Download Identification, Management, and Evaluation of Children with Cancer

I d e n t i fi c a t i o n , M a n a g e m e n t , a n d E v a l u a t i o n
of Children with Cancer-Predisposition
Syndromes
By Sara Knapke, MS, Kristin Zelley, MS, Kim E. Nichols, MD, Wendy Kohlmann, MS,
and Joshua D. Schiffman, MD
Overview: A substantial proportion of childhood cancers are
attributable to an underlying genetic syndrome or inherited
susceptibility. Recognition of affected children allows for
appropriate cancer risk assessment, genetic counseling, and
testing. Identification of individuals who are at increased risk
to develop cancers during childhood can guide cancer surveil-
lance and clinical management, which may improve outcomes
for both the patient and other at-risk relatives. The information provided through this article will focus on the current
complexities involved in the evaluation and management of
children with cancer-predisposing genetic conditions and
highlight remaining questions for discussion.
M
be a feature of some syndromes. For example, over 70% of
patients with early or bilateral Wilms Tumor may have
an inherited or de novo mutation in the WT1 gene.14,15 An
example of specific tumor types associated with an underlying cancer-predisposing gene mutation include adrenocortical tumors and choroid plexus carcinomas, which may be
caused by germline TP53 mutations in 80%16 or 35% to
100%17-19 of patients, respectively. Based on these data, it is
now recommended that all children with adrenocortical
tumors and choroid plexus tumors be offered genetic testing
for TP53 mutations (Li-Fraumeni Syndrome [LFS]).20 In
addition, children with rhabdomyosarcoma younger than
age 3 should be considered for TP53 mutation screening.21
(Some oncologists also will consider testing for TP53 mutations in children with osteosarcoma younger than ages 5 to
10 at presentation based on the strong association between
LFS and osteosarcoma22). All children with bilateral retinoblastoma and up to 20% of children with unilateral retinoblastoma will have heritable retinoblastoma and most will
have a detectable germline mutation of the RB1 gene.23
More than 70% of pediatric patients with malignant paragangliomas (PGL) or pheochromocytomas (PCC) have underlying SDHB mutations (Familial PGL/PCC Syndrome),
and the percentage of affected patients is even higher when
considering other PGL- or PCC-related genes.24,25 Nearly a
third of patients with rhabdoid tumor (soft tissue or brain)
will harbor a SMARCB1/INI1 mutation (Rhabdoid Tumor
Syndrome).26 At least 12 percent of patients with pediatric
(i.e., succinate dehydrogenase [SDH]-deficient) gastrointestinal stromal tumors (GISTs) lacking mutations in the KIT
and PDGFRA genes have germline mutations in the SDHassociated genes.27 Even patients with hepatoblastoma have
a reported 10% risk of having a germline APC mutation
(Familial Adenomatous Polyposis [FAP] Syndrome).28 Unusual cancers diagnosed in children such as colorectal or
thyroid cancer also can indicate an inherited cancerpredisposition syndrome and should trigger the pediatric
ORE THAN 12,060 children and adolescents will be
diagnosed with cancer this year in North America.1
Of these patients, it is estimated that up to 10% will develop
their cancer because of the presence of an underlying cancerpredisposing condition.2-5 However, this 10% estimate has
been extrapolated primarily from adults whose cancers were
associated with germline mutations6 and the actual percentage of childhood cancers caused by underlying genetic mutations remains unclear. In fact, a recent study reported that
up to 29% of children seen in a pediatric oncology survivorship program qualified for consideration of referral to a
cancer genetics clinic based on a significant family history
of cancer, a history of specific tumors in the surviving child,
or the presence of unique physical findings.7 These data
suggest that more than one in four children or adolescents
with a history of cancer may have a genetic cancerpredisposing condition and could therefore potentially benefit from further evaluation and management.8 Mounting
evidence now demonstrates that early cancer detection in
this population may lead to improved survival and treatment outcomes.5,6,9-11 In this chapter, we will outline for the
practicing oncologist how to identify these high-risk pediatric patients based on specific tumor presentation and family
history patterns, and discuss the issues involved in managing children and adolescents with a known genetic predisposition to cancer. Ethical and psychosocial considerations
related to genetic testing for cancer risk in minors and
suggestions for family-centered and multidisciplinary care
will also be explored.
