Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1410_Библиотеки_им_академика_М_И_Перельмана
.pdf
23. Colorectal Cancer: Epidemiology, Etiology 481
synthesis leading to formation of a truncated or shortened
protein product that affects the function of the protein.
• Although only a single abnormal allele is inherited in FAP, sporadic mutations are always acquired resulting in the formation
of hundreds to thousands of colonic adenomas and ultimately
carcinoma.
• The APC protein normally regulates the Wnt (wingless sign-
aling pathway), an important pathway in cell regulation and
development, through modulation of beta-catenin – a critical
protein in the Wnt pathway.
• Normally, the protein product of the APC gene binds beta-
catenin intracellularly forming a multiprotein complex that
inhibits beta-catenin function. The increased functional levels of beta-catenin that result from alterations in APC protein
product function leads to cell proliferation, and enhances cell
to cell adhesion, limiting cell migration. Thus, hyperproliferating cells accumulate and aberrant crypt foci, the earliest phase
of colorectal neoplasia.
• The p53 gene, located on the short arm of chromosome 17
(17p) is an important gatekeeper gene for carcinogenesis – it is
the most frequently mutated gene in human cancers.
• Normally, by slowing the cell cycle, p53 facilitates DNA repair
during replication When repair is not feasible, p53 induces
apoptosis.
• Inactivation of p53 is found in up to 75% of sporadic colorectal
tumors; however, the mutation seems to occur late in the tumorigenic sequence.
• Thus p53 gene mutations do not seem to be initiators of carcinogenesis but act as key limiting factors for malignant transformation.
• In addition, p53 expression may be an independent prognostic
marker in patients with CRC.
• Most studies demonstrate a lower survival rate in patients with
advanced cancers that are p53 negative as compared with those
whose tumors express p53 gene product particularly in those
who receive chemotherapy.
• The “deleted in colorectal cancer” ( DCC ) gene was identifi ed
on the long arm of chromosome 18 (18q). Mutations in this
gene have been found in the majority of CRCs.
• The gene product of DCC is a transmembrane protein that is
important in cell–cell adhesion, and therefore inactivation of
482 The ASCRS Manual of Colon and Rectal Surgery
DCC may enhance the metastatic potential of CRC through
changes in adhesion.
• Similar to p53 , patients who have DCC -positive tumors
may have a better prognosis than those with DCC -negative
(mutated) tumors.
• Because millions of base-pairs must be replicated during mitosis, errors in DNA replication occur and must be corrected by
caretaker genes. The MMR system has a critical function in the
detection and correction of errors in DNA replication, maintaining DNA integrity. MMR genes function as spell checkers
– base-pair mismatches are identifi ed, excised, and the correct
sequence is synthesized and replaced.
• Lack of MMR function results in an accumulation in errors
in DNA replication, increasing the probability that a mutation
in an important gene in cell regulation will occur, will be preserved, and carcinogenesis will thus be initiated or promoted.
• Defects in the MMR system are identifi ed by the detection of
microsatellite instability. Microsatellites are small regions of
DNA located throughout the genome that do not code for individual genes.
• Microsatellites are particularly susceptible to MMR gene
defects, thus in cases of CRC attributable to MMR gene mutations, microsatellite replication errors accumulate, leading to
detectable differences in the pattern of microsatellites in the
tumor and in normal tissue; this is termed microsatellite instability (MSI).
• The National Cancer Institute recommends the testing of fi ve
microsatellite sequences to determine the MSI status of a
tumor. If two or more of the fi ve sequences demonstrate MSI,
the tumor is designated MSI-high (MSI-H). If only one of the
fi ve sequences demonstrates changes in tumor microsatellite markers, the tumor is designated MSI-low (MSI-L). If no
markers are changed, the tumor is microsatellite stable.
• Approximately 15% of CRC is MSI.
• MSI-H tumors are more likely to be high-grade, right-sided,
mucinous, and have tumor-infi ltrating lymphocytes. In addition,
MSI tumors may have a better prognosis than microsatellite
stable tumors, but may be less responsive to chemotherapy.
