Update on Serrated Polyps

Home , Hyperplastic polyp, Sessile serrated lesion

David Hernandez Gonzalo Associate Professor University of Florida

1 2 GOALS AND OBJECTIVES 3

WHO 5th edition updates ✓Describe differences between HPs and SSL. ✓Recognize different types of dysplasia in SSLD and molecular heterogeneity in TSA. ✓Understand differences in serrated lesions of appendix versus colon. ✓Significance of serrated polyps in IBD. ✓WHO 5th updates on serrated polyposis syndrome and SSL terminology. RISK FACTORS 4 SPORADIC CRC

Serrated Serrated pathway 30% Conventional pathway 70%

FIT not useful At best moderate agreement between expert GI pathologists

Proximal SP detection rates: Related to ADR and WT CASE 1: Piecemeal resection with separate fragments (all from same polyp) 5 Just think about it…

59 Female 30 MM polyp hepatic flexure LECTURE OUTLINEE 6

Types of serrated polyps

Serrated lesions Serrated polyps of colon vs in IBD appendix

Serrated Post- polyposis polypectomy update surveillance 7 Microvesicular Serrated hyperplastic adenoma- polyp unclassified Mucin-depleted HP

Traditional Goblet cell serrated SERRATED POLYPS hyperplastic adenoma polyp

Sessile serrated Sessile serrated lesion with lesion dysplasia Microvesicular hyperplastic polyp 8 No NEED to subtype HP in your pathology report

- 40-50% of serrated polyps. Frequently <5mm.

- Dome-shaped pale nodules predominately distal colon.

- 10% in transverse and R colon (probably precursor to SSL)

- BRAF: 80%, KRAS: 0%, CpG island methylation low (+) 9

Funnel-shaped evenly spaced crypts 10

2/3

1/3

Serrations in upper 2/3 of crypts 11

Proliferative zone 12

Mitotic figures Neuroendocrine cells 13

Thickened subepithelial collagen layer 14

Microvesicular mucin

Goblet cells

Cross section: Stellate appearance 15

Serrated Microvesicular adenoma- hyperplastic unclassified polyp

Traditional Goblet cell serrated SERRATED POLYPS hyperplastic adenoma polyp

Sessile serrated Sessile serrated lesion with lesion dysplasia Goblet cell hyperplastic polyp 16 No NEED to subtype HP in your pathology report

- 20-30% of serrated polyps. Most cells: goblet cells.

- Almost exclusively rectosigmoid.

- Precursor lesion of TSA?

- BRAF: 0%, KRAS: 50%, No CpG island methylation. Goblet cell hyperplastic polyp 17

Background colonic mucosa

Increased number of goblet cells compared with the normal mucosa 18

Cross section: Round crypts

Crypts on steroids 19

Serrated Microvesicular adenoma- hyperplastic unclassified polyp

Traditional Goblet cell serrated SERRATED POLYPS hyperplastic adenoma polyp

Sessile serrated Sessile serrated lesion with lesion dysplasia 20

Recommended ESSILE ERRATED ESION terms S S L

5th edition WHO SESSILE SERRATED LESION with DYSPLASIA

Cytologic DYSPLASIA Sessile serrated lesion 21

- 80% proximal to splenic flexure. Mean: 8.5 MM.

- 15-25% of all serrated polyps.

- Tendency to be multiple.

- >90% BRAF, 0% KRAS, CpG-island methylation (++).

Bettington et al. Critical appraisal of the diagnosis of the sessile serrated adenoma. Am J Surg Pathol 2014;38:158-66 Endoscopy findings in SSL Most minimally elevated (Paris Classification Type 0-IIa) 22

NBI (NARROW BAND IMAGING)

Mucus cap 64% Enlarged fold 37%

Mucus cap 64%

Rim of adherent fecal Ill-defined borders-→ material or bubbles 52% incomplete resection rate

Cloud-like surface Dark spots in crypts

Gill P et al. Clin Med 2013 Dec;13(6):557-61 Tate DJ et al. Gastrointest Endosc 2018;87:222-31 Murakami et al. World J Gastroenterol. Aug 7, Attenuation underlying vasculature 32% 2018; 24(29): 3250-3259 Sessile serrated lesion 23 Histology and IHC

- Asymmetric dilatation at the base - Aberrant proliferation - Horizontal growth along muscularis mucosae centers - Exaggerated serrations deep + basilar crypt dilatation

- H&E remains gold standard. - IHC used in different studies: Ki67, MUC2, MUC5AC, MUC6, Maspin, Annexin A10, Hes-11, MLH1, Trefoil factor 1, BRAF mutation specific antibody VE1. 24

Branched crypt not sufficient = Proliferation zone 25

Dilatation at the base

Horizontal growth along Serration at the base muscularis mucosae 26 Sessile serrated lesion 27 How many SSL type crypts needed?