Identification of Children with Cancer Predisposition
There are several ways in which a patient with an underlying cancer-predisposing condition can be identified. Specifically, tumor type and laterality, family cancer history,
and presence of other physical features or medical conditions must be taken into consideration when determining
whether a child has a possible genetic predisposition to
cancer.
Presence of Specific Tumor Patterns
As demonstrated in Table 1, a hereditary pediatric cancer
syndrome can be suggested by the presence of a specific
pattern of cancer presentation or tumor type in an individual. Bilateral tumors in paired organs, multifocal tumors,
and multiple primary cancers in a single individual often
indicate an underlying or inherited genetic cause of cancer.6,10,12,13 In addition, an earlier age of diagnosis can also
576
From the Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Children’s
Hospital of Philadelphia, Philadelphia, PA; Huntsman Cancer Institute, Salt Lake City,
UT; Center for Children’s Cancer Research (C3R), Huntsman Cancer Institute, Salt Lake
City, UT.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests Joshua Schiffman, MD, Division of Pediatric Hematology/
Oncology, Center for Children’s Cancer Research (C3R), Huntsman Cancer Institute, 2000
Circle of Hope, Salt Lake City, UT 84112.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10
CANCER PREDISPOSITION IN CHILDHOOD
Table 1. Differential Genetic Diagnosis by Tumor Type
Tumor Type
Differential Genetic Diagnosis
Gene(s)
Adrenocortical carcinoma
Li-Fraumeni syndrome (LFS)
TP53
Atypical teratoid and malignant rhabdoid tumor
Rhabdoid tumor syndrome
SMARCB1/INI1
Basal cell carcinoma
Nevoid Basal Cell Carcinoma Syndrome (NBCCS)/Gorlin
PTCH1
Choroid plexus carcinoma
LFS
TP53
Cystic nephroma (familial)
Pleuropulmonary blastoma (PPB) family tumor and dysplasia syndrome
DICER1
Desmoid tumors
Familial Adenomatous Polyposis (FAP)
APC
Endolymphatic sac tumors
Von-Hippel Lindau syndrome
VHL
Glioblastoma multiforme
Turcot syndrome/Lynch syndrome
LFS
MLH1, MSH2, MSH6, PMS2
TP53
Hemangioblastoma (retinal/cerebellar)
Von-Hippel Lindau syndrome
VHL
Hepatoblastoma
FAP
Beckwith-Weidemann syndrome
APC
CDKN1C/11p15
Medulloblastoma
Turcot syndrome/FAP syndrome
NBCCS/Gorlin syndrome
APC
PTCH1
Medullary thyroid cancer
Multiple Endocrine Neoplasia type 2
RET
Neuroblastoma (bilateral or multifocal)
Familial Neuroblastoma
ALK, PHOX2B
Optic pathway tumor
Neurofibromatosis type 1
NF1
Ovarian sex cord-stromal tumors
PPB family tumor and dysplasia syndrome
Peutz-Jeghers syndrome
DICER1
STK11
Paraganglioma/Pheochromocytoma
Familial PGL/PCC syndrome
Von Hippel Lindau syndrome
Multiple Endocrine Neoplasia type 2
Neurofibromatosis type 1
SDHB/C/D/AF2
VHL
RET
NF1
Retinoblastoma
Hereditary Retinoblastoma
RB1
Pleuropulmonary blastoma
PPB family tumor and dysplasia/DICER1 syndrome
DICER1
LFS
PPB family tumor and dysplasia/DICER1 syndrome
LFS
TP53
DICER1
TP53
Sarcomas
Rhabdomyosarcoma
Osteosarcoma
Schwannoma (acoustic or vestibular)
Neurofibromatosis type 2
NF2
Sertoli-Leydig cell tumor
PPB family tumor and dysplasia/DICER1 syndrome
DICER1
Wilms tumor (bilateral)
Wilms tumor syndrome
WT1
oncologist to consider a cancer genetics referral.29-32 Pediatric patients presenting with the tumors listed in Table 1
should be considered for referral to a cancer genetics clinic
where they can be seen by a team of specialists including
genetic counselors, oncologists, and geneticists with expertise in cancer predisposition. We believe that the more an
oncologist looks for these presentations, the more pediatric
hereditary cancer syndromes will be identified in patients.8
If recognized, at-risk patients and their families can benefit
from genetic testing, cancer screening, and enrollment in
research protocols.
KEY POINTS
●
●
●
There exists a growing number of hereditary cancer
syndromes with implications in childhood.
