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Flashcards in CM- Colorectal Cancer Deck (44):
1

What is proposed to be a substantial risk for the development of colorectal cancer?
What is the believed mechanism for why this is?

High fat, low fiber diets are proposed to be a cause because colorectal cancer is more prevalent in developed countries. People that move from areas where it is NOT endemic to areas where it is are at an increased risk for development suggesting diet and environment.

Fat: increased cholesterol and bile acid delivery to the intestine where they are metabolized by endemic bacteria into carcinogens

Fiber: should increase stool bulk, diluting the carcinogens. Also, increased transit time through the colon decreasing the time carcinogens are exposed to the colon

2

In addition to increased fiber, what else is hypothesized to decrease the risk for colorectal cancer?

1. vitamins- ACE
2. cruciferous vegetables (green/leafy)
3. calcium
4. chronic use of NSAIDs/aspirin

3

Adenocarcinomas do NOT often arise de novo from normal colonic epithelium.
Describe the adenoma-carcinoma progression.

How long does the progression from normal cells to adenocarcinoma usually take?

1. normal epithelium gets mutations that activate proto-oncogenes or inhibit tumor suppressors

2. hyperproliferating cells get additional gene mutations that lead to a clone of autonomous, neoplastic cells

3. Neoplastic cells are dysplastic (seen on histology) and accumulate to form an adenamatous polyp (adenoma)

4. Additional mutations occur in the adenoma and the cells become highly dysplastic

5. Some cells acquire mutations enabling invasion of other tissues [malignant adenocarcinoma]

This whole progression takes 7-12 years

4

What genes are typically found to be mutated in the adenoma-carcinoma sequence? Put them in order of proposed sequence of mutation.

1. APC deletion (loss of a tumor supressor)
[normal to hyperproliferative epithelium]

2. KRas (oncogene)
[early adenoma --> intermediate]

3. DCC (tumor suppressor loss)
[intermediate-->late adenoma]

4. p53 (tumor suppressor)
[late --> carcinoma]

5

What are the 6 factors that predispose to CRC?

1. Age
2. Diet [high fat, low fiber]
3. Genetic disorders [FAP/HNPCC]** highest risk
4. chronic IBD [crohn or UC]
5. personal Hx of adenomas or prior CRC
6. FHx of CRC or adenoma

6

For a person with chronic IBD, what 2 things increase the risk of colorectal cancer?

1. extent of colonic involvement [pancolitis >> left sided only]

2. duration of disease [appreciable risk after 7 yrs]

7

A personal history of adenomas or prior CRC is associated with an increased risk of developing what?
What factor determines the risk?

They are at risk for developing subsequent metachronous tumors.

Risk increases with the # of adenomas on initial colonoscopy

8

FHx can predispose to colorectal carcinoma even in the absence of FAP and HNPCC. The risk increases with what 2 things?

1. the number of first degree relatives with CRC
2. family members that got it before the age of 50

9

What is the most common NON-neoplastic polyp of the colon?
What size are they and what part of the colon are they generally found?
What is their potential for malignancy?

Hyperplastic polyps are usually less than 5mm and are found in the rectosigmoid.

They have little [if any] malignant potential EXCEPT for:
**>1cm, Serrated hyperplastic polyps in the right colon.

[there serrated polyps were first noted to lead to malignancy in HNPCC and hyperplastic polyposis syndrome]

10

What three features of the adenomatous polyp correlate with malignant potential?
What is considered low, medium and high risk for malignancy?

1. Size
- low = less than 1cm
-med = 1-2 cm
-high = over 2 cm

2. Histology
-low = tubular [branching network of glands]
-med = tubulovillous [ combo]
-high = villous [ fingerlike glands projecting straight down to the center of the polyp]

3. Dysplasia
Mild -> intermediate-> high degree of dysplasia

11

What symptoms are usually associated with adenomotous polyps?
What are rare exceptions?
How are adenomas usually discovered?

Usually, they have no symptoms.
Bleeding is VERY rare (esp. with small polyps) so iron deficient anemias and GI bleeds should NOT be caused by adenomatous polyps.

Rarely, large polyps may cause obstruction or intussusception.

They are discovered incidentally in sigmoidoscopic, colonoscopic or barium enemas for cancer screening.

12

How do symptoms of colon cancer change depending on which part of the colon is involved?

Although uncommon, what can happen in any part of the colon?

Right colon is larger diameter and the stool is still majority liquid so tumors can grow longer w/o causing obstruction. The most common manifestation in the cecum and ascending colon is slow bleeds and iron deficient anemia.

Left colon is more narrow and has more solid stool. Tumors that grow circumferentially interfere with the movement of bowel causing:
-cramping
-alternating diarrhea and constipation
- bowel obstruction
-bleeding (hematochezia)

Uncommonly perforation and peritonitis can occur in both the ascending AND descending colon?

