Disclaimer: I belong to the speakers bureau of the American Serrated Society, often referred to as the ASS

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1 An Exposé on Serrated Lesions of the Colorectum How do you know it is a hyperplastic polyp and not something else? How do you know it is something else and not a hyperplastic polyp? Disclaimer: I belong to the speakers bureau of the American Serrated Society, often referred to as the ASS Polyps with Serrated Architecture Serrated means having saw tooth-like notches along the edge, in this case the lumenal edges of the crypts 1

2 Normal colonic crypts: smooth lumenal surfaces Serrated architecture Normal Serrated In most polyps. the serrations result from small clumps of cells (micropapillary processes) separated by single cells along the sides of the crypts and on the surface 2

3 In some polyps the serrations result from many small crypt-like buds along the sides of the main tubules (ectopic crypt formation) Most serrated polyps are tiny sessile hyperplastic polyps Typical hyperplastic polyp: darker at the base and lighter toward the surface 3

4 Typical hyperplastic polyp: crypts are smaller and at the base and more dilated toward the surface How about some historical serrated vignettes? A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp in the German literature Wattenberg (1959) used the term focal mucosal hyperplasia in an enzyme histochemistry study of colonic things Am J Pathol, 35:113,

5 A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia Basil Morson, perhaps the best known and revered GI pathologist of the mid to late 20 th century, called them metaplastic polyps, to distinguish them from true adenomatous proliferation. Note that this is a resection, not a biopsy Read at the meeting of the American Proctologic Society, June 21-24, 1961 Published in Dis Col Rect, 5: , 1962 A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia In this paper, Morson also said that there is little evidence of any increase in cellular activity in these polyps, so he doubted if the hyperplastic name was appropriate. Dis Col Rect, 5:337,

6 The metaplastic polyp term was acceptable in the UK up until recently when a group of GI pathologists decided it was time to change to the hyperplastic polyp designation, but there are still some holdouts who prefer metaplastic A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia Morson (1962) called them metaplastic polyps Lane and Lev (1963) seem to be either the first or among the first in the United States to call them hyperplastic polyps in a publication, also to distinguish them from adenomas Lane N, Lev R: Observations on the origin of adenomatous epithelium of the colon: Serial section studies of minute polyps in familial polyposis. Cancer 16:751, 1963 They digressed to discuss tiny polyps in general and it was in that digression that they mentioned using the term hyperplastic polyp for polyps with saw-tooth architecture. 6

7 A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia Morson (1962) coined the term metaplastic polyp Lane and Lev (1963) either the first or among the first in the United States to call them hyperplastic polyps in print We probably called them adenomatous polyps until around the late 60s when we started calling them hyperplastic polyps Why did we call them adenomatous polyps back in the old days? Because those were the days when men were men and women were women.and all polyps were adenomatous. This is the part of the polyps on which we concentrated. 7

8 Typical adenoma, right? The proliferative zone at the base of a typical hyperplastic polyp Typical adenoma, right? HPs and adenomas have different proliferative zones HP: at the base Adenoma: at the top 8

9 A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia Morson (1962) coined the term metaplastic polyp Lane and Lev (1963) either the first or among the first in the United States to call them hyperplastic polyps We started calling them hyperplastic polyps by late 60s Elucidation of cell types: mainly absorptive cells as proven by ultrastructural studies Lane et al, early 1970s Alcian blue The absorptive cells contain a little mucin A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia Morson (1962) coined the term metaplastic polyp Lane and Lev (1963) either the first or among the first in the United States to call them hyperplastic polyps We started calling them hyperplastic polyps by late 60s to early 70s Elucidation of cell types: mainly absorptive cells Lane et al, early 1970s Determination of kinetics Lane et al 1973, Hayashi et al

10 Determination of kinetics Kaye, Fenoglio, Pascal and Lane, Gastroenterol, 64:926,1973 The hyperplastic epithelium exhibits a similar progression (of differentiation as normal epithelium), the primary difference being that most of the morphological features of maturing and mature cells are found either lower in the crypt or in exaggerated form at the same level of the crypt when comparted with normal mucosa of the same colon Compared to normal, in HP mucosa, maturation occurs earlier, deeper in the crypts, and by the time the cells reach the surface, they are hypermature, that is, too old, and they have ultrastructural senescent features. In hyperplastic polyps, the surface epithelial basement membrane is thicker than normal as is the layer of fine collagen fibers beneath it, more evidence of hypermaturity. Thick BM Kaye, Pascal, Lane. Gastroenterol, 60:515,1971 Determination of kinetics Hayashi et al found that in HPs Cells on the surface looked hypermature by EM Decreased rate of migration of cells from base to surface by autoradiography Suggested that there is a longer turnover time and delayed migration compared to normal mucosa Hayashi, et al. Gastroenterol 66:347,

