Cancers in Children
Abstract and Keywords
Nearly 12,400 children and adolescents under the age of twenty years will be newly diagnosed with cancer each year in the United States. This means that a newborn has an approximately 1 in 315 chance of developing cancer in the first two decades of life. This chapter reviews the epidemiology of cancer in children. Topics covered include overall incidence, mortality and morbidity, acute lymphoblastic leukemia and acute myeloid leukemia, brain/central nervous system cancers, lymphomas, sympathetic nervous system tumors, soft tissue sarcoma, renal cancers, bone tumors, germ cell tumors, retinoblastoma, and hepatic tumors.
Keywords: cancer risk, cancer epidemiology, cancer prevention, children, tumors, sarcoma
Nearly 12,400 children and adolescents under the age of 20 years will be newly diagnosed with cancer each year in the United States (Ries et al., 1990). This means that a newborn has an approximately 1 in 315 chance of developing cancer in the first two decades of life (Ries et al., 2002). Overall, however, childhood cancer accounts for only a small proportion of the total cancer burden in the United States. Figure 65–1 presents a comparison of the estimated number of malignancies diagnosed each year by site and the estimated number of total cancers diagnosed in children less than 15 years of age (Ries et al., 2003). The total number of incident cases among children is less than the number of incident diagnoses of cancer for all but the rarest of individual adult sites. Nevertheless, cancer is a leading cause of disease-related mortality in US children; approximately 2500 children will die from their malignancy each year (Ries et al., 1999).
In the year 2000, malignant neoplasms comprised about 8% of deaths among 1–4 year olds, 15% among 5–9 year olds, 12% among 10–14 year olds, and 6% among 15–19 year olds, with ranking as the third, second, second, and fourth leading causes of death, respectively (Minino et al., 2002). Accidents are the leading cause of death in children and comprise between 40%–50% of mortality at these ages. The rate of death from cancers in 2000 was 2.8, 2.5, 2.6, and 3.7 per 100,000 at ages 1–4, 5–9, 10–14 years, and 15–19 years, respectively (Minino et al., 2002). Overall, approximately 106,700 person-years of life are lost each year for children who die of cancer (Ries et al., 2003).
OVERALL INCIDENCE
During the period 1995–1999, the incidence rate of cancer for all sites combined was 20.5, 11.1, 12.9, and 20.1 per 100,000 for 0–4, 5–9, 10–14, and 15–19 year olds, respectively (Ries et al., 2002). There is substantial variation in incidence within these age groups. Cancer is more common in males than in females, with the respective male-tofemale ratios being 1.14, 1.28, 1.07, and 1.03. Cancer is also more common in whites than in blacks; corresponding white-to-black ratios are 1.24, 1.28, 1.28, and 1.55 (Ries et al., 2002).
The incidence rate of all childhood cancer sites combined has risen slightly, but significantly, in past decades. During the period 1975–1999, the average annual percentage change (AAPC) in the incidence rate was 0.9 (p < 0.05) for 0–4 year olds, 0.4 (p > 0.05) for 5–9 year olds, 1.0 (p < 0.05) for 10–14 year olds, and 0.6 (p < 0.05) for 15–19 year olds. Incidence has been steady, however, in the most recent period, with corresponding AAPCs for 1987–1999 of 0.4 (p > 0.05), -0.2 (p > 0.05), 1.1 (p < 0.05), and -0.3 (p < 0.05) for each age group, respectively (Ries et al., 2002).
MORTALITY AND MORBIDITY
Improved treatments for childhood cancer over the past 30 years have dramatically increased long-term survival. Five-year relative survival rates of all childhood cancers combined rose significantly (p < 0.05) from 56% during 1974–1976 to 77% during 1992–1998. Each individual cancer type experienced a significant (p < 0.05) improvement in survival, though the extent varied (Jemal et al., 2003). As a result of these advances in treatment, there is a large and growing number of childhood cancer survivors. In the United States in 2000, there were estimated to be nearly 195,000 people who had survived up to 25 years past a diagnosis of cancer between the ages of 0 and 19 years (Ries et al., 2003). Compared with the general population, childhood cancer survivors have an increased risk of second malignancies, heart disease, obesity, neurocognitive complications, and other disorders. In addition, patients and their families can experience substantial psychological trauma during and after treatment (Bhatia and Sklar, 2002; Bhatia, 2002). Care for these survivors requires education, ongoing screening and surveillance, interventions, and support.
OVERVIEW: ETIOLOGY OF CHILDHOOD CANCER BY SITE
The distribution of cancer diagnoses is quite different for children than for adults. Due to this dissimilar distribution of cancer and to the recognition that histology is often more relevant than site, childhood cancer has its own classification system called the International Classification of Childhood Cancer (ICCC) (Kramarova and Stiller, 1996). The most common malignancies diagnosed in children under the age of 15 years (Table 65–1) in order of decreasing incidence are the leukemias (acute lymphoblastic leukemia, acute myeloid leukemia), brain/central nervous system tumors (astrocytoma, primitive neuroectodermal tumors, gliomas, and ependymomas), lymphomas (non-Hodgkin lymphoma, Hodgkin disease) sympathetic nervous system tumors (neuroblastoma), soft tissue sarcomas (rhabdomyosarcoma), renal tumors (Wilms tumor, renal carcinoma), bone tumors (osteosarcoma, Ewing sarcoma), malignant germ cell tumors, retinoblastoma, and hepatic tumors (hepatoblastoma, hepatocellular carcinoma). Other malignancies, including thyroid cancer, melanoma, adrenocortical tumors, and nasopharyngeal cancers, comprise the remainder. Trends in incidence, survival, and mortality vary not only by the type of cancer but also by gender, race, age at onset, clinical characteristics, and molecular abnormalities. This variability strongly suggests separate etiologies for some types of childhood cancer. Moreover, the variability within some childhood cancers has only been recognized with advances in pathology and molecular biology. For example, there is a general trend in epidemiological studies of childhood leukemia to consider more genetically and immunophenotypically defined subgroups such as children with Down syndrome or infants with MLL gene-rearranged leukemia.
This review will focus on the 10 most commonly studied malignancies in children diagnosed under the age of 15 years as shown in Table 65–1. Most etiologic research of childhood cancer consists of ecologic or case-control studies. The number of such studies for each cancer type is roughly correlated with the incidence of the disease. A small portion of childhood cancer can be attributed to cancer-predisposing inherited conditions (shown in Table 65–2). Although some genetic syndromes, such as familial retinoblastoma, may be associated with up to 40% of cases, it is estimated that, overall, only about 5% of childhood cancers are associated with inherited genetic alterations (Volgelstein and Kinzler, 1998).
Figure 65–1. Estimated US cancer cases with actual mortality in 2000, by site.
ACUTE LYMPHOBLASTIC LEUKEMIA AND ACUTE MYELOID LEUKEMIA
Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are malignancies of lymphoid and myeloid progenitor cells, respectively. They comprise the vast majority of childhood leukemias, which represent about a third of childhood cancer diagnoses in the United States (Ries et al., 1999). Internationally, incidence of ALL is roughly correlated with the socioeconomic status of nations. As can be seen in Figure 65–2A, incidence of ALL is highest in Costa Rica and among US Hispanics, with more than 45 cases per million. Slightly lower rates prevail in the rest of North America, Europe, and Oceania, while rates in Asia, Central, and South America are intermediate. The rate of ALL in Africa is nearly 50-fold lower than that in countries with the highest rates. The rate of AML, by contrast, is between 5 and 10 cases per million with the exceptions of Africa and the Maori of New Zealand, among whom rates are lower and higher, respectively (Parkin et al., 1998). The incidence of ALL and AML differs widely by age, sex, and race. In the United States, ALL shows a marked peak in incidence between the ages of 2 and 5 years, with a rate of about 76 cases per million at the maximum (Gurney et al., 1995). Immunophenotyping of ALL reveals that CD 10+ B-cell lineage ALL alone, rather than T-cell or null-cell lineage ALL, forms the majority of the childhood peak, and is for this reason called common ALL or cALL (Greaves et al., 1993). Null-cell ALL occurs mainly in infancy, whereas T-cell ALL incidence climbs steadily from childhood to adolescence (Greaves et al., 1985). Males out-number females by a ratio of 1.2 and whites out-number blacks by a ratio of 2.0 among
Table 65–1. US Incidence Rates (1975–2000) and 5-Year Relative Survival Rates (1985–1999) of Most Common Malignancies Diagnosed in Children
Age-Adjusted Incidence Rate per Million |
Five-Year Relative Survival Rates |
|||
|---|---|---|---|---|
Malignancy |
Age <15 years |
Age <20 years |
Age <15 years |
Age <20 years |
Leukemias (acute lymphoblastic leukemia, acute myeloid leukemia) |
42.0 |
37.2 |
81.8 |
79.1 |
|
Brain/central nervous system tumors (astrocytoma, primitive neuroectodermal tumors, gliomas, ependymomas) |
29.0 |
26.5 |
66.4 |
68.1 |
Lymphomas (non-Hodgkin lymphoma, Hodgkin lymphoma) |
14.8 |
24.0 |
83.4 |
84.9 |
Sympathetic nervous system (neuroblastoma) |
10.5 |
8.1 |
66.0 |
65.4 |
Soft tissue sarcomas (rhabdomyosarcoma) |
10.0 |
11.4 |
73.1 |
70.8 |
Renal tumors (Wilms tumor, renal carcinoma) |
8.6 |
6.8 |
90.4 |
89.8 |
Bone tumors (osteosarcoma and Ewing sarcoma) |
6.5 |
8.5 |
67.5 |
65.3 |
Malignant germ cell tumors |
4.7 |
10.5 |
86.7 |
89.6 |
Retinoblastoma |
4.0 |
3.0 |
94.7 |
94.8 |
Hepatic tumors (hepatoblastoma, hepatocellular carcinoma) |
1.9 |
1.7 |
55.8 |
49.9 |
Thyroid cancer |
1.8 |
5.2 |
97.3 |
98.7 |
Malignant melanoma |
1.5 |
4.6 |
88.0 |
92.1 |
Nasopharyngeal cancer |
0.3 |
0.5 |
N/A |
|
Adrenocortical carcinoma |
0.2 |
0.2 |
N/A |
|
Source: Adapted from Ries, et al. (2003).
