Dr Vikash(Junior Resident 2nd year)

Moderator-Dr. Amrita Ghosh

Kar(Associate Prof)

Depatment of Pathology,IMS BHU

Recent advances In Colorectal

Carcinoma

Introduction

Epidemiology

Etiology

Molecular Pathogenesis

Clinical features

Diagnostic Modalities

Staging and Grading

Spread and Metastasis

Treatment

Prognosis

Introduction - Normal Colon

Mucosa is same from caecum, to rectum, folded in

non distended state but does not exhibit distinct plicae

circulares

Flat surface and nicely parallel crypts “test tubes in a

rack.”

Muscularis mucoa is prominent feature –for rhythmic

contactions

Mucosa consistst of two types of cell-Goblet cells and absorptive cells

Mucularis propia-Inner Circular and outer Longitudinal

Longitudinal layer form three separate longitudinal bands-taeniae coli

Normal constituents of the lamina propria include lymphocytes, plasma cells, and eosinophils. Parts of defense mechanism along with intraepiteliallymphocytes and lymphoid aggregates

Normal colon-contd.

Alcian blue stain goblet cell mucus a greenish-blue

colour, while the absorptive cell remain poorly

stained.Tall columnar absorptive cells – oval basal

nuclei, Goblet cell nulei are small and condensed.

Normal colon-contd.(transverse sec.) Closely packed arrangement of glands.

Lamina propia fill the space between glands and contain

collagen

Epidemiology Third most common cancer in USA after prostate

and lung.

Most curable form of carcinoma of the g.i.t tract.

Non cancerous polyp that can be overtime

become cancerous lesion.

98% of all cancers in large intestine almost

always arise in adenomatous polyp,generally

curable by resection.

Males and females are equally affected.

Mean age -62 year

Although right sided colonic cancer has been

increasing,Rectum is commonest site.

Asian Pacific journal of Cancer prevention ;

vol13,2012

Risk factors Age(Most common)

Dietary factor

High animal fat diet

Low fibre diet

Alcohol

• Inflammatory Bowel disease (UC,

Crohn’s)

• Smoking

• Pelvic irradiation

• Acromegaly

• UreteroSigmoidostomy

• Streptococcus Bovis Bacteremia

Risk factor contd. Polyps

Hereditary Factors

Familial Adenomatous

Polyposis(FAP)-germ line APC

mutation5q21-Accelerated tumor

initiation,100%risk of CRC

Hereditary non-polyposis colorectal

cancer(HNPCC)/Lynch syndrome-

AD,Germ line mutation of DNA

mismatch repair gene

Risk factor-Adenoma( Neoplastic

lesion)

Clonal lesions that shows at least low grade

dysplasia.

Cells lining the crypts and the surface-Tall and

dark (because of depleted mucin)

Nuclei- cigar-shaped and/or pseudostratified

Hyperchromatic nuclei. Overall look blue on

slide

If it will remain untreated-Adenoma ca seq-

Invasive Adenocarcinoma

Adenoma:The adenomatous epithelium is dark due

to crowded and hyperchromatic nuclei and loss of

mucinous goblet cells.

Risk factor for high grade Dysplasia and

Cancer in adenoma

Polyp Size- >1 cm in

Diameter

Histological Architecture-

Adenomatous Polyp with

>25% villous Histology is

risk

Severity of Dysplasia-

High Grade Dysplasia

No of Polyp-3 or more

Most worrisom-Villous

adenoma greater than

4cm.

Classification of Tumors of colon Non neoplastic (Benign) Polyps

Hyperplastic polyps

Hamartomatous polyps

-Juvenile polyps

-Peutz-Jeghers polyps

Inflammatory polyps

Lymphoid polyps

Neoplastic epithelial Lesions

- Adenomas

Malignant

-Adenocarcinoma

-Carcinoid tumor

-Anal zone Carcinoma

-Lymphoma

Mesnchymal tumors

GIST

Other benign lesions-Lipoma, Neuroma ,Angioma

Basic Overview of Classification Polyp- Tumerous mass, Protude in lumen,Sessile or