11 An explanation for the slow migration time in HPs 30 years later: A hyperplastic polyp can be defined as a lesion caused by the inhibition of programmed cell death (that is, inhibition of exfoliation of surface epithelial cells). Serration arises when cells continue to be generated.but are blocked (by the surface cells which are still there) from ascending to their rightful location within the epithelial surface Higuchi and Jass: My approach to serrated polyps of the colorectum. J Clin Pathol 57:682, 2004 Delayed loss Hypermature slow migration Cell crowding Kaye, et al, Gastroenterol, 64:926,1973 Early maturation Dynamics of the Hyperplastic Polyp Possibly an epithelial communication gap Early maturation and delayed turnover Prolonged maturation Cellular crowding Metaplasia Prolonged maturation and cellular crowding absorptive cells Hypermature cells, thick BM serrated lumens 11

12 How do they begin? World s smallest hyperplastic polyp one crypt The usual hyperplastic polyp has mainly tall columnar (absorptive) cells and few goblet cells Some serrated polyps are full of goblet cells with fewer of the columnar cells. A monumental re-evaluation of everything serrated in the colon and rectum 12

13 Usual hyperplastic polyp with dominant absorptive cells was called the microvesicular type serrated polyp The serrated polyp full of goblet cells with fewer absorptive cells was called the goblet cell type serrated polyp We call both of them hyperplastic polyps Some hyperplastic polyps have bonuses 13

14 Prolapse: smooth muscle bundles from the muscularis mucosae penetrate the base of the polyp. Common in rectum, less in sigmoid and hardly ever more proximally Hyperplastic polypitis: intense basal inflammation, cryptitis and apoptosis Pleomorphic nuclei and atypical mitoses, but no neoplastic architectural features Several groups have tried to identify viruses, or at least viral proteins with no luck. Maybe they had the wrong probes. Kambham, et al. Am J Surg Pathol. 29:912,

15 The aerated HP: air pumped in during endoscopy Inverted: downgrowth through a break in the muscularis mucosae The period of complacency For years, we recognized only one colorectal serrated polyp, the hyperplastic polyp, a small bump that was not thought to have any relation to colorectal carcinoma. 15

16 Classic HP Not neoplastic and not associated with neoplasm A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia Morson (1962) coined the term metaplastic polyp Lane and Lev (1963) either the first or among the first in the United States to call them hyperplastic polyps We started calling them hyperplastic polyps by late 60s to early 70s Elucidation of cell types: mainly absorptive cells Lane et al, early 1970s Determination of kinetics. Lane et al 1973, Hayashi et al 1974 Concept of the serrated adenoma Longacre and Fenoglio-Preiser,

17 Serrated adenoma Architecture but not cytologic features of HP Differences included: 1. Goblet cell immaturity 2. Upper zone mitoses 3. Prominent nucleoli 4. No thick collagen table (basement membrane) Longacre, Fenoglio- Preiser, 1990 Mitosis in upper epithelium, near the surface Goblet cell immaturity (small goblet cells) 17

18 Thin basement membrane Prominent nucleoli Over the years, this polyp has gained the name of traditional serrated adenoma, (TSA). A serrated polyp with subtle cytologic features that vaguely resemble those in an adenoma, such as nuclear, elongation hyperchromatism and stratification. Traditional Serrated Adenoma (TSA) 18

19 No pleomorphism. Pink cytoplasm, few goblet cells. Is this really dysplastic???? Traditional serrated adenoma If this is dysplastic, it is a very different dysplasia than in typical adenomas TSA Typical Adenoma These strange pink cells may not be dysplastic, but metaplastic or senescent 19

20 Torlakovic et al. AJSP 32:21-9, 2008 Ectopic crypt formation only found in TSA may account for its protuberant exophytic growth and is the best defining feature of these polyps The pictures from the original serrated adenoma paper have these buds TSAs tend to be exophytic, coarsely villous or filiform Traditional Serrated Adenoma (TSA) Yantiss, et al: AJSP 31:1238,

