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

Sporadic (80%) Hereditary (20%) FAP Lynch syndrome

MAP

Adenoma-carcinoma 70-80% Serrated neoplasia 20-30% APC Wnt MYH MMR MSI CIN MSI/ CIMP

Peutz Jeghers syndrome

STK11/LKB1

Juvenile polyposis syndrome

IBD-associated (1-2%)

APC 10-80 % MSI 2-14 % SMAD4/MADH4/ SMAD4/MADH4/ BMPR1A

Colorectal carcinoma

Sporadic Hereditary FAP Lynch syndrome

MAP

Adenoma-carcinoma Serrated neoplasia Adenoma Adenoma Adenoma Adenoma Serrated polyp PJ polyp

Juvenile polyposis syndrome

IBD-associated

IEN Flat/polypoid Juvenile polyp

Peutz Jeghers syndrome

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)

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/ 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

TA TVA VA

HG adenoma in 1% of TA HG adenoma in 14% TVA or VA

Lash, 2010

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

Depth of invasion

Haggitt levels – pedunculated Kikuchi levels – sessile Ueno: Depth 1-2mm/ width 4-5mm

Tumour grade

HG in 5-10% Common in sessile polyps HG – 50% LN met.

Tumour grade

HG in 5-10% Common in sessile polyps HG – 50% LN met.

LVI

D2-40, CD31, EVG Poor reproducibility LVI – 31%LN met.

LVI

D2-40, CD31, EVG Poor reproducibility LVI – 31%LN met.

Tumour budding

Single cells or clusters <4 cells at invasion front X20 objective (0.785mm2) Tumour budding score

Tumour budding

Single cells or clusters <4 cells at invasion front X20 objective (0.785mm2) Tumour budding score

Margin

Clearance <1mm is (+)

Margin

Clearance <1mm is (+)

Tumour stroma

Lymphoid vs nonlymphoid

Tumour stroma

Lymphoid vs nonlymphoid

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

Egashira 2004

LN metastasis -

Serrated neoplasia sequence (MSI/CIMP pathway)

KRAS/ BRAF promoter methylation hMLH1 MGMT → → → mutations MSI-H/CIMP-H MSI-L MSS Inhibition of apoptosis Jass, 2000 MSI

Classification of serrated polyps

SSA/P HP TSA

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

HP

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

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?

Microvesicular (MVHP)

• Commonest HP
• Entire colon
• “Serration” prominent
• Microvacuolation
• Precursor of SSA/P ?
• BRAF mutation

Serration at basal crypts Dilatation at basal crypts Deep crypt branching

SSA/P

Inverted crypts «Funny» crypts

TSA

Complex crypt architecture Ectopic crypts Cytoplasmic eosinophilia Midphasic nuclei Exaggerated serration

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

• Histopathology. 66, 308-313, 2016

Pattern of luminal serration: slit-like Ectopic crypts Cytoplasmic eosinophilia

Dysplasia in serrated polyps

• LG and HG dysplasia can
• ccur
• Two types of dysplasia:
• Adenomatous dysplasia
• Serrated dysplasia

(Goldstein, 2008)

• enlarged round nuclei
• irregular nuclear

membrane

• prominent nucleoli
• coarse chromatin

Localization and size! Dx: Serrated polyp – «unclassified»

HP / SSA/P? SSA/P / TSA?

Transitional forms?

TSA TSA LG dysplasia TSA HG dysplasia

"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

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

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- 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

Thank you..