Precursors of Colorectal Carcinoma Arzu Ensari, MD, PhD Department of Pathology Ankara University Medical School
Hyperplastic polyp Adenomatous polyp
Colorectal carcinoma IBD-associated (1-2%) Sporadic (80%) Hereditary (20%) Adenoma-carcinoma 70-80% CIN Serrated neoplasia 20-30% MSI/ CIMP APC 10-80 % MSI 2-14 % FAP APC Wnt Lynch syndrome MMR MSI MAP MYH Peutz Jeghers syndrome STK11/LKB1 Juvenile polyposis syndrome SMAD4/MADH4/ BMPR1A
Colorectal carcinoma Sporadic Adenoma-carcinoma Serrated neoplasia IBD-associated IEN Flat/polypoid FAP Hereditary Lynch syndrome Adenoma Serrated polyp Adenoma Adenoma MAP Adenoma Peutz Jeghers syndrome PJ polyp Juvenile polyposis syndrome Juvenile polyp
Molecular classification of CRC
Precursor lesions Non-polypoid lesions ACF (hyperplastic/dysplastic) Flat adenoma IBD-associated IEN (flat) 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) Geboeset 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/ β-catenin KRAS TP53 18q LOH TGFβ CIMP- MSS 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 TA TVA VA
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 neoplasia Category 3 (LG dysplasia LG adenoma) LG IEN 3. High grade neoplasia Category 4.1-4.4 HG dysplasia/ HG adenoma Non-invasive carcinoma (in situ ca) Suspicious for invasive carcinoma Intramucosal carcinoma (invasion of LP) HG IEN ptis 4. Carcinoma 4a. Carcinoma confined to submucosa Category 5 Submucosal invasion (invasion through MM into submucosa) Invasive carcinoma pt1 4b. Carcinoma beyond submucosa Category 5 Invasive carcinoma pt2-t4
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
Depth of invasion Haggitt levels pedunculated Kikuchi levels sessile Ueno: Depth 1-2mm/ width 4-5mm Margin Clearance <1mm is (+) Tumour stroma Lymphoid vs nonlymphoid Tumour grade HG in 5-10% Common in sessile polyps HG 50% LN met. Tumour budding Single cells or clusters <4 cells at invasion front X20 objective (0.785mm 2 ) Tumour budding score LVI D2-40, CD31, EVG Poor reproducibility LVI 31%LN met.
Haggitt levels pt1 CA in adenoma Depth of sm: 9mm Width: 6mm Haggitt 2 Grade 2 Cribriform pattern Lymphatic invasion No lymphoid infilt. Margin free Excision complete Egashira, 2004 LN metastasis +
Kikuchi levels 1-3% 10% 25% pt1 CA in adenoma Depth: 1.38mm Width: 3.5mm Haggitt 4 (sessile) Kikuchi sm3 Grade 1 No LV invasion Lymphoid infilt. + Margin free Excision complete LN metastasis - Egashira 2004
Serrated neoplasia sequence (MSI/CIMP pathway) KRAS/ BRAF promoter methylation hmlh1 MGMT MSI mutations MSI-H/CIMP-H MSI-L MSS Inhibition of apoptosis Jass, 2000
Classification of serrated polyps HP SSA/P TSA 75% of serrated polyps Flat & distal KRAS distal/goblet cell BRAF prox/ microvesic. 25% of serrated polyps Flat & proximal BRAF / MLH-1 methylation <1% of serrated polyps Pedunculated/flat Distal KRAS/BRAF mutation
Resemblance to normal colon HP Dilatation in upper half 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 branching Serration at basal crypts SSA/P Dilatation at basal crypts «Funny» crypts Inverted crypts
Complex crypt architecture TSA Ectopic crypts Exaggerated serration Cytoplasmic eosinophilia 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 forms? SSA/P / TSA? Localization and size! Dx: Serrated polyp «unclassified»
"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 AdenocarcinomaArising from Traditional Serrated Adenoma in the Duodenum YoonKyooPark WooJinJeongGabJinCheon CaseRepGastroenterol2016;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 1:7000-30000 1:5000-10000 1:370 1:25000-300000 1:100000 1: 1000-5000 Polyp type Adenoma >100 Adenoma 10-100 HP, SP Adenoma <10 Peutz jeghers polyp Juvenile polyp Serrated polyp (HP, SSA/P, TSA) Genetic abnormality Germline APC mutations Mutations in MUTYH gene Germline mutations in MMR genes STK11/LKB1 SMAD4/ MADH4/ BMPR1A Germline mutations in senescence genes? Risk 100% 40-100% 70-80% 20-40% 20-70% 25-50% Extra-GI features Osteomas, desmoids, gliomas Extra GI cancers Endometrial cancer Pigmentation malformations -
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