of colorectal cancer among first-degree relatives.
Because of the high rate of cancer development
among individuals with HNPCC, kindreds affected
by this disease often have multiple family members,
across several generations, who have had nonpolypo-
sis colorectal cancer or endometrial cancer.
Additionally, a history of onset of the disease before
50 years of age is common. These findings have
been formalized as the Amsterdam criteria for the
clinical diagnosis of HNPCC. When the Amsterdam
criteria are met, family members can assume they
come from an affected kindred. The question for
them is if they are carriers of the causative mutation.
This question can be answered currently only in
those families with mutations in genes known to
cause an appreciable fraction of the cases of
HNPCC. Half of the cases are caused by mutations
in hMLH1 or hMSH2 and laboratory studies are
available for mutation analysis of these genes. An
individual who is found to carry a mutation is
advised to enter a program of intensive cancer
surveillance. If it is felt to be unlikely that he or she
will be able to comply with the demands of such a
program, the option of a subtotal colectomy may be
offered. Family members who are found not to
carry a mutation can simply be advised to enroll in a
routine program of screening for colorectal cancer
once they reach the age of 50 years. Members of
families in which HNPCC is caused by other
mutations cannot have their individual cancer risk
determined; they are left knowing only that they
have a 50:50 chance of carrying a causative
mutation. Intensive cancer surveillance is recom-
mended for all family members in this circumstance.
When the Amsterdam criteria are not met, there
is a possibility that a familial clustering of cancers
results from a different form of hereditary colorec-
tal cancer—one with a lower rate of development of
cancer—or else the clustering could be a chance
aggregation of sporadic tumors. Mutation analysis
of hMLH1 or hMSH2 would be informative in those
individuals in whom the result was positive, but a
negative result would not exclude the possibility of
HNPCC, as half of the kindreds with this disorder
have a different genetic basis, nor would it exclude
the possibility of other familial cancer predisposi-
tions. Clinical management in this situation is
guided by the epidemiologic finding that, in indi-
viduals who have two or more first-degree family
members with colorectal cancer, the risk of develop-
ing colorectal cancer is multiplied about 2.75 times
(Fuchs
et al.
1994). Because colorectal cancer is
common, there being a lifetime risk of 0.06 in the
general population, even a modest increase in risk is
significant and it is usually felt prudent to offer
intensive cancer surveillance as a clinical option.
Individuals with colorectal cancer who have a
family history of colorectal cancer in a first-degree
relative, who have previously had colorectal cancer
or endometrial cancer, who are younger than 55
years, or who have a tumor with characteristic
pathologic findings, are candidates for examination
of their tumor tissue for microsatellite instability and
mutation analysis (Jass 2000). Mutations of the
DNA mismatch repair enzymes that cause HNPCC
result in insertion and deletion mutations at microsat-
ellite sequences, referred to as microsatellite insta-
bility (Boland 2000). Hypermethylation of the
promoter region of hMLH1, which is not associated
with a familial predisposition to cancer, also causes
microsatellite instability but occurs only in elderly
patients (Jass 2000). In cases in which tumors show
microsatellite instability, histochemical staining of
the tumor tissue or laboratory mutation analysis of
white cells from the patient can be used to identify
individuals with germline mutations in hMLH1 or
hMSH2. Demonstration of such a mutation estab-
lishes a diagnosis of HNPCC. Given this finding,
first-degree family members should undergo evalua-
tion of their carrier status.
Diagnosis
Because of the serious medical and psychological
implications of being diagnosed with cancer, the
diagnosis must be established with certainty. With
very few exceptions, this means that microscopic
examination of the cancerous tissue is required. The
microscopic examination may take the form of surgi-
cal pathologic review of a biopsy specimen, cytopa-
thologic examination of cells exfoliated from the
lesion, or hematologic evaluation of blood or bone
marrow. Despite the generally high specificity of
microscopic examination, it is not usual for the
diagnosis of cancer to be based solely on the micro-
scopic findings. To achieve even greater diagnostic
specificity, clinical, imaging, and laboratory findings
are also considered. Typically, it is only if there is
consistency in all of the findings that the diagnosis of
cancer is made.
Whenever possible, diagnosis includes classifica-
tion of the cancer in terms of its cell type. Classifi-
cation is usually quite easy given the location and
Cancer
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