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Year 2 - MCD - Cancer > 13: Colorectal Cancer (13.02.2020) > Flashcards

13: Colorectal Cancer (13.02.2020) Flashcards

1
Q

Colorectal cancer statistics

A
  • Major Cancer in ‘developed’ countries
  • 4th most common cancer overall
  • 2 leading cause of cancer death overall, behind lung cancer
  • 35K cases p.a. in UK
  • 10% of cancer related deaths (16K p.a.)
  • Ages range 50-80. Sporadic rare < 30
  • High in US, Eastern Europe, Australia
  • Low in Japan, Mexico, Africa
  • Environmental (diet) and genetic factors in aetiology
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2
Q

What are the main parts of the colon?

A
  • caecum
  • ascending
  • transverse
  • descending
  • sigmoid
  • rectum + anus
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3
Q

anatomically, where does the colon start?

A

At the right iliac fossa (first part is the caecum, after the ileocaecal valve)

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4
Q

What does the colon do?

A

Extraction of water from faeces
- (electrolyte balance) -> so supplement patients with more water if they have colon problems because they may be losing more in their stool

Faecal reservoir (evolutionary advantage e.g. sexually favourable if stool is not constantly dripping)

Bacterial digestion for vitamins
(e.g. B and K)

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5
Q

What are the layers of the wall of the colon?

A
  • lumen
  • mucosa
  • submucosa
  • muscularis propria
    • circular layer
    • longitudinal layer
  • serosa
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6
Q

Organisation of the colorectal crypts of Lieberkuhn

A
  • stem cells at the bottom
  • endocrine cells also present
  • proliferation closer to the bottom, differentiation as the cells move up
  • columnar cells
  • goblet cells
  • mesenchymal cells surrounding and holding everything together
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7
Q

Which cells make mucins?

A
  • Goblet cells

- Mucins involved in lubrication of the GI tract, frontline innate host defense

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8
Q

Cell turnover in the colon

A
  • 2-5 million cells die per minute in the colon!
  • Proliferation renders cells vulnerable to cancer
  • APC mutation prevents cell loss -> mutation
  • Normally we have protective mechanisms to eliminate genetically defective cells by;
    • Natural loss
    • DNA monitors
    • Repair enzymes
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9
Q

APC gene and protein

A
  • APC is a tumour suppressor protein
  • It helps control how often a cell divides, how it attaches to other cells within a tissue, and whether a cell moves within or away from a tissue.
  • This protein also helps ensure that the number of chromosomes in a cell is correct following cell division.
  • APC associates with beta-catenin
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10
Q

What is a polyp?

A

A polyp is any projection from a mucosal surface into a hollow viscus, and may be hyperplastic, neoplastic, inflammatory, hamartomatous, etc

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11
Q

What is an adenoma?

A

An adenoma is a benign neoplasm of the mucosal epithelial cells

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12
Q

What are the types of colonic polyp?

A

Metaplastic/Hyperplastic
Adenomas
Juvenile
Peutz Jeghers (familial disorders with mucosal hyperpigmentation)
Lipomas
Others (essentially any circumscribed intramucosal lesions)

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13
Q

Hyeperplastic polyps

A
  • very common
  • <0.5 cm
  • over 90% of all LI polyps
  • Often multiple
  • No malignant potential
  • 15% have k-ras mutation
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14
Q

What are the types of colonic adenoma?

A 
Tubular  (>75% tubular) - 90%
Tubulovillous 	  (25- 50% villous)	10%
Villous   ( > 50% villous)	 
(Flat)
(Serrated) -> saw tooth appearance
  • > tubular has holes (tubules) in it, villous looks like little trees/ finger like projections
  • > villous growth pattern is more likely to become malignant
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15
Q

2 types of adenomas (macroscopic)

A
  • pedunculate (=on a stalk) -> might be easier to cure the patient because you might be able to remove all bad cells by cutting at the stalk
  • sessile -> much closer to other layers, invasion is easier
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16
Q

Tubular adenoma

A
  • Columnar cells with nuclear enlargement, elongation, multilayering and loss of polarity (e.g. nucleus on wrong side of the cell)
  • Increased proliferative activity
  • Reduced differentiation
  • Complexity/disorganisation of architecture
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17
Q

Villous adenoma

A
  • Mucinous cells with nuclear enlargement, elongation, multilayering and loss of polarity
  • Exophytic, frond-like extensions
  • Rarely may have hypersecretory function and result in excess mucus discharge and hypokalemia
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18
Q

Dysplasia

A 
Literal meaning ‘bad growth’
Abnormal growth of cells with some features of cancer
C.f. atypia 
Subjective analysis
Indefinite, low grade and high grade
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19
Q

What is more likely to become malignant, tubular or villous?

A

villous -> requires more monitoring if not removed surgically

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20
Q

What are features that make a polyp more dangerous?

