Precursors of Colorectal Carcinoma Precursors of Colorectal - PowerPoint PPT Presentation

Precursors of Colorectal Carcinoma Precursors of Colorectal Carcinoma Arzu Ensari, MD, PhD Department of Pathology Ankara University Medical School

Hyperplastic polyp Hyperplastic polyp Adenomatous polyp Adenomatous polyp

Colorectal carcinoma IBD-associated (1-2%) Hereditary (20%) Sporadic (80%) APC 10-80 % MSI 2-14 % Lynch syndrome FAP Adenoma-carcinoma Serrated neoplasia 70-80% 20-30% MMR MSI/ MSI CIN APC CIMP Wnt Peutz Jeghers MAP Juvenile polyposis syndrome syndrome MYH SMAD4/MADH4/ SMAD4/MADH4/ STK11/LKB1 BMPR1A

Colorectal carcinoma IBD-associated Sporadic Hereditary IEN Flat/polypoid Lynch syndrome FAP Adenoma-carcinoma Serrated neoplasia Serrated Adenoma Adenoma polyp Adenoma MAP Peutz Jeghers Juvenile polyposis syndrome syndrome Adenoma PJ Juvenile polyp polyp

Molecular classification of CRC

Precursor lesions Non-polypoid lesions • ACF (hyperplastic/dysplastic) • “Flat” adenoma • IBD-associated IEN (f lat) Polypoid lesions • Adenomatous polyps (tubular, tubulovillous, villous) • Serrated polyps (Hyperplastic polyp, sessile serrated adenoma/polyp, traditional serrated adenoma) • IBD-associated IEN (polypoid=DALM) • Hereditary syndromes (FAP, HNPCC, PJS, Juvenile polyposis, Serrated polyposis) Geboes et al, 2005

Pathologist’s task… • Correct classification • Grading of dysplasia • Adequacy of endoscopic intervention • Risk assessment • Guidance for management and surveillance

Adenoma-carcinoma sequence (CIN pathway) APC/ TP53 KRAS → → → → → → CIMP- β -catenin 18q LOH MSS TGF β BRAF & KRAS WT Loss of inhibition of proliferation Fearon & Vogelstein, 1988

Aberrant Crypt Focus • Crypts 2-3 times larger than normal in chromoendoscopy • Microscopic types: • Hyperplastic type (serrated) • Dysplastic type (adenomatous) • Accompanies adenomas, cancer & polyposis syndromes

Classification of adenomas HG adenoma in 1% of TA HG adenoma in 14% TVA or VA Lash, 2010 TVA VA TA

Flat (superficial) adenoma • ≤ 3mm tall, ≤ 2 times as normal mucosa • Predilection to proximal colon • Flat carcinoma can arise de novo ( Wada, 1996; Hurlstone, 2003) • IIa (elevated), IIb (flat), IIc (depressed)

Risk factors in adenomas • Multiplicity (>3) • Size • <1cm size – <1% • 1-2cm – 10% • >2cm – 20-50% • Villous architecture (VA 29.8% > TA 3.9%) • HG dysplasia • Site ? Advanced adenoma: > 1cm OR > 25% villous architecture OR HG dysplasia / IEN Bertario, 2003, Mitchell, 2008

ESGE Vienna WHO TNM 1. No neoplasia Category 1 2. Low grade Category 3 (LG dysplasia LG IEN neoplasia LG adenoma) 3. High grade Category 4.1-4.4 HG IEN pTis neoplasia HG dysplasia/ HG adenoma Non-invasive carcinoma (in situ ca) Suspicious for invasive carcinoma Intramucosal carcinoma (invasion of LP) 4. Carcinoma 4a. Carcinoma Category 5 Invasive pT1 confined to Submucosal invasion (invasion through carcinoma submucosa MM into submucosa) 4b. Carcinoma Category 5 Invasive pT2-T4 beyond submucosa carcinoma

“Malignant” adenoma = pT1 CRC “adenoma in which cancer has invaded through the muscularis mucosa into the submucosa” • 2.6-10% of all polyps • 8-16% LN metastasis • High risk (35%) or low risk (7%) of LN met

Margin Margin Depth of invasion Depth of invasion Clearance <1mm is (+) Clearance <1mm is (+) Haggitt levels – pedunculated Haggitt levels – pedunculated Kikuchi levels – sessile Kikuchi levels – sessile Ueno: Depth 1-2mm/ width 4-5mm Ueno: Depth 1-2mm/ width 4-5mm Tumour grade Tumour grade LVI LVI HG in 5-10% HG in 5-10% D2-40, CD31, EVG D2-40, CD31, EVG Common in sessile polyps Common in sessile polyps Poor reproducibility Poor reproducibility HG – 50% LN met. HG – 50% LN met. LVI – 31%LN met. LVI – 31%LN met. Tumour stroma Tumour stroma Tumour budding Tumour budding Lymphoid vs nonlymphoid Lymphoid vs nonlymphoid Single cells or clusters <4 cells Single cells or clusters <4 cells at invasion front at invasion front X20 objective (0.785mm 2 ) X20 objective (0.785mm 2 ) Tumour budding score Tumour budding score