Identification of cancer predisposition in childhood
can substantially influence the choice of appropriate
screening and management options for the child and
other relatives.
Genetic risk assessment, counseling, and testing are
critical elements in the care of children and families
with cancer-predisposing conditions.
This report focuses on predisposition to solid tumors,
where surveillance is most likely to influence treatment and
outcome. However, it is important to recognize that a number of genetic conditions predispose the patient to the
development of hematopoietic malignancies, myelodysplastic syndrome, or both. The reader is directed to the Seif
reference33 for an in-depth discussion of these conditions.
Family History as a Screening Tool
Evaluation of all children with cancer should include
assessment of the family history. Features of the family
medical history that may indicate the presence of a hereditary cancer syndrome include, but are not limited to (1)
multiple family members on the same side of the family with
the same or related type of cancers, or individuals with
distinct cancer types that are known to group together in
specific cancer-predisposition syndromes (e.g., rhabdomyosarcoma, osteosarcoma, adrenocortical carcinoma, brain tumors, leukemia, and early-onset breast cancer, as is seen in
families with LFS); (2) close relatives with early, multiple, or
bilateral cancers; and (3) a pattern suggestive of generationto-generation transmission (i.e., autosomal dominant inheritance). Therefore, clinicians should collect information on
age of cancer onset, type of cancer and laterality in at least
first- (parents and siblings), second- (grandparents, aunts,
and uncles), and third- (cousins and great grandparents)
577
KNAPKE ET AL
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
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
CANCER PREDISPOSITION IN CHILDHOOD
Table 2. Hereditary Cancer Syndromes with Solid-Tumor Risk and Manifestations in Childhood: Genetics, Risks, Features, and Surveillance
Syndrome
Gene(s)
Inheritance
Cancer/Tumor Risks
Other Features
Cancer Surveillance
Beckwith-Wiedemann
syndrome/idiopathic
hemihypertrophy52,59
Chromosome 11p15
methylation defects;
UPD; CDKN1C
Imprinting/AD
Hepatoblastoma
Wilms tumor
Hemihypertrophy
Macroglossia
Omphalocele
Umbilical hernia
Neonatal hypoglycemia
Ear pits/creases
- Abdominal ultrasound every 3 mo from birth until age
4y
- Serum AFP level every 6–12 wk from birth until
age 4 y
- Renal ultrasound every 3 mo from 4–8 y
Biallelic Mismatch Repair
Gene syndrome53
MLH1, MSH2, MSH6,
PMS2
AR
Lymphoma
Leukemia
Brain tumors
Colorectal
Small bowel
Associated benign tumors:
- GI polyps (adenomas)
Café au lait macules
Axillary and inguinal
freckling
Lisch nodules
- Colonoscopy annually beginning at age 3 or at
diagnosis
- Upper endoscopy (EGD) and video capsule endoscopy
annually
- Ultrasound of head at birth and MRI of brain every
6 mos
- CBC, erythrocyte sedimentation rate, lactate
dehydrogenase every 4 mos
- Urinary and uterine ultrasound annually in adulthood
Familial Adenomatous
Polyposis39
APC
AD
Colon
Small bowel
Pancreatic
Thyroid - papillary
Hepatoblastoma
CNS–medulloblastoma
Bile duct
Gastric
FAP-associated benign tumors:
- Soft tissue tumors (Gardner’s
fibromas, desmoids tumors)
- Osteomas
- GI polyps (adenomas)
Epidermoid cysts
Supernumerary/missing
teeth
Congenital hypertrophy of
the retinal pigmented
epithelium (CHRPE)
- Colonoscopy every12–24 mo from age 10–12 y until
colectomy
- Upper endoscopy (EGD) every 12–36 mo starting at
