SERRATED LESIONS OF COLON AND RECTUM

PRESENTER- Dr. Snehal Kosale (Junior Resident)

Contents

Normal anatomy and histology of colon and rectum

Precancerous lesions Adenomas-

Clinical features,

Colonoscopy findings,

Histopathology

Adenoma Carcinoma sequence Classic

Serrated neoplastic pathways

Serrated polyps Classification

Types

Description

Clinical implications

ANATOMY

ANATOMY

The large bowel comprises the terminal 1–1.5 m of thegastrointestinal tract and is divided into the following regions: Cecum,

Ascending (right) colon,

Transverse colon,

Descending (left) colon,

Sigmoid colon, and

Rectum

The rectum forms the distal 8–15 cm Extraperitoneal

Lies within the pelvis

Ends at the anal canal

Histology

The large bowel wall is composed of four layers: Mucosa,

Submucosa,

Muscularis propria, and

Serosa (or, in the rectum, perimuscular tissues).

The mucosa has three components: Epithelium,

Lamina propria, and

Muscularis mucosae.

The mucosal surface is covered by a single layer of cuboidal to low columnar epithelium.

HISTOLOGY OF COLONIC MUCOSA

The mucosa consists of cells of two types: absorptive cells and mucus

secreting goblet cells arranged in closely packed straight tubular glands

or crypts, which extend down to sit on to the muscularis mucosae.

PRECANCEROUS LESIONS

BACKGROUND

Colon polyps

A polyp is any lesion that is elevated above themucosal surface of the bowel.

Polyps are most common in the colon But may occur in

Esophagus,

Stomach, or

Small intestine.

Polyps without stalks are referred to as sessile whilethose with stalks are termed pedunculated. Proliferation of cells adjacent to the polyp and the effects of

traction on the luminal protrusion, may combine to create astalk.

Colon polyps

In general, intestinal polyps can be classified

Nonneoplastic

Neoplastic.

Non-neoplastic colonic polyps can be further classifiedas

Inflammatory,

Hamartomatous, or

Hyperplastic.

The most common neoplastic polyp is the adenoma

Potential to progress to carcinoma

Adenomas

The most common and clinically important

neoplastic polyps are colonic adenomas

Majority of colorectal adenocarcinomas arise

from adenomas.

Colorectal adenomas are characterized by the

presence of epithelial dysplasia

Adenomas- Colonoscopy

Typical adenomas range from 0.3 to 10 cm in diameter

having a texture resembling velvet or a raspberry, due to

the abnormal epithelial growth pattern.

Adenomas- Histopathology

The hallmark of epithelial dysplasia is

Nuclear Hyperchromasia,

Nuclear Stratification

Nuclear Elongation.

Adenomas- Histopathology

Adenomas can be classified as (on the basis of

their architecture)

Tubular,

Tubulovillous, or

Villous

Villous adenomas have more malignant potential than

the other types.

Adenomas- Histopathology

Tubular adenoma

Closely packed tubular

crypts

<20% villous component

Tubulo-villous adenoma

Both tubular and villous

components

Villous component 20-80%

Hiromi Shinya., William 1. Wolff, Morphology, Anatomic Distribution and Cancer Potential of Colonic Polyps. ANNALS OF SURGERY 1979; Vol 190:6

Adenomas - Screening

As precursors to colorectal cancer (CRC),

All adults should undergo screening colonoscopystarting at age 50 years

Persons with a family history increased risk forCRC earlier in life

If family history is present, then screeningcolonoscopy should be started at least 10 yearsbefore the youngest age at which a relative wasdiagnosed.

Vinay Kumar, Abul K. Abbas, Jon C. Aster. Oral cavity and Gastrointestinal tract, 9 ed. Canada: Elsevier; 2013.

1. CLASSIC PATHWAY

2. MICROSATELLITE INSTABILITY

3. SERRATED NEOPLASTIC PATHWAY

ADENOMA CARCINOMA

SEQUENCE

Adenoma Carcinoma

Sequence - Classic

The classic adenoma-carcinoma sequence,

Accounts for as much as 80% of sporadic colon

tumors

Involves mutation of the APC tumor

suppressor on chromosome 5q early in the

neoplastic process.

For adenoma to develop,

Both copies of the APC gene must be functionally

inactivated.

Adenoma Carcinoma Sequence -

Classic

APC is a key negative regulator of β-catenin, acomponent of the WNT signaling pathway.

β-catenin accumulates and translocates to thenucleus, where it activates the transcription ofgenes which promote proliferation.

This is followed by additional mutations, includingactivating mutations in KRAS, SMAD2, andSMAD4, and the tumor suppressor gene TP53which also promote growth and prevent apoptosis.