Table 65–2. Childhood Cancers Associated with Inherited Syndromes
Inherited Condition |
Associated Childhood Cancers |
|---|---|
Li-Fraumeni syndrome (inherited P53 defect) |
CNS, OS, STS |
Down syndrome (trisomy 21) |
ALL, AML |
Familial adenomatous polyposis |
HB |
Beckwith–Wiedemann syndrome |
WT, HB, STS |
Neurofibromatosis |
ALL, AML, CNS, STS |
Schwachman syndrome |
ALL, AML |
Bloom syndrome |
ALL, AML |
Ataxia telangiectasia |
ALL, NHL |
Wiskott–Aldrich syndrome |
NHL |
X-linked lymphoproliferative disease |
NHL |
Familial retinoblastoma/13q deletion syndrome |
RB, OS |
Langerhans cell histiocytosis |
ALL |
Klinefelter syndrome |
ALL |
Familial monosomy 7 |
AML |
Kostmann granulocytopenia |
AML |
Fanconi anemia |
AML |
Tuberous sclerosis |
CNS |
Nevoid basal cell syndrome |
CNS |
Turcot syndrome |
CNS |
Costello syndrome |
STS |
Aniridia |
WT |
Wilms tumor, aniridia, genitourinary abnormalities, mental retardation (WAGR) syndrome |
WT |
Perlman syndrome |
WT |
Denys–Drash syndrome |
WT |
Simpson-Golabi-Behmel syndrome |
WT |
Gardner syndrome |
HB |
Hemihypertrophy |
HB, WT |
Rothmund–Thomson syndrome |
OS |
Source: Adapted from Ries et al. (1999), Sandlund et al. (1996), Ruymann, et al. (1988), Yang et al. (1995), Gripp et al. (2002).
CNS, central nervous system; OS, osteosarcoma; STS, soft tissue sarcoma; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; HB, hepatoblastoma; WT, Wilms Tumor; NHL, non-Hodgkin lymphoma; RB, retinoblastoma.
Genetic analyses have illuminated much of the natural history of childhood leukemia. A large number of chromosomal rearrangements have been described in ALL and AML, though a few types predominate. About 85% of ALL (Greaves, 1999) and an estimated 60% of AML (Cimino et al., 1993) among children less than 1 year of age displays the MLL-11q23 gene rearrangement. Among children aged 1–15 years with ALL, TEL-AML1 and hyperdiploid rearrangements each account for 25% of cases, the MLL-11q23 gene rearrangement is present in only 5%, and a diverse array of rearrangements account for the remainder (Greaves, 1999). Many chromosomal anomalies have been described in AML at ages greater than 1 year but none predominates (Perkins et al., 1997). Though 5-year survival of childhood leukemia now exceeds 80%, the prognosis for children with specific cytogenetic abnormalities varies widely (Greaves, 2002). The fact that twins concordant for both ALL and AML share the same non-constitutive rearrangements (Ford et al., 1993; Richkind et al., 1998) and that these rearrangements have been detected in neonatal bloodspots (Guthrie cards) (Gale et al., 1997; Wiemels et al., 1999; Fasching et al., 2000; Yagi et al., 2000; Wiemels et al., 2002) strongly suggests that most acute leukemia in childhood is initiated in utero. Among infants, the in-utero MLL-11q23 rearrangement is probably sufficient to cause leukemia, since infant identical twins are nearly 100% concordant for acute leukemia in anecdotal reports (Greaves, 2002). On the other hand, concordance of acute leukemia is a comparatively low 5% among older children (Greaves, 1999), suggesting that a postnatal mutation is also needed for disease to develop at ages 1–15 years (Wiemels et al., 1999; Fasching et al., 2000). Accordingly, the TELAML1 rearrangement, at least, has been found in the Guthrie cards of children who did not develop leukemia (Wiemels et al., 1999; Mori et al., 2002).
Few risk factors for the childhood leukemias are well established, though many have been examined. Down syndrome (Front et al., 1987; Robison et al., 1987), and inherited cancer-predisposing conditions such as ataxia telangiectasia (Mullvihill, 1975; Bloomfield and Brunning, 1976; Bader et al., 1978; German et al., 1979; Woods et al., 1981; Linet, 1985; Hecht et al., 1990) substantially increase the risk of both ALL and AML but account for only a small fraction of cases (Robison and Neglia, 1984; Narod et al., 1991; Watson et al., 1993). In utero diagnostic radiation is also an accepted risk factor for both types of leukemia (Doll and Wakeford, 1997), but its importance has declined along with dosage and frequency of fetal exposure to X-rays (Harvey et al., 1985; Mole, 1990; Rodvall et al., 1990; Shu et al., 2002). Investigations of ionizing radiation from other sources, such as fallout (Cartwright et al., 1988; Gibson et al., 1988; Stevens et al., 1990; Ivanov et al., 1993; Parkin, 1993; Auvinen et al., 1994; Hjalmars et al., 1994; Petridou et al., 1994, 1996; Michaelis et al., 1997) or radon (Alexander et al., 1990; Henshaw et al., 1990; Lubin et al., 1998; Kaletsch et al., 1999; Steinbuch et al., 1999; Axelson et al., 2002; Investigators, 2002), from postnatal X-rays (Linos et al., 1978; Boice, 1986; Infante-Rivard et al., 2000), and occupational (Gardner, 1991; McLaughlin et al., 1993; Parker et al., 1993) or diagnostic (Shu et al., 1994) radiation to the father have sometimes indicated increased risk of leukemia but are, on whole, equivocal. Non-ionizing radiation has not appeared to be associated with leukemia in studies that incorporate measurements of electromagnetic fields (Linet et al., 1997; Anonymous, 1999; McBride et al., 1999), though meta-analysis suggests that the highest level of exposure, to which very few children are exposed, may raise risk of leukemia (Ahlbom et al., 2000; Greenland et al., 2000).
Other familiar sources of carcinogens have been investigated in regards to both leukemias with little suggestion of causation in most cases. Maternal consumption of alcohol while pregnant does not appear to increase the frequency of ALL in offspring, but may increase the risk of AML (Severson et al., 1993; van Duijn et al., 1994; Shu et al., 1996). Studies of parental tobacco use and acute leukemia have reported no association with maternal smoking while pregnant with fair consistency, whereas there have been inconsistent reports of an association with paternal, preconceptional smoking (Stjernfeldt et al., 1992; Severson et al., 1993; Sorahan et al., 1995; Shu et al., 1996; Sorahan et al., 1997; Brondum et al., 1999; Sorahan et al., 2001; Pang et al., 2003).
Occupational or other exposure to chemicals has been associated inconsistently with ALL (Shaw et al., 1984; Lowengart et al., 1987; Buckley et al., 1994; Shu et al., 1999; Schuz et al., 2000; Freedman et al., 2001); exposure to pesticides and benzene has been more consistently associated with AML and accords with adult data (Shu et al., 1988; Buckley et al., 1989). Emerging evidence indicates that low-activity variants of polymorphisms in detoxification metabolism and DNA repair mechanism genes raise the risk of childhood leukemia, which supports the idea of chemical carcinogenesis (Davies et al., 2000; Krajinovic et al., 2002) and in small studies these polymorphisms do appear to modify the risk of some chemical exposures (Infante-Rivard et al., 1999; Infante-Rivard et al., 2000; Infante-Rivard et al., 2002).
