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1Principles of Biomedicine - MD1 > 133 - Dysplasia - Carcinoma Sequence in the Colon > Flashcards

133 - Dysplasia - Carcinoma Sequence in the Colon Flashcards

1
Q

Precursor lesions for colorectal carcinoma

A

– Tubular adenoma: sessile or pedunculated
– Villous adenoma: often large & sessile
– Tubulovillous adenoma: mixed features

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2
Q

Predictors of increased malignant risk:
1
2
3 a, b, c

A

– Polyp size (>1cm)
– Villous morphology
– High grade dysplasia
• Severe crowding with loss of nuclear polarity
• Marked nuclear variation (pleomorphism)
• Cribriform intramucosal growth (gland fusion)

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3
Q

Familial syndrome with a ~100% risk of developing colon cancer

A

Familial adenomatous polyposis

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4
Q

Pedunculated tubular adenoma appearance

A

Pedunculated, red mass on luminal wall of large intestine.
Can bleed into lumen.
Sits atop a stem,

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5
Q

Sessile villous adenoma

A

Can be very large without invasion (in colon)

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6
Q

Risks for early-onset colorectal cancer
1
2

A

1) Familial syndromes

2) Chronic inflammatory bowel disease

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7
Q

Chronic inflammatory bowel diseases that can predispose to early-onset colorectal cancer
1
2

A

1) Ulcerative colitis

2) Crohn’s disease

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8
Q

Familial adenomatous polyposis inheritance

A

• Autosomal dominant syndrome
– APC gene mutation (chromosome 5q21-22)
– > 100 adenomatous polyps in the large bowel
– Extracolonic manifestations

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9
Q

Familial adenomatous polyposis incidence

A

• High incidence of early onset colorectal carcinoma:
– 10% in patients observed for 5 years, 50% over 20 years
– Most progress to carcinoma by age 30
– Role for prophylactic colectomy

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10
Q

Severities of familial adenomatous polyposis

A

• If >1000 polyps
– 60%-80% likelihood of detecting pathogenic APC gene mutation
– 2.3x greater risk of cancer than in patients with 100-1000 polyps

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11
Q

Attenuated familial adenmatous polyposis variant

A

•

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12
Q

Adenomatous polyp histology
1
2
3 a, b, c

A

• Abnormal crypt architecture (tubular or villiform)
• Dysplasia
• No invasion beyond muscularis mucosae
– Absence of lymphatics in lamina propria
– Complete excision curative
– Polypectomy, endoscopic mucosal resection (EMR)

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13
Q 
Features of dysplasia in familial adenomatous polyposis 
1
2
3
4
5
A

– Crowded cells
– Enlarged, hyperchromatic, pseudostratified nuclei
– Abnormal complexity to glandular architecture
– Goblet cell depletion
– Increased mitotic count +/- atypical mitoses

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14
Q

Most common polyp in the bowel

A

Benign lesion. Hyperplastic polyps.

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15
Q

Appearance of villous adenoma

A

Finger-like projections of epithelium.

Have goblet cells

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16
Q

Features of high-grade dysplasia
1
2

A

1) Loss of polarity of epithelial cells

2) Fused glands in the mucosa.

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17
Q

What is an adenomatous polyp?

A

A dysplastic polyp in the bowel

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18
Q

When does an adenomatous polyp become colorectal adenocarcinoma?

A

When it invades beyond the muscularis mucosae.

There is a dermoplastic stromal reaction

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19
Q

Genetic pathways to colorectal cancer

A

1) Chromosomal instability (most common)
2) Microsatellite instability
3) CpG island methylator phenotype

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20
Q

Chromosomal instablity pathway

A

– Familial adenomatous polyposis (1% CRC)

– 75%-85% of sporadic CRC (colorectal cancer)

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21
Q

Common genetic changes in dysplasia carcinoma sequence
1
2
3

A

1) Loss of APC function
2) Chromosomal instability (most common)
3) Accumulated mutations

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22
Q

Loss of APC function
1
2
3

A

1) Decreased cell adhesion and increased cellular proliferation
2) APC mutation an early event in adenoma formation
3) Multiple adenomas in Familial Adenomatous Polyposis

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23
Q

Chromosomal instability
1
2
3

A

– Aneuploid karyotype
– Large chromosome segment deletions and duplications
– Increased nuclear DNA content

24
Q

Accumulated mutations that can lead to colorectal cancer
1
2
3

A

– Proto-oncogenes: K-RAS in ~50%, B-RAF in 10%
– Tumour suppressor genes: Loss of SMAD4/SMAD2 and p53 (late in carcinogenesis)
– Activation of telomerase

25
Q

APC

A

Adenomatous polyposis coli.

A gene. Most commonly inactivated gene in colorectal cancer

26
Q

Most common familial colorectal cancer syndrome

A

Hereditary non-polyposis colorectal cancer (Lynch Syndrome)

27
Q

Proportion of colorectal cancers attributable to Lynch Syndrome

A

~3% (vs 1% for familial adenomatous polyposis)

28
Q

Mean age of colorectal cancer onset with Lynch syndrome

A

45 years

29
Q

Inheritance of Lynch syndrome

A

Autosomal dominant, ~80-85% penetrance

30
Q 
Extracolonic cancers associated with Lynch Syndrome 
1
2
3
4
A

– Endometrium
– Renal pelvis/ureter, stomach, small bowel, ovary
– Glioblastoma multiforme (Turcot syndrome)
– Sebaceous tumours (Muir Torre syndrome)

31
Q

Microsattelite isntability

A

In long tracts of repeating DNA, DNA polymerase can make mistakes (EG: can make six repeats instead of seven).