age 18, lifelong
- Thyroid exam and consider thyroid ultrasound every
12 mo starting at age 18, lifelong
- Consider hepatoblastoma screening:
- Abdominal ultrasound every 3 mo from birth until age
4y
- Serum AFP level every 6–12 wk from birth until
age 4 y
Familial Neuroblastoma
ALK, PHOX2B
AD
Neuroblastoma
Hirschsprung disease
(PHOX2B only)
No published guidelines available
Familial PGL/PCC
Syndrome54
SDHB/C/D/AF2
AD
Paraganglioma
Pheochromocytoma
Possible associations: Renal,
Thyroid
None
- Urine or plasma metanephrines and catecholemines
every 12 mo starting at age 10 y, lifelong
- MRI of neck, chest, abdomen, and pelvis every 12 mo
starting at age 10 y, lifelong
Heritable
Retinoblastoma55
RB1
AD
Retinoblastoma
Pinealomas
Sarcomas
Melanoma
None
- Brain MRI every 6 mo from birth until age 5 y
- Eye exam, frequency determined by ophthalmologist,
from birth until age 5 y
- Thorough annual physical exam and careful attention
to development of any lumps or lesions (because of
the high rate of second cancers, particularly among
those who had RX treatment)
Juvenile Polyposis
syndrome39
SMAD4, BMPR1A
AD
Colon
Gastric
Small intestine
Pancreatic
Associated benign tumors:
- Juvenile GI polyps
Arteriovascular
malformations (SMAD4
only)
- Monitor for rectal bleeding, lifelong
- Colonoscopy/EGD every 12–36 mo starting at
age 15 or if symptoms
- CBC every 12 mo starting in early childhood
- If SMAD4 mutation, surveillance for Hereditary
Hemorrhagic Telangiectasia
Li-Fraumeni syndrome56
TP53
AD
Adrenocortical carcinoma
Choroid plexus carcinoma
Bone and soft tissue sarcomas
Leukemia
Breast
Numerous other
None
- Physical exam (with careful skin and neurologic exam)
every 12 mo, lifelong
- Self breast exam every 1 mo starting at age 18 y,
lifelong
- Clinical breast exam every 6–12 mo starting at
age 20–25 y, lifelong
- Mammogram and breast MRI every 12 mo starting at
age 20–25 y, lifelong
- Colonoscopy (suggested) every 2–5 y starting no later
than age 25 y, lifelong
- Consider additional screening with abdominal
ultrasound, brain MRI, whole body MRI, and
biochemical markers11
Multiple Endocrine
Neoplasia type 150,51
MEN1
AD
Parathyroid adenoma
Gastrinoma
Insulinoma
Anterior pituitary
Forgut carcinoid
Numerous other
MEN1-associated benign tumors:
- angiofibromas
- collagenomas
- lipomas
None
- Annual serum concentration of prolactin from
age 5 y
- Annual fasting total serum calcium concentration
(corrected for albumin) and/or ionized-serum calcium
concentration from age 8 y
- Annual fasting serum gastrin concentration from
age 20 y
579
KNAPKE ET AL
Table 2. Hereditary Cancer Syndromes with Solid-Tumor Risk and Manifestations in Childhood: Genetics, Risks, Features, and Surveillance (Cont’d)
Syndrome
Gene(s)
Inheritance
Cancer/Tumor Risks
Other Features
Cancer Surveillance
- To be considered: annual fasting serum
concentration of intact (full-length) PTH
- Head MRI from age 5 y every 3–5 y
- Abdominal CT or MRI from age 20 y every 3–5 y
- To be considered: yearly chest CT, SRS octreotide
scan
Multiple Endocrine
Neoplasia type 237
RET
AD
Thyroid–medullary
Pheochromocytoma
MEN2-associated benign
tumors (MEN2B only):
- Mucosal neuromas
- Ganglioneuromas
Hyperparathyroidism
Marfanoid habitus (MEN2B only)
- Serum calcitonin every 12 mo
- PTH every 12 mo
- Urine/plasma metanephrines and catecholamines
every 12 mo
- Age at which screening is recommended to begin
varies based on the specific genetic mutation. See
American Thyroid Association Guidelines for
Management of Medullary Thyroid Cancer for
detailed recommendations.