Factors related to birth have also been of interest in leukemia etiology. Maternal age greater than 35 years at the time of a child’s birth (Hemminki et al., 1999; Dockerty et al., 2001) and maternal history of fetal loss also appears (Kaye et al., 1991; Yeazel et al., 1995; Ross et al., 1997; Shu et al., 2002) to be directly associated with ALL, even after controlling for Down syndrome and parity. High birth weight (variously defined, but usually >4000 grams) also is associated with an increased risk of acute leukemia in most large studies (Cnattingius (p. 1254 )
Figure 65–2. (A) International incidence of childhood acute lymphoblastic leukemia, acute myeloid leukemia, and central nervous system tumors 1980–1990.
(Source: Adapted from Parkin et al., 1998.) (B) International incidence of childhood Hodgkin disease, non-Hodgkin lymphoma, and Wilms tumor 1980–1990. (Source: Adapted from Parkin et al., 1998.)
A number of lines of evidence support the notion that childhood ALL is related to some correlate of socioeconomic status, at least at the level of nations since, as we mentioned above, ALL occurs much more frequently in industrialized countries than in developing ones, especially at less than 5 years of age (Parkin et al., 1998). Also, this childhood peak in incidence seems to have emerged over time in populations experiencing economic growth (Fraumeni and Miller, 1967; Hrusak et al., 2002). The fact that cALL comprises most of the childhood peak (Greaves et al., 1993) suggests that higher rates of ALL in industrialized countries are not due to improved reporting, and that it is this form of ALL, specifically, that is associated with some factor related to economic growth. Though there are many such factors, infection has been the focus of research because ALL is a malignancy of immune cell progenitors.
Two main theories endeavor to explain the international variation in childhood leukemia incidence in terms of infection. One theory holds that childhood leukemia (and not a particular subtype) is a rare response to infection of immune cells by a particular agent, most likely a virus (Kinlen, 1988). Alternatively, cALL specifically may result as lymphoblasts proliferate in response to infection in general and thereby acquire mutations necessary to produce leukemia (Greaves, 1988). In both theories the likelihood of leukemia is posited to increase with later age of exposure to infection(s), as in the paradigm of paralytic poliomyelitis (Baccate, 1983). Evidence of the role of infection in leukemogenesis supports both theories so far, since it is difficult to distinguish between the two theories absent the discovery of a leukemogenic microbe.
Leukemia cases show weak but significant spatio-temporal clustering (Alexander et al., 1998) and seasonality (Westerbeek et al., 1998; Ross et al., 1999) both of which are consistent with a role for infections. Other ecologic studies have consistently found raised rates of leukemia following an influx of newcomers to previously isolated areas (termed population mixing), which could facilitate the transmission of infections (Kinlen, 1995). Subsequent studies that used more quantitative measures of population mixing have, in general, found an increased risk of leukemia with greater population growth and diversity of immigrants, but have disagreed about whether this increase is exclusive to rural or to urban areas (Langford, 1991; Stiller et al., 1996; Dickinson et al., 1999; Koushik et al., 2001; Boutou et al., 2002; Dickinson and Parker, 2002; Parslow et al., 2002).
The search for a particular leukemogenic microbe has largely been fruitless. Serologic surveys have been mainly cross-sectional and thus can not determine that infection preceded leukemia (Gahrton et al., 1971; Heegaard et al., 1999; MacKenzie et al., 1999; Groves et al., 2001; MacKenzie et al., 2001; Salonen et al., 2002). Meanwhile, history of infection as established by questionnaire or record abstraction is subject to recall bias and misclassification of asymptomatic individuals (McKinney et al., 1987; Shu et al., 1988; Buckley et al., 1994; Dockerty et al., 1999; McKinney et al., 1999; Schuz et al., 1999; Neglia et al., 2000; Chan et al., 2002; Naumburg et al., 2002; Perrillat et al., 2002). Proxy measures of infection may be both more accurately recalled and less misclassified. Examples are time in attendance at day care and birth order, both of which have shown an inverse association with leukemia (Zack et al., 1991; Westergaard et al., 1997; Infante-Rivard et al., 2000; Dockerty et al., 2001; Chan et al., 2002; Ma et al., 2002b; Perrillat et al., 2002; Shu et al., 2002; Vineis et al., 2003), though not entirely consistently (Neglia et al., 2000; Rosenbaum et al., 2000). Prolonged breast feeding is less common in industrialized nations and has in many studies been inversely associated with leukemia (Parker, 2001; Lancashire and Sorahan, 2003). A benefit of breast feeding, if real, could derive either from its nutritional and immunologic benefits or its provision of early exposure to common viruses and bacteria (Dworsky et al., 1983).
BRAIN/CENTRAL NERVOUS SYSTEM CANCERS (ASTROCYTOMAS, PRIMITIVE NEUROECTODERMAL TUMORS, GLIOMAS, EPENDYMOMAS)
Central nervous system (CNS) cancers are a diverse collection of malignancies that together make up about 16% of childhood cancer. CNS cancers occur mainly in the brain, but can also appear extra-cranially. Because of the diverse histological origins of CNS cancers, there have been proposed alternate classification systems (Kleihues et al., 1993) that do not entirely coincide with the ICCC (Kramarova and Stiller, 1996). Nevertheless, CNS cancers are usually grouped into the following categories for the purpose of study: astrocytomas (49.6% of CNS cancers in the US), primitive neuroectodermal tumors (PNET, 22.9%), other gliomas (15.4%), and ependymomas (9.3%) (Ries et al., 1999). Rates of CNS cancers in the industrialized world range between about 20 and 40 cases per million, whereas rates in the developing world are generally below 20 cases per million, especially in Africa (Fig. 65–2A); a similar gradient in incidence is seen for each of the CNS cancer subtypes (Parkin et al., 1998).
Incidence of CNS malignancy in the United States is highest in early childhood, at about 35 cases per million, and declines to less than 25 cases per million by 15 years of age (Ries et al., 1999) Non-malignant tumors are not covered here, but it should be noted that they can be debilitating. Including benign CNS tumors would raise the above incidence rates by about 25% (Gurney et al., 1999). There is a preponderance of males among PNET and ependymomas, but not among other CNS cancers. The rate of CNS cancers of all subtypes is higher among whites than blacks, with this difference most evident among males (Ries et al., 1999). The incidence of CNS cancers is undoubtedly higher recently than it was in earlier periods, but it appears to have jumped suddenly in the mid 1980s. This suggests that the increase is an artifact of improved diagnostic technology, namely magnetic resonance imaging, rather than a true secular trend (Smith et al., 1998).
Survival of brain tumors varies by subtype but is low; except for astrocytomas, 5-year survival of CNS cancers that occur below 20 years of age is less than 60% (Ries et al., 1999). Relatively few studies of CNS tumor cytogenetics have been conducted that could improve prognosis and treatment, in part because of the difficulty of obtaining adequately sized biopsy samples from such a delicate region. However, it is known that PNETs often have a high frequency of abnormalities, including trisomy of chromosome 7, monosomy of chromosomes 8 and 22, and a doubling of the long arm of chromosome 17 (i.e., i(17q), compared with other CNS tumors and accordingly are more aggressive (Bhattacharjee et al., 1997).
Wide-ranging investigations of potential risk factors for CNS cancers have identified only one with great consistency besides the congenital conditions listed in Table 65–2. Therapeutic radiation to the head raises the risk of CNS cancers several fold, but is of mostly historical interest, and today accounts for only a tiny proportion of cases (Shore et al., 1976; Ron et al., 1988). Experimental evidence has suggested other candidate risk factors such as N-nitroso compounds and polyoma viruses, though a role for them in CNS cancer etiology has not been fully supported in epidemiologic studies (Gurney et al., 2001).
