Adenomatous Polyps

Where is the the *most common* site of metastasis of adenocarcinoma?

**liver** can involve lymph nodes, bones, lungs

*SMAD2 and SMAD4*

effect TGF-beta signaling loss of TGF-B allows unrestrained cell growth

pure squamous cell ca is associated with...

*HPV*

What are two most important prognostic features of adenocarcinoma?

*depth of invasion* *absence of lymph node metastases*

DNA mismatch repair pathway

*microsatellite instability* -mutations accumulate in microsattelite repeats located in coding or promoter regions mutations in *TGF-B and pro-apoptotic BAX*

adenocarcinoma -- two types of tumors

*proximal tumors* *distal tumors*

adenoma architecture (3 types)

*tubular* *tubulovillous* *villous*

adenocarcinoma -- *two major genetic pathways*

1) **APC/beta-catenin pathway** 2) **microsatelite instability pathway** *both pathways involve stepwise accumulation of multiple mutations*

hereditary non-polyposis colorectal cancer

AKA *Lynch syndrome* based on familial clustering of cancers at several sites including: -colorectum, endometrium, stomach, brain, small bowel, skin

What are the most common mismatch repair genes?

MSH2 and MLH1

*APC/beta-catenin pathway*

associated with WNT and the classic adenoma-carcinoma sequence more common APC negatively regulates beta-catenin if it is not mutated, therefore impeding proliferation

*microsatelite instability pathway*

associated with defects in DNA mismatch repair

FAP

associated with extra-intestinal manifestations *Gardner syndrome* and *Turcot syndrome*

familal adenomatous polyposis

autosomal dominant mutation of APC gene

*distal tumors*

carcinomas tend to be annular causing "napkin ring" tumors causing luminal narrowing sometimes obstruction

*R sided tumors*

cause fatigue and jaundice due to iron deficiency anemia

*L sided lesions*

cause occult bleeding, changes in bowel habits and cramping of the LLQ

colorectal adenomas

characterized by *presence of dysplasia* **the majority of adenomas DO NOT progress to adenocarcinomas** clinically silent may secrete protein and potassium causing *hypoproteinemia and hypokalemia*

Gardner syndrome

familial adematous polyposis sebaceous cysts *osteomas especially of skull, mandible, long bones* mutation in gene in 5q *thyroid cancer* *fibromas* high risk of colon carcinoma

HNPCC

inheritance of a faulty DNA mismatch repair gene = microsatellite instability

What happens if intramucosal carcinom invades *muscularis mucosa*?

it is considered invasive and can metastasize

*villous*

larger and more sessile, covered with slender villi more likely to be *harbor foci of invasion, more likely to have foci of dysplasia, and more likely to develop into carcinoma*

dietary factors

may lead to potentially toxic oxidative by products of bacterial metabolism come into contact with mucosa for longer period of time due to dec. stool bulk

*tubulovillous*

mixture of both types

sessile serrated adenoma -most commonly found? -malignant potential? -resemble:

more commonly found in the *Right colon* malignant potential but lack typical cytological features of dysplasia may resemble *hyperplastic polyps* lateral growth and crypt dilation

colonic adenomas

most clinically significant neoplastic polyp small pedunculated to large sessile lesion *precursors to the majority of adenocarcinomas* velvety surface (resemble a *raspberry*)

adenocarcinoma

most common malignancy of the GIT *dietary factors* -high refined carbs and fat, lower intake of fiber

*tumor suppressor gene p53*

mutated in 70-80% of colon cancers

classic adenoma-carcinoma sequence

mutations of *KRAS* tumor progression is also associated with mutations in tumor suppressor genes such as *SMAD2* and *SMAD4*

How is *dysplasia* characterized in colonic adenomas?

nuclear hyperchromasia, elongation, and stratification -disordered cell growth

intramucosal carcinoma

occur when dysplastic epithelial cell penetrate the BM to *invade the laminal propria or muscularis mucosa* lack lymphatic channels

What is the production of mucin associated with in adenocarcinoma?

poorer prognosis

APC gene

produces protein which regulates beta-catenin which acts in the WNT signaling pathway to regulate epithelial proliferation

*KRAS*

promote growth and prevent apoptosis

Turcot's syndrome

rare variant of familial adenomatous polyposis central nervous system tumors especially *glioblastoma*

adenocarcinoma -- histology

tall columnar cells resembling dysplastic epithelium strong *desmoplastic* response causing firmness produce *mucin*

*proximal tumors*

tend to be polypoid, exophytic masses extending along one edge of the colon rarely will cause obstruction

*tubular*

tend to be small, pedunculated with small rounded or tubular glands

tumors of the anal cancal

typical glandular or squamous patterns of differentiation immature cells basaloid pattern mixed with squamous or mucinous differentiation

What are the more common ages and location of non-polyposis colorectal cancer? What causes this ca to occur?

younger ages R colon inherited mutations in genes that encode proteins needed for detection, excision, and repair of errors that occur during DNA rep.