Microsatellite Instability

Pathway Occurs in patients with DNA mismatch repair

deficiency.

Mutations in microsatellite sequences incoding/promoter regions Type II TGF-β receptor- uncontrolled cell proliferation

(inhibits epithelial proliferation)

Pro-apoptotic protein BAX- inhibits survival.

Mutations in the oncogene BRAF along withhypermethylation of CpG islands within genepromoters- CpG island methylator phenotype(CIMP) also occur.

Microsatellite Instability

Pathway

Thus, signature of this pathway of

carcinogenesis is the combination of

Microsatellite instability,

BRAF mutation, and

Methylation of specific targets (MLH1)

The pathways for left sided and right sided colon differ and are

now cumulatively called

‘THE SERRATED NEOPLASTIC PATHWAY’

Left colon

Traditional SNP

Distal Hyperplastic Polyps

Traditional serrated adenoma

Silencing of tumor suppressor genes MSS (CIMP-L)

Serrated adenocarcinoma

The Serrated Neoplastic

Pathway

Right colon

Sessile SNP

Proximal HyperplasticPolyps

Sessile serrated Lesion leading to Serrated

Adenoma

MLH1 hypermethylationMSI (CIMP-H)

Serrated adenocarcinoma

K-ras mutation BRAF mutation

SERRATED POLYPS

Serrated Polyps

Serrated polyp is a general term for any polyp

that shows a serrated (sawtooth or stellate)

architecture of the epithelial compartment.

It is a heterogeneous group of lesions that

mainly include

Hyperplastic polyp,

Sessile serrated lesions

Traditional serrated adenoma

Serrated Polyps -Why so

important?

High frequency in proximal colon:

Missed in colonoscopy

Flat/SessileMorphology:

Easily Overlooked

Ill-defined Borders:

Incomplete Resection

Putative rapidgrowth of MSI

cancers

Aggressive biological behavior

and poorer outcomes of BRAF, MSS

cancer

SERRATED LESIONS

WHO Classification of Serrated

Lesions (2010)

Hyperplastic polyp (HP) Microvesicular HP (MVHP)

Goblet cell rich HP (GCHP)

Mucin poor HP (MPHP)

Sessile serrated adenoma/polyp (SSA/P) SSA/P with atypia

Adenomatous

Serrated

SSA/P without atypia

Traditional serrated adenoma (TSA)

Snover D et al. WHO classification of tumours. Pathology and genetics. Tumours of the digestive system. 4th edition. Berlin: Springer-Verlag. 2010.

HYPERPLASTIC POLYPS

(HP)

Hyperplastic Polyps-

Introduction Formerly called

metaplastic polyps

More common on leftside of colon and inmales

Characteristics Small <10mm

Sessile

K-ras mutation morecommon

Otori K, Yoda Y, Sugiyama K et al. High frequency of K-ras mutations in human colorectal hyperplastic polyps. Gut 1997; 40:6660-663

Hyperplastic Polyps-

Progression

Inhibition of Apoptosis

Epithelial Cell Accumulation

Luminal Inbudding

Serrated or saw tooth

Appearance

NO genuine nuclear dysplasia. Only minor nuclear enlargement with reactive

changes

Immunohistochemistry

Immunohistochemistry shows regularly

expanded proliferative and luminal

compartments with Ki67 observed in the crypt

bases

Hyperplastic Polyps-

Subtypes Microvesicular Hyperplastic Polyp (MVHP)

Have microvesicular mucin

Goblet Cell rich Hyperplastic Polyp (GCHP) Mostly have goblet cells and less serrations

Small in size

Mucin poor hyperplastic polyp

Although pathological and molecular differences, NO clinical implication.

Microvesicular HP

Mostly right colon

Cells havemicrovesicular mucindroplets that impart ahazy, basophilicquality to thecytoplasm

Minimal nuclearatypia and mildnuclear stratificationoccurs in crypts andsurface

H/E stained sections showing hypermucinous

surface cells with few goblet cells and papillary

tufting

Hamilton S, Aoltonen L. Pathology and genetics of tumours of the digestive system (WHO classification of tumours). Internayional agency for research on

cancer, 2000:314

HYPERPLASTIC POLYP –MICROVESICULAR SUBTYPE

Serration and goblet cells are generally limited to the

superficial half of the crypt

Goblet Cell Rich HP

Found in the left colon

Crowded crypts containing a

disproportionately high number of mature

goblet cells

Minimal serrations

Hamilton S, Aoltonen L. Pathology and genetics of tumours of the digestive system (WHO classification of tumours). Internayional agency for research on

cancer, 2000:314

HYPERPLASTIC POLYP –GOBLET CELL RICH SUBTYPE

Mucin Poor HP

Rare Hyperplastic polyp

Show a relative lack of gobletcells and microvesicularmucin

Epithelial cells are smallerwith less cytoplasm

Uniform and prominentserrations with amicropapillary pattern may beseen

Nuclear hyperchromasia andanisocytosis may beprominent

Hyperplastic Polyposis

Syndrome (HPS)

Familial clustering of multiple/ large (>3 cm) hyperplastic polyps

Predominantly distal location in colon

Usually asymptomatic

Associated with an increased risk (approx. 25%) of CRC with MSI.