When fed to pregnant animals, nitrosamides and nitrosoureas are potent inducers of brain tumors in offspring (Ivankovic, 1979). Cured meats are a major source of nitrite precursors, which are converted into N-nitroso compounds in vivo (Leaf et al., 1989; Lijinsky, 1999). Though a majority of case-control investigations of cured meat consumption by pregnant mothers have indicated higher risk of CNS cancers, internal inconsistency in these studies (e.g., finding higher risk for consumption of some cured meats but not others) makes an association less certain (Preston-Martin et al., 1982; Kuijten et al., 1990; Bunin et al., 1993, 1994; Cordier et al., 1994; McCredie et al., 1994; Sarasua and Savitz, 1994). Also, cured meat consumption has not so far been shown to increase the level of DNA-damaging adducts in vivo (Gurney et al., 2002). Nitrosable drugs could also be a source of nitrosamides but have shown inconsistent associations with CNS tumors (Olshan and Faustman, 1989; Carozza et al., 1995; (p. 1256 ) McKean-Cowdin et al., 2003). Interestingly, Vitamins E and C inhibit the activity of N-nitroso compounds (Ivankovic et al., 1975) and consumption of vitamins in fruits, vegetables, and supplements by pregnant mothers has been inversely associated with CNS cancers in some studies (Preston-Martin et al., 1982; Bunin et al., 1993; Cordier et al., 1994; McCredie et al., 1994; Preston-Martin et al., 1998a, 1998b). By contrast with nitrosoamides and nitrosoureas, the other class of Nnitroso compounds, nitrosoamines, does not induce CNS cancers in experimental animals (Preussman and Stewart, 1984). Products that contain nitrosamines, such as beer, cigarettes, etc., are not associated with CNS cancer in humans (Howe et al., 1989; Gold et al., 1993; Bunin et al., 1994; Filippini et al., 1994; McCredie et al., 1994; Norman et al., 1996a, 1996b; Hu et al., 2000; Filippini et al., 2002).
Laboratory evidence supports the plausibility of a role for polyoma viruses including SV40, BK, and JC virus in the etiology of CNS cancers. Components of polyoma viruses are mutagenic and bind to proteins that regulate the growth and death of cells (Barbanti-Brodano et al., 1998). Moreover, polyoma viruses induce brain tumors in test animals (Kirchstein and Gerber, 1962). Polyoma virus DNA has been detected in human brain tumors, but it is unclear whether this is a cause or result of cancer (Gurney et al., 2001). Follow-up studies of children immunized with SV40-contaminated polio vaccine, which is the only epidemiological evidence on the subject, has not confirmed an association of CNS cancer with polyoma viruses (Olin and Gesecke, 1998; Strickler and Goedert, 1998a; Strickler et al., 1998b; Fisher et al., 1999; Carroll-Pankhurst et al., 2001; Engels et al., 2003). However, these studies were based on possibly incorrect assumptions about exposure to SV40 (Vilchez et al., 2003) and, moreover, as ecologic studies they cannot definitively rule out an association.
Studies of pesticides (Gold et al., 1979; Howe et al., 1989), epilepsy (Gold et al., 1979; Kuijten et al., 1993; McCredie et al., 1994; Gurney et al., 1997), brain injury (McCredie et al., 1999), electromagnetic fields (Gurney et al., 1996; Preston-Martin et al., 1996a, 1996b; Anonymous, 2000) and other potential risk factors (Gurney et al., 1997; Holly et al., 2002) indicate no association or have methodological problems that cast doubt on any observed associations. Many associations of CNS tumors have been reported with parental occupations, but these have seldom been replicated (Olshan et al., 1986; Nasca et al., 1988; Wilkins and Koutras, 1988; Wilkins and Sinks, 1990; Cordier et al., 1997; McKean-Cowdin et al., 1998; Cordier et al., 2001). Recently, however, it has appeared that living on a farm or having a parent that does farm work raises the risk of CNS cancer (Bunin et al., 1994; Kristensen et al., 1996; Holly et al., 1998; Efird et al., 2003).
LYMPHOMAS (HODGKIN DISEASE, NON-HODGKIN LYMPHOMA)
Lymphomas represent the third most common type of malignancy in children in the United States. About 1700 children under the age of 20 are diagnosed with lymphoma each year in the United States, including approximately 900 cases of Hodgkin disease and 800 cases of non-Hodgkin lymphoma (NHL); miscellaneous lymphoreticular neoplasms make up another 80 or so cases (Ries et al., 1999). As there are distinct clinical presentations of Hodgkin disease and NHL, they will be discussed separately with respect to etiology.
Hodgkin Disease
Hodgkin disease (HD), a malignancy of the B-lymphocyte lineage, is characterized by the presence of Reed-Sternburg cells (Jarrett and Onions, 1992). As with adults, HD in children is often classified into four histological subtypes including lymphocytic predominance, mixed cellularity, lymphocytic depletion, and nodular sclerosis. Nodular sclerosis is by far the most common, with approximately 70% of cases, followed by mixed cellularity (16%), lymphocytic predominance (7%), and cases not otherwise specified (6%) (Ries et al., 1999). Lymphocytic depletion type is extremely uncommon among children. There are also some age- and sex-dependent differences in these types, with nodular sclerosis more common among females 15–19 years of age compared with males, and mixed cellularity occurring more often among younger than older children (Ries et al., 1999).
Internationally, high rates of Hodgkin disease occur in Costa Rica and Israel (non-Jews), intermediate rates in US whites and Germany, and low rates in Africa (Parkin et al., 1998) (Fig. 65–2B). Overall, the US incidence rate was 13.6 per million for the period 1975–2000 (Ries, 2003). The incidence rate, however, is highly age dependent with rates increasing from <1 per million for children under the age of 5 years to 36 per million for children 15–19 years. Incidence rates are slightly higher in girls compared with boys, although in the youngest age group (<5 years) the incidence rate is higher in males (1.6/million and 0.3/million, respectively) (Ries et al., 1999). While black children have slightly lower incidence rates overall, incidence rates are essentially equivalent up until about 10 years of age. Overall, the incidence rates for HD in children have been declining in the United States. For all children under the age of 19 years, the incidence rate decreased from about 14.5 per million during the period 1975–1979 to 12.1 per million for the period 1990–1995 (Ries et al., 1999). Five-year survival rates exceed 90%, with whites experiencing higher survival rates than blacks (92% vs. 84%).
Etiologic studies of HD in children suggest at least two distinct entities: one type of HD manifests with Epstein Barr virus (EBV) sequences present in the Reed-Sternberg cells (Stiller and Boyle, 1998). This type of HD is often seen in developing countries or in populations with lower socioeconomic status; it is also more common in males, and younger ages, and often is associated with the mixed cellularity subtype. The other type of HD appears in older adolescents of higher socioeconomic status; this type often appears as the nodular sclerosis subtype (Stiller and Boyle, 1998). A recent study examined Reed-Sternberg cells in children with HD from various countries for overall EBV infection and specifically tested for two strains, EBV1 and EBV2, in a subset of cases (Weinreb et al., 1996). EBV1 was found in 60% of cases, including 80% of children from the United Kingdom, 95% Greece, 100% South Africa, 100% Australia, 45% Costa Rica, but only 28% Kenya. In contrast, EBV2 was found in only 16% of all cases, but included 83% of children from Egypt and 36% from Kenya. Interestingly, some cases from the United Kingdom, Kenya, and Australia exhibited both strains of EBV.
There is a strong genetic predisposition to risk, as monozygotic twins of adult patients have a nearly 100-fold increased risk (Mack et al., 1995). Further evidence of genetic susceptibility is apparent from observations of a high incidence among some populations in Southeast Asia, while a low incidence is observed among populations of East Asia (Varghese et al., 1996; Stiller and Boyle, 1998). These differences appear to be independent of socioeconomic status.
Epidemiologic studies have tended to focus on three distinct age groups: children (ages 0–14 years), young adults (approximately 15–34 years) and older adults (50+ years) (MacMahon, 1966; Grufferman and Delzell, 1984; Varghese et al., 1996; Stiller and Boyle, 1998). The young adult group is primarily suspected to have an infectious etiology (Gutensohn and Cole, 1981). Studies have shown that young adults from higher socioeconomic status families are at increased risk of developing HD (Gutensohn and Delzell, 1982; Gutensohn and Shapiro, 1982; Grufferman and Delzell, 1984; Stiller and Boyle, 1998). Further, individuals from small families (e.g., few siblings) appear to be at an increased risk (Grufferman and Delzell, 1984). One case-control study of childhood HD reported that children diagnosed at less than 10 years of age lived in areas with a significantly lower socioeconomic status than controls, although this difference was not apparent for children diagnosed between 10 and 14 years of age (Gutensohn and Shapiro, 1982). In the largest current case-control study to date, which includes over 500 HD cases and controls, a few preliminary findings have been published: a protective effect for breastfeeding was noted (Grufferman, 1998), which confirms reports in smaller studies (Davis et al., 1988; Schwartzbaum et al., 1991). Further, there was a suggestion that first-degree relatives of patients younger than 15 years of age at diagnosis have an increased risk of malignancy (Grufferman, 1998).
(p. 1257 ) Non-Hodgkin Lymphoma
In contrast to adults, where low- and intermediate-grade tumors are common, high-grade tumors affect more than 90% of children with non-Hodgkin lymphoma (NHL) (Sandlund et al., 1996). These high-grade types include: lymphoblastic lymphomas, Burkitt type lymphoma (small noncleaved cell), diffuse large B-cell lymphomas, and anaplastic lymphoma (Ries et al., 1999). Burkitt lymphomas accounts for almost half of all cases diagnosed in Africa. Whereas Epstein Barr virus is linked with Burkitt lymphoma in African children, EBV is rarely associated with Burkitt lymphoma in the United States.