21 In some studies there was an associated lesion, such as a hyperplastic polyp or an SSA, which may or may not be a precursor. Williard et al (Cleveland), AJSP, 2014;38: % of 55 left sided TSAs, mostly HPs Bettington, et al (Australia), Mod Pathol, 2014; 38% of 200 pancolonic TSAs, mostly SSAs TSA: risk of cancer unknown, probably small But for the cancers that arise in TSAs there is a precursor 21

22 Typical adenoma Traditional serrated adenoma Mixture of typical adenoma and traditional serrated adenoma: TSA with cytologic dysplasia TSA Cytologic Dysplasia looks like typical adenoma Cytologic Dysplasia TSA Carcinoma 22

23 Traditional Serrated Adenoma Rex. et al, Am J Gastro, 2012;107:1315 TSAs appear to be molecularly diverse with KRAS or BRAF mutations or neither, and either low or high levels of CIMP. No hypermethylation of MLH1 and not MSI Commonly hypermethylation of the DNA repair gene MGMT which has been associated with both CIMP-low and -high CRCs Colorectal Serrated Polyps as of a few years ago All were called hyperplastic polyps increase with age more often distal in general no direct link to carcinoma cause unknown hyperplastic mucosa is sometimes a type of reactive or regenerative mucosa as in ulcerative colitis and prolapsed mucosa Colorectal Serrated Polyps Now Most are still hyperplastic polyps They have no direct link to carcinoma The cause is still unknown Some serrated polyps actually are called adenomas: TSAs Other serrated polyps have a carcinoma link 23

24 A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia Morson (1962) coined the term metaplastic polyp Lane and Lev (1963) either the first or among the first in the United States to call them hyperplastic polyps We started calling them hyperplastic polyps by late 60s to early 70s Elucidation of cell types: mainly absorptive cells Lane et al, early 1970s Determination of kinetics. Lane et al 1973, Hayashi et al 1974 Concept of the serrated adenoma Longacre and Fenoglio-Preiser, 1990 Carcinoma associated serrated polyps Torlakovic and Snover, 1996 Serrated adenomatous polyposis Torlakovic and Snover, Gastroenterol. 110:748, patients, many serrated polyps, many large (1.5cm +) Location: 3 diffuse, 2 left, 1 right 4 CA, 2 numerous adenomas This is what we now call the serrated polyposis syndrome 24

25 Serrated adenomatous polyposis Torlakovic and Snover, Gastroenterol. 110:748, 1996 These carcinoma associated serrated polyps were different than hyperplastic polyps. They were bigger Dilated crypts mostly at base Horizontally oriented basal crypts Goblet cells at crypt base Nuclear abnormalities A large sessile serrated polyp with complex architecture Typical HP Dilated basal crypts with lateral growth 25

26 A horizontal crypt with goblet cells at the base Mucin in dilated crypts Maturation (goblet cells) at the base Serrations at the base Enlarged vesicular nuclei with nucleoli along the sides of the crypts (these are hard to find) 26

27 Abnormal proliferation: Mitoses in the upper crypts We now know that these serrated polyps are common. They do not have traditional dysplasia, but they are cancer associated. In general, these serrated polyps are Large Right sided Have architecture that differs from the common hyperplastic polyp Have altered proliferative dynamics Have unusual endoscopic features In addition to the changes outlined in the original polyposis paper, these polyps have other common features, including: 27

28 Exaggerated serrations along the sides Additional features Stratified (floating) goblet cells Often covers adipose tissue resembling a lipoma Inverted into lymphoid follicle 28

29 Endoscopic: often called flat with a mucus covering What is the best name for these cancer associated serrated polyps? The two most commonly used names are sessile serrated adenoma sessile serrated polyp 29

30 How the name sessile serrated adenoma started Torlakovic, Snover and friends, AJSP, 2003 stated we recommend that, for practical purposes, large lesions with abnormal proliferation, dilated distorted crypts, dilatation of the base of the crypts, and/or focal nuclear atypia with pseudostratification..be given a different (from hyperplastic polyp) designation, sessile serrated adenoma. There were folks who did not want to call these adenomas, since they lacked typical adenoma like dysplasia. They proposed calling them sessile serrated polyps instead What is the established name for these polyps? The two most commonly used names are sessile serrated adenoma sessile serrated polyp WHO, 2010: SSA/P Regardless of the name, the important thing is to recognize that these are the carcinoma-associated serrated polyps 30

