Colorectal Cancer Flashcards by Katerina Efstathiou

What are the characteristics of malignancy pathology?

Abnormal signal transduction
Loss of apoptosis
Tissue invasion & Metastasis

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Abnormal signal transduction, what happens?

Ligand-independent signalling
Structural changes to receptors
EGFR- epidermal growth factor receptors are over expressed ligands & TGF-a (transforming growth factor)
Things attach to ligands–> signal transduction–> activate transcription of genes.

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What can neutralise ligands?

Monoclonal Antibodies (Abs)

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What mitogen is involved in colorectal cancers abnormal signal transduction? + what does it do?

RAS mitogen

Deregulation

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What happens?

Mutations–> ⬆️⬆️ transcription –> overexpression of receptors
⬆️⬆️ potential to be triggered by ligands
↪️ ⬆️⬆️ Growth tp express receptors.

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What happens during Loss of Apoptosis?

Too little apoptosis + ⬆️ cell proliferation (can be genetic)
There are 2 pathways acitivating apoptosis:
Extrinsic & intrinsic

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Whats the extrinsic pathway?

Death Receptors-

Activation of tumour necrosis Factor family (caspases enzymes)

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Whats the intrinsic pathway?

Mitochondrial activation, by damaged DNA.

Apoptosis inhibitor proteins) (IAP

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What happens in tussue invasion & metastasis?

Malignant cells enter blood stream/lymph.
EGFR pathway aCtivates & promotes metastasis
MMP released; breaks basement membrane
↪️ enter blood by tight junctions
↪️tissue invasion
⭐️marks territory once in.

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What are some common metastatic sites?

Liver, lung, brain & bone marrow.

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What do you check in moles?

Appearance
Colour
Diameter
Border

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What 2 genes are asscw/ breast cancer? What types of genes are they?

BRAC1 & BRAC2
They are both tumour supressors.
If invaded, no more effect of protection.

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What are some common genes implicated w/ colorectal cancer? Ascc mutations

APC-->T suppressor
RAS--> oncogene
Kras- oncogene. 
TP53--> T supressor
SMAD4--> T supressor

How? Impaired cellular stress & DNA damage response.

APC( adenomatous polyposis coli)

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Whats the Jukes classification of colorectal cancer?

A- mucosa of bowel
B. Through mucosa muscularis
C. Local nodes invaded.
D. Metastasis.

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What drugs can be pritective of colorectal cancer?

Aspirin & NSAIDs

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What 2 types of colon diases do we have?

FAP- familial adenomatous polyps —> 100% cancer
Autosomal dominant condition

HNPCC

What happens when we have mutations?

Mutator genes–> results in hypermutation

Oncogenes–> activated– overexpression! selective growth advantage to cell.

Whats the volegram for colorectal cancer?

Normal–> hyperplastic–>early adenoma–>

Late adenoma–> T2M0N0 –> T4N0M0—> T1M1..

Colorectal C

Most are sporadic! 5-10% Hereditary polyposis colorectal cancer (HNPCC)
Or FAP.
May also occur on backround of 10Y pancolitis, UC, or colonic Crohns disease.

Sporadiac colorectal cancer

2nd most commom cauce of cancer death.
Incidence imcreases w/age, >50Y.
Rare in Africa and Asia due to diff env fx.
Aerological fx- high in animal meat and animal fat and low in fibre.

⭐️Activation of tumor- promoting genes/ oncogenes - Kras, c-myc
⭐️ inactivation of tumour supressor genes (MCC, DCC, p53) .
Risk of tumor increases w/ increased genetic abnormalities.

Pathology of colorectal C

Other than backround of IBD
Start as benign adenomas (aka adeno-carcinoma) sequence.
Spread- direct invasion through bowel wall, later- invasion of blood vessels + lymphatics + Liver !!! Lymp after GI goes to liver.

Stages for classification?

TNM- tumour, node, metastasis and modified Dukes criteria
Dukes A. Tumour confined to bowel wall
Dukes B. T extendinh through bowel wall
Dukes C. Regional lymph nodes involved
Dukes D. Distant metastasis

Cfs

Mostbare in Left side of colon
Rectal bleeding +’stenosis
W/ sx of imcreasing intestn obstruction like bowel habbit alterations + colicky abdo pain.

Carcinoma of caecum and ascwnding colon- Fe anaemia and RIF mass.
O/E unhelpful altho mass
Hepatomegaly when liver metastisised.

Invx

Double contrast barium enema or colonoscopy
FBC- anaemia, abn LfTs- 2o liver
Faecal occult blood tests- population screen, not dx.

Tx- surgical w/ tumor resection and end-to-end anastomosis of bowel. Adjuvant chemo w/ 5-Fluoroutacil + leucovorin ⬆️ survival in Dukes C (TNM III) and some Dukes B. Pre-op radio might help in rectal cancer Radio also in pallative in pts w/ locally advanced disease. Pts w/ 2-3 liver metastasis in 1 lobe may be offered liver resection. Pts unresecrable: chemo in form of 5-Fluorouracil + leucovorin in combo w/ irinotecan or oxplatinin- increase median survival + improve QOfLife.

Prognosis

5Y survival 40% | >95% in dukes A- confined to bowel wall.

Screening

High risk individuals Fmembers w/ HNPCC first degree or 1st degree with colon cancer offered colonoscopy. Mass screening FOB test w/ colonoscopy if +ve. (Sigmoidoscopy shown to reduce mortality?! ) but not adopted yet.

HNPCC

Autosomal dominat transmission w/ incomplete penetrance. Mutation in 1/6 repair genes --> leading to widespread genome instability. Mutations in 2 of these: hMLH1 and hMSH2 account for >95% of HNPCC families. Risk of camcer at any age, usually right sided. Many also have increased incidence of gynae, urinary, biliary and other malignancies.

What are the dx criteria for HNPCC?

Amsterdam criteria - fhx 3> relatives w/ HNPCC- assc cancer- colorectal, endometrial, small bowel, ureter, or renal pelvis) one of whome is a 1st degree relative and FAP excluded. Families w/ colorectal cancer involving at least 2 generations One or more cancers diagnosed before the age of 50.

RED FLAGS FOR COLORECTAL CANCER

2 week referral immediately if: Palpable rectal mass (any age) Iron deficiency anaemia in men at any age Iron def anaemia in non menstruating women any age Rectal bleed + changed bowel habits >6w for >40Y Rectal bleed for >6w >50Y ``` Wt loss Anaemia Abdo pain Mucus passed PR Anorexia Altered blood PR Change in bowel habbit ```

O/E | Of bleed

Rectal cancers-80% at fingertip of rectum so PR exam. Blood on toilet paper or on top of motion-> cause likely to be seen on proctoscopy. (Rigit sigm) Blood mixed w/ stool: Young middle aged men: gastroenteritis- campylobacter or colitis Inv- abdo exam + PR exam FBC, CRP, stool studies- FOB, microscopy, cultures and sensitivity Coeliac studies and clotting screen. Palpable- fast track surgical,assesment if necs.

DDx for PR bleed?

``` Haemorrhois Anal fistula Diverticulitis, IBD Colitis DIC, clotting problems, / Anticoagulation/NSAIDs therapy Trauma Gastroenteritis Colorectal malignancy⭐️ ```