Internationally, the highest incidence rates of NHL occur in Uganda and Egypt, intermediate rates occur in Spain, Germany, and New Zealand (Maori), and low rates in India and US blacks (Parkin et al., 1998) (Fig. 65–2B). In the United States, NHL comprises approximately 6% of all childhood cancers diagnosed under the age of 15 years. During the period 1990–1995, the age-specific annual incidence rates were 5.8, 8.7, 10.8, and 14.7 per million for ages 0–4, 5–9, 10–14, and 15–19 years, respectively (Ries et al., 1999). Nearly 70% of cases occur in males. Black children have notably lower incidence rates of NHL than white children, with an overall incidence of 6.8 per million compared to 8.9 per million for children under the age of 15 years, respectively. Five-year survival rates for childhood NHL approach 75%.
Genetic factors associated with NHL include those associated with congenital immunodeficiency syndromes and are listed in Table 65–2 (e.g., ataxia-telangiectasia, Wiskott–Aldrich Syndrome, X-linked lymphoproliferative disease) (Sandlund et al., 1996). As with adults, children with acquired immunodeficiency syndrome (AIDS) and children who have received prior immunosuppressive therapy are at increased risk (Filipovich et al., 1992; Penn, 1994; Granovsky et al., 1998).
There have been few etiologic studies of NHL and most have included only small numbers of cases. In a medical-record–based study of 34 cases of NHL diagnosed before 30 years of age and 68 matched controls, Roman et al., 1997) reported that viral infection during pregnancy was documented in the medical records of two case mothers and no control mothers. Another case-control study of 31 children with NHL reported that cases were significantly lighter at birth than corresponding controls (McKinney et al., 1987). In a nested-case control study of 1.7 million live births in Sweden, Adami et al. (1996) compared selected maternal and perinatal factors from the Swedish Medical Birth Registry for 168 cases of NHL and 840 matched controls. Very few factors were statistically significant. Paracervical anesthesia during labor as well as C-section was more common in the cases compared with the controls. Another study of 82 lymphoma cases from Shanghai reported that breastfeeding may be protective (Shu et al., 1995). In a case-control study of 268 children with NHL in the United States, a statistically significant association was found with reported pesticide exposure in the home (odds ratio = 7.3, p = 0.05 for use of pesticides most days in the home) (Buckley et al., 2000). Finally, as with childhood leukemia, population mixing has been implicated in etiology (Kinlen et al., 1995; Dickinson and Parker, 2002; Hemminki and Li, 2002).
SYMPATHETIC NERVOUS SYSTEM TUMORS (NEUROBLASTOMA)
Approximately 700 children in the United States are diagnosed with a sympathetic nervous system tumor each year, the vast majority (650) of which are neuroblastomas (Ries et al., 1999). Neuroblastoma is an embryonal malignancy that arises from the primordial neural crest cells that form the adrenal medulla and sympathetic nervous system (Brodeur, 1997). Some of the highest incidence rates (13–15 cases/million) of neuroblastoma are reported in US whites, France, Canada, Japan, and Israeli Jews, whereas considerably lower rates (2–5 cases/million) are reported in Costa Rica and Uruguay (Parkin et al., 1998). Some areas, such as Japan and the province of Quebec instituted mass screening programs for neuroblastoma, which resulted in a notable increase in incidence rates (Ross and Davies, 1999).
In the United States, the incidence of neuroblastoma is highly age dependent. In the first year of life the rate is 64 per million, while in the second year it is considerably lower (29/million) (Ries et al., 1999). Overall, incidence rates are only slightly higher in males than in females, although this difference is most pronounced in infancy (69.3/million vs. 59.6/million, respectively). Rates in white infants are somewhat higher than in black infants, although the overall rates across all ages are not that different. Overall trends in incidence have been relatively stable over the period 1976–1994, although there is a suggestion of the disease being diagnosed at earlier ages (Ries et al., 1999). This may be due to a general awareness in the United States of neonatal screening programs in other countries, which might enhance physician diagnosis.
Five-year survival rates for neuroblastoma are dependent on the age at diagnosis, the tumor histology, and the cytogenetics. In some neuroblastomas, the oncogene, n-Myc, is amplified, which is associated with a very poor prognosis (Brodeur, 1997). For infants, 5-year survival rates are about 85%, whereas for children older than 1 year of age, rates are around 55% (Ries et al., 1999).
A small proportion of neuroblastoma cases exhibit a genetic predisposition to the disease (Brodeur, 1997). In contrast to a median age of diagnosis of 22 months, these familial cases typically manifest the disease in the first year of life (Kushner et al., 1986). As with other embryonal tumors, etiologic studies have focused on exposures preconceptionally as well as in utero. A few studies have reported positive associations between farm residence or parental employment in agriculture, although findings have been inconsistent (Spitz and Johnson, 1985; Bunin et al., 1990b; Wilkins and Sinks, 1990; Kristensen et al., 1996; Kerr et al., 2000). Paternal employment in electronics-related occupations including electricians, linemen, and repairmen has been also associated with an increased risk, as has exposure to electromagnetic fields and aromatic hydrocarbons (Spitz and Johnson, 1985; Bunin et al., 1990b; Wilkins and Sinks, 1990). Daniels et al. (2001) recently examined the association between residential exposure to pesticides and neuroblastoma in a case-control study in the United States and Canada that included 538 cases and 538 controls selected through random-digit dialing. They found that parental report of pesticide use in the garden and home were modestly (odds ratios 1.6–1.7) associated with neuroblastoma. In an analysis from this same study (Olshan et al., 1999a), an increased risk was observed for fathers employed as broadcast/telephone operators, electrical power workers, landscapers/groundkeepers, and painters. Maternal occupations that were associated with elevated odds ratios included farmers/farm workers, florist and garden workers, and hair dressers.
Perinatal factors have also been explored. Maternal use of sex hormones including oral contraceptives or infertility drugs has been associated with an increased risk of neuroblastoma in several studies (Kramer et al., 1987; Schwartzbaum, 1992; Michalek et al., 1996). Olshan et al. (1999b) found no association with oral contraceptive use before or during pregnancy; however, they did report an increased risk in males. Interestingly, other studies have reported a similar phenomenon (Michalek et al., 1996; Schuz et al., 2001). A few studies have reported that maternal medication use during pregnancy such as amphetamines, diuretics, and tranquilizers is associated with an increased risk (Kramer et al., 1987; Schwartzbaum, 1992), although these data are less consistent. Some studies have reported that increased birth weight is associated with an increased risk (Yeazel et al., 1997; Suminoe et al., 1999), others low birth weight (Daling et al., 1984; Johnson and Spitz, 1985; Hamrick et al., 2001), and some have found no association (Neglia et al., 1988; Buck et al., 2001). A few studies have reported positive associations with either maternal cigarette smoking or alcohol consumption before or during pregnancy, whereas others have not (Schwartzbaum, 1992; Yang et al., 2000; Buck et al., 2001). One recent study (Olshan et al., 2002) found that maternal vitamin use during pregnancy may reduce the risk of neuroblastoma, similar to a smaller case-control study in New York state (Michalek et al., 1996). These observations are consistent with the observed reduction in risk of neural tube defects and oral clefts seen with maternal vitamin use (Shaw et al., 1995; Botto et al., 1999; Werler (p. 1258 ) et al., 1999). Breastfeeding has also been associated with a decreased risk (Daniels et al., 2002).
Few studies have had the statistical power to evaluate risk of neuroblastoma by grade, or N-myc status. A recent large case-control study evaluated the role of N-myc status and/or stage in a number of analyses and found no notable effects on the odds ratios (Yang et al., 2000; Daniels et al., 2001; Hamrick et al., 2001; Daniels et al., 2002; Olshan et al., 2002).
SOFT TISSUE SARCOMA (RHABDOMYOSARCOMA)
Soft tissue sarcomas (STS) encompass tumors that occur in connective tissue, such as muscles, tendons, and fat. Approximately 900 children under the age of 19 years are diagnosed with a STS each year in the United States, representing 7.4% of all childhood malignancies (Ries et al., 1999).
Internationally, incidence rates of STS are highest in Uganda, intermediate in the United States (whites and blacks) and Israeli Jews, and lowest in Thailand and India (Parkin et al., 1998). In the United States, males have slightly higher rates than females, and blacks slightly higher rates than whites (Ries et al., 1999). For children ages 0–14 years, rhadomyosarcomas represent about 50% of all STS diagnosed, with an incidence rate of approximately 4.6 per million. Nearly 75% of rhabdomyosarcomas have an embryonal histology. Other types of STS include fibrosarcomas, synovial sarcomas, leiomyosarcoma, lipsarcoma, malignant fibrous histiosarcoma, and others. The overall 5-year survival rates for STS are approximately 70% (Ries et al., 1999), although children with rhadomyosarcoma experience slightly poorer 5-year survival rates of around 64%. Younger children fare better than older children with rhabdomyosarcoma, as do whites compared with blacks, and males compared with females.