4th edition WHO 5th edition WHO 1

At least 2 contiguous crypts

Single unequivocal architecturally distorted, dilated, and/or horizontally branched crypt is sufficient Serrated polyps (MVHPs or SSAs) with any SSA-like crypts had clinical features more in common with the SSA than the MVHP (Bettingtom M et al. Am J Surg Pathol 2014 Feb;38(2):158-66) 28 HP VS SSL

Location Histology Size -20% SSL may occur distal to splenic flexure (architecture) -HP diagnosis of exclusion in R side (absence of SSL-type crypt) - Obtain deeper H&E levels - Well-oriented tissue Pai RK et al. Perineurial-like Stromal Proliferations 29 Am J Surg Pathol 2011;35:1373–1380

EMA

Mucosal herniation in SSL, often in association with lipomatous areas or lymphoid aggregates. DON’T CONFUSE WITH INVASION

Hu K, Shen S, Zhang L. Herniation of crypts in hyperplastic polyp and sessile serrated adenoma: a prospective study. Am J Cancer Res 2018 Jan 1;8(1):144-153. PITFALL ALERT! Mucosal prolapse in HPs can distort the crypt architecture and mimic a SSL 30

INSERT PICTURE HP WITH PROLAPSE

8 MM rectal HP with prolapse 31

Traditional Microvesicular serrated hyperplastic adenoma polyp

Serrated Goblet cell adenoma- SERRATED POLYPS hyperplastic unclassified polyp

Sessile serrated Sessile serrated lesion with lesion dysplasia Sessile serrated lesion with dysplasia 32

➢ 4-8% of SSL contain dysplasia. ➢ MOST advanced subtype of serrated polyp. ➢ 85% in proximal colon. >90% BRAF mutated. 0% KRAS mutated. ➢ CpG-island methylation (+++).

Size SSLD Study 1 SIZE SSLD Study 2

<10 MM >10 MM 40% <10 MM >10 MM >10 MM 46% <10 MM 60% 54% <10 MM >10 MM

Study 1: Liu et al. Modern Pathology 2017 30, 1728-1738 Study 2: Bettington et al. Gut 2017;66:97-106 Sessile serrated lesion with dysplasia 33 Abrupt transition: - Increased complexity in crypt architecture and various forms of cytologic atypia. - Don’t assess dysplasia at 40x.

Don’t biopsy only the egg yolk SSLD under narrow band imaging Ma MX, Bourke MJ. Sessile serrated adenomas: how to detect, characterize and resect. Gut Liver 2017 Nov 15;11(6):747-760 Sessile serrated lesion with dysplasia 34

SSLD under narrow band imaging CLASSIC SERRATED PATHWAY 35

HP BRAF mutant MSI (microvesicular) SSLD CIMP-H CRC (MMRD) CDKN2A Older age silencing Women>men BRAF mutation MLH1 silencing Proximal >>Distal Wnt pathway activation (RNF43 mut) Good prognosis Mucinous, medullary, signet ring, TILs.

Normal SSL BRAF mutant MSS mucosa BRAF mutation SSLD CIMP-H CRC TP53 mutation (MMRP) CDKN2A Wnt pathway activation Younger age silencing Women=men Proximal >distal Poor prognosis, LVI, +LNs NO BRAF mutation Adenoca NOS, serrated MLH1 silencing adenocarcinoma Wnt pathway activation SSL SSLD BRAF wild type MSI (MMRD) CIMP-H CRC Progressive CpG DNA Methylation Sessile serrated lesion with dysplasia 36 Types of dysplasia No NEED to subtype, recognize morphologic heterogeneity

WHO 4th edition: 2 patterns: adenomatous and serrated.

