25. Tumors of the Small and Large Bowel Flashcards
1
Q
Though the small intestine makes up 75% the length of the GI tract, what % of the tumors are found there?
A
3-6%
2
Q
What is the most common tumor of the SI?
A
Adenoma near the ampulla
3
Q
What are four RFs for small intestine adenocarcinoma?
A
Crohn’s disease
Adenomas
Celiac disease
Familial polyposis syndrome
4
Q
What is the most common non-epithelial tumor in the GI tract? What is it derived from?
A
GIST
Mesenchymal origin, from interstitial cells of Cajal (pacemaker cells)
5
Q
What are three syndromes associated with GIST?
A
- Carney triad: GIST, pulmonary chondroma, extra-adrenal paragnaglioma
- Neurofibromatosis
- Carney-Stratakis syndrome
6
Q
What can be used to treate GIST and CML?
A
Gleevec/imatinib
7
Q
Where is GIST most commonly located?
A
Stomach (60%)
SI (30%)
Colon (4%)
8
Q
What % of GIST tumors have a c-kit mutation?
A
85%
9
Q
What are three specific markers for GIST?
A
c-kit (CD117)
DOG1
CD34
10
Q
What are three muscle markers that can be used for GIST but are not necessarily specific?
A
Actin
Desmin
S-100
11
Q
What two tyrosine kinase receptors can get mutated in GIST, and in what region of the receptor?
A
C-kit: juxtamembrane domain
PDGFRA: tyrosine kinase II domain
12
Q
What are neuroendocrine tumors of the GI that secrete bioactive compounds?
A
Carcinoid tumors
13
Q
What are components of carcinoid syndrome?
A
Vasomotor distrubances Intestinal hypermotility (diarrhea) Wheezing Hepatomegaly Cardiac involvement
14
Q
What condition can lead to MALT lymphoma?
A
H. pylori gastritis
15
Q
What is a polyp?
A
Epithelium-derived tumor mass which protrudes into the gut lumen
16
Q
What are the two main types of polyp by shape?
A
Pedunculated polyp
Sessile polyp
17
Q
A non-neoplastic polyp is a result of:
A
Abnomal mucosal maturation, inflammation, architectural distortion
**no malignant potential
18
Q
Neoplastic polyps arise from:
A
Proliferation and dysplasia (adenomas)
**precursor for carcinoma
19
Q
What are the three main types of non-neoplastic polyps?
A
Hamartomatous
Inflammatory
Lymphoid
20
Q
What is a hamartoma?
A
Benign tumor that is composed of mature, histologically normal elements that grow in a disorganized manner due to developmental error
21
Q
What is a choistoma?
A
Like a hamartoma, but in an abnormal location
22
Q
Where do 80% of juvenile, hamartomatous polyps occur? Shape?
A
Rectum
Pedunculated (1-3 cm)
23
Q
Histologic appearance of juvenile, hamartomatous polyps
A
Expanded lamina propria with variable inflammation
Abundant cystically dilated and tortuous glands
*non-neoplastic
24
Q
What is Juvenile polyposis syndrome?
A
Over 5 juvenile polyps in the stomach, SI, colon, rectum
25
What mutations are associated with juvenile polyposis syndrome?
SMAD4 (20%)
BMPR1A (20%)
**NOT PTEN
26
Juvenile polyposis syndrome is associated with risk for:
Adenomas
| 10-50% lifetime incidence of colon cancer
27
What mutation is Peutz-Jeghers syndrome associated with (hamartomatous polyps)
STK11
28
What is seen in Peutz-Jeghers syndrome?
Multiple GI hamartomatous polyps
| Hyperpigmentation--mucosal and cutaneous (fingers)
29
What is there an increased risk for with Peutz-Jeghers syndrome?
Intussusception
| Cancer of the pancreas, breast, lung, ovary, uterus (50% cumulative lifetime risk for cancer)
30
What are the characteristics of Peutz-Jeghers Polyp?
Large and pedunculated
Connective tissue and smooth muscle extends into the polyp
Abundant glands rich in goblet cells
31
What is Cowden syndrome?
AD condition with:
- Hamatomatous GI polyps
- Facial trichilemmomas
- Oral papillomas
- Acral keratoses
32
What is Cowden syndrome associated with a risk for?