As rhabdomyosarcomas comprise the largest homogeneous group of malignant STS in children, epidemiologic studies have focused on this subtype. A few known risk factors for STS exist. Several studies have linked major birth syndromes and defects (including Beckwith–Wiedemann, Costello syndrome, neurofibromatosis, and genitourinary anomalies) with rhabdomyosarcoma (Table 65–2), although these associations occur in only a small fraction of cases (Ruymann et al., 1988; Yang et al., 1995; Gripp et al., 2002). Other genetic conditions, such as Li-Fraumeni syndrome, are also associated with an increased risk (Wexler and Helman, 1997).
Few case-control studies have investigated the etiology of STS or rhabdomyosarcoma (RMS). In a case-control study of 52 cases of STS (36 RMS) and 326 controls in Italy, a non-statistically significant increased risk was reported with older maternal age and in utero exposure to radiation (Magnani et al., 1989). A case-control study of 43 childhood STS and 86 matched controls enrolled in the Inter-Regional Epidemiological Study of Childhood Cancer reported that maternal toxemia during pregnancy and fewer previous pregnancies were associated with an increased risk (Hartley et al., 1988). In a small (33 cases and 99 controls) case-control study in North Carolina, positive associations were reported with paternal cigarette smoking, advanced maternal age, and lower socioeconomic status (Grufferman et al., 1982). The largest case-control study to date, 322 cases and 322 age-, sex-, and race-matched controls, reported that low socioeconomic status, diagnostic X-rays during pregnancy, and parental use of marijuana and cocaine may increase risk (Grufferman, 1991; Grufferman et al., 1993).
RENAL CANCERS (WILMS TUMOR, RENAL CARCINOMA)
Wilms tumor (WT), or nephroblastoma, is a cancer of kidney cell progenitors. It is the most common renal tumor, especially in the first 10 years of life when it constitutes about 95% of such malignancies. Among children aged 10–14 years renal carcinoma makes up about one-third of kidney cancers, the rest being WT (Ries et al., 1999). The rate of WT in most nations ranges between 4 and 10 cases per million and is lower, in general, in developing countries than in industrialized ones (Fig. 65–2B). Renal carcinoma is universally rare in children (Parkin et al., 1998). Like other embryonal tumors, incidence of WT is greatest in infancy, at 18.3 cases per million, declines to 5.6 cases per million at 4 years of age, and thereafter has a rate of less than 1 case per million. The rate of renal carcinoma is below 1 case per million for all age groups less than 20 years of age (Ries et al., 1999). The rate of WT is higher in females than in males and higher in blacks than in whites; these disparities are greatest among 0–4 year olds and lessen with age (Ries et al., 1999). WT registered no significant change in incidence between 1974 and 1991, except among males ages 5–9 years, whose rate changed by an average of 4.6% per year (95% CI: 1–9.4) (Gurney et al., 1996).
Wilms tumor may involve one or, as in 5%–10% of cases, both kidneys (Bonaiti-Pellie et al., 1992), which suggests a two-hit mutation model of tumorigenesis as with retinoblastoma (Knudson et al., 1972). In support of this contention, bilateral WT occurs significantly earlier than does unilateral disease (Breslow et al., 1988). However, the fact that unilateral cases with the Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome also were younger than unilateral cases without WAGR suggested that more than one locus is involved in WT oncogenesis (Breslow et al., 1988, 1996). Several loci involved in Wilms tumorigenesis have now been identified. WT1 encodes a transcription factor and tumor suppressor at the 11p13 locus; mutation or deletion of which leads to WT in a minority of cases (Dome et al., 2002). The WT2 locus at 11p15 encodes a variety of genes, including the one for insulin-like growth factor 2 (IGF-2) (Dome et al., 2002). Overexpression of IGF-2, as has been observed in WT, may promote cell growth and lead to cancer (Ogawa et al., 1993; Rainier et al., 1993). Linkage analysis has also identified two other putative WT loci called FWT1 and FWT2 (for familial WT) at 17q and 19q, respectively, and still more loci may play a part in Wilms tumorigenesis (Dome et al., 2002).
Besides congenital conditions, few risk factors for WT display great consistency. Isolated reports have linked WT with parental exposure to pesticides (Olshan et al., 1993; Sharpe et al., 1995; Schuz et al., 2001). Exposures to the mother during pregnancy or birth have been of interest; use of coffee or tea (Bunin et al., 1987; Olshan et al., 1993; Schuz et al., 2001), hair dye (Bunin et al., 1987; Olshan et al., 1993), and medications (Lindblad et al., 1992; Sharpe and Franco, 1996) have been associated with WT in some studies but not others. Studies of paternal occupation have suggested an increased risk in children of fathers who work with hydrocarbons, lead, or other metals (Fabia and Thuy, 1974; Kantor et al., 1979; Wilkins et al., 1984a; Wilkins et al., 1984b; Bunin et al., 1989b; Olshan et al., 1990). These associations were often strongest for exposure before conception of the child with WT. Significant associations of WT with high birth weight have been observed, though among various subsets of cases (Daling et al., 1984; Bunin et al., 1987; Leisenring et al., 1994; Heuch et al., 1996; Yeazel et al., 1997; Smulevich et al., 1999; Schuz et al., 2001). Two studies found no significant association of WT with birth weight (Lindblad et al., 1992; Olshan et al., 1993). Still, the frequent overexpression of IGF-2 found in WT lends support to an association with birth weight (Ogawa et al., 1993).
BONE TUMORS (OSTEOSARCOMA, EWING SARCOMA)
Osteosarcoma (OS) and Ewing sarcoma (ES) comprise 56% and 34%, respectively, of malignant bone tumors in children. They originate from different tissues; OS arises from primitive bone-forming mesenchymal stem cells, whereas ES arises from the neural crest (Ries et al., 1999). The two tumors display contrasting patterns of international incidence. OS incidence ranges mainly between 1 and 4 cases per million and shows no striking associations across nations. The rate of ES among black Africans and black Americans, however, <1 case per million, is very low compared with rates of between 2 and 4 cases per million for white Americans and Europeans (Parkin et al., 1998). In the United States incidence of both cancers is extremely low in early childhood, grows steadily during the ages of 5–9 years, and peaks in mid adolescence at about 11 cases per million for OS and 6 cases per (p. 1259 ) million for ES. The rate of both cancers is slightly higher among males than among females until 15 years of age, when the gap widens. Whereas the rate for OS among blacks is slightly higher than that for whites, nearly all ES occurs among whites (Ries et al., 1999). The rate of OS among children aged less than 15 years rose by a significant 2.4% (95% CI: 0.3–4.7) annually between 1974 and 1991, mainly among 5–9 year olds. The rate of ES rose a significant 3.4% annually (95% CI: 0.2–6.6) among 10–14 year olds; no significant rise was seen among other age groups (Gurney et al., 1996).
The cytogenetics of OS are complex, with no single genetic rearrangement predominating (Bridge et al., 1997). By contrast, about 90% of ES displays the t(11;22) translocation (Ladanyi et al., 1993). The EWS gene on chromosome 22 is therein fused with a variety of other genes to produce a dominant-acting oncoprotein (Arvand and Denny, 2001). Survival of OS and ES varies by histologic subtype (Ferrari et al., 2001), but is low compared with other childhood cancers (Table 65–1) (Ries et al., 2003).
Osteosarcoma has long been a recognized consequence of the inherited cancer-predisposing Li-Fraumeni and retinoblastoma syndromes (Hansen et al., 1985), but these rare conditions account for few cases. The close correlation between the incidence of OS and the childhood growth curve (Fraumeni and Miller, 1967), as well as the frequent occurrence of the diseases in the long bones of the lower limbs during adolescence (Ries et al., 1999), suggests an etiology linked with bone development. Veterinary studies show that large breeds of dogs develop OS at a much higher rate than do small breeds (Tjalma, 1966), as do dogs that are spayed or neutered at an early age (Cooley et al., 2002). Some reports have indicated that OS cases are taller at diagnosis than are controls (Fraumeni and Miller, 1967; Gelberg et al., 1997), whereas other studies have not borne this out (Operskalski et al., 1987; Buckley et al., 1998). Other factors that might reasonably be related to growth, such as birth weight and the age at onset of secondary sexual characteristics, have shown no consistent pattern (Hartley et al., 1988; Gelberg et al., 1997; Buckley et al., 1998). Parental adult height also has not been associated with OS (Budkley et al., 1998). The association of ES with factors related to growth is similarly mixed (Fraumeni and Miller, 1967; Hartley et al., 1988; Winn et al., 1992; Buckley et al., 1998).