Williams GT et al. Metaplastic polyps and polyposis of the colorectum. Histopathology 1980;40:155-170.

Legett BA et al, Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol 2001;25:177-184.

Definition of HPS

Greater than five hyperplastic polyps proximal to the sigmoid of which two are >10 mm.

Greater than 30 hyperplastic polyps of anysize, proximal to the sigmoid colon.

Any number of hyperplastic polyps with a firstdegree relative with known HPS.

SESSILE SERRATED LESIONS

(SSL)

Sessile Serrated Lesions

(SSL) According to European

guidelines of 2011, SSL

More common in the rightside of colon and infemales

Endoscopically- Large

Sessile

Yellow in color

May have a mucus capwhich when present maybe missed

Quirke P et al. Quality assurance in pathology in colorectal cancer screening and diagnosis-European recommendations. Virchow Arch 2011;

4581:1-19

SSL - Progression

Inhibition of Apoptosis

Epithelial Cell Accumulation

Luminal Inbudding

Serrated or saw tooth

Appearance

SSL without atypia

Distorted architecture due to altered proliferative zone

Proliferative zone oftendisplaced from base toside

Crypts may herniatethrough muscularismucosae k/a invertedgrowth pattern

Pronounced serrationreaching upto the bases

SSL without atypia

Crypts are dilated

and branched with L

or inverted T shaped

Crypts are irregular,

branched

Dilatation of crypt

bases

SSL with atypia-

adenomatous More commonly found in the

cecum and ascending colon

Similar to conventional adenomatous polyps

An abrupt transition to dysplastic crypts resembling adenomatous crypts

Showing relatively small rounded and fairly uniform nuclei

Suggestion of residual serration

SSL with atypia- serrated

Glands retain a

serrated architecture

Have ample

eosinophilic

cytoplasm

Nuclei are typically

Vesicular

Basally located

Criteria For

Serrated Lesions

Serrated appearance at the base of the crypts

Horizontalisationof crypts with

branching

Dilatation of the crypts

Increase in epithelium-stroma ratio

> 50%

Mitoses on the surface of the crypts

Cellular atypia: Enlarged nucleus, overproduction of

mucin

2 of 6 criteria must be present for diagnosing sessile serrated

lesions

TRADITIONAL SERRATED

ADENOMAS

Traditional Serrated Adenoma-

TSA

Rare subtype (<6% of serrated polyps)

Occur in older adults particularly females

Located in the left colon

Endosopically-

Polypoidal lesions: Reddish discoloration and granulo-lobular appearance

Sessile lesions: Larger, proximally located, white mucosa

Torkalovic EE, Gomez DK et al. Sessile serrated adenoma (SSA) vs traidtional serrated adenoma (TSA). Am JSUrg Pathol 2008; 32:21-29

Traditional Serrated Adenoma-

Progression

Fully developed TSA with multiple

ectopic crypts lining villi.

Early TSA- an outward

growth creates ectopic

growth

Traditional Serrated Adenoma-

TSA

Prominent serration

Diffuse low grade dysplasia

(10% high grade dysplasia)

Luminal infoldings

perpendicular to the main

axis of the crypts called

‘ectopic crypt foci’

Traditional Serrated Adenoma-

TSA

Abundant eosinophilic cytoplasm

Centrally placed, pencillate nuclei

Nuclearstratification

Nuclear hyperchromasia

Features of Serrated Adenomas

WHO

Classification

Prevalence Shape Distribution Malignant

Potential

Hyperplastic polyp Very

common

Sessile/ flat Mostly distal Very low

Sessile serrated

adenoma/polyp

Common Sessile/ flat 80% proximal Significant

Traditional serrated

adenoma

Rare Sessile/

Pedunculated

Mostly distal Significant

SERRATED

ADENOCARCINOMA

Serrated Adenocarcinoma

End point of the serrated pathway

Reported to account for 7.5% of all colorectal carcinomas

More common in right colon

Left sided occur from microsatellite stable (MSS) or show low microsatellite instability (MSI) and arise from TSA

Right sided occur from high frequency of microsatellite instability (MSI) and arise from SSL

SERRATED ADENOCARCINOMA

Serrated Adenocarcinoma

Cells are cuboidal to

short columnar

Moderate

eosinophilic

cytoplasm

Very large nuclei

Open chromatin

Prominent nucleoli.

