13 & 14 - Colon Cancer Flashcards
(76 cards)
1
Q
Third most common cancer in the USA
A
Colon Cancer
2
Q
Leading cause of cancer death in non-smokers
A
Colon cancer
3
Q
Majority of colorectal cancers
A
Sporadic
4
Q
Risk in general population of colorectal cancer
A
6 - 8%
5
Q
Risk for those with personal history of colorectal neoplasia
A
15% - 20%
6
Q
Risk for those with IBD
A
15% - 40%
7
Q
Risk for those with Lynch Syndrome
A
80%
8
Q
Risk for those with FAP
A
100%
9
Q
Strongest risk factor for colorectal cancer in general population
A
Age
Upswing begins at 50
10
Q
Other risk factors for CRC
A
High red meat diet Prior history of adenoma or cancer Family history of adenoma or cancer High fat diet smoking obesity
11
Q
Protective factors for CRC
A
High physical activity Aspirin/NSAID use High vegetable/fruit diet High fiber diet High folate/methionine diet High calcium intake postmenopausal hormone therapy
12
Q
First degree family history of CRC
A
Shift screening 10 years earlier
13
Q
Hereditary Colorectal Cancer Syndromes
A
Familial Adenomatous Polyposis (FAP)
Lynch Syndrome
Both involve germline inheritance of gene mutations
Autosomal dominant
14
Q
Sporadic Cancer
A
Tumor initiation 30 - 50 years
Tumor progression 10 - 20 years
Carcinoma 6% risk - mean age 66 years
15
Q
FAP
A
Tumor initiation 5 - 20 years
Tumor progression 10 - 20 years
Carcinoma 100% risk - mean age 40 years
16
Q
Lynch Syndrome
A
Tumor initiation 30 - 50 years
Tumor progression 1 - 3 years
Carcinoma 80% risk - mean age 40 years
17
Q
Clinical Features of FAP
A
1% of all CRC 100 - 1000s of adenomas APC gene mutations Risk of extracolonic tumors (desmoids, duodenal cancer, thyroid, brain) Risk of CRC 100% if untreated
18
Q
Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)
A
Associated with FAP
19
Q
Desmoid Tumor
A
Fibrous, non-malignant, obstruction is greatest risk
Surgery increases their risk.
They grow back bigger.
20
Q
Diagnosis of FAP
A
APC gene mutations in >90% with classic polyposis
Family history: AD inheritance
Prevalence 1/8000
De novo mutations - 30% of carriers have no family history
21
Q
Management of FAP
A
Sigmoidoscopy at 10 - 12 years and every 2 years to assess polyp burden
Colectomy
Upper GI surveillance for adenomas
Genetic counseling
22
Q
Lynch Syndrome
A
Most common hereditary CRC syndrome 5% of all CRC Defective DNA mismatch repair Mutations in MLH1, MSH2, MSH3, PMS2 Lifetime risk of CRC = 70 - 80% Risk is markedly lower if we begin colonoscopies early
23
Q
Lynch Syndrome - Clinical Features
A
Striking family history (multiple generations) Early (but variable) age at CRC diagnosis (mean 45 years) Multiple primary cancers Extracolonic cancers: Endometrium Ovary Urinary tract Stomach Small bowel Sebaceous carcinomas of skin
24
Q
Lynch Syndrome - Mechanism
A
Failure of mismatch repair (MMR) genes
Microsatellite instability
25
Lynch Syndrome - Amsterdam Criteria
```
Three or more CRC diagnoses in a family
Two or more generations
1 case is a first degree relative of the other two
One is affected by age 50
FAP excluded
```
26
Lynch Syndrome - Revised Bethesda Guidelines
CRC
27
Lynch Syndrome Screening Recommendations
Colonoscopy starting at age 20 - 25, repeat every 1 - 2 years
Transvaginal ultrasound & endometrial aspirate annually starting at age 25 - 35
28
Asymptomatic, no risk factors
```
Start screening at age 50
Colonoscopy
Flexible sigmoidoscopy
CT colonography
Double contrast barium enema
Fecal stool tests (Guaiac-based fecal occult blood test or fecal immunohistochemical test) - Can't detect polyps, though...