32
Q

What drives microsattelite instability pathway?

A

Defective DNA mismatch repair.
Germline mutation in MSH2 or MLH1 (in over 90%).
OR sporadic MLH1 hypermethylation

33
Q

Effect of defective DNA mismatch repair

A

• Widespread mutations in DNA microsatellites
– mononucleotide repeats (AAAAAAA..)
– dinucleotide repeats (CACACACACA…)
– involve non-coding and coding DNA
– mutations in proto-oncogenes, tumour suppressor genes and DNA repair genes

34
Q

Type of polyp that often arises in proximal colon

A

Sessile serrated adenoma

35
Q 
Features of sessile serrated adenoma 
1
2
3
4
5
A

– Saw-tooth architecture of glands
– More complex branching than in a hyperplastic polyp
– “Boot-leg” angulation and dilatation at base of crypts.
– Elongated, vesicular nuclei, prominent nucleoli
– Increased atypia with dysplasia

36
Q

Mutation common in sessile serrated adenoma

A

BRAF V600E mutation

37
Q

Why are sessile serrated adenomas hard to detect?

A

Sessile (hard to detect with a colonoscope)

38
Q

Macroscopic features of colorectal cancer

1) a, b
2) a, b
3) a, b, c, d

A

1) Growth patterns
– Proximal colon: bulky, polypoid, exophytic
– Distal colon and rectum: annular, stenosing, ulcerated

2) Cut surface
– Typically firm and white, may appear necrotic
– Mucoid in mucinous tumours

3) Invasion assessment
– muscularis mucosae and muscularis propria
– lymph nodes
– infiltration of adjacent organs
– perforation into peritoneal cavity
39
Q 
Dukes' classification of CRC
1
2
3
4
A
  • Dukes A - Invades into, but not through bowel wall
  • Dukes B - Invades through bowel wall, but not involving lymph nodes
  • Dukes C - Lymph node metastases
  • (Dukes D - Distant metastases)
40
Q 
Australian Clinicopathological staging of CRC
1
2
3
4
A
  • ACPS A – Invades beyond muscularis mucosa
  • ACPS B – Invades beyond muscularis propria
  • ACPS C – Lymph node metastases
  • ACPS D – Distant metastase
41
Q

What is Dukes’ staging system based on?

A

Pathological examination of resected tumour

42
Q

TNM staging system

A

T = Depth of Tumour invasion

N = Lymph Node metastases

M = Distant metastases

43
Q 
T stages of TNM staging system
1
2
3
4
5
A
  • T is (in situ) - Carcinoma in situ (intraepithelial or invasion of lamina propria) - equivalent to adenomatous polyp
  • T1 (Stage 1; Dukes A) - Invades beyond muscularis mucosae
  • T2 - Invades into muscularis propria
  • T3 (Stage 2; Dukes B) - Invades beyond muscularis propria, into subserosa or pericolic or perirectal fat
  • T4 - Invades other organs/structures or perforates visceral peritoneum
44
Q

N stages of TNM staging system
1
2
3

A
  • N0 - No lymph node metastases
  • N1 (Stage 3; Dukes C) - Metastases in 1-3 lymph nodes
  • N2 - Metastases in 4 or more lymph nodes
45
Q

M stages of TNM staging system
1
2
3

A
  • Mx - Distant metastases can’t be assessed
    • M0 - No distant metastases
    • M1 (Stage 4; Dukes D) - Distant metastases
46
Q 
Things in a stage 2 CRC
1
2
3
4
5
A

1) High grade
2) T3 with localised perforation or T4
3) Close, indeterminate or positive margins
4) Lymphovascular invasion
5) Under 12 nodes examined

47
Q

Are CRC tumours with glands better or worse than solid ones?

A

Better, as they are more differentiated

48
Q

Possible pre-operative therapy for CRC

A

Preoperative (neoadjuvant) chemoradiotherapy can downgrade tumour before surgery

49
Q

When is pre-operative neoadjuvant therapy useful?

A

Stages 1 and 2 CRCs. Not very helpful with stages 3 and 4

50
Q

How can a dysplasia be treated?

A

Complete resection can be curative

51
Q

Targeted therapies for some CRCs

A

Epithelial growth factor receptor (EGFR) monoclonal antibodies

52
Q

EGFR therapies
1
2

A

1) Cetuximab

2) Panitumumab

53
Q

Cancers from which mutations are EGFR therapies ineffective to treat?

A

K-RAS and B-RAF

54
Q

Common therapy given for colon cancer

A

5-fluorouracil

55
Q

Why might you not treat a microsatellite-instability CRC patient with 5-fluorouracil?

A

Because immune system can target tumours, and 5-fluorouracil can inhibit this

1Principles of Biomedicine - MD1 (157 decks)

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