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COLONIC POLYPS AND NEOPLASTIC DISEASE
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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.
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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/β-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/β-catenin pathway. The classic adenomacarcinoma
sequence, which accounts for as much as 80% of sporadic colon
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tumors, typically involves mutation of the APC tumor suppressor early
in the neoplastic process.
The APC protein normally binds to and promotes degradation of βcatenin. With loss of APC function, β-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-β receptor and the pro-apoptotic
protein BAX. Because TGF-β inhibits colonic epithelial cell
proliferation, type II TGF-β 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 .
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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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