Neurofibromatosis
type 151
NF1
AD
Schwannoma
Pheochromocytoma
Optic pathway tumor
Neurofibromas
JMML
AML
Café au lait macules
Axillary and inguinal
freckling
Lisch nodules
Tibial bowing
Developmental delay/
intellectual disability/
autism
- Annual physical exam by a physician who is familiar
with the individual and with the disease
- Annual ophthalmologic exam in early childhood, less
frequent exam in older children and adults
- Regular developmental assessment by screening
questionnaire (in childhood)
- Regular blood pressure monitoring
- Other studies only as indicated based on clinically
apparent signs or symptoms
- Monitoring of those who have abnormalities of CNS,
skeletal system, or cardiovascular system by an
appropriate specialist
Neurofibromatosis
type 251
NF2
AD
Vestibular schwannoma
Meningioma
Schwannoma
Glioma
Neurofibroma
Posterior subcapsular
lenticular opacities
Cataract
Hearing loss
Focal weakness
Tinnitus
Balance dysfunction
Seizure
Focal sensory loss
Blindness
- Cranial MRI annually beginning at age 10–12 y until
at least fourth decade of life
- Routine complete eye exam
- Hearing evaluation including BAER testing
Nevoid Basal Cell
Carcinoma (Gorlin)
syndrome51
PTCH1
AD
Basal cell carcinoma
Medulloblastoma
Jaw keratocysts
Macrocephaly
Palmar/plantar pits
Bifid ribs
Calcification of the falx
- Monitoring of head circumference through childhood
- Developmental assessment and physical exam every
6 mo
- Orthopantogram every 12–18 mo starting at ⬎ 8 y
- Skin exam at least annually
Peutz-Jeghers syndrome56
STK11
AD
Colorectal
Gastric
Small intestine
Pancreatic
Breast
Ovarian
Cervix
Uterus
Testes
Lung
PJS-associated benign tumors:
- Peutz-Jeghers GI polyps
- Sex cord tumors with annular
tubules (SCTAT)
Mucocutaneous pigmentation
- Clinical breast exam every 6 mo starting at age 25 y,
lifelong
- Mammogram and breast MRI every 12 mo starting at
age 25 y, lifelong
- Colonoscopy and EGD every 2–3 y starting in late
teenage years, lifelong
- MRCP and/or endoscopic ultrasound every 12–24
mo, starting at age 25–30 y, lifelong
- CA 19–9 every 12–24 mo starting at age 25–30 y,
lifelong
- Small bowel visualization, baseline at age 8–10 y,
follow-up based on findings
- Pelvic exam and pap smear every 12 mo starting at
age 18–20 y
- Consider transvaginal ultrasound starting at age
18–20 y
- Testicular exam every 12 mo starting at age 10 y
- Education about symptoms of lung cancer and
smoking cessation
Pleuropulmonary blastoma
(PPB) Family Tumor
and Dysplasia
syndrome/DICER1
syndrome
DICER1
AD
PPB
Rhabdomyosarcoma
Thyroid
Ovarian Sertoli-Leydig cell
tumors and dysgerminoma
Testicular seminoma
Other gonadal germ cell tumors
Leukemia
Associated benign tumors:
- Multinodular goiter
- Cystic nephroma
Pulmonary cysts
No published guidelines available
580
CANCER PREDISPOSITION IN CHILDHOOD
Table 2. Hereditary Cancer Syndromes with Solid-Tumor Risk and Manifestations in Childhood: Genetics, Risks, Features, and Surveillance (Cont’d)
Syndrome
Gene(s)
Inheritance
Cancer/Tumor Risks
Other Features
Cancer Surveillance
PTEN Hamartoma Tumor
syndrome56
PTEN
AD
Breast
Thyroid
Endometrial
Renal
Associated benign tumors:
- Multinodular goiter
- Cystic nephroma
PTEN-associated benign tumors:
- Lipomas
- Thyroid nodules/goiter
- Hamartomatous GI polyps
Macrocephaly
Arteriovascular malformations
Developmental delay/
intellectual disability/
autism
- Physical exam every 12 mo starting at age 18 y,
lifelong
- Thyroid ultrasound every 12 mo starting at age
18 y, lifelong
- Self breast exam every 1 mo starting at age 18 y,
lifelong
- Clinical breast exam every 6–12 mo starting at
age 25 y, lifelong
- Mammogram and breast MRI every 12 mo starting
at age 30–35 y (or 5–10 y before earliest age of
diagnosis in family, whichever comes first)
- Patient education about signs and symptoms of
endometrial cancer and encourage prompt followup if issues arise
- Counsel about risk-reducing mastectomy and
hysterectomy on a case-by-case basis
- Colonoscopy (suggested) every 5–10 y, more
frequently if symptoms or polyps, starting at age
35 y, lifelong
Rhabdoid syndrome
SMARCB1/INI1
AD
Rhabdoid tumors
Schwannomatosis
None
No published guidelines available
von-Hippel Lindau
syndrome57
VHL
AD
Hemangioblastoma (retinal/
cerebellar)
Renal Cell Carcinoma
Pancreatic–neuroendocrine
Pheochromocytoma
Endolymphatic sac tumors
Epididymal tumors
Renal and Pancreatic cysts
- Ophthalmologic screening every 12 mo starting at
age 1 y, lifelong
- Physical exam, blood pressure monitoring, and
neurologic assessment every12 mo starting at age
2 y, lifelong
- Urine/plasma catecholamine metabolites every