• A number of MMR genes ( MLH1 , MSH2 , MSH3 , MSH6 , and
PMS1 ) have been identifi ed. Germline mutations in the MLH1
and MSH2 genes are responsible for the majority (>90%)
23. Colorectal Cancer: Epidemiology, Etiology 483
of cases of the hereditary nonpolyposis colorectal cancer
(HNPCC) syndrome (discussed fully elsewhere in the text),
whereas approximately 5–10% of HNPCC cases are attributable to mutations in the MSH6 gene.
• In their landmark article, Vogelstein et al. (Fig. 23.6 ) described
the pathogenesis of colon cancer as one that follows a predictable sequence of events, from adenoma to carcinoma, with histologic changes developing as genetic mutations are acquired
over time.
– Initially, a mutation in a gatekeeper gene such as the APC
gene occurs resulting in proliferation of the colorectal
mucosa and leads to the fi rst histologically detectable
event, the aberrant crypt focus. In aberrant crypt foci, the
crypts have larger diameters than normal and stain more
darkly with methylene blue.
– With additional genetic changes, cells within the aber-
rant crypt become dysplastic and an adenoma forms.
Fig. 23.6. The adenoma to carcinoma sequence of colorectal carcinogenesis.
(Reprinted from Hardy RG, Meltzer SJ, Jankowski JA. ABC of CRC. Molecular
basis for risk factors. Br Med J 2000;321:886–889, with permission of the BMJ
Publishing Group.)
484 The ASCRS Manual of Colon and Rectal Surgery
– Further genetic alterations are acquired, resulting in an
increase in the size of the adenoma. However, the majority of adenomas do not develop into carcinoma.
– Therefore, additional genetic alterations are required
before the severity of dysplasia increases, and eventually,
particularly with mutations in tumor promoters such as
p53 , carcinoma develops. This pathway to carcinogen-
esis is termed the chromosomal instability pathway.
– Tumors forming through this pathway demonstrate
extensive cytogenetic abnormalities, such as aneuploidy,
and visible chromosomal losses and gains.
• CRC most frequently demonstrates chromosomal instability,
indicating this is the most common genetic cause of colorectal
carcinogenesis.
• Although MSI-H tumors may arise from adenomas, there is
increasing evidence that sporadic MSI-H tumors also arise
from hyperplastic polyps and serrated adenomas.
• Serrated adenomas are polyps that in the past would have been
classifi ed as hyperplastic polyps but have architectural features
both of hyperplastic polyps and cytologic features of classic
adenomas.
• Because only 70% of all colorectal carcinomas are believed to
arise from classic adenomas, serrated adenomas may be the precursor lesion for a substantial number of cancers. However, the
risk associated with serrated adenomas, in terms of progression
to cancer, is unknown and currently under investigation.
• Development of CRC in UC represents a third pathway to the
carcinogenesis in the colon. Most cancers develop in UC without a precursor polyp and therefore a direct dysplasia to carcinoma sequence is postulated. Genetically, cancers associated
with UC seem to be heterogenous; aneuploidy and disruption
of p53 may occur as early events, however MMR genes may
also be affected.
24. Screening for Colorectal Neoplasms
A. Introduction
• Evidence is mounting that colorectal adenocarcinoma can be
prevented by detecting and removing adenomatous polyps, and
that detecting early-stage cancers reduces mortality from the
disease.
• Both polyps and early-stage cancers are usually asymptomatic;
cancers that have grown large enough to cause symptoms have
a much worse prognosis.
• Most people will be of average risk and require screening for
colorectal cancer and polyps beginning at age 50. However, a
substantial number of people are at increased risk because of
an inherited predisposition to the disease and need screening or
treatment as early as puberty.
• Germline and somatic truncating mutations of the adenomatous polyposis coli gene are thought to initiate colorectal tumor
formation in familial adenomatous polyposis (FAP) and sporadic colorectal carcinogenesis, respectively. Genetic testing
for FAP can help guide surveillance and treatment of patients
at risk for the disease.