Pedunculated

Non-Neoplastic polyps----No malignant potential per

se

Abnormal Mucosal maturation and decrease

turn over-Hyperplastic polyp

Due to inflammation regenerating mucosa-

Inflammatory polyp/Pseudopolyp

Malformation of gland and Stroma-

Harmatomatous Polyp

Adenomatous Polyp/Adenoma- Neoplastic, Due to

proliferation and Dysplasia

Precursors of carcinoma

Hyperplastic polyp -Surface epithelium showing bland, basally

placed nuclei. The epithelial cells are an admixture of goblet cells

and columnar cells with apical microvesicular mucin vacuoles

Hyperplastic polyp:Luminal serration that is more

pronounced

in the upper portions of the crypt

Inflammatory Polyp- Benign mucosa with crypt

abscess

Hamartomatous polyp-Juvenile Polyps(50 to 100 polyps)

-Peutz-Jeghers Polyps(melanotic mucosal

lesion)

Occurs singly and no malignant potential

But, Some rare Autosomal Syndromes occurs in

Hamartomatous polyp

-Juvenile Polyposis Syndrome-SMAD4 or

BMPRA gene

-Peutz-Jeghers Syndrome-LKB1/STK11 germline

mut.

-Cowden Syndrome(acral keratoses, oral

papilloma)

-Cronkhite-Canada Syndrome(Non-hereditary)

Juvenile polyp Cystically dilated glands and an expanded lamina propria, Benign epithelium in juvenile polyps.Life time risk approaches approx 40%.

Juvenile polyp:Dilated crypts and inflamed stroma

Peutz-Jeghers polyp:Lobular pattern of colonic crypts divided by smooth muscle bundles.Life time risk for CRC approaches 40%.

Serrated polyps

Newer term

General term for any polyp that shows

serrrated(sawtooth or stellate)

architecture.

Heterogenous Group

Hyperplastic Polyp

Sessile serrated Adenoma/Polyp

Traditional serrated adenomaBelived to be precursor lesions for cancer that have CpG island

methylator phenotype(CIMP) Pathway mutation and MSI

pathway mutation

Sessile serrated

Adenoma/Polyp

Currently used interchangeably

Proximal colon & female

Histologically

Exaggerated crypt serration

Serration throughout crypt length

Hypermucinous epithelium

Crypt Dilatation, Branching

Horizantal Crypt extension

Lack dysplastic nuclear that characterize

conventional adenomas.

Relatively new entity that used to be classified

as HP in past

SSA/Ps –Precursor lesion for

CRC with MSI and prob. Also

for CpG island methylated

carcinoma.

Serrated Polyposis

New term used by WHO

Historically called Hyperplastic polyposis

Defined by

-5 serrated polyps proximal to sigmoid

colon with 2 or more polyps >1cm.

-Any number of serrated polyp proximal to

sigmoid colon who has a 1st degree relative

having serrated polyposis

->20 serrated polyps of any size

throughout colon.

Sessile serrated adenoma:Superficial resemblance to

hyperplastic polyps. Hyperserration and prominent

mucin cells at the base of the crypt,crypt dilatation.

Sessile serrated polyp/Adenoma: Basal

serration,Crypts Branching.L hape/inverted T-

shapes/anchor shapes

Traditional serrated

Adenoma(TSA)

Uncommon type of true adenoma.

Low grade nuclear dysplasia similar to that

seen for conventional

adenoma

Shows a serrated architecture similar to

that seen for HP and SSA/P.

Prominent cytoplasmic eosinophilia and a

villous growth pattern are characteristic

Traditional serrated adenoma: Luminal serration,

low

grade cytologic dysplasia and cytologic eosinophilia

Neoplastic Polyp-

Adenoma/Adenomatous polyp

Adenocarcinoma –approx 5% of all adenoma.

Also depend on size and histological type-

Invasive cancer is found in 0.5% of adenoma < 1 cm

5.0% - 1 to 1.9 cm

10% > 2 cm

Tubular- 2 to 3%

Tubulovillous-6 to 8%

Villous- 10 to 18%

Adenomatous polyp - Dysplastic changes are

sharply segregated from the normal goblet cells.

Tubular adenoma from a resection specimen. The head of the polyp is divided into lobules.

Villous adenoma. The lesion is spreading and

sessile

Tubular Adenoma:<25% villous component

Tubular adenoma.The neoplastic glands form

tubules

Tubular adenoma.The nuclei are elongated and dysplastic. Some nuclear palisading is noted. The nuclei do not reach the cell surface. The apical portion of the cell shows mucin production. These adenomatous changes are considered low-grade dysplasia.