```
29
Screening for patients risky enough to warrant colonoscopy
```
History of adenomas
History of CRC
Family history of adenomas
Family history of CRC
IBD
Hereditary CRC Syndromes
```
30
Right colon symptoms
Occult bleeding
Obstruction
Anemia
Abdominal Mass
31
Left colon symptoms
```
Gross bleeding
Obstruction
Anemia
Change in bowel habits
Pain
```
32
Metastatic CRC Spread
Lymphatics:
Mesenteric nodes
Virchow's nodes
Hematogenous spread:
Liver via portal circulation
33
Types of polyps
Adenomas
Serrated sessile polyps
Hyperplastic polyps
34
Adenomas
True pre-malignant lesions that have a risk for developing cancer
Blue means dysplasia
Lack of surface maturation
Proliferation extends to surface
35
Hyperplastic polyps
```
Benign
Pink
Saw tooth shape of surface epithelium
Normal surface maturation
No dysplasia
Proliferation restricted to crypts
```
36
Pedunculated Adenomas
Nice stalk
| Easier to excise than sessile
37
Sessile Adenomas
Gotta resect
38
Polypectomy is effective/curative if
Stalk margin has normal colonic mucosa
No lymphatic/vascular invasion
Tumor is not poorly differentiated
39
Dysplastic Crypt
Earliest sign of an adenoma/adenocarcinoma to come
Never catch it at this point
If you can catch it (probably via familial setting) you can cure it before ever forming a polyp
40
WNT Pathway
At rest, WNT is inactive
APC destroys beta catenin
WNT signaling prevents APC's action and beta catenin remains intact. Proliferation!
41
FAP - with regard to WNT pathway
Always on!
You don't even need WNT.
It is a problem with APC
Beta Catenin never gets degraded!!
42
Key protein in sporadic cases
Always MLH1 - but not due to a mutation
| It is epigenetics! The promoter is methylated!
43
MSH2 deficiency - Sporadic or Lynch?
LYNCH!!!
44
2 Molecular categories of CRC
Microsatellite Instability
| Chromosombal Instability
45
CRC - Microsatellite Instability
Nucleotide-level mutations
Hypermutated (many at high frequency)
15% of CRC
Leads to HNPCC/Lynch (Germline Mutation of MLH1, MSH2, MHS6, PMS2, MMR genes)
OR
Leads to Sporadic MSI+ (Epigenetic silencing of MLH1 by hypermethylation of its promotor region)
46
CRC - Chromosomal Instability
More macro genetic mutations
Non-hypermutated (low frequency)
85% of CRC
Leads to FAP (Germline mutation of APC gene)
OR
Leads to Sporadic CIN (Acquired mutations of APC, p53, DCC, KRAS, LOH)
47
What genetic testing do we do on all cases of CRC?