13

What are the 3 diagnostic tests used for colonic polyps and CRC?

1. barium enema
2. sigmoidoscopy
3. colonoscopy

14

What are the pros and cons of barium enemas for identifying polyps?

Pros:
1. inexpensive
2. good sensitivity (60-80%)
3. no sedation
4. widely available

Cons:
1. if you find a polyp, you need to do a colonoscopy anyway to biopsy/remove
2. false + due to retained stool in the bowel

15

What are the pros and cons of sigmoidoscopy for identifying colon polyps?

Pros:
1. highly sensitive (90%)
2. can biopsy/remove polyps if they're found

Con:
1.Only does the distal colon/rectum and polyps are usually evenly spread out throughout the colon

16

What are the pros and cons of colonoscopy for identifying colon polyps/CRC?

Pros:
1. highly sensitive (90%)
2. can biopsy/remove polyps

Cons:
1. expensive
2. require sedation and extensive bowel prep (time consuming)

17

What is treatment for hyperplastic polyps? Why?

They are removed by colonoscopy because they cannot be differentiated grossly from adenomatous (neoplastic) polyps.

After you do histology exam on the polyp, you see that it is a benign lesion and the person is not required to be entered into regular surveillance program for detecting neoplasm

18

What is treatment for adenomatous polyps?

Remove them at colonoscopy.

Diminutive polyps (less than 5mm) rarely harbor malignancy, however, until techniques are developed to predict biological behavior of adenomas, remove ALL polyps.

19

What is considered to be "carcinoma in situ"?
What is intramucosal carcinoma?

How are they treated?

Carcinoma in situ = highly dysplastic/malignant appearing epithelial cells that do not extend below the basement membrane of their glands.

Intramucosal carcinoma = malignant looking cells penetrate the BM and extend into the lamina propria but do not go past the muscularis mucosa.

Both are considered non-invasive because lymphatics are not in the mucosa (therefore there is essentially no metastatic potential). Removal of these lesions is CURATIVE.

20

What is treatment for malignant polyps? What features have been identified that can estimate the risk of leaving residual tumor?

Malignant tumors extend below the muscularis mucosa and therefore have access to lymphatics (metastatic potential)

Treatment:
colonoscopic polypectomy is curative for MOST however there is potential for residual cancer in the bowel wall and regional lymphatics.

The chance of residual is increased with:
1. degree of differentiation
2. invasion of veins/ lymphatics
3. involvement of polypectomy margin
4. invasion of the subucosa in the bowel wall

21

Are pedunculated or sessile malignant polyps more likely to have an adverse outcome?

Sessile because they lack a stalk and therefore is higher chance of submucosal involvement

Pedunculated have a stalk and the risk for adverse outcome is low if the carcinoma is confined to the submucosa of the stalk and does not reach the submucosa of the bowel wall

22

What are the 4 indications for surgical resection in patients with endoscopically-removed malignant polyps?

1. poorly differentiated
2. cancerous cells within 2mm of polypectomy margin
3. invades lymphatics or veins
4. invades submucosa of the bowel wall

23

A patient is found to have colorectal cancer. What should you do before initiating definitive therapy?

A complete colonoscopy to look for:
1. synchronous masses
2. adenomatous polyps

24

What is the treatment for colorectal cancers?
What adjuvant can be given for higher stage tumors? (that have regional/distal mets)?

Surgical removal of:
1. the involved bowel (with 5cm of uninvolved bowel on each side)
[if doing sphincter-sparing, need 2cm blow tumor]

2. lymphatics associated with that region of bowel

For stage C (III)- patients get 5-FU and levamisole
For B and C - patients get chemo and radiation

25

What are the 4 common screening procedures for CRC?

1. fecal occult bloot test (FOBT)
2. barium enema
3. sigmoidoscopy
4. colonoscopy

26

What is CRC surveillance?
What screening procedure is used?

Surveillance is doing colonscopies on high risk people (fam hist, prior Hx, diet, age, genetics, IBD) to identify curable neoplasias

27

How does the fecal occult blood test work?
What are the pros and cons?

1. stool is applied to guaiac-impregnated paper
2. H2O2 developer is applied
3. paper is oxidized to blue (quinine) in the presence of heme or hemoglobin (pseudoperoxidase activity)

Pros: cheap, fast, non-invasive
Cons: too many false - and false +, low sensitivity

28

What give false negatives on FOBT?

1. Vit C because it inhibits oxidation
2. sampling error
3. need atleast 1-2ml of blood to record on the test
4. .card storage >1 wk

29

What gives false positives on FOBT?