Thyroid and breast cancer
| **polyps themselves have no malignant potential
33
What is Cronkhite Canada syndrome?
Non-herediatry syndrome with
- GI hamartomatous polyps
- Nail atrophy and alopecia (ectodermal abnormalities)
34
What are inflammatory polyps?
Psuedopolyps that form from regenerating mucosa adjacent to ulceration (usually with severe IBD)
35
What are lymphoid follicles?
Mucosal bumps that are caused by intramucosal lymphoid follicles (normal)
36
What are the two serrated polyps?
| What are the two types of polyps with malignant potential?
Hyperplastic and sessile serrated polyps
| Sessile serrated polyps and adenomatous polyps
37
What are serrated polyps?
Smooth protrusions of mucosa, usually at the tops of mucosal folds
Serrated lumnia and increased numbers of goblet cells
38
Where are most serrated polyps found?
Rectosigmoid colon
39
What is the prevelance of the two types of serrated polyps?
Hyperplastic 60-90% (MC)
| Sessile serrated 10-30%
40
What kind of mutation is associated with sessile serrated polyps?
BRAF V600E mutations
41
What do adenomas/adenomatous polyps arise from?
Arise from epithelial proliferative dysplasia
| Precursor lesions for adenocarcinoma
42
What are the three architectural types of adenomas/adenomatous polyps?
Tubular adenoma
Villous adenoma
Tubulovillous adenoma
43
Prevalence of adenomas?
| With adenomas, __fold greater risk for developing carcinoma
Common, 40-50% after 60
| 4 fold
44
Morphology and location of tubular adenomas
Small and pedunculated from dysplastic epithelium (elongated, psuedostratified, hyperchromatic nuclei with loss of mucin production)
90% in the colon
45
Morphology and location of villous adenoma?
Villous projections that are large and sessile
| Retrosignoid colon of older people
46
Why does invasion occur more readily with villous adneoma than tubular?
No stalk to act as a buffer zone--cancer invasion occurs directly into the colon wall, lymphatics
47
While cancer is rare in TAs under 1 cm, the risk of cancer approaches __% in sessile, villous adenomas over 4 cm
40%
48
Clinical presentation of adenomatous polyps
Asymptomatic or
| Present with rectal bleeding or anemia
49
When is endoscopic removal of pendunculated adenomatous polyps sufficient?
- Resection margins negative
- No vascular or lymphatic invasion
- Carcinoma not poorly differentiated
50
Colon and rectum cancer is the ___ deadliest cancer
Second
51
98% of colorectal cancer is what type?
Adenocarcinoma
52
Where are the most common locations for colorectal cancer?
```
Rectosigmoid colon (55%)
Cecum and ascending colon (22%)
Transverse colon (11%)
Descending colon (6%)
```
53
In what geographic locations are the highest death rates from colorectal cancer?
```
US
Australia
New Zealand
Eastern Europe
**linked to diet
```
54
What dietary practices are risk factors for colorectal carcinoma?
```
Excess dietary intake
Low fiber
High content of refined carbs
Red meat
Decreased intake of nicronutrients
Obesity and physical inactivity
```
55
Presentation of right sided colon cancer? Type of lesions?
Non-obstructive
Fatigue, weakenss, IDA
**Polypoid, exophytic lesions
56
Presentation of left sided colon cancer? Type of lesions?
Obstructive
Occult bleeding, changes in BMs, abdominal discomfort
Annular "napkin ring" constrictions
**Infiltrative
57
What classic presentation is colon cancer until proven otherwise?
IDA in a older male
58
What is the idea behind the 'adenoma-carcinoma sequence'?
Populations with a high prevalence of adenomas have a high prevalence of colon cancer, and vice versa
Distribution of the two is similar
59
What is typically the first mutation to occur in the multi-hit devo of adenoma-carcinoma?
Inactivating mutation in APC (5q11)
| **also beta catenin
60
What is the result of dysfunction of APC?
Increased WNT signaling, which leads to decreased cell adhesion and increased cell proliferation
61
What mutation occurs late in the multi-hit development of adeomas and carcinoma?
Loss of p53
62
Along with p53, APC, and beta catenin, what are other mutations involved in the development of colorectal cancer?