A
  • if it is villous

- if it is not pedunculated = sessile

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21
Q

FAP

A

= familial adenomatous polyposis coli (APC, FAP)

  • 5q21 gene mutation
  • Site of mutation determines clinical variants (classic (1000s polyps), attenuated (100s polyps), Gardner (also in other body parts), Turcot (also brain tumours) etc)*
  • Many patients have prophylactic colectomy<30
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22
Q

Colonic adenoma

A

25% of adults have adenomas at age 50

5% of these become cancers if left

Large polyps have higher risk than small ones (so 5% > 1 cm 50-60, 15% at 75)

Lead time 10years?

Cancers stay at a curable stage c. 2 years

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23
Q

colonic polyp vs adenoma

A

?

24
Q

Progression from adenoma to carcinoma

A
  • Most CRCs arise from adenomas
  • Residual adenoma in ~ 10-30% of CRCs
  • Adenomas and Ca similar distribution
  • Adenomas usually precede cancer by 10 years
  • Endoscopic removal of polyps decreases the incidence of subsequent CRC
25
Q

Genetic pathways of colon cancer development

A

1) Adenoma has APC mutation, for it to become cancer it needs other mutations e.g. p53 or kras, Smads or telomerase activation (normal -> abnormal epithelium -> adenoma -> carcinoma)

2) Microsatellite Instabiilty
- Microsatellites are repeat sequences prone to misalignment. Some microsatellites are in coding sequences of genes which inhibit growth or apoptosis e.g.TGFbR11

  • Mismatch repair genes (MSH2, MLH1 + 4 others). Recessive genes requiring 2 hits.
  • HNPCC- germline mutation in these genes
26
Q

HNPCC

A
  • hereditary non polyposis coli = Lynch syndrone
  • gremline mutation in one of the DNA repair genes
  • can still survive with the other working copy but in th tumour the second copy is destroyed.
27
Q

What are the 2 main pathways of genetic predisposition to colorectal cancer?

A

FAP - inactivation of APC tumour suppressor genes

HNPCC - microsatellite instability

28
Q

Why is APC especially important in colorectal cancer?

A
  • APC holds beta-cateinin in place
  • if APC lets go of beta catenin, beta catenin goes into the cell and makes the cell proliferate etc.
  • this is normal e.g. when the cells are in the process of dividing
  • however, if there is a problem with APC and it is not turned off then there is uncontrolled proliferation and a polyp can be made.
29
Q

Dietary RFs for CRC

A

High Fat, Low Fibre, High Red meat, Refined carbohydrates

  • Food Contains 5-10K Bioactive Chemicals
  • Food contains Carcinogens
  • It also contains AntiCancer Agents!
  • Heat modifies chemicals further
  • Bacteria modify food residues
30
Q

What specific things in food cause cancer?

A
  • heterocyclic amines -> meat cooked at high temperatures, this is fomed form L-phenylalanine. This forms complexes with DNA and causes mutations.
  • folate DEFICIENCY -> coenzyme for nucleotide synthesis and DNA methylation.
  • MTHFR deficiency (methylenetetrahydrochloride) if absent leads to DNA instability -> strand breaks and uracil incorporation-> mutations; also Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation -> Gene activation and silencing)
31
Q

Anticancer Foods

A
  • Vitamin C - ROS scavenger
  • Vitamin E - ROS scavenger
  • Isothiocyanates (cruciferous veg)
  • Polyphenols (green tea, fruit juice) -> Activate MAPK ->
    Regulates Phase2 detoxifying enzymes as well as other genes (e.g.glut-S transferase) and reduce DNA oxidation
  • Garlic associated apoptosis
    (Ajoene, allicin)
  • Green tea
    EGCG-induced telomerase activity!
32
Q

Clinical presentation of CRC

A

Change in bowel habit
Bleeding PR
Unexplained Iron deficiency anaemia

Mucus PR
Bloating
Cramps (‘colic’)
Constitutional (weight loss, fatigue

33
Q

Distribution of colonic cancer

A

Caecum/Ascending Colon 22%

Transverse Colon 11%

Descending Colon 6%

Rectosigmoid 55%

34
Q

Problem with colorectal cancer in the caecum

A
  • it can grow and grow and grow and cause no obstruction because of how large the caecum is.
35
Q

Macroscopic features of CRC

A

Small carcinomas may be present within larger polypoid adenomas, pedunculated or sessile

36
Q

Microscopic structures of CRC

A

Adenocarcinomas Grade 1-3
Mucinous carcinomas
Signet ring cell
Neuroendocrine

37
Q

Grading of CRC

A

proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina

~ 10% well differentiated
~ 70% moderately differentiated
~ 20% poorly differentiated

