133 - Dysplasia - Carcinoma Sequence in the Colon Flashcards
Precursor lesions for colorectal carcinoma
– Tubular adenoma: sessile or pedunculated
– Villous adenoma: often large & sessile
– Tubulovillous adenoma: mixed features
Predictors of increased malignant risk:
1
2
3 a, b, c
– Polyp size (>1cm)
– Villous morphology
– High grade dysplasia
• Severe crowding with loss of nuclear polarity
• Marked nuclear variation (pleomorphism)
• Cribriform intramucosal growth (gland fusion)
Familial syndrome with a ~100% risk of developing colon cancer
Familial adenomatous polyposis
Pedunculated tubular adenoma appearance
Pedunculated, red mass on luminal wall of large intestine.
Can bleed into lumen.
Sits atop a stem,
Sessile villous adenoma
Can be very large without invasion (in colon)
Risks for early-onset colorectal cancer
1
2
1) Familial syndromes
2) Chronic inflammatory bowel disease
Chronic inflammatory bowel diseases that can predispose to early-onset colorectal cancer
1
2
1) Ulcerative colitis
2) Crohn’s disease
Familial adenomatous polyposis inheritance
• Autosomal dominant syndrome
– APC gene mutation (chromosome 5q21-22)
– > 100 adenomatous polyps in the large bowel
– Extracolonic manifestations
Familial adenomatous polyposis incidence
• 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
Severities of familial adenomatous polyposis
• 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
Attenuated familial adenmatous polyposis variant
•
Adenomatous polyp histology
1
2
3 a, b, c
• 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)
Features of dysplasia in familial adenomatous polyposis 1 2 3 4 5
– Crowded cells
– Enlarged, hyperchromatic, pseudostratified nuclei
– Abnormal complexity to glandular architecture
– Goblet cell depletion
– Increased mitotic count +/- atypical mitoses
Most common polyp in the bowel
Benign lesion. Hyperplastic polyps.
Appearance of villous adenoma
Finger-like projections of epithelium.
Have goblet cells
Features of high-grade dysplasia
1
2
1) Loss of polarity of epithelial cells
2) Fused glands in the mucosa.
What is an adenomatous polyp?
A dysplastic polyp in the bowel
When does an adenomatous polyp become colorectal adenocarcinoma?
When it invades beyond the muscularis mucosae.
There is a dermoplastic stromal reaction
Genetic pathways to colorectal cancer
1) Chromosomal instability (most common)
2) Microsatellite instability
3) CpG island methylator phenotype
Chromosomal instablity pathway
– Familial adenomatous polyposis (1% CRC)
– 75%-85% of sporadic CRC (colorectal cancer)
Common genetic changes in dysplasia carcinoma sequence
1
2
3
1) Loss of APC function
2) Chromosomal instability (most common)
3) Accumulated mutations
Loss of APC function
1
2
3
1) Decreased cell adhesion and increased cellular proliferation
2) APC mutation an early event in adenoma formation
3) Multiple adenomas in Familial Adenomatous Polyposis
Chromosomal instability
1
2
3
– Aneuploid karyotype
– Large chromosome segment deletions and duplications
– Increased nuclear DNA content
Accumulated mutations that can lead to colorectal cancer
1
2
3
– 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
APC
Adenomatous polyposis coli.
A gene. Most commonly inactivated gene in colorectal cancer
Most common familial colorectal cancer syndrome
Hereditary non-polyposis colorectal cancer (Lynch Syndrome)
Proportion of colorectal cancers attributable to Lynch Syndrome
~3% (vs 1% for familial adenomatous polyposis)
Mean age of colorectal cancer onset with Lynch syndrome
45 years
Inheritance of Lynch syndrome
Autosomal dominant, ~80-85% penetrance
Extracolonic cancers associated with Lynch Syndrome 1 2 3 4
– Endometrium
– Renal pelvis/ureter, stomach, small bowel, ovary
– Glioblastoma multiforme (Turcot syndrome)
– Sebaceous tumours (Muir Torre syndrome)
Microsattelite isntability
In long tracts of repeating DNA, DNA polymerase can make mistakes (EG: can make six repeats instead of seven).
What drives microsattelite instability pathway?
Defective DNA mismatch repair.
Germline mutation in MSH2 or MLH1 (in over 90%).
OR sporadic MLH1 hypermethylation
Effect of defective DNA mismatch repair
• 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
Type of polyp that often arises in proximal colon
Sessile serrated adenoma
Features of sessile serrated adenoma 1 2 3 4 5
– 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
Mutation common in sessile serrated adenoma
BRAF V600E mutation
Why are sessile serrated adenomas hard to detect?
Sessile (hard to detect with a colonoscope)
Macroscopic features of colorectal cancer
1) a, b
2) a, b
3) a, b, c, d
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
Dukes' classification of CRC 1 2 3 4
- 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)
Australian Clinicopathological staging of CRC 1 2 3 4
- ACPS A – Invades beyond muscularis mucosa
- ACPS B – Invades beyond muscularis propria
- ACPS C – Lymph node metastases
- ACPS D – Distant metastase
What is Dukes’ staging system based on?
Pathological examination of resected tumour
TNM staging system
T = Depth of Tumour invasion
N = Lymph Node metastases
M = Distant metastases
T stages of TNM staging system 1 2 3 4 5
- 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
N stages of TNM staging system
1
2
3
- N0 - No lymph node metastases
- N1 (Stage 3; Dukes C) - Metastases in 1-3 lymph nodes
- N2 - Metastases in 4 or more lymph nodes
M stages of TNM staging system
1
2
3
- Mx - Distant metastases can’t be assessed
• M0 - No distant metastases
• M1 (Stage 4; Dukes D) - Distant metastases
Things in a stage 2 CRC 1 2 3 4 5
1) High grade
2) T3 with localised perforation or T4
3) Close, indeterminate or positive margins
4) Lymphovascular invasion
5) Under 12 nodes examined
Are CRC tumours with glands better or worse than solid ones?
Better, as they are more differentiated
Possible pre-operative therapy for CRC
Preoperative (neoadjuvant) chemoradiotherapy can downgrade tumour before surgery
When is pre-operative neoadjuvant therapy useful?
Stages 1 and 2 CRCs. Not very helpful with stages 3 and 4
How can a dysplasia be treated?
Complete resection can be curative
Targeted therapies for some CRCs
Epithelial growth factor receptor (EGFR) monoclonal antibodies
EGFR therapies
1
2
1) Cetuximab
2) Panitumumab
Cancers from which mutations are EGFR therapies ineffective to treat?
K-RAS and B-RAF
Common therapy given for colon cancer
5-fluorouracil
Why might you not treat a microsatellite-instability CRC patient with 5-fluorouracil?
Because immune system can target tumours, and 5-fluorouracil can inhibit this