31 At the U of M, we call them SSAs. We are not annoyed by their lack of typical dysplasia. Since they have much the same cancer association as usual adenomas, I just assume that they are a different type of dysplasia. Paraphrased from Snover DC: Hum Pathol 42:1-10, 2011 SSA/P is characterized by movement of the proliferative zone away from its usual location at the base resulting in distortion and basal maturation Normal colonic mucosa: uniform MIB 1 staining of basal crypts 31

32 SSA Mib1 loss at base of crypts SSA Mib1 higher in the crypts SSAs have other abnormal proliferation changes as seen by MIB1 (KI67) staining In typical hyperplastic polyps, the proliferation is symmetrical and limited to the basal 1/3-1/2 with little variation among crypts. In typical SSA/Ps, the proliferation is irregular with variation among crypts and even asymmetric within a crypt Torlakovic, et al AM J Surg Pathol, 32:21,

33 Asymmetric MIB1 Skip area Top but not bottom Mid and upper crypt Left but not right Basal The major serrated polyp problem What are the minimal H&E criteria for the diagnosis of the SSA/P? How do we tell an SSA/P from a hyperplastic every time? Most of the features are architectural, so little polyps have less to look at. We need solid diagnostic criteria! A histologic distinction between hyperplastic polyp and sessile serrated adenoma cannot be achieved in all cases. Higuchi and Jass: My approach to serrated polyps of trhe colorectum. J Clin Pathol 57:682,

34 Worry about big rightsided polyps, because of the cancer risk. Don t worry too much about small left sided polyps until we get more data. Chung, et al. Am J Surg Pathol, 32:407, 2008 There are exceptions An easy exception A 1mm rectal polyp with great crypts A tiny left sided serrated lesion with one expanded basal crypt and slight superficial complexity in 2 34

35 SSA minimal criteria for DX So much Not one of these fabulous textbooks of GI pathology, written or edited by giants in our field, for has a useful the set of minimal diagnostic giants!!! criteria for serrated polyps of any type! Minimal criteria for SSA What do we always do when we want information? We search for the ultimate in expert information covering serrated things Serrated polyps American Serrated Society 35

36 WHO 2010 if more than 2 or 3 contiguous crypts demonstrate features of SSA, the lesion should be classified as SSA/P Is it 2 or is it 3? It can t be both I am not sure what specific features are required The latest straight poop on serrated polyps from the experts with suggestion for minimal criteria for SSA Am J Gastroenterol 107: ,

37 Presumably there must be a polyp. No one is talking of using these or any other criteria for flat mucosa. Within this polyp: We recommend that the presence of at least one 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. This was not accepted by all the 7 pathologist authors of the 2012 paper 37

38 I wonder if they would have preferred this one For the Guiness Book: the world/s record architecturally distorted, dilated, horizontally branched basal crypt Are there special stains that help us tell SSA from HP? 1. CDX2 was more likely to be located to the crypt base in SSA and more diffuse throughout the crypt in HP (Wu et al, AJCP, 129:416, 2008) 2. Nuclear β-catenin occurred in 40% of SSA but in no HP (Wu et al, AJCP, 129:416, 2008) 3. MUC6 was expressed in all 26 SSA but in none of 48 HP (Owens et al, Mod Pathol. 21:660, All of these are based on the authors knowing how to tell SSA from HP before they stained them, indicating that light microscopic diagnosis in better than anything else. 38

39 Are all pathologists in general practice aware of these serrated polyps and the differences that separate them into specific types? Probably not all, but most do. We pathologists who do a lot of postgraduate teaching have been pushing serrated stuff for at least 10 years, maybe more. As a result, more older pathologists in general practice have been diagnosing them The younger pathologists in general practice grew up with them in residency. Some SSAs have foci of adenoma-like dysplasias and even carcinomas. This complex is referred to as the serrated pathway to colonic CA Sessile serrated adenoma Cytologic dysplasia Like TSAs, SSAs can develop cytologic dysplasia, one step closer to CA 39

40 The cytologic dysplasia is often serrated SSA/P with cytologic dysplasia In the Serrated Pathway, SSA/P with cytologic dysplasia is thought to be the precursor of the associated carcinomas. Serrated Dysplasia SSA Serrated Carcinoma 40

