Chapter17: INTESTINES:Adenocarcinoma Flashcards
What is the most common malignancy of the GI tract and is a major cause of morbidity and mortality worldwide?
Adenocarcinoma of the colon is the most common malignancy of the GI tract and is a major
cause of morbidity and mortality worldwide.
In contrast, _the small intestine, which accounts for
75% of the overall length of the GI tract, is an uncommon site for benign and malignant tumors_.
Among malignant small intestinal tumors, adenocarcinomas and carcinoid tumors have roughly
equal incidence, followed by lymphomas and sarcomas.
Hence, our discussion is focused on
colorectal adenocarcinomas.
What is the epidemiology of Adenocarcinoma?
This represents nearly 15% of all cancer-related deaths, and is second only to lung cancer.
What age does colorectal cancer peaks?
Colorectal cancer incidence peaks at 60 to 70 years of age, and fewer than 20% of cases occur before age 50.
Which gender is more often affected by colorectal carcinoma?
Males are affected slightly more often than
females.
Colorectal carcinoma is most prevalent what countries?
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.
In Japan, where incidence was
previously very low, rates have now risen to intermediate levels (similar to those in the United
Kingdom), presumably as a result of changes in lifestyle and diet.
What are the dietary factors most closely associated with increased colorectal cancer?
- low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat.
Although these associations are clear, the mechanistic relationship between diet and risk
remains poorly understood.
What is the hypothesis behind how reduced fiber content contributes to carcinoma of the colon?
However, it is theorized that reduced fiber content leads to decreased stool bulk and altered composition of the intestinal microbiota.
This change may
increase synthesis of potentially toxic oxidative by-products of bacterial metabolism, which
would be expected to remain in contact with the colonic mucosa for longer periods of time as a
result of reduced stool bulk.
Deficiencies of vitamins A, C, and E, which act as free-radical scavengers, may compound damage caused by oxidants.
High fat intake enhances the hepatic
synthesis of cholesterol and bile acids, which can beconverted into carcinogens by intestinal
bacteria.
In addition to dietary modification, pharmacologic chemoprevention has become an area of
great interest.
Why?
Several epidemiologic studies suggest that aspirin or other NSAIDs have a protective effect.
This is consistent with studies showing that some
NSAIDs cause polyp regression in FAP patients in whom the rectum was left in place after colectomy.
It is suspected
that this effect is mediated by inhibition of the enzyme cyclooxygenase-2 (COX-2), which is highly expressed in 90% of colorectal carcinomas and 40% to 90% of adenomas.
COX-2 is necessary for production of prostaglandin E2, which promotes epithelial proliferation,
particularly after injury.
Of further interest, COX-2 expression is regulated by TLR4, which recognizes lipopolysaccharide and is also overexpressed in adenomas and carcinomas.
What is the pathogenesis of Colorectal cancer?
The combination of molecular events that lead to colonic adenocarcinoma is heterogeneous
and includes genetic and epigenetic abnormalities.
At least two distinct genetic pathways have
been described.
- In simplest terms, these are the APC/β-catenin pathway, which is associated with WNT and the classic adenoma-carcinoma sequence; and the
- microsatellite instability pathway, which is associated with defects in DNA mismatch repair (see Table 17-10 ).
Both pathways involve the stepwise accumulation of multiple mutations, but the genes involved and
the mechanisms by which the mutations accumulate differ.
Epigenetic events, the most common of which is methylation-induced gene silencing, may enhance progression along both pathways
What accounts for as much as 80% of sporadic colon tumors?
The classic adenoma-carcinoma sequence, which accounts for as much as 80% of
sporadic colon tumors, typically includes mutation of APC early in the neoplastic process
( Fig. 17-49 ).
Explain how the mutation of APC or epigenetic events can lead to development of adenocarcinoma.
Both copies of the APC gene must be functionally inactivated, either by mutation or epigenetic events, for adenomas to develop.
APC is a key negative regulator of β-catenin, a component of the WNT signaling pathway (see Chapter 7 ).
The APC protein normally binds to and promotes degradation of β-catenin.
With loss of APC function, β-catenin accumulates and translocates to the nucleus, where it activates
the transcription of genes, such as those encodingMYC and cyclin D1, whichpromote
proliferation.
This is followed by additional mutations, including activating mutations in KRAS, which also promote growth and prevent apoptosis.
The conclusion that mutation
of KRAS is a late event is supported by the observation that mutations are present in fewer than 10% of adenomas less than 1 cm in diameter but are found in 50% of adenomas greater than 1 cm in diameter and 50% of invasive adenocarcinomas.
Neoplastic progression is also associated with mutations in other tumor suppressor
genes such as those encoding SMAD2 and SMAD4, which are effectors of TGF-β signaling.
Because TGF-β signaling normally inhibits the cell cycle, loss of these genes may allow unrestrained cell growth.
The tumor suppressor p53 is mutated in 70% to
80% of colon cancers, but is uncommonly affected in adenomas,why?
suggesting that p53 mutations also occur at late stages of tumor progression
. “Loss of function” of p53 and
other tumor suppressor genes is often caused by chromosomal deletions, pointing out
that chromosomal instability is a hallmark of the APC/β-catenin pathway.
Alternatively, tumor suppressor genes may be silenced by methylation of a CpG-rich zone, or CpG island, a 5′ region of some genes that frequently includes the promoter and transcriptional start site.
Expression of telomerase also increases as lesions become more advanced.
What is the hallmark of the APC/β-catenin pathway?
. “Loss of function” of p53 and
other tumor suppressor genes is often caused by chromosomal deletions, pointing out
that chromosomal instability
What is microsatellite instability?
