CasaD - Colorectal Cancer Flashcards by Rama Jha

Cancer Epidemology?

MAJOR cancer of the developed world

• 4th most common world-wide

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Causative factors of colorectal cancer?

Environment (diet)
&
Genetic factors

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Function of the colon?

Extraction of water from faeces
• electrolyte balance

Faecal reservoir
• evolutionary advantage

Bacterial digestion for vitamin
• e.g. B & K

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Anatomy of the colorectal?

Smooth folded mucosa
• w. THICK muscle layer

Cancer type = adenocarcinoma (glandular)

Cells divide in the crypts of Lieberkuhn
• and are shunted UP

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Explain how Turnover causes the development of colorectal cancer

Turnover:
• 2-5m cells per minute die in the colon
• = high proliferation rate (cells are vulnerable to mutation)

APC mutation PREVENTS cell loss and causes cell proliferation

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What normal protective mechanisms does the colorectal have in regards to turnover?

Normal protective mechanisms include: 
 – natural loss
 – DNA monitors
&amp; 
 – repair enzymes

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Define polyp

Polyp = any projection from a mucosal surface into a hollow viscus

& may be:
hyperplastic, neoplastic, inflammatory, hamartomatous etc.

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Define adenoma

A benign neoplasm of the mucosal epithelial cells

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What different colonic polyp types can there be

Polyp types include:
• Metaplastic /hyperplastic

Adenomas
Juvenile, Peutz Jeghers, lipomas, others – (don’t need to know much about these)

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Explain HYPERPLASTIC polyps

 Very common growths <0.5cm

 Constitute 90% of all colon polyps

 Often come in multiples

 They have NO malignant potential
• but 15% have a K-Ras mutation

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What are the different colonic adenoma types?

Tubular
– 90% adenomas (>75% tubular)

Tubulovillous
– 10% adenoma (25-50% villous)

Villous
– (>50% villous).

Other
– flat, serrated

The more villous, the worse

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Relationship with colorectal cancer and villous?

The MORE villous = the WORSE

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Anatomy of the 2 types of adenoma?

Adenomas on a stalk
• pedunculated

Flat & raised adenoma
• sessile

BOTH can be tubular, villour etc.

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Tubular microstructure of adenomas?

COLUMNAR cells with:
• nuclear enlargement
• elongation
• multi-layering and loss of polarity

 Proliferation increases
 Reduced differentiation
Complexity/disorganisation of architecture

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Villous microstructure of adenomas?

MUCINOUS cells with
• nuclear enlargement
• elongation
• multi-layering and loss of polarity

 Exophytic
– front-like extensions
 Rarely, may hyper-secrete resulting in excess mucus discharge and hypokalaemia.

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Define dysplasia

Abnormal growth of cells with SOME features of cancer

(i.e. UC leads to dysplasia)

Indefinite
• has both HIGH & LOW-grade

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APC?

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Adenomatous Polyposis

Explain APC

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APC/FAP (familial adenomatous polyposis)

o 5q21 gene mutation

o Site of mutation determines clinical variants
– i.e. classic, attenuated, Gardner, Turcot

o Many patients of FAP have a prophylactic colectomy

Epidemology of colonic adenomas?

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25% of adults have adenomas at age 50 –> 5% become cancers if left.
• adenomas precede carcinomas by about 15 years

Larger polyps have a greater chance of becoming cancerous than smaller polyps.

Cancers stay at a curable stage for about 2 years.

Progression from adenoma to carcinoma?

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Most colorectal cancers arise from adenomas
• with 10-30% of CRCs having a residual adenoma

Endoscopic removal of polyps DECREASES the incidence of subsequent CRC

Genetic pathways in colorectal cancer?

•

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(1) Adenoma Carcinoma Sequence

(2) Microsatellite Instability

Explain (1) in genetic pathways in Colorectal Cancer

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Adenoma Carcinoma Sequence

APC = best known genes that is damaged
Others = K-Ras, Smads, p53, telomerase activation

Explain (2) in genetic pathways in Colorectal Cancer

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Microsatellite Instability

Microsatellites are repeat sequences prone to misalignment
• some microsatellites are in coding sequences of genes which inhibit growth or apoptosis

Mismatch repair genes
• are recessive genes requiring 2 hits (loss of this greatly increases chances of CRC)
• HNPCC – Hereditary Non-Polyposis Colorectal Cancer – germ-line mutations

2 main pathways for genetic predisposition for colorectal cancer?