38
Q

Dukes Classification

A

Dukes A - growth limited to mucosa/submucosa
- nodes negative
Dukes B - growth into or beyond musc propria
- nodes negative
Dukes C1 - nodes positive
- apical LN negative
Dukes C2 - apical LN positive

39
Q

Survival probabilities according to stage of disease

A
  • in situ: 100%
  • A: 98%
  • B1 and B2: 71%
  • C1 and C2: 42%

=> prognosis worsens as the extent of invasion increases

40
Q

Clinical Features that affect prognosis

A
  • asymptomatic diagnosis -> improved prognosis
  • rectal bleeding as presenting symptom improves the prognosis
  • Bowel obstruction/perforation: diminished prognosis
  • Tumour location: Colon better than rectum; Left colon better than right colon (closer to anus, presents earlier)
  • Age: below 30 is worse prognosis
  • preoperative serum CEA: Diminished prognosis with high CEA level
  • distant mets: Markedly diminished prognosis
41
Q

Pathological features that affect prognosis

A
  • increased bowel wall penetration diminishes prognosis
  • 1-4 invaded lymph nodes os better than more than 4 invaded lymph nodes
  • well > poorly differentiated
  • Mucinous (colloid) or signet ring cell diminishes prognosis
  • venous/lymphatic/perineureal invasion diminishes prognosis
  • Local inflammation and immunologic reaction improves prognosis
42
Q

Treatment options for CRC

A

=> depends on stage

  1. Surgery
  2. Surgery, 5FU
  3. Surgery, 5FU/Leucovorin
  4. Surgery, Metastatectomy, Chemo, Palliative RT
43
Q

5FU as therapy for CRC

A
  • Fluorouracil is also known as FU or 5FU and is one of the most commonly used drugs to treat cancer (also e.g. breast, oesophagus, stomach)
  • anti-metabolite
44
Q

screening for high risk colon cancer

A

Previous adenoma
1st Degree relative affected by colorectal cancer before the age of 45
2 affected first degree relatives
evidence of dominant familial cancer trait including colorectal, uterine, and other cancers
UC and Crohn’s disease
Hereditable cancer families (include other sites)

45
Q

What is screening?

A

Screening is the practice of investigating apparently healthy individuals with the object of detecting unrecognised disease or people with an exceptionally high risk of developing disease, and of intervening in ways that will prevent the occurrence of disease or improve the prognosis when it develops.

46
Q

NHS screening for colon cancer

A

FOB/FIT kit

Positives referred for:
60-75 years
colonoscopy
55-60 years 
sigmoidoscopy
47
Q

MCQ 1: 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

A

D/ Colorectal malignancy must be excluded in the first instance

48
Q

MCQ 2: 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

A

A/ Many carcinomas are derived from adenomas

49
Q

Differentiate between tubular and villous adenomas

A

Tubular:

  • columnar cells (with nuclear enlargement, elongation, multilayering and loss of polarity and reduced differentiation and increased proliferative activity)
  • complexity and disorganisation in architecture.

Villous:

  • mucinous cells (with nuclear enlargement, elongation, multilayering and loss of polarity)
  • more dangerous
  • Exophytic, frond-like extensions
  • Rarely may have hypersecretory function and result in excess mucus discharge and hypokalemia
50
Q

What are microsatelites?

A
  • a tract of repetitive DNA in which certain DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times.
  • occur at thousands of locations within the organisms genome.
  • ave a higher mutation rate than other areas of DNA leading to high genetic diversity
  • often referred to as STRs (short tandem repeats)
  • prone tuo mutations because of their repeating nature.
51
Q

Where is the APC mutation found?

A

5q21

52
Q

Short summary of the progression form adenoma to carcinoma

A

1st hit -> 2nd hit -? protooncogene mutation -> homozygous loss of additional tsg -> additional mutations, gross chromosomal alterations

(APC, kras, p53, smads, beta-catenin, MSH2, many genes)

You need APC mutation to get a polyp but for it to become malignant you need other tsg mutations e.g. k-ras or p53

53
Q

Importance of the APC mutation in CRC?

A
  • APC holds beta-catenin in cytoplasm if APC doesn’t work the beta-catenin moves from the. cytoplasm to nucleus -> increased cellular proliferation
  • at the base of the cells you want cell division
  • when the cells migrate up the crypts the APC is turned off
  • if there is a mutation in APC or beta-catenin -> uncontrolled proliferation.
54
Q

CEA

A

carcinoembryonic antigen

  • diminished CRC prognosis with high CEA level
55
Q

How does the location of CRC affect the prognosis?

A

?Colon better than rectum

?Left colon better than right colon

(closer to the anus presents earlier)

56
Q

Leucovorin

A
  • colonic aacid
  • used with 5-FU in CRC

(medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning)

Year 2 - MCD - Cancer (15 decks)

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