Adenoma with high-grade dysplasia:Dysplastic nuclei

extending to the cell surface. Mitosis is also present at

the surfac

Villous adenoma: >75% villous component.

Long villi are arranged in parallel, perpendicular

to the mucosa

Villous adenoma low grade-High-power view

showing elongated nuclei with some palisading

Tubulovillous Adenoma: Admixture of villous and tubular structures.

Pitfall in assessment of

Adenomatus polyp

Adenomatous elements misplaced/herniated into

the submucosa

Secondary to traumatization(Twisting and torsion of

the stalk)

Distinguished form true invasion-

-Lobular configuration of herniated elements

-Lack of overt high grade atypia

-Inflammatory cells around entrapped elements

-Lack of desmoplastic reaction

-Presence of hemosiderin or hemorrhage

Pseudoinvasion in a tubular adenoma.Presence of hemorrhage and hemosiderin

Familial Syndromes Uncommon Autosomal dominant disorders

Importance-Propensity for malignant

transformation

Provide insight in the Molecular Pathogenesis

Peutz-Jeghers Syndrome-

Hamartomatous polyp

Juvenile Polyposis Syndrome

Cowden Syndrome

Familial Adenomatous polyp(FAP)-

Adenoma

HNPCC/Lynch syndrome-Adenoma-

Familial Adenomatous

Polyposis(FAP)

APC mutation on chromosme 5q21

Autosomal dominant disorder in which patients develop

numerous colorectal adenomas as teenagers.

At least 100 polyps are necessary for a diagnosis of classic

FAP, and as many as several thousand may be present

Adeno ca develop in 100% of untreated pt below 30 yr.

Prophylactic colectomy

Extaintestinal manifestation-congenital hypertrophy RPE

Some FAP patients without APC loss have mutations of the

base-excision repair gene MUTYH/MYH

MUTYH gene prevent mutation

following oxidative DNA damage.

Attenuated form of FAP/MUYTH

polyposis

•Delayed polyp development,

•Presence of fewer than 100 adenomas,

•Delay appearance of colon carcinoma >50

year or above

•Life time risk of cancer around 50%

FAP-Practically all of the polyps are small and

sessile

Diagnosis of FAP1.100 colorectal adenomatous

polyp

2.Germ line mutation of APC

gene

3.Family history of FAP and any

number of adenomas at a young

age

Hundreds of small polyps are present

throughout this colon with a dominant polyp

(right).

Three tubular adenomas are present in this

single microscopic field.

Familial polyposis involving the entire bowel

Other variants of FAP Gardner syndrome-

-Intestinal Adenoma

-Osteoma of mandible,skull,long bones

-Epidermal cysts

-Desmoid tumor

-Thyroid tumor

-Dental abnormalities(Supenumerary teeth,unerupted

teeth)

Turcot Syndrome-

-Intestinal adenomas

-CNS abnormality(medulloblastoma/glioblastoma)

Two third have APC mutation and rest one third have DNA

mismatch repair gene defect

HNPCC/Lynch syndrome Inherited mutations in genes that encode proteins

responsible for the detection, excision, and repair of

errors that occur during DNA replication(Mismatch

repair gene).

Life time risk of cancer-66% for men and 43% for

women

MSH2 and MLH1 (Mainly).Others mismatch repair

genes are PMS1,PMS2,MSH6

Inherit one mutated DNA repair gene and one

normal allele

Familial clustering of cancers at several sites-

colorectum,endometrium,Stomach,Ovary,Uterus,Br

ain,Small bowel,skin

Features of Colorectal carcinoma in

HNPCC(MSI-H phenotype)

Young age

Right sided location

Mucinous features

Poor differentiation

Lymphocytes infilteration

Lack of necrosis

Microsatellite instability high(MSI-H) colorectal carcinoma.

These cancers are typically right sided and large.

