2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

degree relatives and consider referral for any concerning
features in the family history.
There are a number of potential limitations to the use of
family history as a screening tool, such as adoption of the
patient or another family member without information
about biologic relatives, small family size, limited or no
contact with relatives, and early death from noncancer
related causes. In addition, for some hereditary cancer
syndromes, there are a number of de novo or new dominant
mutations or alternative inheritance patterns (i.e., autosomal
recessive) and, in these cases, family history would
not be fully informative. As family histories evolve over
time, it is also possible that members may not have yet
demonstrated features of a particular hereditary cancer
syndrome. This is especially true in pediatrics where parents
will be younger than those of adult patients. For this
reason, frequent updating of the family history is indicated.
Many cancer syndromes are also characterized by reduced
penetrance and may not exhibit a clear inheritance pattern.
Medical History and Physical Features Concerning for a Hereditary
Cancer Syndrome
Medical history and physical examination are important
components in the evaluation of children for a cancerpredisposing
syndrome. Several hereditary cancer syndromes
are characterized not only by the development of
cancer, but also by the presence of certain physical or
developmental manifestations that might provide important
clues to the diagnosis (Table 2). These may include congenital
anomalies or dysmorphic features, along with developmental
delays, intellectual disabilities, autism, or autism
spectrum disorders. Other associated features may include
skin findings, macrocephaly, and benign tumors or polyps.
In many cases, one or more of these features precede the
development of cancer and serve as an early clue to the
diagnosis. The presence of one or more of these features in a
child diagnosed with cancer should raise suspicion for a
hereditary cancer syndrome and prompt referral to a geneticist
or genetic counselor. Referral to other specialties may
also be necessary to evaluate and manage the physical or
neurocognitive issues related to these genetic conditions.
Management of Children with Cancer Predisposition
Surveillance. Recognition of hereditary cancer syndromes
in children is necessary to facilitate appropriate surveillance
and management of individuals who are predisposed to
malignancies. Surveillance and management guidelines exist
or are being developed for several hereditary cancer
syndromes with onset in childhood (Table 2). The primary
goal of cancer surveillance is to detect cancer at the earliest
and most curable stage with the least amount of complications
and late effects from treatment. For this reason, cancer
surveillance protocols are most suited for solid tumors, such
as hepatoblastoma and Wilms tumor, where outcome is
directly linked to stage at diagnosis. By detecting cancer at
an early stage, cancer surveillance protocols aim to improve
overall survival and decrease morbidity in individuals at
increased risk for tumor development. Cancer surveillance
has the potential benefits of increasing the cure rate for
cancers and reducing or eliminating the need for chemotherapy,
radiation therapy, or both, which can have substantial
side effects. However, cancer surveillance also can result in
increased worry about cancer, an increased rate of biopsies
578
or invasive procedures because of false-positive results, and
increased cost of care. Benefits and disadvantages of surveillance
may differ from one genetic syndrome to another, and
the benefits of each syndrome-specific protocol must outweigh
the disadvantages. We recommend an open discussion
with patients and their families about both the advantages
and the risks involved in early cancer screening.
Several factors must be considered in the development
and implementation of an effective cancer surveillance protocol.
First, there must be a benefit to early cancer detection
in individuals with cancer-predisposing conditions. Second,
the age-specific cancer risks for the hereditary cancer syndrome
must be known and considered high enough to
warrant surveillance. This information is needed to know to
whom surveillance should be offered, when to initiate surveillance,
and the duration of surveillance. The surveillance
method and interval must also be carefully considered in
light of the specific cancer risks associated with a given
syndrome. Ideally, surveillance methods should be readily
available, safe, and have high sensitivity and specificity.
Whenever possible, screening tools that involve no or minimal
radiation should be used, as patients with hereditary
cancer syndromes may be at increased risk for developing
radiation-induced cancers. Finally, there must be effective
treatment methods available for the cancer(s) identified
through screening.
For some hereditary cancer syndromes, such as hereditary
retinoblastoma, surveillance and management guidelines
are well established and have been shown to improve outcomes
for affected individuals. 34,35 For other syndromes,
such as LFS, there is ongoing debate about the optimal
surveillance protocol. The development of an effective surveillance
protocol for individuals diagnosed with or at risk
for LFS has been complicated by the variability in type,
location, and age of onset of tumors, as well as the increased
risk for multiple primary tumors and radiation-induced
cancers. 36 This raises many questions about the optimal
method(s), interval, and duration of surveillance. Several
groups have begun to offer a combined modality surveillance
protocol for LFS utilizing rapid whole-body magnetic resonance
imaging (MRI), brain MRI, abdominal ultrasound,
complete blood count, and biochemical markers. Recent data
have shown that this surveillance protocol may indeed be
effective and improves the survival of patients with LFS
through early tumor detection. 11 Further prospective studies
will be necessary to validate the effectiveness of this
surveillance protocol in both children and adults.
It is important to note that surveillance protocols may
change over time as new evidence becomes available. Therefore,
clinicians should refer to the literature and resources
such as the National Comprehensive Cancer Network
(NCCN) for the most up-to-date surveillance guidelines.
Risk-Reduction Strategies
KNAPKE ET AL
For some pediatric cancer syndromes, early identification
of high-risk children allows for the elimination or dramatic
reduction of risk through prophylactic surgery. For example,
multiple endocrine neoplasia type 2 (MEN2) and FAP are
classic examples of when surgery to remove the at-risk
organ may be considered early in the patient’s lifetime to
prevent the development of cancer. MEN2 is caused by
mutations in RET and is associated with nearly a 100%
lifetime risk for medullary thyroid cancer (MTC), as well as