Git 8-csbrp

Case

• Male aged 65yrs presented with the complains of progressive generalized weakness for the past 6months

• o/e pallor+, koilonychia+, smooth bald tongue+• HGB: 6gm/dl, MCV: 67fl, MCH: 20pg, RDW: 19,

TLC: 7,000cell/cumm, DLC: normal, PLT: 2lakhs/cumm

• What is the type of anemia?• What you would like the elicit in the history?

Case…. continued

• Male aged 65yrs presented with the complains of progressive generalized weakness for the past 6months

• o/e pallor+, koilonychia+, smooth bald tongue+• HGB: 6gm/dl, MCV: 67fl, MCH: 20pg, RDW: 19, TLC:

7,000cell/cumm, DLC: normal, PLT: 2lakhs/cumm• No h/o hemorrhoids, peptic ulcer, hematuria• Stool for ova/parasites: Negative• Stool for occult blood: Positive• What is the next step?

Case…. continued

• Colonoscopy: Large mass in the caecum

• Diagnosis: Carcinoma of colon

Terms

• Loss of heterozygosity – LOH• Constipation / obstipation

Colorectal CarcinomaColorectal Carcinoma

Dr.CSBR.Prasad, M.D.,

AdenocarcinomaAdenocarcinoma

AdenocarcinomaAdenocarcinoma

Small intestine: •Uncommon site for neoplasms•Tumors that may occur:– Adenocarcinoma– Carcinoid– Lymphoma– Sarcoma

Large intestine:•Common site for adenocarcinoma

Colorectal carcinoma - Colorectal carcinoma - AdenocarcinomaAdenocarcinoma

Colorectal carcinomaColorectal carcinoma

• Mostly Adenocarcinomas• 60-70yrs• < 20% of cases occur before 50yrs• M>F• Most common in developed countries– 30x less common in India / Africa


Risk factors:•Low Dietary fiber•Diet rich in fat and refined carbohydrates•Deficiencies of vitamins A, C, and E


Risk factors:

•High fat intake enhances the hepatic synthesis of cholesterol and bile acids, which can be converted into carcinogens by intestinal bacteria

Colorectal Colorectal carcinomacarcinoma


Risk factors:•Dietary modification•Pharmacologic chemoprevention


Risk factors:Dietary modification– Low fat & High fiber diet


Risk factors:Pharmacologic chemoprevention – Aspirin or other NSAIDs have a

protective effect

PathogenesisPathogenesis

• Heterogeneous genetic abnormalities• Genetic and Epigenetic abnormalitiesTwo distinct genetic pathways:1.APC/β-catenin pathway – associated with WNT and the classic adenoma-

carcinoma sequence

2.The microsatellite instability pathway

APC/β-Catenin Pathway

• APC (WNT signaling pathway) - control cell fate, adhesion, and cell polarity during embryonic development

• APC gene (5q21) down-regulate growth-promoting signals – ‘Tumor suppressor’

• An important function of the APC protein is to down-regulate β-catenin

APC/β-Catenin PathwayWNT signals through a family of cell surface receptors called frizzled (FRZ)

• 80% of sporadic colon tumors• Mutation of APC (LOH)• Additional mutations:– Activating mutations in KRAS– Mutations in SMAD2 and SMAD4– p53 mutation – Methylation of promoter region– Increase expression of telomerase

PathogenesisPathogenesis 1- Adenoma-carcinoma sequence 1- Adenoma-carcinoma sequence

PathogenesisPathogenesis 1- Adenoma-carcinoma sequence 1- Adenoma-carcinoma sequence

PathogenesisPathogenesis 2- Microsatellite instability 2- Microsatellite instability

• DNA mismatch repair deficiency • Accumulation of mutations in microsatellite repeats

(Microsatellite instability)• Most of them are silent• Mutation resulting in MSI involving:– type II TGF-β receptor (uncontrolled cell growth)– the pro-apoptotic protein BAX (survival of genetically

abnormal clones)• Mutations in the oncogene BRAF• Hypermethylation of MLH1• KRAS and p53 are not typically mutated


Thus, the combination of the following is the signature of this pathway of carcinogenesis:– MSI– BRAF mutation, and – Methylation of specific targets, such as MLH1


PathogenesisPathogenesis 3- Hypermethylation of 3- Hypermethylation of promoter & absence of MSIpromoter & absence of MSI

• Increased CpG island methylation in the absence of microsatellite instability

• Many of these tumors harbor KRAS mutations, but p53 and BRAF mutations are uncommon

Morphology and molecular alterations

• Sessile serrated adenomas: Mismatch repair deficiency and MSI

• Tumors with prominent mucinous differentiation and peritumoral lymphocytic infiltrates: – MSI– Frequently located in the right colon

Morphology – Carcinoma of Colon• Can occur in any part of the colonIn the proximal colon: – Polypoid, exophytic masses– Rarely cause obstruction– Symptoms occur LATELY

In the distal colon:– Annular lesions – “Napkin-ring” constriction – Luminal narrowing > Obstruction– Symptoms occur EARLY

Carcinoma colonCarcinoma colonExophytic type Napkin ring type

Napkin rings

Carcinoma colonCarcinoma colon

Exophytic type Napkin ring type

Colorectal carcinoma – infiltration in to the muscle coat

Morphology – Microscopic features

• Most tumors are composed of glands lined by tall columnar cells with features of malignancy

• Invasive tumors elicits desmoplastic response• Poorly differentiated tumors form few glands • Some produce abundant mucin - poor

prognosis• Some poorly differentiated tumors composed

of signet-ring cells



Clinical FeaturesClinical Features

• Right sided tumors: – Go undetected for long periods– Present with fatigue and weakness due to iron

deficiency anemia • Left-sided tumors: – Occult bleeding– Changes in bowel habits– Cramping left lower quadrant discomfort

Clinical FeaturesClinical Features

Clinical MAXIMClinical MAXIM: :

•The underlying cause of iron deficiency anemia in an older man or postmenopausal woman is GI cancer until proven otherwise

The two most important Prognostic Factors

1. Depth of invasion • Invasion into the muscularis propria confers

significantly reduced survival

2. Lymph node metastases

Metastases

• Metastases may involve regional lymph nodes, lungs and bones

• but LIVER is the most common site of metastatic lesions (as a result of portal drainage of the colon)

• Mets in the liver are often umbilicated

Umbilicated liver mets

Metastatic colorectal carcinoma

HNPCCHNPCC

E N D

Dr.Denis Burkitt Burkitt’s Lymphoma

Dr.Denis Birkitt Fiber and Colonic carcinoma

America is a constipated nation.... If you pass small stools, you have to have large hospitals – Denis Burkitt

Trosseau syndrome (migrating thrombophlebitis)

Sister Joseph Lilly nodule

Health & Medicine

Git 8-csbrp