MSI-H cancer-Numerous tumor-infiltrating

lymphocytes (TILs)

Amsterdam Criteria II for Lynch

Syndrome

There should be at least three relatives with a Lynch

syndrome-associated cancer (colorectal cancer,

cancer of the endometrium, small bowel, ureter or

renal pelvis)

All of the following criteria should be present

1. One should be a first-degree relative of the other

two

2. At least two successive generations should be

affected

3. At least one should be diagnosed before the age

of 50 years

4. Familial adenomatous polyposis should be

excluded in colorectal cancer case(s), if any

Carcinogenesis and Molecular

Pathogenesis Two distinct genetic pathway

1.APC/β catenin pathway

Associated with WNT signaling pathway and the

chromosomal instability pathway(CIN).

2.Microsatellite instability pathway(MSI pathway)

Associated wuth defect in DNA mismatch repair gene

Overview of Molecular

Pathogenesis

Clasical adenoma-carcinoma sequence-

80% of sporadic-Typically include mutation

of APC early in neoplastic process.

In patient with DNA mismatch repair def. ,

Mutation accumulate in Microsatellites

repeats- Codition referred as –Microsatellite

instability(MSI)-MSI high or MSI-H tumors-

Mutation in TGFβ(inhibit cell prolif) and

proapop BAX

A subset of microsatellite unstable colon

cancer without mutation in DNA mismatch

repair gene-CpG island hypermeth.

Phenoty(CIMP)-MLH1 promoter region

hypermethylation and its repair fn. And

activating mutation in oncogene BRAF

A small group display increased CpG island

hypermethylation in absence of

microsatellite instability associated with

KRAS mutation

Overview Both MSI and CIN describes pathogenesis—Loss of

function of tumor suppressor gene and/or gain of

function of Oncogenes.

Last decade epigenetic instability has gained

attention.

Implicated in pathogenesis of almost one third of

colorectal cancers.

Epigenetic Modification includes—

-DNA methylation

-Histone alteration

-Chromatin remodelingBest characterized epigenetic modification is silencing of

genes (tumor suppressor and/or MMR genes) through

hypermethylation of their promotor region.

Epigenetic instability

Promoter Hypermethylation of MLH1

gene –demonstrated in majority of CRC

with a MSI phenotype.

Methylation of cytosine residue in CpG

island is a common phenomenon—

cause loss of function of tumor

suppresor gene without mutations.

CIMP pathway occurs in some MSI-H or

MSS tumor

APC/β Catenin pathway

APC Tumor suppresor gene (5q21)

Downregulate Growth promotimg Signals (β-catenin)

Component of WNT Signaling Pathway

Catenins—Proteins found in complexes with cadherin cell adhesion molecule.

β- catenin participate in the WNT signaling pathways as a growth promoting signals.

WNT signaling pathway

WNT signaling pathway

Passes signals from cell surface

receptors to the nucleus through

cytoplasm

Causes expression of target genes (

transcription regulator genes-cMYC and

Cyclins).

Major role in controlling cell

fate,adhesion and cell polarity during

embryonic development

WNT signaling is also require for self

Chromosomal instability

pathway(CIN)

Incresed rate of chromosome

missegregation in mitosis

Due to

--Gain/loss of

chromosome(Aneuploidy)

--Gross chromosomal rearrangment

Earliest event involved in CIN is APC gene

mutation(80%)

-K-RAS mutation

-p53 gene mutation

Late event – DCC (deleted in colonic

carcinoma) gene mutation

Advance event-DPC4/SMAD4 mutation

(18q21)

CIN forms the basis of

Adenoma- Carcinoma

sequence

MICROSATELLITE INSTABILITY

Pathway (MSI)

Satellite DNA?

Microsatellite DNA?

Why it is more liable to be unstable?

How this instability leads to colorectal

carcinoma?

Satellite DNA

Satellite DNA is composed of tandemly repeating DNA (non-coading regions)

Tandem repeats occur in DNA where a pattern of two or more nucleotides is repeated .

A-T-T-C-G-A-T-T-C-G-A-T-T-C-G

Microsatellite DNA

If the number of nuleotide repeat is 1-4

Dinuleotide repeat

When exactly two nuleotide are

repeated.eg-ACACACAC

Such region in DNA are commonly affected

in HNPCC.

Microsatellite are more prone to get unstable

compared to other neutral region of DNA.

This instability is due to any errors ,most likely

error is

-Slippage during DNA replication.

Such error is normally repaired by Mismatch

repair enzymes which are encoaded by

Mismatch repairs genes.