Liu C et al paper quoted in WHO 5th edition: 4 types of dysplasia.

Brisbane (Australia)

Liu C et al. Mod Pathol 2017;30:1728-1738 Adenomatous dysplasia (21%)

Top-down dysplasia - Most MLH1 proficient - Basophilic cytoplasm and elongated nuclei

Liu C et al. Mod Pathol 2017;30:1728-1738 MLH1 38

Serrated dysplasia (12%)

- Packed glands with cells with large nuclei, prominent nucleoli and eosinophilic cytoplasm.

- Mitoses frequent (atypical).

- Most MLH1 proficient.

MLH1

Liu C et al. Mod Pathol 2017;30:1728-1738 MINIMAL DEVIATION DYSPLASIA (19%) 39

MLH1

Subtle architectural and cytological changes + Loss of MLH1 (by definition)

Liu C et al. Mod Pathol 2017;30:1728-1738 40

DYSPLASIA NOT OTHERWISE

SPECIFIED MLH1 (79%)

- FULL DEPTH - VARIABLE PATTERNS - MAJORITY MLH1 DEFICIENT

Liu C et al. Mod Pathol 2017;30:1728-1738 CpG Island Methylation in Sessile Serrated Adenomas Increases With Age 41 SSL with dysplasia

SSL

Data obtained from Bettington et al. Gut. 2017 Jan;66(1):97-106 Liu C et al. Gastroenterology 2018 Nov;155(5):1362-1365. ANSWER TO CASE 1: Any stain you would like to order? 42

59 Female 30 MM polyp hepatic flexure SSL with dysplasia 43

Loss of MLH1 in SSLD 44

Serrated Microvesicular adenoma- hyperplastic unclassified polyp

Traditional Goblet cell serrated SERRATED POLYPS hyperplastic adenoma polyp

Sessile serrated Sessile serrated lesion with lesion dysplasia Traditional serrated adenoma 45

- 2-5% of all serrated polyps. - Mean 64 y/o. = - Protuberant polyp in distal colon and rectum. Proximal TSAs may be flat. - MMR retained in essentially ALL TSAs. - 50% BRAF, 40% KRAS, 10% WT. - Mucin rich variant of TSA. - Can have superimposed intestinal or serrated dysplasia. Mention dysplasia in TSA only when there is HGD. Pine cone like or coral shaped appearance 46

Hasewaga et al. Endoscopic discrimination of sessile serrated adenomas from other serrated lesions. Onco Lett. 2011 Sep 1; 2(5): 785–789 VAST MAJORITY OF TSA>10 mm HAVE THESE 3 FEATURES 47

BRIGHTLY EOSINOPHILIC CELLS ECTOPIC CRYPT FORMATION SLIT LIKE SERRATIONS PENCILLATE NUCLEI (62% OF TSAS)

NORMAL DUODENUM 48

TSA PRECURSOR: SSL

Bettington et al. Modern Pathology 20015:28,414-427 TSA WITH SUPERIMPOSED INTESTINAL DYSPLASIA 49 DIAGNOSIS: TSA TSA with HGD 50 BRAF KRAS BRAF/KRAS WILD TYPE Alternate serrated pathway 51 Normal Normal MVHP Normal Goblet cell mucosa mucosa SSL mucosa HP Wnt Wnt activation activation through through RNF43 mut RSPO Ordinary TSA: fusions 80% TSA TSA TSA

Traditional serrated TP53 mut TP53 mut adenoma Advanced TSA (TSA HGD) TSA with HGD TSA with HGD TSA with HGD 20% CDKN2A silencing (p16)

Carcinoma BRAF KRAS BRAF/KRAS WT CIMP-H CIMP-L CIMP-L MSS MSS MSS 5th edition WHO + 52 Serrated Microvesicular adenoma- hyperplastic unclassified polyp

Traditional Goblet cell serrated SERRATED POLYPS hyperplastic adenoma polyp

Sessile serrated Sessile serrated lesion with lesion dysplasia Serrated adenoma-unclassified 53 - Dysplastic serrated polyps that don’t qualify for TSA, TVA or SSLD. Included within this group is the recently described serrated tubulovillous adenoma