Some evidence points to a genetic predisposition for ES. Most striking is the above-mentioned rarity of ES among black children both in the United States (Ries et al., 1999) and in Africa (Parkin et al., 1998). Also, ES tumors are more evenly distributed among the bones of the body, unlike OS, which occurs mainly in the long bones of the lower limbs (Ries et al., 1999). However, there is little evidence of a higher risk of ES among family members of cases (Hartley et al., 1991), though risk of other cancers may be raised (Novakovic et al., 1994).
Exploratory analyses of a wide range of other factors have not revealed any notable risk factors for OS or ES (Operskalski et al., 1987; Hartley et al., 1988; Winn et al., 1992; Buckley et al., 1998). With the exception of farm work, which has been associated with ES in several studies (Holly et al., 1992; Winn et al., 1992; Hum et al., 1998; Valery et al., 2002), few parental occupational exposures have been consistently associated with bone cancer (Operskalski et al., 1987; Hartley et al., 1988; Buckley et al., 1998; Hum et al., 1998). Radium and fluoride, of concern since they are incorporated into bone, have mostly not been associated with OS or ES in case-control studies (McGuire et al., 1991; Finkelstein, 1994; Gelberg et al., 1995; Moss et al., 1995; Finkelstein and Krieger, 1996). Radiotherapy is an established risk factor for bone sarcomas, but is mostly of historical interest (Tucker et al., 1987; Newton et al., 1991). Two ecological analyses have suggested a higher incidence of bone tumors in urban areas (Larsson and Lorentzon, 1974; Silva and Subrarnian, 1975). Two other studies showed no evidence of clustering of bone tumors (Glass and Fraurneni, 1970; Silcocks and Murrels, 1987).
GERM CELL TUMORS
Germ cell tumors (GCTs) arise from the primordial germ cells during fetal development. The tumors that can develop are extremely heterogeneous, and often manifest a more benign rather than malignant phenotype, particularly in the younger age groups (Castleberry, 1997). GCTs are grouped by both location and cells of origin and include: intracranial and intraspinal, other, unspecified non-gonadal tumors such as those in the sacrococcygeal or mediastinal regions, gonadal tumors of the testes or ovaries, gonadal carcinoma of the testes or ovaries, and other, unspecified gonadal tumors (Ries et al., 1999).
With the exception of slightly higher incidence rates reported in Japan (9.6 cases/million) and New Zealand (Maori, 8.2 cases/million), there is little variation in the rates of GCTs; most areas range from 1–7 cases/million (Parkin et al., 1998). Collectively, the annual incidence rate of malignant GCTs in the United States is low; only about 5 cases per million children occur under the age of 15 years, and about 12 cases per million under the age of 20 years. The incidence rate is only slightly higher in males than in females. Black children have somewhat lower rates than white children (Ries et al., 1999). Notably, black males have lower rates of testicular GCTs compared with white males (1.2 vs. 9.1/million, respectively). Overall, incidence rates are elevated in infancy and then decline until about the age of 10 years, where they rapidly rise for both males and females. Comparing the periods 1975–1979 and 1990–1995, the overall incidence rate of GCTs in children increased from 8.5 per million to 12.0 per million. Much of this increase, however, is likely due to the inclusion of tumors that once would have been considered borderline malignant (Ries et al., 1999). Overall, 5-year survival rates for children diagnosed with a GCT are quite good, approaching 90%.
Due to its rarity, very few epidemiologic studies have explored risk factors for malignant GCTs in children, although some studies have focused on testicular tumors in adolescent and adult populations. Cryptorchidism is one of the few established risk factors for testicular GCTs (Strader et al., 1988). Maternal exogenous estrogen exposure and/or high endogenous hormone levels during pregnancy may also be associated with an increased risk of testicular GCTs, although the evidence is inconsistent (Henderson et al., 1979; Depue et al., 1983; Walker et al., 1988). Other purported risk factors include radiation exposure during pregnancy, pre-term birth, congenital malformation, viral infections such as mumps, and certain parental occupational exposures (Li et al., 1972; Li et al., 1973; Henderson et al., 1979; Schottenfeld et al., 1980; Birch et al., 1982; Depue et al., 1983; Algood et al., 1988; Kardaun et al., 1991). In the most recent case-control study to date, Shu et al. (1995) compared responses on a structured self-administered questionnaire from parents of 105 patients with malignant GCT and 639 community controls. They found that infants born at term had a 70%–75% reduction in the risk of a malignant GCT compared with children born before 38 weeks gestation. Further, this same study found that certain parental self-reported exposures to chemicals and solvents were associated with an increased risk. High birth weight, prolonged breast feeding, and maternal urinary tract infection during pregnancy were also associated with an increased risk. In contrast, maternal cigarette smoking was associated with a decreased risk. Given the heterogeneity of GCTs, it will be important for future studies to investigate risk factors by subtype.
The Children’s Oncology Group has recently completed the largest case-control study of childhood malignant GCTs to date. This study included over 300 cases in the United States and Canada and 400 controls selected through random-digit dialing. Hypotheses to be tested in this study include potential associations with maternal exogenous estrogen use and prenatal occupational exposures. Analyses are underway and should be available within the next few years.
RETINOBLASTOMA
Retinoblastoma (RB) is a malignant tumor of the primitive neuroectodermal cells of the retina and affects approximately 300 children in the United States each year, accounting for about 3% of all malignancies diagnosed in children under the age of 15 years. There is little international variation in incidence rates, with most countries reporting an incidence of between 3–8 cases/million (Parkin et al., 1998). The majority (63%) of RBs are diagnosed in children under the age of 2 years, and nearly all (95%) cases are diagnosed before the age of (p. 1260 ) 5 years (Ries et al., 1999). Males and females are equally affected, as are blacks and whites. Incidence rates for RB in the United States have remained essentially stable over the past 20 years (about 4 cases/million). Recent 5-year survival estimates are quite good (93%).
The study of RB led to the two-hit theory of carcinogenesis (Knudson, 1971). It was later demonstrated that inactivation of both alleles of the retinoblastoma (RB1) gene at chromosome band 13q14 was required for the cancer to develop (Cavenee et al., 1983; Dryja et al., 1986). About 10% of children with RB inherit a mutated RB1 gene from one of their parents. In this familial form, all cells harbor the RB1 gene mutation, and nearly all children will have a “second hit” occur in the retinal cell sometime after conception. Another form of heritable RB, which affects another 30% of children with RB, arises from an RB1 gene mutation that occurred in the germ cells of one of their parents. This is referred to as sporadic heritable RB, as neither parent is afflicted, but the child has an RB1 gene mutation in all of their cells. As with familial RB, over 90% of individuals carrying one mutated RB 1 gene will eventually develop the disease (Ries et al., 1999). Finally, the remaining 60% of RB patients have non-heritable disease. This type of RB develops as the result of two somatic RB 1 gene mutations occurring in a single cell sometime after conception.
The heritable forms of RB typically are diagnosed in the first year of life and often both eyes are affected. In contrast, the non-heritable form manifests at a slightly older age and usually only one eye is affected (Ries et al., 1999). Interestingly, the vast majority of new germinal mutations in sporadic heritable RB occur in the paternal RB1 allele (Dryja et al., 1989). Thus, preconceptional exposures of the father (not the mother) would be etiologically relevant in sporadic heritable RB. In contrast, postconceptional factors likely play a role in non-heritable RB.
Due to the extreme rarity of the disease, there have been very few etiologic studies of RB. One of the largest case-control studies of RB, conducted in the former Children’s Cancer Group, included 201 RB cases (19 familial, 67 sporadic heritable, and 115 non-heritable) and 201 controls. The authors reported that paternal employment in the military and metal manufacturing was associated with an increased risk of sporadic heritable RB (Bunin et al., 1990a). For non-heritable RB, increased risks were observed with paternal occupations as welders and machinists. Other findings from this same study suggested that maternal morning sickness medication, and gestational exposure to X-rays were associated with an increased risk, whereas maternal anemia, multivitamin use during pregnancy, and peri-conceptional use of barrier contraceptives or spermicides were associated with a decreased risk (Bunin et al., 1989a). At least three studies have reported that advanced paternal age is associated with an increased risk of sporadic heritable RB (DerKinderen et al., 1990; Moll et al., 1996; Dockerty et al., 2001); two of these studies also demonstrated that maternal advanced age was a risk factor (DerKinderen et al., 1990; Moll et al., 1996).
