Neoplasms of Lower GI Tract (use ppt for pics, chart @ end)

Question 1

Right sided mass

Answer 1

stool semi-liquid, so might not detect mass

Question 2

left sided mass

Answer 2

stool progressively well formed/solid, so more likely to get stuck/be detected if mass present

Question 3

Where are epithelial stem cells?

Answer 3

base of crypts

Question 4

Polyp

Answer 4

• sessile vs. pedunculated, neoplastic vs non-neoplastic

Question 5

adeoma

Answer 5

precurtsor to malignancy

Question 6

adenocarcinoma

Answer 6

invasive

Question 7

Pedunculated vs sessil

Answer 7

pedunculated has stalk

Question 8

Inflammatory polyps

Answer 8

Often present with bleeding
Often due to mucosal prolapse (very common in the rectum)
Cycles of injury and healing result in “polyp” formation = inflamed colonic mucosa with ulceration/erosion, epithelial hyperplasia

Question 9

Hamartomatous polyps

Answer 9

Most occurring in childhood (pre-pubertal)
Hamartoma: “tumor-like” over-growth / mature tissue / developing where it is normally present (e.g. colonic tissue developing in the colon)
Juvenile (sporadic and syndromic) and Peutz-Jeghers (syndromic)

Key Points
Polyps: Variable locations in lower GI system

Benign features histologically but syndromic juvenile polyps often have foci of dysplasia

May portend:

Risk of future GI carcinoma (increase frequency of screening)

Both Peutz-Jeghers and Juvenile polyposis = 40% cumulative risk for CA

Extra-GI manifestations

Need to consider familial screening (genetic counseling) in some cases

Types
Juvenile
Peutz-Jeghers
Others: Cowden, Cronkhite-Canada

Question 10

Extra-GI manifestations of Peutz Jeghers

Answer 10

Mucocutaneous pigmented lesions; increased risk of thyroid, breast, lung, pancreas, gonadal, and bladder cancers

Question 11

Extra-GI Manifestations of juvenile polyposis

Answer 11

Pulmonary arteriovenous malformations, digital clubbing

Question 12

Hyperplastic Polyps

Answer 12

Location: left colon including rectum (90%)

increases w/ age

small (

Question 13

Hyperplastic polyp histology

Answer 13

Smooth, nodular lesion with flat base
	 sessile 
Need microscopic evaluation to definitively distinguish 
Hyperplastic polyp
Adenomatous polyp

composed of mixed absorptive and goblet cells; cells are crowded, possibly due to delayed shedding of epithelium  “hyperplastic.” A serrated architecture results. This is a benign, usually non-neoplastic lesion to be distinguished from SSPs

Question 14

Serrated polyps

Answer 14

Not pre-malignant: hyperplastic (left sided)
Crypts with “star-shaped” / “serrated” appearance- Cytology: Not dysplastic
- Have been considered for decades “non- neoplastic

Premalignant:
Sessile Serrated Polyps/Adenoma (tend to be right sided) –> alternate pathways to carcinoma than the usual adenomatous polyp
Microsatellite Instability pathway
DNA hypermethylation pathway (CpG island methylation)

Architecture: looks like “serrated” knife
- Cytology: Dysplastic epithelium may or may not be present
Pre-neoplastic = DEFINITELY can progress to adenocarcinoma

Question 15

Adenomas

Answer 15

Size is variable – range from a few mm to several cm (10 cm or more)
In nearly 50% of Western adults by age 50

Present throughout the colon

Have epithelial cytologic dysplasia ranging from low grade to high grade (carcinoma in situ)

Villous adenomas contain foci of invasion more frequently than tubular adenomas but SIZE MATTERS (correlates with risk of malignancy )
Presence of high grade dysplasia increases risk of malignant transformation in that polyp but not in the rest of the colon

Question 16

Adenomatous changes on histology

Answer 16

1. Cells
   
   • Piling up on each other (no respect!)
2. Nuclei
   
   • Darker
     (hyperchromasia)
   • Progressive loss of basal-orientation
3. Cytoplasm - Reduced compared to nucleus
   (increased N:C ratio)
   
   • Reduced mucin production
4. Mitotic Figures - Increased mitotic activity

Question 17

Villous adenoma

Answer 17

Lesion is sessile – No stalk
Architecture: multiple, slender villi (finger-like projections)