Defect in MMR gene

Reduced capacity of cells to repair

specific types of DNA damage

Increased rate of mutation

accumulation in

microsatellite DNA

Colorectal Carcinoma(CRC)

Mismatch repair genes(MMR)

MSH2(2p21)

,MSH3,MSH4,MSH5,MSH6

MLH1(3p21.3), MLH2,MLH3

PMS1,PMS2

As majority of microstaellite are

located in non-coding region, these

mutations are generally silent

Some microsatellite which are present

in the coding region of the gene are

involved in the regulation of cell

growth, like thoe encoading

Type II TGF-β receptor

Proapoptotic protein BAX

Defect in MMR gene

Mutation—HNPCC

CpG island Hypermethylation

in MMR Gene---Sporadic

Colorectal Carcinoma

CpG Island Hypermethylation

What is CpG?

Term like CpG site and Cpg Island?

What is methylation?

What is Hypermethylation?

How Hypermethylation leads to Carcinoma?

CpG Sites

Region of DNA where a cytosine occurs next

to a guanine.

DNA methylation occurs at these sites by an

enzyme –DNA methyltransferase

In Humans, 80 to 90% of all CpGs are

Methylated.

This methylation results in conversion of

cytosine to 5- Methylcytosine

The remaining 10%

nonmethylated CpGs are

grouped in a cluster forming

CpG island, and is usually

located in the promoter region

toward 5’ end.

The unique property of Cpg

island is that it is unmethylated

in germ line.

Methylation of CpG island

within the promoters of gene

Silencing of tumor suppressor

gene Colorectal cancer

Susceptible Tumor Supressor genes which

shows ‘CpG island methylator phenotype’

positivity(CIMP+) –

MLH1

p16

MGMT

IGF2

RUNX3

SOCS1

NEUROG1

Ref – Recent advances in histopathology 23rd

edition

The Bethesda Guidelines

MSI testing is recommended in people with any of

the following features-

1.Colorectal cancer diagnosed in a patient who is less than

50 years of age

2. Presence of synchronous colorectal, or other Lynch

syndrome-related tumors,regardless of age

3. Colorectal cancer with the MSI-H histology,diagnosed in

a patient who is less than 60 years of age

4. Colorectal cancer diagnosed in one or more first-degree

relatives with a Lynch syndrome-related tumor, with one of

the cancers being diagnosed under age 50 years

5. Colorectal cancer diagnosed in two or more first- or

second-degree relatives with Lynch syndrome-related

tumors,regardless of age

MSI Testing

~15% of CRCs

Detected by PCR amplification of microsatellite loci in DNA extracted from CRC specimen.

Newer tests-Nuclei acid flourescencelabelling,laser scanning,Flourscence PCR PCR amplification

To identification of risk of hereditary cancer cancer and predict the outcome of CRC.

To detect MLH1 And MSH2 germlinemutation.

Test is PCR based and done on formalin fixed paraffin-

embedded tissues.

Done by Bethesda panel

Sensitivity-55-84% Specificity-90% (PCR)

Analyzing two mononucleotide repeats(BAT-25 and BAT-

26) and three dinuleotide repeats(D2S123,D5S346 and

D17S250).

MSI-H-Two or more(>40%) of five microsatellite marker

show instability.

MSI-Low-only one marker show instability

MSS-No marker

Indirect analysis can be done by IHC stain of MMR

proteins(90%).

Does not discriminate germline from epigenetic and may

miss rare mutation.

M.Fleming et al;J gastro oncol sept 2012:3(3):153-173

MSI tumor showing loss of MLH1.Benign colonic

crypts and infl. Cells-Internal control

Same case. Loss of PMS2.Loss of MLH1 is always accompanied by loss of PMS2

Normal expression of MSH2

Normal Expression MSH6

MSI testing is done because-

Survival advantage for MSI-H Carcinoma

over MSI-Low and MSI stable cancer.

MSI-H predict poor response to fluorouracil-

based chemotherapy regimens; better

response to irinotectan based chemotherapy

regimen.

M.fleming et al ;J gastointes oncol.Sept 2012;3(3):153-173

EGFR and Colorectal cancer

EGFR protein Expression

65-70% cases of CRCs –Overexpression of EGFR

Mainly Advance stage CRC(metastatic)

Panitumumab

Clinical Features Asymptomatic for years.