Haggitt levels • pT1 CA in adenoma • Depth of sm: 9mm • Width: 6mm • Haggitt 2 LN metastasis + • Grade 2 • Cribriform pattern • Lymphatic invasion • No lymphoid infilt. • Margin free • Excision complete Egashira, 2004

Kikuchi levels 10% 1-3% 25% • pT1 CA in adenoma • Depth: 1.38mm • Width: 3.5mm • Haggitt 4 (sessile) • Kikuchi sm3 LN metastasis - • Grade 1 • No LV invasion • Lymphoid infilt. + • Margin free • Excision complete Egashira 2004

Serrated neoplasia sequence (MSI/CIMP pathway) → → → mutations promoter methylation MSI-H/CIMP-H KRAS/ MSI hMLH1 MSI-L BRAF MGMT MSS Inhibition of apoptosis Jass, 2000

Classification of serrated polyps SSA/P HP TSA 75% of serrated polyps 75% of serrated polyps 25% of serrated polyps 25% of serrated polyps <1% of serrated polyps <1% of serrated polyps Flat & distal Flat & distal Flat & proximal Flat & proximal Pedunculated/flat Pedunculated/flat KRAS–distal/goblet cell KRAS–distal/goblet cell BRAF / MLH-1 BRAF / MLH-1 Distal Distal methylation methylation KRAS/BRAF mutation KRAS/BRAF mutation BRAF–prox/ microvesic. BRAF–prox/ microvesic.

Resemblance to normal colon Dilatation in upper half HP Narrow crypt base Serration in upper half Undifferentiated cells

Microvesicular (MVHP) • Commonest HP • Entire colon • “Serration” prominent • Microvacuolation • Precursor of SSA/P ? • BRAF mutation Goblet cell (GCHP) • Second common • Left colon • Hyperplastic goblet cells • “Serration” subtle • KRAS mutation • Precursor of TSA? Mucin-poor (MPHP) • Very rare • “Serration” prominent • Nuclear atypia present • Mutation?

Deep crypt branchin g Serration at basal crypts Dilatation at basal crypts SSA/P Inverted crypts «Funny» crypts

Complex crypt architecture Ectopic crypts TSA Cytoplasmic eosinophilia Exaggerated serration Midphasic nuclei

Morphologic variants of TSA Chetty R. J Clin Pathol 2016;69:6–11 Flat Filiform Mucin-rich/ goblet cell rich

ECF in TSAs • Kim - 79% • Wiland - 62% • Vayrynen - 100% • O’Brien - ECFs related to villous morphology rather than serrated morphology Pattern of luminal serration: slit-like Ectopic crypts Cytoplasmic eosinophilia Histopathology. 66, 308-313, 2016

Dysplasia in serrated polyps • LG and HG dysplasia can occur • Two types of dysplasia: • Adenomatous dysplasia • Serrated dysplasia (Goldstein, 2008) • enlarged round nuclei • irregular nuclear membrane • prominent nucleoli • coarse chromatin

HP / SSA/P? Transitional Localization and size! forms? Dx: Serrated polyp – «unclassified» SSA/P / TSA?

"Traditional serrated adenoma or serrated tubulovillous adenoma: Which is which?" C Cansiz Ersöz, S Yüksel, A Kirmizi, B Savas, A Ensari Virchows Archiv, Volume 469, Supplement 1, September 2016, PS-16-047, S158 TSA TSA LG dysplasia TSA HG dysplasia

CK20 CDX2 MUC5AC Muc6 Muc2 p53 Ki67 B-catenin MLH1 PMS2 p16

Other sites in GIT • TSA were reported in the oesophagus, stomach, duodenum, pancreas, and gallbladder

Slow-Growing Early Adenocarcinoma Arising from Traditional Serrated Adenoma in the Duodenum Yoon Kyoo Park Woo Jin Jeong Gab Jin Cheon Case Rep Gastroenterol 2016;10:257–263 35 gastric TSA 74.3% carcinoma

G A S T R I C T S A

ESGE, 2012

Polyposis syndromes • Rare • Otosomal dominant (except MAP) • High risk for GI and extra-intestinal cancer • Characterized by the predominant polyp • Phenotypic overlaps • Classification • polyp type, age of presentation, GI distribution, polyp number, extraintestinal findings, genetic abnormality

Colorectal polyposis syndromes FAP MAP Lynch Synd PJS JPS SPS Incidence 1:7000- 1:5000- 1:370 1:25000- 1:100000 1: 1000- 30000 10000 300000 5000 Polyp type Adenoma Adenoma Adenoma Peutz jeghers Juvenile polyp Serrated >100 10-100 <10 polyp polyp (HP, HP, SP SSA/P, TSA) Genetic Germline APC Mutations in Germline STK11/LKB1 SMAD4/ Germline abnormality mutations MUTYH gene mutations in MADH4/ mutations in MMR genes BMPR1A senescence genes? Risk 100% 40-100% 70-80% 20-40% 20-70% 25-50% Extra-GI Osteomas, Extra GI Endometrial Pigmentation malformations - features desmoids, cancers cancer gliomas

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