K-RAS
LOH
SMAD2 and 4
63
When colorectal cancer is insidiously infiltrative and difficult to identify grossly, what is this usually associated with?
Ulcerative colitis
64
What does that T of TMN classification represent?
Depth of invasion
65
What are the T stages of the TMN classification?
Tis: In situ (LP invasion)
T1: Invasion of submucosa
T2: Invasion of muscularis propria
T3: Penetration of muscularis propria into serosa
T4: Invasion into other structures/organs
66
What are stages 0-IV of colon carcinoma
```
Stage 0: in situ
Stage I: T1 or T2, N0, M0
Stage II: T3 or T4, N0, M0
Stage III: Any T, + nodes, M0
Stage IV: Any T, any N, M1
```
67
What is the difference between N1 and N2 in stage III?
N1: 1-3 positive LNs
N2: 4 or more positive LNs
68
What is the most important prognostic factor for colorectal carcinoma?
Stage of the tumor at the time of diagnosis
69
What is the 5 yr survival for stage I, II, III, IV?
I: 93.2%
II: 85%
III: 70%
IV: 8.1%
70
What are the different ways the colon carcinoma can metastasize?
What % of patients have mets at the time of dx?
- Direct extension into adjacent structures
- Met through LNs and vessels
* *25-30%
71
What are the four non-specific agents that can be used for colorectal carcinoma (more SEs)
5FU
Capecitabine
Irinotecan
Oxaliplatin
72
What are the three drugs that can be used for targeted therapy of colorectal cancer (picked based on the mutation prolife of the cancer present)
Bevacizumab
Cetuximab
Panitumumab
73
What are the two types of biomarkers with respect to their function?
Prognostic: info about the patient's overall outcome, regardless of therapy
Predictive: info about the effects of a particular therapeutic intervention
74
What receptor stimulates key processes involved with tumor growth and progression--proliferation, angiogenesis, invasion, and metastasis?
EGFR
| **overexpressed in a range of solid tumors
75
What 3 major pathways are activated by EGFR?
1. RAS-RAF-MAP kinase
2. PI3K-AKT
3. PLCy
76
What are the three domains of EGFR?
```
Extracellular domain
Transmembrane domain
Intracellular domain (tyrosine kinase)
```
77
What are the 4 subsets of EGFR?
ErbB1/EGFR/Her1
ErbB2/Her2
ErbB3/Her3
ErbB4/Her4
78
What subset of EGFR is expressed in COLON cancer, lung, and head and neck cancers?
ErbB1/EGFR/Her1
79
What are the two monoclonal antibodies to EGFR?
Cetuximab
| Ranitumumab
80
It is not the EGFR expression that dictates response to anti-EGFR therapy, but rather:
Constituativly active proteins downstream of EGFR, like K-RAS, B-Raf, PI3K, and PTEN
81
What is the major negative predicator of efficiency of EGFR monocloncal antibody tx (cetuximab and reanitumab)?
K-RAS mutation **
| BRAF mutation
82
What are the uncommon and autosomal dominant herediatary syndromes that involve the GI tract?
1. Peutz-Jeghers, Cowden disease, Juvenile
2. FAP- Gardner's and Turcot's syndromes
3. MYH associated polyposis (MAP)
4. Lynch syndrome
83
Inheritance and penetrance of familial adenomatous polyposis
Autosomal dominant
| Very penetrant
84
How many colonic adenomas are typically present in FAP?
500-2,500 (minimum of 100)
85
Tx for FAP?
Prophylactic colectomy, because colon adenocarcinoma occurs in 100%
86
FAP is due to inheritance of germline mutations in:
APC gene in chrom 5q11
87
What % of people with FAP have no fam hx (de novo, somatic mutations)
25%
88
What is the age of onset for FAP?
median 16
Range 5-38 years
Colorectal cancer in late 30s early 40s
89
What is attenuated FAP
<100 polyps
| Some residual low level of APC resulting in fewer polyps
90
What is Gardner syndrome?
Adenomatous polyposis
Osteomas
Epidermoid cysts
Desmoid tumors
91
What is Turcot syndrome?
Adenomatous polyposis
| Medulloblastoma
92
Where in the chromosome coding for APC are mutation leading to classical FAP? Attenuated? Garner?
