serrated pathway to colorectal neoplasia
TRANSCRIPT
SERRATED PATHWAY TO COLORECTAL NEOPLASIA
~Dr. Pallavi PrasadSenior Resident PathologySGPGIMS, lucknow
Various polyposis including serrated polyposis syndrome
Serrated adenocarcinomas: types, histology and clinical significance
Molecular pathways for different serrated lesions (HPP, SSA, TSA)
Guidelines for management and surveillance of serrated lesions
OUTLINE :
POLYPOSIS SYNDROMES INCLUDING
SERRATED POLYPOSIS AND
DIAGNOSTIC CRITERIA
Familial adenomatous polyposis (FAP)
• 100s-1000s of polyps throughout the bowel. • indistinguishable by either light or electron microscopic
criteria from sporadic adenomatous polyps.• ‘colonic aberrant crypts’, flat adenomas, depressed adenomas
or villous adenomas.• AD• APC gene : chromosome 5q21• germline mutation of the base-excision repair gene MUTYH.
Familial adenomatous polyposis (FAP)
• KRAS mutations -1/4th cases
• other portions of GIT : stomach, small bowel.
• Carcinomas ~ 20 years earlier than the ordinary CRCs (early
30s)
prophylactic colectomy must be performed at 20-25 years of
age
Familial adenomatous polyposis (FAP)
Other GI polyps and malignant lesions:
• Fundic gland polyps in the stomach
• Adenomatous polyps in the stomach and small bowel
• Periampullary carcinoma
• Duodenal cancer
• Congenital hypertrophy of the retinal pigmented epithelium
(CHRPE)
Juvenile polyposis
1 of these three criteria :-
multiple (3-10) juvenile polyps of the colorectum
Any no. of juvenile polyps in a person with a family H/O
juvenile polyposis
Extracolonic juvenile polyposis
• inherited inactivating mutations of SMAD4 or BMPR1A genes.
Peutz Jeghers syndromePJS type polyps Family H/O Characteristic mucocut
pigmentationSTK11 mutation
>=2 histologically confirmed
+ +
+ +
+ +
+
PTEN hamartoma tumor syndrome
• AD
• facial trichilemmomas
• acral keratoses
• oral mucosal papillomas
• colorectal polyps
• increased incidence of malignancy in various sites
• germline mutation in the PTEN gene.
MUTYH associated polyposis
• 1-10 colonic adenomas before 40 yr of age• 10s-100s of colonic adenomas and/or hyperplastic polyps• Colonic polyposis (i.e. > 100 colonic polyps) in the absence of
a germline APC mutation• Colorectal cancer with the somatic KRAS mutation• Family H/O colon cancer (with or without polyps) consistent
with autosomal recessive inheritance
• Biallelic MUTYH mutation
Lynch Syndrome
• onset of colorectal cancer at an early age (~45 yr)• proximal (right sided) colon cancer• High r/o multiple primary colorectal tumors (synchronous or
metachronous)• Specific pathological features of lynch syndrome: Poorly differentiated Mucinous Signet cell features Crohn’s like lymphocytic reaction Excess of tumor infiltrating lymphocytes
Lynch Syndrome
• Increased risk of cancer at extracolonic sites:
endometriumPancreas,
hepatobiliary tract
ovary
Brain (turcot’s syndrome)
Stomach, small bower
Upper urothelial tract
Sebaceous adenomas, Ca,
keratoacanthomas
Lynch Syndrome • hereditary non-polyposis colorectal cancer syndrome• AD• germline mutation in DNA mismatch repair gene (MSH2,
MLH1, MSH6, and PSM2) “first hit,” • Inactivation of the remaining normal allele “second hit.” • loss of mismatch repair function & accumulation of mutations
in repeated DNA sequences (microsatellites)
increased susceptibility to accumulate mutations in genes
with microsatellite regions
Process of DNA mismatch repair
Lynch Syndrome
• Two of the MMR genes, MSH3 and MSH6, themselves contain
coding microsatellites that can be mutated in MSI-high (MSI-
H) cancers : mutational targets.
• BRAF gene is almost never mutated in Lynch syndrome–
associated CRCs.
Serrated Polyposis Syndrome
= hyperplastic polyposis syndrome
• Multiple, small, sessile polyps, throughout the colorectum
• Variable in histological appearance, even within the same
patient (majority SSA/Ps and MVHPs).• M=F; 42- 66 years
• 2 clinical subtypes : • Type1 : multiple, more proximal, larger SSA/Ps (carcinoma)• Type 2: numerous small HPs, throughout the colon.