41 The SSA component Serrated cytologic dysplasia The carcinomas are often serrated 41

42 SSA Mucinous carcinoma Mucinous carcinoma with some serrated tubules A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia Morson (1962) coined the term metaplastic polyp Lane and Lev (1963) either the first or among the first in the United States to call them hyperplastic polyps We started calling them hyperplastic polyps by late 60s to early 70s Elucidation of cell types: mainly absorptive cells Lane et al, early 1970s Determination of kinetics. Lane et al 1973, Hayashi et al 1974 Concept of the serrated adenoma by Longacre and Fenoglio-Preiser, 1990 Carcinoma associated serrated polyps by Torlakovic and Snover, 1996 Concept of the serrated pathway to colorectal carcinoma: Jass 2000 Goldstein 2003, O Brien

43 Serrated pathway to colon carcinoma per 2012 Expert Review Panel, Am J Gastroenterol 107:1315, 2012 If SSAs have such a solid carcinoma link, how does the diagnosis of SSA affect patient management? Probably the diagnosis of sessile serrated adenoma leads to clinician amputation of the first 2 words, so they are treated as adenomas. Sessile serrated adenoma Adenoma Since they tend to be large, often 1 cm or more, then they qualify as advanced adenomas for surveillance purposes. A brief serrated history Feyrter (1929) and Westhues (1934) credited as being the first to use the term hyperplastic polyp Wattenberg (1959) used the term focal mucosal hyperplasia Morson (1962) coined the term metaplastic polyp Lane and Lev (1963) either the first or among the first in the United States to call them hyperplastic polyps We started calling them hyperplastic polyps by late 60s to early 70s Elucidation of cell types: mainly absorptive cells Lane et al, early 1970s Determination of kinetics. Lane et al 1973, Hayashi et al 1974 Concept of the serrated adenoma by Longacre and Fenoglio-Preiser, 1990 Carcinoma associated serrated polyps by Torlakovic and Snover, 1996 Concept of the serrated pathway to colorectal carcinoma: Jass Time to get a gang together to recommend surveillance 43

44 The latest straight poop on serrated polyps from the experts with suggestion for minimal criteria for SSA Am J Gastroenterol 107: , 2012 The 2012 Multi-Society Task Force guidelines for Polyp Surveillance Recommendations for Surveillance and Screening Intervals in Individuals with Baseline Average Risk Lieberman, et al, Gastroenterol, 2012;143:

45 2014 Serrated Polyposis, aka Serrated Adenomatous (Hyperplastic) Polyposis WHO 2010 diagnostic criteria 1. At least 5 serrated polyps proximal to the sigmoid with 2 or more being >10mm, or 2. Any number of serrated polyps proximal to the sigmoid in an individual who has a first degree relative with serrated polyposis, or 3. >20 serrated polyps of any size but distributed throughout the colon The number of polyps is cumulative, so add them all up periodically Serrated polyposis (Spanish simplification) Type 1: Large and right-sided serrated polyps Type 2: numerous small serrated polyps throughout the colon Clin Gastroenterol Hepatol Jun;11(6):

46 Patients with SPS have an increased risk of CRC, although it is low even in experienced endoscopy centers in Spain, about 1.9% in 5 years. Carvallal, et al, Gut 2016;65: Rex, et al, Am J Gastroenterol 107: , 2012 Finally, not every serrated thing is HP SSA/P TSA 46

47 Diverticulosis associated polypoid prolapsed mucosa in sigmoid colon Serrated change in ulcerative colitis Can be flat or polypoid 2 recent partially complete studies both suggest that flat serrated change in UC correlates with an increased risk of progression to dysplasia, but the results were not statistically significant. We need more data. Atwaibi, Battts, Weinberg McCabe: Flat Serrated Change: Does It Predict the Development of Colonic Mucosal Dysplasia in Inflammatory Bowel Disease? Poster at DDW,

48 The serrated colorectal polyp story There are 3 serrated polyps Hyperplastic polyp, still the most common Sessile serrated adenoma/polyp, the most difficult to diagnose Traditional serrated adenoma, interesting but not a major concern as a carcinoma precursor When we look at a serrated lesions of the colorectum, what can we tell? We can tell if that serrated polyp is a hyperplastic polyp We can tell if that serrated polyp is a traditional serrated adenoma We can tell if that serrated polyp is a sessile serrated adenoma, as long as it is big enough We have trouble telling a big hyperplastic polyp from a serrated polyp that has a few hints that it is a sessile serrated adenoma It takes To be a GI pathologist 48