Tumors of the Small and Large Intestines Flashcards
The small intestine is an uncommon site for benign or malignant tumors despite its great length and its vast pool of dividing mucosal cells. True or false?
True.
What is a polyp?
A polyp is a mass that protrudes into the lumen of the gut; traction on the mass may create a stalked, or pedunculated, polyp. Alternatively, the polyp may be sessile, without a definable stalk.
What are juvenile polyps?
They are essentially hamartomatous proliferations, mainly of the lamina propria, enclosing widely spaced, dilated cystic glands. They occur most frequently in children younger than 5 years old but also are found in adults of any age; in the latter group they may be called retention polyps.
The colon, including the rectum, is host to more primary neoplasms than any other organ in the body. True or false?
True.
What are the four subtypes of adenomatous polyps?
- Tubular adenomas – mostly tubular glands, recapitulating mucosal topology
- Villous adenomas – villous projections
- Tubulovillous adenomas – a mixture of the above
- Sessile serrated adenomas – serrated epithelium lining the crypts
Maximum diameter is the chief determinant of the risk of an adenoma’s harboring carcinoma; architecture does not provide substantive independent information.
True.
How do the different types of adenoma present clinically?
The smaller adenomas are usually asymptomatic, until such time that occult bleeding leads to clinically significant anemia. Villous adenomas are much more frequently symptomatic because of overt or occult rectal bleeding. The most distal villous adenomas may secrete sufficient amounts of mucoid material rich in protein and potassium to produce hypoproteinemia or hypokalemia. All adenomas, regardless of their location in the alimentary tract, are to be considered potentially malignant.
How many colonic adenomas do individuals with familial adenomatous polyposis (FAP) typically develop?
500-2500 colonic adenomas; a minimum number of 100 is required for the diagnosis. Also, individuals with FAP exhibit an almost 100% lifetime incidence of duodenal adenomas. The risk of colonic cancer is virtually 100% by midlife, unless a prophylactic colectomy is performed.
Which genetic defect underlies FAP?
The genetic defect underlying FAP has been localized to the APC gene on chromosome 5q21.
Which other cancer syndromes seem to share the same genetic defect as FAP?
Gardner syndrome and the much rarer Turcot syndrome. These syndromes differ from FAP with respect to the occurrence of extra-intestinal tumors in the latter two: osteomas, gliomas, and soft tissue tumors, to name a few.
What are Peutz-Jeghers polyps?
Peutz-Jeghers polyps are uncommon hamartomatous polyps that occur as part of the rare autosomal dominant Peutz-Jeghers syndrome, characterized in addition by melanotic mucosal and cutaneous pigmentation.
What is the genetic lesion responsible for Peutz-Jeghers syndrome?
The syndrome is caused by germ-line mutations in the LKB1 gene, which encodes a serine threonine kinase.
What is Cowden syndrome and mutations in which gene cause it?
Cowden syndrome is characterized by hamartomatous polyps in the GI tract and by an increased risk of neoplasms of the thyroid, breast, uterus, and skin. This syndrome is caused by germ-line mutations in the PTEN (phosphatase and tensin homologue) tumor suppressor gene.
What is the function of the PTEN gene product?
PTEN, mutated in a large number of human cancers, encodes a phosphatase that has the ability to regulate many intracellular signaling pathways. It acts as a growth inhibitor by interrupting signals from several tyrosine kinase receptors (e.g., epidermal growth factor receptor) and by favoring apoptosis through the BAD/BCL2 pathways.
What is hereditary nonpolyposis colorectal cancer syndrome (HNPCC, also known as Lynch syndrome)?
HNPCC is caused by germ-line mutations of DNA mismatch repair genes. Individuals affected by this syndrome are at a high risk of developing colorectal cancers and other tumors such as cholangiocarcinomas.
Why is a diet low in fiber thought to contribute to increased colon cancer risk?
It is theorized that reduced fiber content leads to decreased stool bulk, increased fecal retention in the bowel, and an altered bacterial flora of the intestine. Potentially toxic oxidative byproducts of carbohydrate degradation by bacteria are therefore present in higher concentrations in the stool and are held in contact with the colonic mucosa for longer periods of time. Moreover, high fat intake enhances the synthesis of cholesterol and bile acids by the liver, which in turn may be converted into potential carcinogens by intestinal bacteria. Refined diets also contain less of vitamins A, C, and E, which may act as oxygen radical scavengers.
How are aspirin and other NSAIDs thought to exert a protective effect against colon cancer?
It is suspected that this effect is via inhibition of cyclooxygenase-2 (COX-2). This enzyme is overexpressed in 90% of colorectal carcinoma and 40% to 90% of adenomas. How COX-2 promotes carcinogenesis is not clear. Some of its effects may be mediated by production of prostaglandin E2 (PGE2), which seems to favor epithelial cell proliferation, inhibit apoptosis, and enhance angiogenesis. PGE2 may promote angiogenesis by enhancing production of vascular endothelial growth factor.
Which two pathogenically distinct pathways are believed to be responsible for the development of colon cancer?
- APC/β-catenin pathway ( or the adenoma-carcinoma sequence)
- Mismatch repair (or microsatellite instability) pathway
Describe the adenoma-carcinoma sequence.
Initially, there is localized epithelial proliferation. This is followed by the formation of small adenomas that progressively enlarge, become more dysplastic, and ultimately develop into invasive cancers. Such an adenoma-carcinoma sequence accounts for about 80% of sporadic colon tumors.
List the genetic correlates of the adenoma-carcinoma sequence.
- Loss of the APC tumor suppressor gene. This is believed to be the earliest event in the formation of adenomas.
- Mutation of K-RAS. Mutated RAS is trapped in an activated state that delivers mitotic signals and prevents apoptosis.
- 18q21 deletion. Loss of a putative cancer suppressor gene on 18q21 has been found in 60% to 70% of colon cancers. Three genes have been mapped to this chromosome location: DCC (deleted in colon carcinoma), SMAD2, and SMAD4.
- Loss of p53. Loss of this tumor suppressor gene is noted in 70% to 80% of colon cancers.
What is the link between the functions of the APC protein and those of β-catenin?
Normal APC promotes the degradation of β-catenin; with loss of APC function, the accumulated β-catenin translocates to the nucleus and activates the transcription of several genes, such as MYC and cyclin D1, which promote cell proliferation.
What do the SMAD genes encode?
They encode components of the transforming growth factor β (TGF-β) signaling pathway. Because TGF-β signaling normally inhibits the cell cycle, the loss of these genes may allow unrestrained cell growth.
Inherited mutations in which genes give rise to HNPCC?
Inherited mutations in one of five DNA mismatch repair genes (MSH2, MSH6, MLH1, PMS1, and PMS2) give rise to HNPCC. Of these, MLH1 and MSH2 are the ones most commonly involved in HNPCC-derived and sporadic colon carcinomas with DNA mismatch repair gene defects.
What is the consequence of loss of DNA mismatch repair genes?
Such loss leads to a hypermutable state in which simple repetitive DNA sequences, called microsatellites, are unstable during DNA replication, giving rise to widespread alterations in these repeats. The resulting microsatellite instability (MSI) is the molecular signature of defective DNA mismatch repair.