• Hereditary nonpolyposis colorectal cancer (HNPCC) is thought
to be the result of DNA mismatch repair defi ciency, and genetic
testing for HNPCC may ultimately prove to have clinical value
for patients in HNPCC families.
D.E. Beck et al. (eds.), The ASCRS Manual of Colon and Rectal Surgery, 485
DOI: 10.1007/978-0-387-73440-8_24, © Springer Science + Business Media, LLC 2009
486 The ASCRS Manual of Colon and Rectal Surgery
B. Classifi cation of Risk and Screening
Recommendations
• The cornerstone in determining a patient’s risk for developing colorectal cancer is the family history. Failure to properly
investigate a patient’s family history of colorectal neoplasia
can lead to inappropriate and inadequate treatment of both the
patient and at-risk family members.
Average Risk
• As can be seen in Table 24.1 , the majority of patients who
develop colorectal cancer have no identifi able risk factors.
• Specifi cally, average-risk persons have no symptoms associated with colorectal cancer, no personal history of colorectal
cancer or adenomatous polyps, no family history of colorectal
neoplasia, no infl ammatory bowel disease, and no unexplained
anemia.
• Screening recommendations (Table 24.2 ): The AHCPR panel
recommended that average-risk persons should undergo one of
the following screening regimens, beginning at age 50:
– Fecal occult blood testing annually
– Flexible sigmoidoscopy every 5 years
– Fecal occult blood testing annually and fl exible sig-
moidoscopy every 5 years
– Air contrast barium enema every 5–10 years
– Colonoscopy every 10 years
• Several large randomized controlled trials have shown that
annual or biennial testing for fecal occult blood with complete diagnostic evaluation of the colon (primarily with colonoscopy) for patients with a positive FOBT reduces mortality
from colorectal cancer.
Table 24.1. Patients with colorectal cancer.
75% Average risk (sporadic)
15–20% Family history of colorectal cancer
3–8% HNPCC
1% FAP
1% Ulcerative colitis
24. Screening for Colorectal Neoplasms 487
affected family member, whichever is earliest
b
a
a
40 years, or 10 years before diagnosis of the youngest
b
5 years
FOBT annually
Flexible sigmoidoscopy every 5 years
Colonoscopy every 10 years
1. Colonoscopy every 5 years
FOBT annually fl exible sigmoidoscopy every
Air contrast barium enema every 5–10 years
2. Air contrast barium enema every 5 years
Genetic counseling
Puberty
1–2 years
Consider genetic testing
7–8 years after the diagnosis of pancolitis; 12–15
1–2 years
Genetic counseling
Consider genetic testing
years after the diagnosis of left-sided colitis
Table 24.2 Screening for colorectal cancer and polyps.
Risk category Screening method Age to begin screening
Average risk Choose one of the following: 50 years
Family history Choose one of the following:
HNPCC Colonoscopy every 1–3 years 21 years
FAP Flexible sigmoidoscopy or colonoscopy every
Rigid proctoscopy is rmmended as an adjunctive examination to allow adequate visualization of the distal rectum. Furthermore, fl ex-
The American Cancer Society recommends the combination of yearly FOBT and fl exible sigmoidoscopy as preferable to either exami-
a
Ulcerative colitis Colonoscopy with biopsies for dysplasia every
ible sigmoidoscopy may be necessary to more completely evaluate a tortuous or spastic sigmoid colon
b
nation alone
488 The ASCRS Manual of Colon and Rectal Surgery
• However, because of the lack of sensitivity of FOBT, the
American Cancer Society recommends combining annual
FOBT with fl exible sigmoidoscopy every 5 years rather than
using FOBT alone as a screening method.
• A major drawback to using FOBT as a screening technique is
poor compliance. Only 38%–60% of the patients in prospective trials completed all the planned FOBT tests, and use of
FOBT in the general population is estimated to be lower than
in the research environment.