Finally, a recent study from the Netherlands explored potential associations between in vitro fertilization (IVF) and risk of RB (Moll et al., 2003). Five cases of retinoblasoma were diagnosed in children conceived through IVF during the period November 2000 through February 2002. Based on the number of children born after IVF, and the incidence estimates of the number of RB cases expected, the authors estimated a relative risk of 7.2 for developing RB in children conceived through IVF. This intriguing observation deserves further exploration.
HEPATIC TUMORS (HEPATOBLASTOMA, HEPATOCELLULAR CARCINOMA)
Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are cancers of immature and differentiated liver cells, respectively. HB is the most common malignancy of the liver in persons aged less than 15 years; between 1990–1995 it comprised about 90% of hepatic tumors at those ages (Ries et al., 1999). Internationally, incidence of HB ranges mainly between 0.5 and 2 cases per million, and HCC even lower, though these estimates are often unstable due to the rarity of these cancers (Parkin et al., 1998). In the United States, incidence is greatest in infancy, at 8.7 cases per million, declines to 0.3 cases per million at 4 years of age, and thereafter becomes even more rare (Ross and Gurney, 1998; Ries et al., 1999). Males are slightly more commonly diagnosed with HB than are females (male: female ratio = 1.2), whereas rates are roughly similar for blacks and whites (Ries et al., 1999). HB incidence appears to be rising recently. Between 1973 and 1992, the rate of HB among 0–4 year olds increased by an average of 5.2% per year (95% CI: 1.9–8.6%); the rise in incidence was significant among females but not males (Ross and Gurney, 1998). The addition of chemotherapy to surgery for HB has improved survival such that 75%–80% of cases can be cured (Carceller et al., 2001). HCC is extremely rare below the age of 15, with a maximum incidence of 0.3 cases per million. However, by ages 15–19 years HCC has an incidence of 0.9 cases per million and is many times more common than HB (Ries et al., 1999).
Because of its rarity, most knowledge about risk factors for HB has been gleaned from case reports or series. Some HBs display sporadic mutations of the APC gene (Oda et al., 1996) and, accordingly, the rate of HB is vastly increased in children who are potentially carriers of the familial adenomatous polyposis gene (i.e., APC) (Giardiello et al., 1991). Incidence is also increased among children with Beckwith–Wiedemann syndrome (DeBaun et al., 1998), which has lead to the suggestion that screening children with these conditions may be an effective way to reduce mortality due to HB (Giardiello et al., 1991; McNeil et al., 2001). Genetic analyses indicate that some HBs display abnormal imprinting of IGF-2 alleles (Ross et al., 2000).
Case-control studies of HB are few. An exploratory study that consisted of 75 cases and 75 controls found that mothers of children with HB were significantly more often occupationally exposed to metals, petroleum products, and paints and pigments before or during pregnancy, while fathers of children with HB were significantly more often occupationally exposed only to metals (Buckley et al., 1989). The study did not find evidence of hypothesized associations of HB with hepatitis, maternal alcohol consumption, or maternal smoking. A smaller study found parental smoking significantly increases risk of HB (Pang et al., 2003). However, that finding may have been confounded by low birth weight, which can be caused by smoking (Horta et al., 1997) and seems to be a risk factor for HB.
A Japanese report first noted that the percentage of HB cases that weighed 1500 grams or less at birth increased significantly between the late 1980s and the early 1990s, when survival of very low birth weight babies improved (Ikeda et al., 1997). Subsequent studies confirmed that the rate of HB was significantly higher among very low birth weight babies compared with those with normal birth weight in Japan (Tanimura et al., 1998), and that the proportion of low birth weight among US HB cases was unusually high (Feusner and Plaschkes, 2002). Two reasons are possible for these data. The first is that improved treatment of low birth weight babies is allowing HB cases to survive (where in the past they would have died either before birth or shortly thereafter). Alternatively, treatment for low birth weight itself may cause HB. Though one study conducted in response to recent revelations suggested that HB in very low birth weight infants may be related to the length of therapy for prematurity (Maruyama et al., 2000), more studies are needed before it can be determined which explanation is correct.
There are few studies of HCC at ages younger than 20 years. However, chronic hepatitis B and C virus infections, host responses to these pathogens, and exposure to cofactors such as aflatoxin are established risk factors for HCC in adults (Kasai et al., 1996). Findings that hepatitis B vaccination has reduced incidence of HCC in adolescents strongly suggests that the etiology among the young is similar to that in adults (Chang et al., 2000; Lee et al., 2003).
FUTURE DIRECTIONS
Due to its heterogeneity and rarity, investigators conducting etiologic studies of childhood cancer in the United States have often collaborated (p. 1261 ) with hospitals and institutions affiliated with the National Cancer Institute pediatric cooperative clinical trials groups. Importantly, hospitals and institutions affiliated with the former Children’s Cancer Group and the Pediatric Oncology Group are estimated to treat nearly 90% of all malignancy diagnosed in children less than 15 years of age (Ross et al., 1996). In 2000, the NCI pediatric cooperative clinical trials groups were merged to form the Children’s Oncology Group (COG). Over 220 hospitals and institutions in the United States and Canada are affiliated with the COG. The administrative structure of COG consists of disease and scientific discipline committees, including the Epidemiology Committee.1
The mission of the COG Epidemiology Committee is to promote and facilitate research investigating the causes of childhood cancer. Recognizing recent accomplishments, as well as challenges, the Epidemiology Committee has proposed several areas for future directions in childhood cancer research in the United States including formation of a North American Pediatric Cancer Registry; conduct of studies to improve methodological approaches; and expanded investigations of gene-environment interactions, familial cancer syndromes, and viruses in childhood cancer etiology. Each of these is described briefly below.
Formation of a North American Pediatric Cancer Registry
Since the hospitals and institutions affliated with the COG treat the majority of children with cancer (Ross et al., 1996), the COG Epidemiology committee, in collaboration with the National Cancer Institute, and State, Provincial, and regional cancer registries are working to establish the Childhood Cancer Research Network (CCRN). The CCRN will form the basis of a North American pediatric cancer registry. Currently, the protocol for registration to the CCRN is being piloted at 10% of COG institutions. The protocol requests that once a child is diagnosed with cancer, a consent form be administered to the parent (and child, if age eligible) to be registered to the CCRN with personal identifiers. Additionally, a consent form is administered to request permission to be contacted in the future to consider taking part in a non-therapeutic study. Establishing the CCRN should help to overcome several challenges (e.g., small numbers of cases, lack of participation by some hospitals and institutions, and delays in obtaining human subjects approval) in conducting etiologic studies of childhood cancer in COG and provide an unequaled resource for research in the United States and Canada.
Conduct of Studies to Improve Methodological Approaches
As we have described previously, several case-control studies of childhood cancer suggest an important role for specific parental and childhood exposures in etiology. However, studies of childhood cancer often rely solely on questionnaire data obtained from interviews conducted with the parents of children with and without cancer. While a few studies have incorporated additional measures of exposure (e.g., electromagnetic field levels) (Linet et al., 1997), more studies with adjunct measurements are needed. Further, there is difficultly in recruiting appropriate control groups for case-control comparisons. Most large-scale case-control studies of childhood cancer in the United States have used random digit-dialing for recruitment of controls. With the increasing use of answering machines, caller identification, and cell phones, acceptable alternatives to random-digit dialing must be identified. Alternative control groups that could be explored include birth roster controls, which have been successfully used in smaller studies (Buck et al., 2001; Ma et al., 2002a; Ma et al., 2002b). One proposed study will examine the feasibility of using birth certificate controls on a national basis.
Expanded Investigations of Gene-Environment Interactions, Familial Cancer Syndromes, and Viruses in Childhood Cancer Etiology
As summarized in Table 65–2, known familial cancer syndromes are relevant to the development of childhood cancers (reviewed in Volgelstein and Kinzler, 1998). Studies of familial cancer clusters have, and will continue to lead to the discovery of cancer-predisposition genes. For most children, however, the etiology of cancer is probably multifactorial and related to a combination of genetically determined host susceptibility factors and exposures to carcinogens. As we have described, a wide range of environmental factors are associated with an increased risk of leukemia and other childhood cancers. These observations provide support that environmental exposures in the context of host (or parental) genetic susceptibility to genotoxic damage may be the major determinants of childhood cancer risk. However, further identification of the importance of gene-environment interactions, as well as major gene effects and viruses are needed. Some new studies being proposed by the COG Epidemiology Committee include studies of childhood leukemia that include the incorporation of genetic polymorphism in both the mother and infant to evaluate the role of gene-environment interactions, mechanistic studies of pregnancy to evaluate placental transfer as well as potential modifications by genotype, characterization of the role of polyomaviruses in the development of cancer in families with a history of Li-Fraumeni syndrome, and collection of family history at defined intervals to identify evolving familial cancer syndromes.
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Notes:
(1) J. A. Ross is currently Chair of the COG Epidemiology Committee.