Adenomatous(dysplastic)
histologic features

Question 18

Colorectal cancer

Answer 18

3rd most common in men and women

Question 19

Common mutation in Adenoma

Answer 19

APC @ 5q21

Later events: Beta catenin, K-RAS, loss of p53/SMAD2 and 4 tumor suppressor genes

Question 20

RFs/ PRotective factors for colorectal cancer

Answer 20

age
country of birth
FAP/HNPCC
longstanding UC

moderate:
high red meat diet
previous adenoma or cancer
pelvic irradiation

modest
high fat diet
smoking/alc
obesity 
cholecystectomy

Protective
phys activity
aspirin/NSAIDs

fruit/veg/fiber/folate methionine
Ca
Postmenopausal hormone therapy

Question 21

Main molecular pathways

Answer 21

WNT/APC/beta-catenin – classical adenoma-carcinoma sequence
K-Ras/MAP kinase/PI3 kinase signaling pathways—activating mutations
Microsatellite Instability – defects in mismatch repair proteins

methylation induced gene silencing enhances progression along pathway

Question 22

most CR cancers are

Answer 22

sporadic (followed by familial)

Question 23

WNT signaling altered in what % of CRC pts?

Answer 23

92%

Question 24

WNT pathway

Answer 24

Wnt protein ligands are critical for development

Animals lacking Wnt homologs fail to develop entire organs. (fly wnt-1 mut =wingless)

Wnt ligands drive proliferation of their target tissues/organs

The Wnt pathway regulates the levels of cytoplasmic beta-catenin

***WNT pathwayd involves APC and Beta-catenin (made often, degraded fast) Need all components in “destruction complex”: APC, Beta catenin, axin, etc. (Dishevelled activated and allows Beta catenin to escape destruction and act on genes)

Question 25

Where is beta-catenin turned off

Answer 25

@ top of crypt (if stays on, accumulation of cells @ site of future polyp formation) ``` Polyps represent An increase in the size of the proliferating crypt compartment ```

Question 26

FAP

Answer 26

Familial Adenometous Polyposis (Aut dom) APC mutations can run in families, producing Familial Adenomatous Polyposis (FAP) FAP patients have increased risk of colon cancer, but these account for a small fraction of the total cases of colon cancer (~5%) Most people who acquire colon cancer without FAP acquire spontaneous somatic mutations in APC In FAP: 100% will develop invasive adenocarcinoma, often before age 30

Question 27

Cetuximab

Answer 27

EGFR inhibitor (monoclonal antibody)

Question 28

Hereditary Non-Polyposis Colorectal Cancer aka Lynch Syndrome

Answer 28

Develop colon cancer at an earlier age than sporadic forms Tend to be right-sided Inherit mutation of mismatch repair gene allele, acquire the second allele mutation over time leading to microsatellite instability

Question 29

Advancing vs early colon carcinoma

Answer 29

``` Change in bowel habits and indicators Constipation Urgency Narrowing of stool Cramping / pain Blood Loss Blood in stool or bleeding from rectum (BBBPR) Anemia (iron-deficiency) Unexplained weight loss ``` ``` Early Colon Carcinoma No symptoms most often Nonspecific findings Fatigue Weight loss Anemia ```

Question 30

Detection of neoplasms

Answer 30

Visualization +/- Biopsy = Colonoscopy = Barium enema = Other options Blood Detection in Stool - Hemorrhage of ulcerated lesion DNA / Mutation Detection in Stool - Shed neoplastic cells vs. normal colonic epithelial cells

Question 31

Carcinoma

Answer 31

Invasion of dysplastic epithelial cells into and beyond the lamina propria Adenomas at risk: 4 cm: high risk (~40% in one study) of identification of invasive component within lesion

Question 32

typical adenocarcinoma histology

Answer 32

gland formation mucin production Neoplastic glands (adenocarcinoma) invading into muscularis propria, inciting a “desmoplastic” (fibrotic) response. There is “dirty necrosis” in the lumen of some of the glands (arrow), a fairly common finding in colon carcinoma.

Question 33

Prognosis

Answer 33

Most important prognostic factors: Depth of invasion Presence or absence of lymph node metastasis Distant metastasis

Question 34

Where does colon cancer most commonly metastasize to?

Answer 34

LIVER

Question 35

Therapy for colon cancer

Answer 35

Surgery Local excision – e.g. polypectomy Colonic resection Radiofrequency ablation Cryosurgery Chemotherapy -Only treatment = palliative -Adjunctive treatment Pre or Post-Operative Radiation therapy Targeted Therapy - Monoclonal antibodies - Angiogenesis inhibitors