```
KRAS
BRAF
PIK3CA
MMR
Lynch
```
48
TNM Classification (Tumor Node Metastasis) - Tumor
T - Primary Tumor
Tx - Primary tumor cannot be assessed
T0 - No evidence of primary tumor
Tis - Carcinoma in situ (intraepithelial or intramucosal invasion of lamina propria)
T1 - Tumor invades submucosa (start to develop risk of invasive tumor/metastatic invasion)
T2 - Tumor invades muscularis propria
T3 - Tumor invades through muscularis propria into subserosa or into pericolic/perirectal fat
T4 - Tumor directly invades other organs or structures and/or perforates the visceral peritoneum
49
TNM Classification (Tumor Node Metastasis) - Node
N0 - No regional lymph node metastasis
N1 - Metastasis in 1 to 3 regional lymph nodes
N2 - Metastasis in 4 or more regional lymph nodes
50
TNM Classification (Tumor Node Metastasis) - Metastasis
M0 - No distant metastasis
| M1 - Distant metastasis
51
Stage 1 Colorectal Cancer
25% of CRC
Cancer has grown through mucosa and invades muscularis
Treatment - Surgery to remove the tumor & some surrounding lymph nodes
5-year Survival 90%
Once you reach 5 years, recurrence is unlikely
52
Stage 2 Colorectal Cancer
30% of CRC
Cancer grows beyond muscularis of the colon or rectum, but has not spread to lymph nodes
Treatment (colon) - Surgery +/- adjuvant chemo
Treatment (rectal) - Sugery, radiation, chemo
53
Stage 3 Colorectal Cancer
25% of CRC
Cancer has spread to regional lymph nodes
Treatment (Colon) - Surgery and adjuvant chemo
Treatment (Rectal) - Surgery, radiation & Chemo
Survival - 40% to 80%
54
Stage 4 Colorectal Cancer
20% of CRC
Cancer has spread to other areas of the obdy
Treatment - Chemotherapy, surgery to remove mets (liver/lung) in carefully-selected patients
Survival - Evolving
55
CRC Prognosis Depends on
Histo (poor differentiation, vascular invasion)
Depth of invasion
Nodal involvement
Genetic alterations: -18Q LOH (bad), MSI (good)
56
CRC Treatment
Surgery (Stage 1, 2, 3) - Try to remove isolated mets
Radiation (Rectal cancer) - Prevent local recurrence
Pharmaceuticals (Stage III Node+ and IV)
57
CRC Pharmaceuticals
5-Fluorouracil
Irinotecan
Oxaliplatin
58
5-Fluorouracil
Pyrimidine antimetabolite
59
Irinotecan
Topoisomerase I inhibitor
| Prevents re-ligation after cleavage of DNA by Topoisomerase I
60
Oxaliplatin
Alkylating agent
| Causes formation of bulky DNA adducts
61
Irinotecan - Side Efects
Alopecia
| GI toxicity
62
5-Fluorouracil - Side Effects
Gi toxicity
63
Oxaliplatin - Side Effects
Neuropathies
| Cold tingly
64
CRC Biologics
```
Bevacizumab
Regorafenib
Aflibercept
Cetuximab
Panitumumab
```
65
Bevacizumab
Ab against VEGF-A
| May block angiogenesis and also stabilize leaky vasculature
66
Regorafenib
Multi-targeted TKI
67
Aflibercept
Binds to circulating VEGF
Costs $11,000/month
Prolongs survival by 1.4 months
68
Cetuximab
Antibodies against EGFR
| KRAS mutation means this drug won't work!!
69
Panitumumab
Antibodies against EGFR
| KRAS mutation means this drug won't work!!
70
Bevacizumab Toxicities
```
Bleeding
Thrombosis
Hypertension
Wound healing complications
Half life of about 3 weeks, wait at least 2 half lives before major surgery
```
71
Cetuximab & Panitumumab Toxicities
Horrible rash
| Rash predicts better outcome though so haaaayyy
72
Types of cancers with a LOT of mutations
```
Melanoma
Lung Cancer
Bladder Cancer
Esophagus
Colorectum
```
Mostly associated with toxins
73
CTLA4
On T Cells
Brake on the immune system
Prevents T Cells from attacking body
PD1 is another receptor that does the same thing
74
Who responds to PD1 inhibitors?
Mismatch Repair cancers!
| Tumors with a ton of mutations!!
75
Survival for those with metastatic disease
Systemic chemo - 3 years
Sometimes treat neoadjuvantly
If the metastases are "limited" you can CURE!
76
Can you resect a liver met? - Criteria
Ability to resect all evident disease
Ability to leave a sufficient hepatic remnant (at least 2 contiguous remaining segments, adequate inflow and outflow, adequate hepatic volume and function) - >20% desirable