Left Side colonic carcinomas

Occult bleeding

Change n bowel habit

Crampy left lower quadrant discomfort

Right sided colonic carcinomas

Fatigue

Weakness

Iron deficiency anaemia

Fe def. anaemia in an older man means git

cancer until proven otherwise

Morphology

50% Rectosigmoid area(involvment of the

proximal colon is increasing)

Right Sided tumor more common in the

Elderly

Blacks

Patient with diverticular disease

Gross A. Proximal colon

Polypoid

Bulky mass, well defined/rolled margin

and a sharp dividing line with the normal

bowel

Ulcerative

Less elevated surface and is centrally

ulcerated

These tumor rarely cause obstruction

B.Distal Colon

Annular lesion producing

“Napkin-ring” constrictions and

luminal narrowing.

These tumor can cause

obstruction.

MICROSCOPIC Adenocarcinoma

Infiltration of glands of variable differentiation lined by anaplastic

epithelial cells

Lining cells are fully stratified and have large hyperchromatic nuclei

and prominent nucleoli

Prominent mitotic activity often with atypical forms

Invasion promotes a characteristic robust desmoplastic tissue

reaction and necrosis.

---Grade I

◆ Composed predominantly of well-formed glands

in a desmoplastic stroma

— Grade II

◆ Less well-formed glands with focal cribriform

architecture

— Grade III

◆ Tumor grows in solid sheets with no distinct

gland formation

Well diferentiated->95%

gland forming

Moderately differntiated-

50-95%

Poorly differntiated-

<50%

Moderately differentiated adenocarcinoma

Complicated glandular structures in a desmoplastic

stroma

Desmoplastic reaction:Proliferation of spindle

cells surrounding an adenocarcinomatous gland

Necrotic debris (“dirty necrosis”) within the lumina

of adenocarcinomatous glands

MUCINOUS Adenocarcinoma

Accounts for about

10% of colorectal

malignancies

Production of excess

mucin with associated

malignant epithelial

glands and free-

floating,malignant cells

75% to 80% of the

tumor must be

mucinous to be linked

to a worse prognosis

High association With

MSI.

Mucinous adenocarcinoma : Abundant

extracellular mucin

Mucinous adenocarcinoma with signet-ring cells

and extracellular mucin pools.

Signet Ring Adenocarcinoma/Linitis

plastica-type carcinoma Rare

Tumor grow as diffuse

infilteration in wall

More than 50% have

intracellular mucin .

One third cases assoc.

with MSI

Worst prognosis

Metastatic-Lymph

node,Peritoneal sur.

IHC-CK7-/CK20+

Primary

Signet ring cell carcinoma:>50% of cells showing

prominent intracytoplasmic mucin vacuoles

MEDULLARY carcinoma Rare

Common in Proximal colon

Female Prdominance

Tumor cells have eosinophilic or

amphophilic cytoplasm with rounded nuclei

with prominent nucleoli

Closely packed, trabecular or solid patterns

Invariably associated with MSI

Good prognosis

Medullary carcinoma-Pushing border at the tumor

edge

Medullary carcinoma:Poorly differentiated

histology ,Prominent nucleoli and tumor-infiltrating

lymphocytes

Medullary carcinoma:This histologic pattern of colonic

carcinoma is characterized by syncytial groups of highly

anaplastic epithelial cells without lumen formation.Solid

growth pattern in nest. A brisk peritumoral lymphocytic

response is present.

Tumor stained with antibody to MSH2

Nuclei express MSH2

Tumor nuclei fail to express MLH1 protein

(endothelial cells and lymphocytes show positive

staining

SERRATED Adenocarcinoma

Newly described entity

7.5% of all CRC and 17.5% of proximal carcinoma

Common in proximal colon

Derived from serrated adenoma

MICROSCOPIC

Serrated, Mucinous or Trabecular pattern of growth

Abundant eosinophillic cytoplasm,Vesicularnuclei and Prominent nucleoli

Preseved polarity

No necrosis

Serrated cancer with distinct nuclei and

prominent nucleoli

Mucinous component (arrow)

Balls or papillary rods floating in mucin (arrows)

SQUAMOUS Differentiation

Common in Proximal colon.

Usually associated with glandular

elements(adenosquamous

carcinoma)

Occasionally seen in pure

form(squamous cell carcinoma)

Evidence of Human Papilloma virus

16 involvement in the pathogenesis

of some rectal cases.