12 mo starting at age 2 y, lifelong
- Abdominal ultrasound every 12 mo from age
8–20 y
- Abdominal CT or MRI every 24 mo, to be
alternated with annual abdominal ultrasound
starting at age 20 y
- Brain/spine MRI every 12 mo starting at puberty
- Audiology assessment every 2–3 y from ages
2–10 y, and then as symptoms arise
Wilms tumor syndromes58
WAGR
Denys-Drash
Familial Wilms
Frasier
WT1
AD
Wilms tumor
Aniridia (WAGR syndrome)
Genitourinary defects
Developmental delay/
intellectual disability/
autism
- Renal ultrasound every 3 mo from birth until age
8y
Abbreviations: AD, autosomal dominant; AML, Acute myeloid leukemia; AR, autosomal recessive; AFP, alpha-fetoprotein; BAER, brainstem auditory evoked response;
CA 19-9, carbohydrate antigen 19-9; CBC, complete blood count; CHRPE, congenital hypertrophy of the retinal pigmented epithelium; CNS, central nervous system;
CT, computed tomography; EGD, esophagogastroduodenoscopy; GI, gastrointestinal; JMML, juvenile myelomonocytic leukemia; MEN2, multiple endocrine neoplasia
type 2; mo, month (s); MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; PPB, pleuropulmonary blastoma; PTH, parathyroid
hormone; SCTAT, sex cord tumors with annular tubules; SRS, somatostatin receptor scintigraphy; WAGR, Wilms tumor, aniridia, genitourinary anomalies, and mental
retardation syndrome; wk, week(s); XRT, radiation; y, year(s).
an increased risk for hyperparathyroidism and pheochromocytoma. Although all individuals with a RET mutation have
an increased risk for MTC, there are direct genotypephenotype correlations that predict the age of onset and
determine timing for prophylactic thyroidectomy.37 Studies
have found that genetic identification of children at risk for
MEN2 and prophylactic thyroidectomy has greatly reduced
the likelihood of developing MTC in this population.38
Similarly, the identification of the APC gene as the cause
of FAP has allowed for genetic testing to identify children
with this condition. Individuals with APC mutations associated with a classic FAP phenotype develop hundreds to
thousands of colonic polyps beginning in adolescence and
have a risk of colon cancer that approaches 100% if untreated. Current guidelines recommend beginning surveillance for colon polyps at age 10. When polyps become too
numerous to follow endoscopically, colectomy is recommended.39 Use of genetic testing to evaluate at-risk children
for a familial APC mutation is more cost-effective than
relying on colon examinations to determine whether a child
has inherited this condition.40 Because of the morbidities
associated with colectomy, alternatives to surgery are being
sought. Nonsteroidal anti-inflammatory inhibitors, such as
sulindac, and Cox-2 inhibitors have been found to reduce
polyp development in adults with FAP.41,42 Studies have
now begun to look at the potential utility of these medications in children43 and an international clinical trial is
currently enrolling children with a molecular diagnosis of
FAP in a 5-year trial comparing the rate of polyp development with celecoxib compared with placebo.44
Genetic Risk Assessment and Counseling
Elements of an appropriate cancer genetic evaluation
include collection of a thorough personal and family medical
history, genetic risk assessment through pedigree analysis
and published literature, genetic testing when appropriate
for specific cancer syndromes, informed consent, results
disclosure, and psychosocial assessment.45 This process is
often complex and may also require other essential components including medical records ascertainment and review,
health insurance preauthorization for testing, and facilitating communication with other at-risk family members about
complex results.
Benefits of cancer genetic risk assessment, counseling,
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KNAPKE ET AL
and testing include identification of at-risk individuals and
families. In cases where a causative gene mutation can be
identified, mutation-specific testing can identify those individuals in the family who have inherited the genetic risk
factor and warrant high-risk screening and management.
Single-site mutation testing can also identify those individuals in the family who did not inherit the condition and,
therefore, are not predicted to be at increased risk and can
forego additional measures. Many family members often
have increased anxiety and worry about the risk for cancer
in the family, and appropriate risk assessment and identification of a specific cause can provide accurate information
and, in some cases, help to empower family members and
alleviate emotional burden.