- All the following criteria used in Bettington’s paper: (i) >25% villous component (ii) morphological serration in >50% of the polyp (iii) TSA-type cytology and slit-like serrations in <10% of the polyp

Bettington et al. Serrated tubulovillous adenoma of the large intestine. Histopathology 2016, 68, 578–587 54 LECTURE OUTLINEE 55

Types of serrated polyps

Serrated lesions Post- of colon vs polypectomy appendix surveillance

Serrated Serrated polyps polyposis in IBD update 1. NO ROBUST GUIDELINES, EXPERT RECOMMENDATIONS. 56 2. YOUR CLINICIANS MAY BE USING DIFFERENT GUIDELINES. 3. OTHER GUIDELINES: MULTI-SOCIETY TASK FORCE ON CRC: LOCATION NOT INCLUDED. ALL HP 10 Y

Surveillance intervals after endoscopic resection of serrated lesions International Serrated Consensus Panel Number Histology Size Location Interval in years Any number HP <10mm Rectosig 10 years moid ≤3 HP ≤5 MM Proximal 10 years to sigmoid ≥4 HP Any size Proximal 5 years to sigmoid ≥1 HP >5 MM Proximal 5 years to sigmoid Surveillance intervals after endoscopic resection of serrated lesions International Serrated Consensus Panel 57

Number Histology Size Location Interval in years <3 SSL or TSA <10 MM Any 5 years 1 SSL or TSA ≥10 MM Any 3 years * ≥3 SSL or TSA <10 MM Any 3 years ≥2 SSL ≥10 MM Any 1-3 years Any SSL with Any Any 1-3 years dysplasia

• Hyperplastic polyps >10mm proximal to sigmoid are clinically managed as SSA/P (3 years)

- NO SPECIFIC GUIDELINES FOR ADVANCED TSA (TSA WITH HGD) OR SERRATED ADENOMA UNCLASSIFIED. - NO SPECIFIC GUIDELINES FOR SYNCRONOUS ADENOMAS WITH SERRATED POLYPS. OUTLINEE 58

Types of serrated polyps

Serrated lesions Post- of colon vs polypectomy appendix surveillance

Serrated Serrated polyposis update polyps in IBD UNIFOCAL MULTIFOCAL (≥2) Reviewed by 3 INDEX SYNCHRONOUS SYNCHRONOUS GI pathologists POLYP 59 1 TSA VISIBLE DYSPLASIA VISIBLE DYSPLASIA

97 HP 25.8% 12% 134 IBD PATIENTS: 147 SERRATED 25 SSP 36.0% 44.5% POLYPS AT INDEX COLONOSCOPY 12 SPU 25.0% 66.7%

SYNCHRONOUS RISK: INDEX SSP AND SPU HAD A HEIGHTENED RISK OF SYNCHRONOUS MULTIFOCAL VISIBLE DYSPLASIA (<1 YEAR OF INDEX COLONOSCOPY) METACHRONOUS RISK: - 61% OF IBD PTS WITH INDEX SSP (6 YEARS FOLLOW-UP) DEVELOPED METACHRONOUS VISIBLE DYSPLASIA OR ADDITIONAL SSPs. - LARGER BASELINE SSP INCREASE RISK OF METACHRONOUS VISIBLE DYSPLASIA (10% INCREASE FOR EVERY 1 MM INCREASE IN SIZE). CONTROL GROUP RISK OF METACHRONOUS SSP OR VISIBLE DYSPLASIA COMPARED TO CONTROL 139 NON-IBD GROUP: TREND BUT NOT STATISTICALLY SIGNIFICANT: Difference in early risk of metachronous (after 1 year of IC) visible adenomatous dysplasia with cumulative rates at 3 years: 30.8% IBD vs 6.1% (non IBD)(p=0.078)

Jackson WE et al. The significance of sessile serrated polyps in inflammatory bowel disease. Inflamm Bowel Dis 2016;22:2213-2220 HOW WE SIGN OUT THESE CASES 60

Comment: A study by Shen et al., suggested that regardless of the histologic type of serrated polyp, the incidence of development of a significant neoplastic lesion that would warrant colectomy (flat dysplasia or adenocarcinoma) was extremely low in IBD patients. However, another study by Jackson et al., suggested that IBD patients with an index SSA/P or other serrated lesions may have a heightened risk of synchronous multifocal visible dysplasia and early metachronous visible dysplasia. Overall, further larger studies may be required to determine if IBD patients with SSA/P or other serrated lesions require increased surveillance, more than what is currently recommended for non-IBD patients with sporadic serrated polyps.