CLINICAL IMPLICATIONS

Clinical Implications

Irrespective of size SSLs may progress

rapidly to MSI carcinomas

Polyp size >2 cmThorough examination of

resection margins

Polyp morphology-

Serrated Polyps

Comment on margins as free/involved

Clinical Implications

Distal serrated adenocarcinomas have a

worse prognosis compared with non-serrated

and proximal cancers.

Therefore, important to distinguish SSLs and

TSAs

Associated malignancies may have a different

prognosis and treatment.

Mäkinen MJ. Colorectal serrated adenocarcinoma. Histopathology 50, 131–150 (2007)

Laiho P, Kokko A, Vanharanta S et al. Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis. Oncogene 26, 312–

320 (2007).

Garcia-Solano J, Perez-Guillermo M, Conesa-Zamora P et al. Clinicopathologic study of 85 colorectal serrated adenocarcinomas: further insights

into the full recognition of a new subset of colorectal carcinoma. Hum. Pathol.41, 1359–1368 (2010).

Clinical Implications

The presence of large, serrated polyps (>1

cm) are an independent risk factor for the

presence of CRC

The data by Goldstein et al suggest that

surveillance colonoscopy intervals for SSAs

should be at least as frequent as those

recommended for conventional adenomas.

Hiroaka S, Kato J, Fujiki S et al. The presence of large serrated polyps increases the risk of colorectal cancer.Gastroenterology 139,

1503–1510 (2010)

Schriener MA, Weiss DG, Lieberman DA et al. Proximal and large hyperplastic and nondysplastic serrated polyps detected by

colonoscopy are associated with neoplasia. Gastroenterology 139, 1497–1502 (2010).

Guidelines for endoscopic

surveillanceSerrated Lesion Lesion Size Recommended

Surveillance

(years)

Hyperplastic Polyp <10 mm 10

Sessile Serrated Lesion <10 mm 5

Sessile Serrated Lesion >10 mm 3

Mixed Hyperplastic/

Adenomatous Polyp

Mixed serrated/ adenoma

Any size 1

Traditional Serrated Adenoma Any size 1

Hyperplastic/ Serrated Polyposis Any size 1

References

Snover D et al. WHO classification of tumours. Pathology and genetics. Tumours of the digestive system. 4th edition. Berlin: Springer-Verlag. 2010.

Vinay Kumar, Abul K. Abbas, Jon C. Aster. Oral cavity and Gastrointestinal tract, 9 ed. Canada: Elsevier; 2013.

Hiromi Shinya., William 1. Wolff, Morphology, Anatomic Distribution and Cancer Potential of Colonic Polyps. ANNALS OF SURGERY 1979; Vol 190:6

Hamilton S, Aoltonen L. Pathology and genetics of tumours of the digestive system (WHO classification of tumours). Internayional agency for research on cancer, 2000:314

Hamilton S, Aoltonen L. Pathology and genetics of tumours of the digestive system (WHO classification of tumours). Internayional agency for research on cancer, 2000:314

Torkalovic EE, Gomez DK et al. Sessile serrated adenoma (SSA) vs traidtional serrated adenoma (TSA). Am JSUrg Pathol 2008; 32:21-29

Torkalovic EE, Gomez DK et al. Sessile serrated adenoma (SSA) vs traidtional serrated adenoma (TSA). Am JSUrg Pathol 2008; 32:21-29

Mäkinen MJ. Colorectal serrated adenocarcinoma. Histopathology 50, 131–150 (2007)

Laiho P, Kokko A, Vanharanta S et al. Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis. Oncogene 26, 312–320 (2007).

Garcia-Solano J, Perez-Guillermo M, Conesa-Zamora P et al. Clinicopathologic study of 85 colorectal serrated adenocarcinomas: further insights into the full recognition of a new subset of colorectal carcinoma. Hum. Pathol.41, 1359–1368 (2010).

Hiroaka S, Kato J, Fujiki S et al. The presence of large serrated polyps increases the risk of colorectal cancer.Gastroenterology 139, 1503–1510 (2010)

Schriener MA, Weiss DG, Lieberman DA et al. Proximal and large hyperplastic and nondysplasticserrated polyps detected by colonoscopy are associated with neoplasia. Gastroenterology 139, 1497–1502 (2010).

Torlakovic E, Snover DC. Serrated adenomatous polyposis in humans. Gastroenterology 110, 748–755 (1996)