Criteria for the diagnosis of serrated polyposis (‘hyperplastic polyposis’)
At least five histologically diagnosed serrated polyps proximal
to the sigmoid colon (two are >10 mm in dia) or,
Any number of serrated polyps occurring proximal to the
sigmoid colon in an individual who has a 1st degree relative
with serrated polyposis or,
>20 hyperplastic polyps of any size but distributed throughout
the colon
Serrated Polyposis Syndrome
• Increased risk of carcinoma (x5.4)
• Screening age :
>40 yrs
10 yrs younger than the age of diagnosis of youngest relative
SERRATED PATHWAY CARCINOMAS
• The “serrated neoplastic pathway” describes the progression
of serrated polyps, including SSAs and TSAs to colorectal
cancer.
• These findings are particularly relevant to prevention of
interval cancers through colonoscopy surveillance programs
—an important issue for colonoscopists.
Proximal colon-missed by colonoscopy
Flat/sessile morphology
Ill-defined borders of SSAs
Rapid growth of MSI cancers
Interval colon cancer
(2.9-7.9%)
Serrated pathway carcinomas
• Diverse range of histological appearances, molecular profiles
and biological behaviours.
• Share serrated pathway histogenesis..
• Most arise in distal colon or rectum
• MSI-H or MSI-L
• Worse prognosis than CRC developing along the ‘adenoma
carcinoma’ pathway• Tumour budding, infiltrative growth pattern and lymphatic
invasion
Serrated pathway carcinomas
• > in women
• m/c : caecum or ascending colon > rectum
Three major histological patterns:
well to moderately differentiated adenocarcinoma with
serrated morphology
mucinous adenocarcinoma
trabecular
Serrated pathway carcinomas
Histological criteria of serrated morphology carcinomas
Epithelial serrations Eosinophilic or clear cytoplasm Abundant cytoplasm Vesicular nuclei with peripheral chromatin condensation &
single prominent nucleolus Distinct nucleoli Absence of necrosis (or <10% necrosis) Intracellular and extracellular mucin Cell balls and papillary rods*
Well-differentiated adenocarcinoma
mucinous
trabecular
BRAF mut tumours : located mainly proximally, CIMP-H and
either MSI or MSS
KRAS mut tumours : distal, CIMP-L , MSS.
• Mucus production, with high levels of expression of MUC2,
MUC5B, MUC5AC and MUC6
• poor differentiation
• tumour-infiltrating lymphocytes
• Crohn’s-like peritumoral lymphocytic response
Serrated pathway carcinomas
• The most reliable histological marker of serrated pathway
histogenesis is the finding of a contiguous residual serrated
polyp, SSA or TSA.
Serrated pathway carcinomas
MOLECULAR PATHWAYS FOR DIFFERENT SERRATED LESIONS
Genetic Alterations In Serrated Lesions And Progression To Cancer
Adenoma-carcinoma sequence
APC
KRAS
p53
SMAD4
Serrated pathways
BRAF
KRAS
h-MLH-I
p16
MGMT
• BRAF : (proto-oncogene) B-Raf (Raf kinase family of
phosphorylating enzyme) cell division and
differentiation.
• Malignant melanoma and carcinomas of the lung and
colorectum.
• > 30 mutations recognised in the BRAF gene.
• V600E mutation = most common (90% of BRAF mutations).
valine (V) to glutamate (E)
BRAF
• in cancer cells with MSI and in serrated polyps
• A single, activating, point mutation in BRAF (V600E)
KRAS
constitutive signaling of the mitogen-activated protein kinase
(MAPK) pathway
cell proliferation, survival, inhibition of apoptosis
• never in conventional adenomas and HNPCC.
• BRAF mutation correlates with CIMP.
• most SSAs (75%–83%) have a BRAF mutation + CIMP-H
• mutated very early in the serrated pathway, in 70%–76%
MVHP, pts with HPS.
• in serrated hyperplastic aberrant crypt foci - earliest
histologically evident lesions in the serrated pathway.
BRAF
• p16 : encodes cyclin-dependent kinase inhibitor 2A cell
cycle control.
• mutated in several different cancers.
• MGMT : encodes the MGMT protein (methyl guanine
methyltransferase)
hypermethylation of promoter sequence
DNA repair
• KRAS :
• KRAS protein (proto-oncogene) Ras family of proteins
signalling in normal cells.
• In carcinomas of the pancreas, lung, colorectum.
• In CRC, KRAS mutation : predictor of a poor response to EGFR
inhibitors such as cetuximab .
CIMP
Epigenetic phenomenon
Generally all MSI-H cancers CIMP high
CIMP• > a/w BRAF mutation
• >1cm polyps with high grade dysplasia
• Corelates with MSI status
• in serrated polyps from patients with HPS, supporting the
importance of CIMP in the serrated pathway.
