133 - Dysplasia - Carcinoma Sequence in the Colon

Question 1

Precursor lesions for colorectal carcinoma

Answer 1

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

Question 2

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

Answer 2

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

Question 3

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

Answer 3

Familial adenomatous polyposis

Question 4

Pedunculated tubular adenoma appearance

Answer 4

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

Question 5

Sessile villous adenoma

Answer 5

Can be very large without invasion (in colon)

Question 6

Risks for early-onset colorectal cancer
1
2

Answer 6

1) Familial syndromes

2) Chronic inflammatory bowel disease

Question 7

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

Answer 7

1) Ulcerative colitis

2) Crohn’s disease

Question 8

Familial adenomatous polyposis inheritance

Answer 8

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

Question 9

Familial adenomatous polyposis incidence

Answer 9

• 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

Question 10

Severities of familial adenomatous polyposis

Answer 10

• 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

Question 11

Attenuated familial adenmatous polyposis variant

Answer 11

•

Question 12

Adenomatous polyp histology
1
2
3 a, b, c

Answer 12

• 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)

Question 13

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

Answer 13

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

Question 14

Most common polyp in the bowel

Answer 14

Benign lesion. Hyperplastic polyps.

Question 15

Appearance of villous adenoma

Answer 15

Finger-like projections of epithelium.

Have goblet cells

Question 16

Features of high-grade dysplasia
1
2

Answer 16

1) Loss of polarity of epithelial cells

2) Fused glands in the mucosa.

Question 17

What is an adenomatous polyp?

Answer 17

A dysplastic polyp in the bowel

Question 18

When does an adenomatous polyp become colorectal adenocarcinoma?

Answer 18

When it invades beyond the muscularis mucosae.

There is a dermoplastic stromal reaction

Question 19

Genetic pathways to colorectal cancer

Answer 19

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

Question 20

Chromosomal instablity pathway

Answer 20

– Familial adenomatous polyposis (1% CRC)

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

Question 21

Common genetic changes in dysplasia carcinoma sequence
1
2
3

Answer 21

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

Question 22

Loss of APC function
1
2
3

Answer 22

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

Question 23

Chromosomal instability
1
2
3

Answer 23

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

Question 24

Accumulated mutations that can lead to colorectal cancer
1
2
3

Answer 24

– 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

Question 25

APC

Answer 25

Adenomatous polyposis coli. | A gene. Most commonly inactivated gene in colorectal cancer

Question 26

Most common familial colorectal cancer syndrome

Answer 26

Hereditary non-polyposis colorectal cancer (Lynch Syndrome)

Question 27

Proportion of colorectal cancers attributable to Lynch Syndrome

Answer 27

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

Question 28

Mean age of colorectal cancer onset with Lynch syndrome

Answer 28

45 years

Question 29

Inheritance of Lynch syndrome

Answer 29

Autosomal dominant, ~80-85% penetrance

Question 30

``` Extracolonic cancers associated with Lynch Syndrome 1 2 3 4 ```

Answer 30

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

Question 31

Microsattelite isntability

Answer 31

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

Question 32

What drives microsattelite instability pathway?

Answer 32

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

Question 33

Effect of defective DNA mismatch repair

Answer 33

• 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

Question 34

Type of polyp that often arises in proximal colon

Answer 34

Sessile serrated adenoma

Question 35

``` Features of sessile serrated adenoma 1 2 3 4 5 ```

Answer 35

– 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

Question 36

Mutation common in sessile serrated adenoma

Answer 36

BRAF V600E mutation

Question 37

Why are sessile serrated adenomas hard to detect?

Answer 37

Sessile (hard to detect with a colonoscope)

Question 38

Macroscopic features of colorectal cancer 1) a, b 2) a, b 3) a, b, c, d

Answer 38

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 ```

Question 39

``` Dukes' classification of CRC 1 2 3 4 ```

Answer 39

* 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)

Question 40

``` Australian Clinicopathological staging of CRC 1 2 3 4 ```

Answer 40

* ACPS A – Invades beyond muscularis mucosa * ACPS B – Invades beyond muscularis propria * ACPS C – Lymph node metastases * ACPS D – Distant metastase

Question 41

What is Dukes' staging system based on?

Answer 41

Pathological examination of resected tumour

Question 42

TNM staging system

Answer 42

T = Depth of Tumour invasion N = Lymph Node metastases M = Distant metastases

Question 43

``` T stages of TNM staging system 1 2 3 4 5 ```

Answer 43

* 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

Question 44

N stages of TNM staging system 1 2 3

Answer 44

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

Question 45

M stages of TNM staging system 1 2 3

Answer 45

* Mx - Distant metastases can’t be assessed • M0 - No distant metastases • M1 (Stage 4; Dukes D) - Distant metastases

Question 46

``` Things in a stage 2 CRC 1 2 3 4 5 ```

Answer 46

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

Question 47

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

Answer 47

Better, as they are more differentiated

Question 48

Possible pre-operative therapy for CRC

Answer 48

Preoperative (neoadjuvant) chemoradiotherapy can downgrade tumour before surgery

Question 49

When is pre-operative neoadjuvant therapy useful?

Answer 49

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

Question 50

How can a dysplasia be treated?

Answer 50

Complete resection can be curative

Question 51

Targeted therapies for some CRCs

Answer 51

Epithelial growth factor receptor (EGFR) monoclonal antibodies

Question 52

EGFR therapies 1 2

Answer 52

1) Cetuximab | 2) Panitumumab

Question 53

Cancers from which mutations are EGFR therapies ineffective to treat?

Answer 53

K-RAS and B-RAF

Question 54

Common therapy given for colon cancer

Answer 54

5-fluorouracil

Question 55

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

Answer 55

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