IMMUNOHISTOCHEMICAL

Features Conventional Adenocarcinoma of colon

express MUC1 and MUC3

Mucinous carcinoma express MUC2

CRCs invariably positive for

cytokeratin(CK)-positive for CK20 and

negative for CK7.-Primary

Positive for CEA

Poitive for CDX2,in majority of CRCs.

Tumor associated glycoprotein(TAG-72) is

present in 100% of invasive colorectal

carcinoma.

Electron Microscopic Features

Prominent collections of microfilaments that are related to brush border are characteristic of adenocarcinoma of colon

Inset, Microfilaments entering border and mucin secretoryproduct

DIAGNOSTIC MODALITIES

CYTOLOGY

Its an accurate way of diagnosing CRC.

Little Practical value

Low-lying rectal lesions can be easily

sampled.

Brush cytology can also be performed

via the fiberoptic scope.

It is a sensitive technique , perhaps

even more so than than endoscopic

biopsy,but it has not yet found

widespread acceptance.

BIOPSY

There is a need of POSITIVE BIOPSY

before radical urgery for CRC.

In large lesions, several biopsies should

be taken from diverse areas.

Biopsy from center—Only granulation

tissue

Biopsy from the very Periphery—Only

hyperplastic colonic epithelium

VARIOUS SCREENING

MODALITIES

Colonoscopy

Virtual Colonoscopy

Sigmoidoscopy

Fecal occult blood test

Double contrast barium enema

Digital rectal examination

STAGING AND GRADING

STAGING AND GRADING

In 1937, DUKES proposed staging for

rectal carcinoma

In 1954, Astler and Coller proposed

different staging system

American joint committee on

Cancer(AJCC)

The union Internationale Countre Le

Cancer(UJCC)

Dukes’ Stage ‘A’

The tumor

involve the

wall of the

Bowel only.

Treatment is

Surgery to

remove the

tumor and

some

surrounding

Lymph

Nodes

Dukes’ stage ‘B’

The cancer extend through the wall has not spread to the Lymph Nodes.

Colon cancer is treated with Surgery and, in some cases, Chemotherapy after Surgery.

Rectal cancer is treated with surgery,radiationtherapy and chemotherapy

Dukes’ Stage ‘C’

The cancer has spread to the regional lymph nodes.(Lymph node near the colon and rectum)

C1:: regional L.N

C2::Mesentric B.V

Colon Cancer-Surgery and chemotherapy

Rectal Cancer-Surgery,radiation and Chemotherapy

Dukes’ Stage ‘D’

Spread outside of the

colon or rectum to other

areas of the body

Traetment:Chemothera

py

Surgery to remove the

colon or rectal tumor

may or may not be done

Additional Surgery to

remove metastasis may

also be done in carefully

selected patients.

Astler and Coller Staging system

Stage A

Limited to mucosa

Stage B1

Involving the muscularis propia but not penetrating it

Stage B2

Penetrating through Muscularis propia

Stage C1

Confined to the bowel wall but with nodal metastasis

Stgae C2

Penetrating through the wall and with nodal metastasis

TNM Classification

Spread and Metastasis

Common site

Regional lymph nodes

Liver

Other relative common site –

Peritoneum,Lung,Ovaries

Minimum no. of nodes recovered from a

surgical specimen of colorectal carcinoma

should be 14 or 15.

Liver Metastasis-More common in the tumor

showing evidence of blood vessels invasion.

Treatment

Chemotherapy

Radiotherapy

Photodynamic Therapy

Radical Surgery

Gene Therapy

Immunotherapy-Cetuximab (anti-

EGFR)-use in colon cancer

Prognosis The 5 year survival rate after curative

resection for CRC range between 40% and

60%.

Local recurrence and/or regional lymph

node metastasis occur in over 90% of the

faliure cases.

Over two-thirds of the recurrences are

evident within the first 2 year and 91% by 5

years.

The prognosis of colorectal carcinoma is

related to a number of clinical and

pathologic parameters.

Prognosis

Stage III cancers treated with a fluorouracil

adjuvant regimen, MSS cancers with loss

of heterozygosity of 18q –Worse survival

MSI-H cancers have been associated with

improved 5-year survival compared with

MSS and MSI-L cancers .

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