• also in serrated polyps (proximal SSA)
• Yang et al detected CIMP, in order of increasing frequency :
MVHP (47%) < SSA (75%) < TSA (80%)
CIMP• Methylation of CIMP loci was even detected in histologically
normal colorectal mucosa of HPS patients (Worthley et al) .
• Together these data indicate that although the cellular
methylation machinery might be disrupted at early stages of
tumorigenesis, concurrent, high-level methylation of specific
CIMP loci facilitates the transition from MVHP to SSA.
MSI
• a hallmark of colorectal cancer arising in the context of
Hereditary Non Polyposis Colorectal Cancer (HNPCC) or Lynch
syndrome
loss of mismatch repair genes(MMR)
increased susceptibility to accumulate mutations in genes
with microsatellite regions
MSI • microsatellite : tract of repetitive DNA in which certain DNA
motifs (ranging in length from 2–5 base pairs) are repeated,
typically 5-50 times.
• occur at thousands of locations in the human genome.
• high mutation rate and high diversity in the population.
• in non-coding DNA : biologically silent
• In regulatory or coding DNA : phenotypic changes and diseases.
MSI• panel of 5 microsatellites sequencing [Bethesda panel] :
• two mononucleotide markers (BAT 25 and BAT 26)
• three dinucleotide microsatellites (D5S346, D2S123 and
D17S250)MSI-H (high MSI)
• >=2 unstable markers
MSI-L (low MSI)
• 1 unstable marker
MSS(Microsatellite stable)
• No unstable marker
MSI
• Presence of mutations in genes with microsatellite region =
MSI target genes.
• MSIH tumors exhibited a distinct genetic pathway of the MSS
and MSIL tumors.
• Stefanius et al : 20.6% of serrated cancers showed MSI-H.
Diagram representing the main pathways and molecularalterations of sessile serrated neoplasia, conventional adenomatouspathway, and alternative pathway.
Molecular pathways underlying various hyperplastic
polyps
EGFR
BRAF mutation occur early in the development of hyperplastic aberrant crypt foci.
BRAF corelates strongly with CIMP-H phenotype.
MVHPs and SSA/Ps have nearly overlapping molecular patterns (CIMP, KRAS, BRAF)..
Molecular pathways underlying
Sessile serrated adenomas/polyps (SSA/SSAPs)
DNA mismatch repair proteins are
intact in all cases.
Role of MGMT.
Molecular pathways underlying
traditional serrated adenomas
(TSAs)
•
GUIDELINES FOR MANAGEMENT AND SURVEILLANCE OF SERRATED
POLYPS
• low-risk adenomas (<3 tubular adenomas, < 10 mm in
diameter, low-grade dysplasia only)-surveyed at 5- to 10-year
interval
• high-risk adenomas (>=3 adenomas, size >10 mm or larger,
high-grade dysplasia, significant villous histology) are
surveyed at 3-year intervals
Arch Pathol Lab Med.2015;139:730-741. Molecular and Histologic ConsiderationsIn the Assesment of Serrated Polyps
US Multi society task force (2012)
Key messages
• ‘Serrated neoplasia’ refers to a range of colorectal lesions with
varying degrees of malignant risk, together with distinct forms
of adenocarcinoma.
• Bowel Cancer Screening Programmes have highlighted to
histopathologists the importance of recognizing and
understanding the biological significance of the spectrum of
serrated lesions.
• The optimal terminology, minimum diagnostic criteria and
most appropriate management strategies for some serrated
lesions (especially the sessile serrated lesion) are still in
evolution.
Key messages
Further reading :
• Arch Pathol Lab Med.2015;139:730-741. Molecular and
Histologic Considerations in the Assesment of Serrated Polyps.
• J Clin Pathol 2014;67:865–874. Bateman AC. Pathology of
serrated colorectal lesions.
• World J Gastroenterol 2014 March 14; 20(10): 2634-2640.
Serrated pathway in colorectal carcinogenesis.
• Histopathology 2015;66, 49–65.Colorectal serrated pathway
cancers and precursors.
• American journal of gastroenterology 2009;13 Role of
serrated pathway in colorectal cancer pathogenesis.
8(6):2088-2100.
• Journal of colon and rectal cancer 2013;1(1). Serrated lesions
of colorectum: A new pathway in colorectal carcinogenesis.
• Gastroenterology 2010;138:2088–2100. Role of the Serrated
Pathway in Colorectal Cancer Pathogenesis
• Histopathology 2013, 62, 367–386. The serrated pathway to
colorectal carcinoma: current concepts and challenges.
• American Journal of Clinical Pathology 2012,137,847-859.
Molecular Testing in Colorectal Cancer
THANK YOU