated mismatch repair deficient tumors is unclear although when a precursor could be identified they histologically resembled conventional tubular and tubulovillous adenomas. The possibility that the serrated precursor was overrun by the dysplastic component could not be entirely excluded. Recently, Sekine and colleagues has identified a small subset of sessile serrated polyp that harbor KRAS mutations [61]. This finding has yet to be confirmed by others but could potentially result in KRAS mutated mismatch repair deficient tumors.
Conclusions
Serrated polyps are routinely encountered in colonoscopy specimens and pose multiple diagnostic challenges. Over the past few decades our improved understanding of these polyps has resulted in refined diagnostic criteria for sessile serrated polyp and traditional serrated adenoma. Multiple morphologic subtypes of sessile serrated polyp with dysplasia have been recently recognized and correlated with MLH1 expression. The molecular abnormalities seen in serrated polyps have also been more fully characterized and correlated with histologic subtype. Traditional serrated adenomas are the most molecularly heterogenous but molecular heterogeneity also exists in sessile serrated polyps with dysplasia. Finally, our knowledge of the risk of metachronous and synchronous lesions in patients with serrated polyps has expanded. Additional studies using strict diagnostic criteria will help us answer whether hyperplastic polyp and sessile serrated polyp are two stages of the same lesion or distinct entities and aid in further refining risk stratification of subsequent neoplasia and development of improved post-polypectomy surveillance guidelines.
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Pai, R.K., Bettington, M., Srivastava, A. et al. An update on the morphology and molecular pathology of serrated colorectal polyps and associated carcinomas. Mod Pathol 32, 1390–1415 (2019). https://doi.org/10.1038/s41379-019-0280-2
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DOI: https://doi.org/10.1038/s41379-019-0280-2
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