There are also potential disadvantages of and obstacles to
cancer genetics evaluations. For example, although the
sensitivity and utility of genetic testing continues to improve, a causative gene mutation cannot be identified in
some cases even when there is a high suspicion of a specific
diagnosis. Therefore, clinical judgment and expertise must
be applied in these cases to develop an acceptable screening
and management plan for the patient as well as at-risk
family members. In addition, there are also some cases with
striking features of a hereditary cancer syndrome that do
not fit a specific diagnosis or may represent a previously
undescribed syndrome. Research studies as well as advances
in gene finding and exome sequencing may be beneficial in
such cases. However, these newer genomic technologies may
lead to the identification of more variants of unknown
significance for which it can be difficult to counsel the
patient and his or her family. Advancements in genetic
information and testing continue to change at a rapid pace.
Therefore, there needs to be a clear expectation in the
pediatric cancer genetics clinic for periodic follow-up and
recontact with families in the event that new information is
obtained. The results of genetic testing should not stand
alone in risk assessment but rather be one tool in the genetic
cancer risk assessment process.
Ethical and psychosocial considerations remain critical in
the assessment and care of children with potential cancerpredisposition syndromes. For example, with respect to the
informed consent process, clinicians need to consider the
child’s capacity for autonomy as well as participation in
assent/consent. In addition, much historic debate has occurred about genetic testing in minors.46-49 A distinction
between diagnostic and presymptomatic or predictive testing is relevant. Although diagnostic testing is generally
acceptable in children with features of a genetic condition,
predictive testing is generally reserved for those conditions
for which clinical management would be altered during
childhood.48 Regarding the psychosocial effects on the family
experience, it is important to explore implications on emotional well-being, family dynamics, risk perception, influ-
582
Table 3. Cancer Genetic Services Resources
Resource
Web site
National Society of Genetic Counselors
Find a Genetic Counselor Tool
National Cancer Institute
Cancer Genetic Services Directory
www.nsgc.org
http://cancer.gov/cancertopics/genetics/
directory
ence on other siblings, reproductive decision-making, and
financial consequences.
Because of all of these potential risks and benefits, it is
important that “discussions on genetic testing are done in a
sensitive, comprehensive, and inclusive manner by fully
trained specialist health professionals, such as genetic counselors and clinical geneticists, in a relaxed and comfortable
environment.”48 After identifying individuals and families
who might be at increased risk for cancer, referral to a
program with expertise in childhood cancer predisposition is
indicated. Many health care systems may have genetic
counselors or other specialists with genetic expertise on site.
Others may need to seek out and establish appropriate
referral practices to another organization in their area.
Resources for finding local genetic specialists can be found in
Table 3. If cancer genetics services are not available nearby,
an increasing number of programs also offer their services
through a telemedicine service model. When possible, it also
may be beneficial to establish relationships with cancer
genetics programs that practice through a multidisciplinary
approach to care. A growing number of cancer genetics
programs have established specific clinics related to pediatric cancer predisposition and integrate expertise from clinical geneticists, pediatric oncologists, and other relevant
subspecialists.
Conclusion
In an era of personalized medicine, identification of disease susceptibility is no longer solely for academic interest
but is becoming an accepted and clinically relevant element
in the current management of patients. Therefore, it is
imperative for clinicians to recognize those children and
families who will benefit most from a cancer genetics referral, and assist in the follow-up and management of these
individuals. Although a great deal of knowledge about
cancer-predisposing conditions affecting children now exists, the scope of genomic information is expanding at a
rapid pace and the future of this field will become increasingly complex. These new genetic data must be carefully
examined through clinical, translational, and basic research
protocols to ensure their effective translation to the optimized care of children at increased genetic risk for cancer.
Acknowledgements
K.E.N. acknowledges support in part by the Grundy Vision of
Life Fund. W.K. and J.D.S. acknowledge the use of the Genetic
Counseling Shared Resource supported by P30 CA042014
awarded to Huntsman Cancer Institute.
CANCER PREDISPOSITION IN CHILDHOOD
Authors’ Disclosures of Potential Conflicts of Interest
Author
Sara Knapke*
Kristin Zelley*
Kim E. Nichols*
Wendy Kohlmann
Joshua Schiffman*
Employment or
Leadership
Positions
Consultant or
Advisory Role
Stock
Ownership
Honoraria
Research
Funding
Expert
Testimony
Other
Remuneration
Myriad
*No relevant relationships to disclose.
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