- Familial adenomatous polyposis (FAP) is characterized by hundreds to thousands of colon polyps and is caused by a germline mutation in the APC gene. Prophylactic colectomy is recommended by age 20-25 to prevent early onset colorectal cancer which can occur in the early 30s. - Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, is characterized by early onset colorectal cancer, often in the proximal colon, and increased cancer risks at extracolonic sites. It is caused by a germline mutation in a DNA mismatch repair gene. - Serrated polyposis syndrome, formerly known as hyper

1. ~Dr. Pallavi Prasad
Senior Resident Pathology
SGPGIMS, lucknow

2. 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 :

4. 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.

5. 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

6. 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)

7. 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.

8. Peutz Jeghers syndrome
PJS type polyps Family H/O Characteristic mucocut
pigmentation
STK11
mutation
>=2 histologically
confirmed
+ +
+ +
+ +
+

9. 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.

10. 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

11. 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

12. Lynch Syndrome
• Increased risk of cancer at extracolonic sites:
endometrium
Pancreas,
hepatobiliary tract
ovary
Brain (turcot’s
syndrome)
Stomach, small
bower
Upper urothelial tract
Sebaceous
adenomas, Ca,
keratoacanthomas

13. 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

14. Process of DNA mismatch repair

15. 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.

16. 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.

17. 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

18. Serrated Polyposis Syndrome
• Increased risk of carcinoma (x5.4)
• Screening age :
 >40 yrs
 10 yrs younger than the age of diagnosis of youngest relative

19. SERRATED PATHWAY
CARCINOMAS

20. • 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.

21. Proximal colon-missed by colonoscopy
Flat/sessile morphology
Ill-defined borders of SSAs
Rapid growth of MSI cancers
Poorer outcome of BRAF mutated
MSS cancers
Interval colon cancer
(2.9-7.9%)

22. Serrated pathway carcinomas
• Diverse range of histological appearances, molecular profiles
and biological behaviours.
• Share serrated pathway histogenesis..

23. • 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

24. • > 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

25. 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*

26. Well-differentiated adenocarcinoma

28. mucinous

29. trabecular

30.  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

31. • The most reliable histological marker of serrated pathway
histogenesis is the finding of a contiguous residual serrated
polyp, SSA or TSA.
Serrated pathway carcinomas

33. 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

34. • 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)

35. 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

37. • 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

39. • 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

40. • 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 .

41. CIMP
Epigenetic phenomenon
Generally all MSI-H cancers CIMP high

42. 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%)

43. 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.

44. 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

45. 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.

46. 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)
MSI-L
(low MSI)
MSS
(Microsatellite
stable)
• >=2 unstable
markers
• 1 unstable
marker
• No unstable
marker

47. 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.

48. Diagram representing the main pathways and molecular
alterations of sessile serrated neoplasia, conventional adenomatous
pathway, and alternative pathway.

49. Molecular pathways underlying various hyperplastic
polyps

50. 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)

51. DNA mismatch repair proteins are
intact in all cases.
Role of MGMT.
Molecular pathways underlying
traditional serrated adenomas
(TSAs)

53. •

55. • 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 Considerations
In the Assesment of Serrated Polyps
US Multi society task force (2012)

58. 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.

59. • 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

60. 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.

61. • 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

62. THANK YOU