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colorectal carcinoma

الكلية كلية طب حمورابي     القسم الكلية ذات القسم الواحد     المرحلة 4
أستاذ المادة هديل عبد الاله رزوقي كربل       23/10/2016 19:57:30
COLONIC POLYPS AND NEOPLASTIC DISEASE L6

Polyps are most common in the colon but may occur in the esophagus, stomach, or small intestine. Those without stalks are referred to as sessile. As sessile polyps enlarge, proliferation of cells adjacent to the polyp and the effects of traction on the luminal protrusion, may combine to create a stalk. Polyps with stalks are termed pedunculated.
In general, intestinal polyps can be classified as non neoplastic or neoplastic.
The most common neoplastic polyp is the adenoma, which has the potential to progress to cancer. Non-neoplastic colonic polyps can be further classified as inflammatory, hamartomatous, or hyperplastic.

Adenomas
colonic adenomas, benign polyps that give rise to a majority of colorectal adenocarcinomas. Most adenomas, however, do not progress to adenocarcinoma. Colorectal adenomas are characterized by the presence of epithelial dysplasia.
MORPHOLOGY
Typical adenomas range from 0.3 to 10 cm in diameter and can be pedunculated or sessile.
Histologically, the cytologic hallmark of epithelial dysplasia is nuclear hyperchromasia, elongation, and stratification.
Pedunculated adenomas have slender fibromuscular stalks containing prominent blood vessels derived from the submucosa.
Adenomas can be classified as tubular, tubulovillous, or villous.
Tubular adenomas tend to be small, pedunculated polyps composed of small, rounded or tubular glands.
villous adenomas, which often are larger and sessile, are covered by slender villi. Although most colorectal adenomas are benign lesions, a small proportion may harbor invasive cancer at the time of
detection. Size is the most important characteristic that correlates with risk of malignancy. For example, while cancer is extremely rare in adenomas less than 1 cm in diameter, some studies suggest that nearly 40% of lesions larger than 4 cm in diameter contain foci of cancer. In addition to size, high-grade dysplasia is a risk factor for cancer in an individual polyp.

Familial Syndromes

Familial Adenomatous Polyps
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder marked by the appearance of numerous colorectal adenomas by the teenage years. It is caused by mutations of the adenomatous polyposis coli gene (APC). Acount of at least 100 polyps is necessary for a diagnosis of classicFAP.
Colorectal adenocarcinoma develops in 100% of patients with untreated FAP, often before age 30.

Adenocarcinoma
Adenocarcinoma of the colon is the most common malignancy of the gastrointestinal tract and is a major contributor to morbidity and mortality worldwide.

Epidemiology
Colorectal cancer incidence peaks at 60 to 70 years of age, and less than 20% of cases occur before age 50. Males are affected slightly more often than females. Colorectal carcinoma is most prevalent in the United States, Canada, Australia, New Zealand, Denmark, Sweden, and other developed countries. The incidence of this cancer is as much as 30-fold lower in India, South America, and Africa.
The dietary factors most closely associated with increased colorectal cancer rates are low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat.

PATHOGENESIS
The combination of molecular events that lead to colonic adenocarcinoma is heterogeneous and includes genetic and epigenetic abnormalities. At least two distinct genetic pathways APC/?-catenin pathway and the microsatellite instability pathway, which is associated with defects in DNA mismatch repair.
Both pathways involve the stepwise accumulation of multiple mutations, but the genes involved and the mechanisms by which the mutations accumulate differ.
The APC/?-catenin pathway. The classic adenomacarcinoma sequence, which accounts for as much as 80% of sporadic colon tumors, typically involves mutation of the APC tumor suppressor early in the neoplastic process.
The APC protein normally binds to and promotes degradation of ?-catenin. With loss of APC function, ?-catenin accumulates and translocates to the nucleus, where it activates the transcription of genes, such as those encoding MYC and cyclin D1, which promote proliferation. This is followed by additional mutations, including activating mutations in KRAS, which also promote growth and prevent apoptosis.
The tumor suppressor gene TP53 is mutated in 70% to 80% of colon cancers but is uncommonly affected in adenomas, suggesting that TP53 mutations also occur at late stages of tumor progression.
The microsatellite instability pathway. In patients with DNA mismatch repair deficiency.
Mutations accumulate in microsatellite repeats, a condition referred to as microsatellite instability. These mutations generally are silent, because microsatellites typically are located in noncoding regions, but other microsatellite sequences are located in the coding or promoter regions of genes involved in regulation of cell growth, such as those encoding the type II TGF-? receptor and the pro-apoptotic protein BAX. Because TGF-? inhibits colonic epithelial cell proliferation, type II TGF-? receptor mutants can contribute to uncontrolled cell growth, while loss of BAX may enhance the survival of genetically abnormal clones.
By contrast, KRAS and TP53 typically are not mutated.

MORPHOLOGY
Overall, adenocarcinomas are distributed approximately equally over the entire length of the colon. Tumors in the proximal colon often grow as polypoid, exophytic masses.
By contrast, carcinomas in the distal colon tend to be annular lesions that produce “napkin ring” constrictions and luminal narrowing.
The general microscopic characteristics of right- and left sided colonic adenocarcinomas are similar. Most tumors are composed of tall columnar cells that resemble dysplastic epithelium found in adenomas .The invasive component of these tumors elicits a strong stromal desmoplastic response, which is responsible for their characteristic firm consistency. Some poorly differentiated tumors form few glands .
Others may produce abundant mucin that accumulates within the intestinal wall, and these carry a poor prognosis. Tumors also may be composed of signet ring cells that are similar to those in gastric cancer.

Clinical Features
Cecal and other right-sided colon cancers most often are called to clinical attention by the appearance of fatigue and weakness due to iron deficiency anemia. Thus, it is a clinical maxim that the underlying cause of iron deficiency anemia in an older man or postmenopausal woman is gastrointestinal cancer until proven otherwise. Left-sided colorectal adenocarcinomas may produce occult bleeding, changes in bowel habits, or cramping left lower quadrant discomfort.
Although poorly differentiated and mucinous histologic patterns are associated with poor prognosis, the two most
important prognostic factors are depth of invasion and the presence or absence of lymph node metastases.


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