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FAP
• inactivation of APC TSG

HNPCC
• microsatellite instability

Dietary factors that predispose to colonic carcinoma?

High fat Low fibre High red meat Refined carbohydrates High oC cooking can modify chemicals further in the food • induce mutagenic chemicals

Explain HCAs

Heterocyclic Amines These include PhIP • PhIP is oxidised • turns into N-OH-PhIP + deoxyguanosine • This then turns MUTAGENESIS

Explain 2 specific dietary deficiencies that can lead to colorectal cancer

Dietary deficiencies: FOLATES:  Folates are co-enzymes needed for nucleotide synthesis and DNA methylation MTHFR – Methylenetetrahydrofolate Reductase:  Deficiency leads to disruption in DNA synthesis causing DNA instability --> mutation.  Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation --> gene activating & silencing effects

Food can also have anti-carcinogenic elements - what are these?

Vitamin C and E – ROS scavengers Isothiocyanates – cruciferous vegetables ``` Polyphenols – green tea and fruit juice – can activate MAPK pathways --> regulating phase 2 metabolisms to detoxify enzymes as well as other genes = thus reduce DNA oxidation – EGCG-induced telomerase activity – Garlic associated apoptosis ```

Clinical presentation of colorectal cancer?

 Change in bowel habit Pre-rectal bleeding – Patients & doctors rationalise these symptoms as getting old!  Unexplained iron deficient anaemia  Other – mucus pre-rectal production, bloating, cramps (“colic”), weight loss and fatigue

Macroscopic features of colorectal cancer?

Small carcinomas may present w. larger polypoid adenomas | • pedunculated OR sessile

Distribution of colon cancer around the colon?

Caecum/ascending colon - 22% Transverse colon - 11% Descending colon - 6% Recto-sigmoid - 55%

Microscopic features of carcinomas?

Almost all are adenocarcinomas:  Mucinous carcinoma  Signet ring cell carcinoma  Neuroendocrine carcinoma (rare).

How is colorectal cancer graded?

Defined by the proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina: o 10% = well differentiated o 70% = moderately differentiated o 20% = poorly differentiated.

Explain the Dukes Classification

Dukes A • growth limited to mucosa/submusoca • nodes negative Dukes B • growth beyond Muscularis propria • nodes negative Dukes C1 • nodes positive • apical lymph node negative Dukes C2 • apical lymph nodes (LN) positive Apical lymph nodes – highest lymph node to have been removed. If +ve, chance of spread to lymph. The scale has a worse prognosis as you go down A --> C2.

Clinical features affecting prognosis?

 Diagnosis of asymptomatic patients +ve  Rectal bleeding as presenting symptom +ve  Bowel obstruction -ve  Tumour location ±ve  Age <30 -ve  Preoperative serum CEA (high) -ve  Distant metastasis -ve

Pathological features affecting prognosis?

 Decreased bowel wall penetration +ve  Decreased regional LN involvement +ve  Poor differentiation -ve  Mucinous/signed ring cell type -ve  Venous invasion -ve  Lymphatic invasion -ve  Peri-neural invasion -ve  Local inflammation and immunologic reaction +ve

Treatment options for colorectal cancer?

Grade 1 • surgery Grade 2 • surgery • 5FU Grade 3 • surgery • 5FU/Leucovorin Grade 4 • surgery • metastatectomy/ chemo/ palliative RT

Screeing prerequisities for those at HIGH RISK for Colon Cancer?

 Previous adenoma  1st degree relative affected by CRC before age 45  Two affected 1st degree relatives  Evidence of dominant familial cancer trait  UC and Crohn’s disease  Heritable cancer families

NHS screening for colon cancer?

They look for FOB – Faecal Occult Blood. • from 55+, a FOB test kit is send to people If positive, an endoscopy is performed • 55-60yo = sigmoidoscopy • 60+ = full colonoscopy

A 76 year old man presents with new onset rectal bleeding to the GP: A/ Haemorrhoids must be excluded in the first instance B/ Factor 5 leiden abnormalities are the likely cause C/ The GP should reassure and send the patient home D/ Colorectal malignancy must be excluded in the first instance E/ Crohn's disease must be excluded in the first instance

With respect to the aetiology of colorectal adenocarcinoma: A/ Many carcinomas are derived from adenomas B/ Adenomas are invasive tumours C/ Ulcerative colitis is the underlying cause in many cases D/ Many carcinomas are derived from hyperplastic polyps E/ Angiodysplasia is the underlying cause in many cases

CasaD - Colorectal Cancer Flashcards

(41 cards)