Near N terminal
Near C terminal
Between (causes desmoids)
93
What is a herediatary colorectal cancer syndrome that looks like attenuated FAP (20-100 adenomatous polyps) but is caused by a different mutation (not APC)
MYH associated polyposis (MAP)
94
Inheritance pattern for MYH associated polyposis. Age of presentation
Autosomal recessive
| Older age of presentation
95
MAP is due to mutations in the MYH gene, which encodes what kind of protein?
DNA repair protein involved in base excision repair (repairs oxidation-induced DNA damage by removing A mis-paired with G)
96
What are the two common mutations in MYH associated polyposis?
494A->G
1145G->A
**present in 85-90%
97
What is lynch syndrome associated with an increased risk for?
Colorectal cancer
| Extra-intestinal cancer: endometrial cancer, ureter, renal pelvis)
98
What is the genetic defect in lynch syndrome?
DNA mismatch repair genes (microsatellite instability pathway)
99
What is Muir-Torre syndrome?
Subtype of Lynch syndrome
| Associated with multiple sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas
100
What are two histological presentation of Lynch syndrome tumors?
Mucinous features and chronic inflammation
| Mucionous faatures and signet ring features
101
What is the role of MSH2 and MSH6? PMS2 and MLH1
Find the mismatch
| Read the mismatch and remove mutant strand
102
What is the dominant protein in the MSH2/6 relationship?
| MLH1/PMS2?
MSH2
| MLH1
103
What happens with a sporadic (12%) or hereditary (3%) loss of mismatch repair (MMR) function?
Random accumulation of mutations during cell divisions
Mutant in important oncogenes/tumor suppressor genes
Further acceleration of tumor devlopment
Cancer
104
What is negative IHC with a MSH2 mutation?
MSH2 negative
| MSH6 negative
105
What is negative with a MSH6 mutation?
MSH6
106
What is negative with a PMS2 mutation?
PMS2
107
What is negative with a MLH1 mutation?
MLH1
| PMS2
108
Interpretation of a tumor that is + for MSH2, MSH6, MLH1, PMS2
Sporadic cancer, LS unlikely
109
Interpretation of a tumor that is - for MLH1, PMS2? Etiology?
LS or sporadic caner
| MLH1 mutation or MLH1 hypermethylation
110
Interpretation of a tumor that is - for MSH2 and MSH6? Etiology
LS
| MSH2 mutation
111
Interpretation of a tumor that is - for MSH6? Etiology
LS
| MSH6 mutation
112
Interpretation of a tumor that is - for PMS2? Etiology
LS
| PMS
113
What are sensitive markers for defective function of mismatch repair?
Microsatellites: with DNA slippage, MMR should repair the loss of DNA. Failure of system leads to variation in the size of microsatellites
114
What are the three outcomes of microsatellite testing?
Microsatellite stable (MSS): no markers show MSI
Microsatellite instability-LOW (MSI-L): one marker shows MSI
Microsatellite instability-HIGH (MSI-H): at least 2 markers show MSI
115
What is the difference in the response of MSI-L vs MSI-H to adjuvant chemo?
MSI-L have better outcomes with adjuvant chemo
| MSI-H have better outcomes without adjuvant chemo
116
What mutation has never been reported in a patient with lynch syndrome, but it present in 68% of patients with MSI CRC that is not related to lynch syndrome?
BRAF mutation
117
Do must people with MSI phenotypes and CRC have sporadic mutations or lynch syndrome?
SPORADIC
118
What are the types of cancer that can occur in the anal canal?
```
Basaloid carcinoma
Squamous cell carcinoma
Adenocarcinoma
Paget's disease
Small-cell carcinoma
Melanoma
```
119
What is the MC tumor of the appendix?
Carcinoid (20-39 yrs)
120
What is a mucocele?
Obstructed appendix containing insipissated mucin (not truely a tumor)
121
What is a mucinous cystadenoma of the appendix?
Mucus secreting epithelial tumor of the appendix
122
Where in the appendix are carcinoid tumors found?
At the distal tip
123
What is a condition that can result from mucin produced by mucinous adenocarcinoma of the appendic?
Psuedomyxoma peritonei: mucin into the peritoneal cavity, encasing the organs