1. red meat hemoglobin in stool
2. vegetable peroxidases (Broc, cauli, turnips)
3. other GI blood loss (NSAIDS)
4. Fe leads to misinterpretation

30

What is FOBT used for?

Screening large populations of middle aged people and then giving colonoscopy to those with + result can reduce CRC mortality.

31

Why is barium enema not typically used as a screening tool for CRC?

It is more uncomfortable and expensive than FOBT and less sensitive than endoscopy

32

What is the current recommendations for screening/surveillance in patient with average risk for CRC?

Average risk means the person is over 50.
The recommendation is to get a colonoscopy screening! But the algorithm shows people over50 can get:
1. annual FOBT and/or
2. 5 year sigmoidoscopy
3. 5 year double contrast barium enema
4. 10 year colonoscopy

If the colonoscopy is negative (no polyps or cancer), repeat colonoscopy in 10 years.

If the FOBT or sigmoidoscopy is positive, the patient should get a colonoscopy. If it is negative --> upper GI tract evaluation
If colonoscopy is + --> treatment and followup

33

What is FAP?
What is the inheritence pattern of FAP?
What does it lead to?

FAP is caused by a mutation in APC tumor suppressor gene on 5q
. In familial adenomatous polyposis, it is passed down in an autosomal dominant fashion.

The inherited germline mutation leads to hyperproliferative cells in the colonic mucosa predisposing them to more mutations including the deletion of the second APC gene (loss of heterozygosity).

Loss of heterozygosity leads to diffuse adenomas that can progress to cancer.

34

Alteration of what gene can lead to a FAP-like presentation even with normal APC tumor suppressor genes?

MYH impairs the function of APC causing phenotypic FAP

35

What is the inheritence of FAP?
What is the gene mutation associated with it?
What is the median age to develop diffuse adenomatous polyps?
By the 3-5 decade of life, what percent will have CRC?
In addition to the colon, where else can polyps arise?

1. AD
2. APC gene on 5q
3. 16
4. 100%

It can cause gastric and duodenal polyps (esp. at the ampulla of Vader)

36

What is Gardner's syndrome?

1. soft tissue tumors (epidermal cyst)
2. dental abnormalities
3. osteomas

In patients with FAP

37

What extra-intestinal manifestations does FAP have?

1. congenital hypertrophy of the retinal pigment epithelium (CHRPE)
2. epidermal cyst
3. poor dentition
4. brain tumors
5. thyroid tumors
6. osteomas

38

What is HNPCC?
What is the inheritence pattern?
What genes are mutate?
What does this lead to?

It is an autosomal dominant disorder that predisposes people to the development of CRC.

It is a mutation in one of 5 DNA mismatch repair genes (MSH2, MLH1, PMS1 PMS2 MSH6)

Microsatellites are prone to errors in base pairing. If mismatch repair is inactive, errors accumulate and predispose to malignant progression. [microsatellite instability]

39

How does the clinical presentation of HNPCC differ from FAP?
1. describe the colonic presentation
2. describe age of onset, lifetime risk

HNPCC has few or no polyps when they are found to have CRC. Tumors tend to be right sided.

The mean age of diagnosis is 45 (after FAP, before average risk) and the lifetime risk of development is 80%.

40

What extracolonic manifestations are associated with HNPCC?

Tumors of:
1. endometrium
2. ovary
3. uroepithelium
4. stomach
5. small bowel
6. hepatobiliary system

41

What is the Amsterdam/Bethesda criteria essentially?

before genetic testing for mutations in mismatch repair genes, it was the standard for assessing if someone had HNPCC.

1. 3 family members with colon cancer (atleast 1 first degree)
2. 2 successive generations
3. 1 diagnosed before 50
4. FAP should be excluded

42

What is familial colon cancer type X?
How should you screen/treat?

Meet the Amsterdam criteria but lack the genetic markers of HNPCC.
Start colonoscopies 10 years younger than the youngest member that had polyps. Repeat 2-5 years

43

What is treatment/management for HNPCC?

1. Subtotal colectomy (attach ileum to rectum and remove whole colon) if there isn't initial rectal involvement
2. Proctocolectomy if rectal involvement
3. Females finish having families then get hysterectomy/bilateral salpingo-oopherectomy (reduce risk of ovarian/endometrial cancer)

4. EGD and colonoscopy every year (EGD bc of risk of stomach cancer)

44

What 5 factors are considered when making a screening plan for CRC for patients with IBD?

What is surveillance?

1. age of onset of IBD
2. duration of disease
3. involvement of colon (pancolitis > left colitis > proctitis)
4 PSC
5. genetic susceptibility

Surveillance is :
- 1st colonoscopy 8 years after IBD if pancolitis and 15 if left-sided or proctitis
- repeat every 1 to 2 years