References: Shen J et al. Clinical, pathologic, and outcome study of hyperplastic and sessile serrated polyps in inflammatory bowel disease. Hum Pathol. 2015 Oct;46(10):1548-56. Jackson WE. Et al. The Significance of Sessile Serrated Polyps in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016 Sep;22(9):2213-20 LECTURE OUTLINEE 61

Types of serrated polyps

Serrated lesions Post- of colon vs polypectomy appendix surveillance

Serrated Serrated polyps polyposis in IBD update Serrated polyposis syndrome 62

5th edition WHO At least 5 serrated polyps proximal to the rectum all ≥ 5 mm, Criterion 1 with at least 2 ≥ 10 mm. (25% pts)

More than 20 serrated polyps of any size but distributed Criterion 2 throughout the large bowel, with at least 5 proximal to the (45% pts) rectum.

WHO 4th edition: Criterion B omitted At least 1 serrated polyp in a first degree relative of pts with SPS

Omitted due to the unknown genetic inheritance Serrated polyposis syndrome Serrated polyposis syndrome 63

• M=F 5-6th decade. No extracolonic manifestations. • Unknown etiology (RNF43 mut in 3%). • Any serrated polyp subtype counts. • Polyp count cumulative over multiple colonoscopies. • Relatively frequent: 1:238 screening colonoscopies. • Up to 29 % of pts develop CRC. Around half in rectosigmoid. • 1/3 of patients have at least 1 first degree relative with CRC. • Half of CRC may arise through adenoma-carcinoma sequence.

Vemulapalli KC, Rex DK. Gastrointest Endosc. 2012 Jun;75(6):1206-10 IJspeert JEG, et al. Gut 2017;66:1225–1232. LECTURE OUTLINEE 64

Types of serrated polyps

Serrated Post- lesions of polypectomy appendix surveillance

Serrated Serrated polyposis polyps in IBD update 65 Prominent sawtooth luminal infolding Undulating epithelial growth

3 non-mucinous adenoca

Pai RK et al. Serrated lesions of the appendix frequently harbor KRAS mutations and not BRAF mutations indicating a distinctly different serrated neoplastic pathway in the appendix. TSA Human Pathology. 2014 Feb;45(2):227-35 66

Serrated Serrated nondysplastic nondysplastic

2/6 (33%) 11/19 (58%) Resembling colorectal HP KRAS Resembling colorectal SSL mutation

Serrated Serrated dysplastic dysplastic

4/7(57%) Resembling colorectal SSLD BRAF V600E mutations identified in only 5 (4%) appendiceal lesions: 1 HP, 1 SSA/P, 2 SSA/P with dysplasia, 1 non-serrated dysplastic lesion. 4th edition WHO: HP, SSA/P and TSA. SERRATED LESIONS OF THE APPENDIX 67 5th edition WHO Polyp type Architecture Hyperplastic polyp Discrete polyp or circumferential mucosal involvement; villous growth uncommon

Sessile serrated lesion without Often with circumferential mucosal dysplasia involvement; villous growth uncommon

Sessile serrated lesion with dysplasia Often with circumferential mucosal - Low-grade involvement; villous growth variable - High-grade

NO NEED TO SUBTYPE DYSPLASIA: Conventional adenomatous dysplasia, TSA-like and serrated dysplasia. SUMMARY 68 ➢SSL quadruple threat precursors for interval CRC: (not seen by endoscopist/pathologist, incompletely resected, inadequate surveillance, rapid progression) ➢Recognize morphologic heterogeneity of dysplasia in SSLD. MLH1 loss in approx. 75%. ➢SSL in IBD may be a marker for higher risk of synchronous visible neoplasia. ➢Serrated pathway -genetic and epigenetic events: BRAF or KRAS, variable CIMP leading to MSI CRC (immune checkpoint inhibitors) or MSS CRC. ➢Serrated lesions of the appendix frequently harbour KRAS mutations. ➢SPS is under-recognized. Stay vigilant. THANK YOU