In patients with DNA mismatch repair deficiency (due to loss of mismatch repair genes, as discussed earlier) mutations accumulate in microsatellite repeats, a condition referred to as microsatellite instability.
While these mutations are generally silent
because microsatellites are typically in noncoding regions, some microsatellite sequences are located in the coding or promoter region of genes involved in regulation of cell growth, such as those encoding the type II TGF-β receptor and the pro-apoptotic
protein BAX ( Fig. 17-50 ).
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.
Mutations in the oncogene BRAF and silencing of distinct groups of genes due to CpG island hypermethylation are also common in cancers that develop through DNA mismatch repair defects. In contrast, KRAS and p53 are not typically mutated.
Thus, the
_combination of microsatellite instability, BRAF mutation, and methylation of specific
targets, such as MLH1, is the signature of this pathway of carcinogenesis_
A third group of colon cancers with increased CpG island methylation in the absence of microsatellite instability also exists.
Many of these tumors harbor what mutations?
- KRAS mutations*, but
- *p53 and BRAF mutations are uncommon.**
In contrast, p53 mutations are common in colon cancers that do not display a CpG island methylator phenotype
FIGURE 17-49 Morphologic and molecular changes in the adenoma-carcinoma sequence.
It is postulated that loss of one normal copy of the tumor suppressor gene APC occurs early.
Individuals may be born with one mutant allele, making them extremely prone to develop colon cancer, or inactivation of APC may occur later in life.
This is the “first hit” according to
Knudson’s hypothesis ( Chapter 7 ).
The loss of the intact copy of APC follows (“second hit”).Other mutations include those on KRAS, losses at 18q21 involving SMAD2 and SMAD4, and inactivation of the tumor suppressor gene p53, lead to the emergence of carcinoma, in which additional mutations occur.
Although there seems to be a temporal sequence of changes, the accumulation of mutations, rather than their occurrence in a specific order, is most critical.
FIGURE 17-50 Morphologic and molecular changes in the mismatch repair pathway of colon carcinogenesis.
Defects in mismatch repair genes result in microsatellite instability and permit accumulation of mutations in numerous genes. If these mutations affect genes
involved in cell survival and proliferation, cancer may develop
While morphology cannot reliably predict the underlying molecular events that led to
carcinogenesis, certain correlations have been associated with mismatch repair deficiency and
microsatellite instability
What are these molecular alterations are common in what morphology?
These molecular alterations are common in sessile serrated adenomas.
In addition, invasive carcinomas with microsatellite instability often have prominent mucinous differentiation and peritumoral lymphocytic infiltrates.
These tumors, as well as those
with a CpG island methylator phenotype, are frequently located in the right colon.
Tumors with
microsatellite instability can be recognized by the absence of immunohistochemical staining for mismatch repair proteins or by molecular genetic analysis of microsatellite sequences.
It is important to identify those with HNPCC because of the implications for genetic counseling, the
elevated risk of a second malignancy of the colon and other organs, and, in some settings,
differences in prognosis and therapy.
Overall, adenocarcinomas are distributed approximately where?
equally over the entire
length of the colon.
Tumors in the proximal colon often grow as what?
polypoid, exophytic masses that extend along one wall of the large-caliber cecum and ascending colon; these tumors rarely cause obstruction.
What is the appearance of carcinomas in the distal colon?
tend to be annular lesions that produce “napkin-ring” constrictions and luminal narrowing ( Fig. 17-51 ), sometimes to the point that obstruction occurs.
Tumors in the proximal colon often grow as polypoid, exophytic masses
that extend along one wall of the large-caliber cecum and ascending colon; these tumors
rarely cause obstruction. In contrast, carcinomas in the distal colon tend to be annular lesions
that produce “napkin-ring” constrictions and luminal narrowing ( Fig. 17-51 ), sometimes to
the point that obstruction occurs
Both forms grow into the bowel wall over time and may be palpable as firm masses.
What is the general microscopic characteristic of right- and left-sided colonic adenocarcinomas?
similar
Most tumors are composed of tall columnar cells that
resemble dysplastic epithelium found in adenomas ( Fig. 17-52A ).
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 ( Fig. 17-
52B ).
Others may produce abundant mucin that accumulates within the intestinal wall, and these are associated with poor prognosis.
Tumors may also be composed of signet-ring cells
that are similar to those in gastric cancer ( Fig. 17-52C ). Others may display features of
neuroendocrine differentiation.
What is responsible for the characteristic firm consistency in adenocarcinoma?
The invasive component of these tumors elicits a strong stromal desmoplastic response, which is responsible for their characteristic firm consistency
FIGURE 17-51 Colorectal carcinoma.
- A, Circumferential, ulcerated rectal cancer. Note the anal mucosa at the bottom of the image.
- B, Cancer of the sigmoid colon that has invaded through the muscularis propria and is present within subserosal adipose tissue (left). Areas of chalky necrosis are present within the colon wall (arrow).
FIGURE 17-52 Histologic appearance of colorectal carcinoma.
- A, Well-differentiated adenocarcinoma. Note the elongated, hyperchromatic nuclei. Necrotic debris, present in the gland lumen, is typical.
- B, Poorly differentiated adenocarcinoma forms a few glands but is largely composed of infiltrating nests of tumor cells.
- C, Mucinous adenocarcinoma with signet-ring cells and extracellular mucin pools.
FIGURE 17-53 Metastatic colorectal carcinoma.
- A, Lymph node metastasis. Note the glandular structures within the subcapsular sinus.
- B, Solitary subpleural nodule of colorectal carcinoma metastatic to the lung.
- C, Liver containing two large and many smaller metastases. Note the central necrosis within metastases.