• The restriction of frequently ingested foods and medications,
combined with the natural aversion to stool sampling, makes
annual FOBT unappealing to many persons.
• FOBT should not be confused with random stool guaiac testing, which is the analysis of stool found on digital rectal examination for blood. The lack of adequate diet and medication
restriction before the test, potential for trauma to the anal canal
during digital rectal examination, and the inability to reliably
obtain stool from the distal rectum make the test unreliable. To
date, random stool guaiac examination has not been demonstrated to have benefi t in screening for colorectal cancer.
• The effectiveness of sigmoidoscopy as a screening tool depends
on its ability to detect cancers and adenomatous polyps in
the distal colon. If adenomatous polyps are found at fl exible
sigmoidoscopy, colonoscopy should be strongly considered
because almost one-third of such patients will have neoplastic
lesions in the proximal colon.
• The effi cacy of sigmoidoscopy in reducing mortality from colorectal cancer has never been proven by a randomized, controlled
trial, although case-control studies have shown a benefi t.
• The American Cancer Society recommends combining fl exible
sigmoidoscopy every 5 years with annual FOBT, rather than using
fl exible sigmoidoscopy alone as a screening method. Although
this combined approach may detect more proximal neoplasms
than fl exible sigmoidoscopy alone, 15–25% of patients with
negative fl exible sigmoidoscopy and negative FOBT will have
neoplastic lesions in the proximal colon at colonoscopy, calling
the rationale for this approach into question.
• The effi cacy of barium enema in preventing colorectal cancer
mortality has never been evaluated in a controlled trial, but can
be inferred from the fact that detecting polyps and early-stage
cancers by other methods reduces the incidence and mortality
from colorectal cancer.
24. Screening for Colorectal Neoplasms 489
– Air contrast barium enema will detect 50–80% of polyps
<1 cm, 70–90% of polyps >1 cm, and 50–80% of Stage I
and II adenocarcinomas.
– Single column barium enema is less sensitive and should
be combined with fl exible sigmoidoscopy if used as a
screening tool.
– Rigid proctoscopy should be considered as an adjunct
examination because the balloon on the enema catheter
often prevents adequate imaging of the distal rectum.
– Another major limitation of barium enema as a screen-
ing method is that patients usually require colonoscopy
if lesions are detected.
• Colonoscopy is the only screening technique that allows the
detection and removal of premalignant lesions throughout the
colon and rectum, and is the fi nal common pathway for any
positive screening test.
• It remains the gold standard to evaluate the colonic mucosa.
• The ability of colonoscopy to reduce colorectal cancer mortality has been demonstrated indirectly through studies showing
that detecting and removing polyps reduces the incidence of
colorectal cancer and that detecting early cancers lowers the
mortality from the disease.
• Compliance with screening colonoscopy may be superior to
that of other methods because no confi rmatory examinations
are required, and thus, patients are subjected to a single bowel
preparation.
• CT colography ( virtual colonoscopy ) was developed in an
attempt to increase compliance with colorectal cancer screening, based on the impression that persons would be more
inclined to have a “scan” than a “scope.”
– The technique involves thin-section computed tomogra-
phy (CT) with three-dimensional computer reconstructions to examine the colonic mucosa (Fig. 24.1a, b ).
– Although the technique has the advantages of being
noninvasive and not requiring sedation, a vigorous oral
laxative preparation is required, because adherent stool
is diffi cult to differentiate from neoplasia on CT. In
addition, a rectal catheter and air insuffl ation is used to
distend the colon.
– CT colography may ultimately prove to be as reliable as
colonoscopy in detecting colorectal neoplasia.
490 The ASCRS Manual of Colon and Rectal Surgery
a
b
Fig. 24.1 . ( a ) CT colography of an 87-year-old patient with a large tumor of the
splenic fl exure who could not undergo colonoscopy. The circumferential cancer
can be seen occupying the lumen of the colon. ( b ) This image is of the transverse
colon proximal to the cancer.
Соседние файлы в папке Библиотека им академика М.И. Перельмана