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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 137BIncidence, Origins, Epidemiology

, PhD.

In the United States, it is estimated that approximately 8700 new cases of cancer are diagnosed annually in children under the age of 15 years. Although pediatric cancers represent only approximately 2% of all cancers diagnosed in the U.S. each year, it remains the leading cause of death due to disease. 1 It has long been observed that, internationally, there are striking differences in the annual incidence of reported childhood cancers. 2 However, a number of possible explanations must be considered when interpreting international data, including potential differences in medical care systems, diagnostic acumen, differences in classification, thoroughness of cancer surveillance and reporting, the size of the population and accuracy of census, and the true occurrence of cancer among the various populations.

Summarized below is a brief description of the incidence and epidemiology of the major forms of childhood cancer. Incidence data are provided for the United States and are derived from the National Cancer Institute’s Surveillance, Epidemiology and End Results Program (SEER). The SEER pediatric monograph (http: // represents one of the most current and extensive assessments available. 3 Summarized in Table 137B.1 are the age-adjusted rates for childhood cancers in the United States between 1974 and 1991. 4

Table 137B.1. Age-adjusted Annual Incidence Rates per Million Population for Cancer in Children < 15 Years of Age in United States (1974–1991).

Table 137B.1

Age-adjusted Annual Incidence Rates per Million Population for Cancer in Children < 15 Years of Age in United States (1974–1991).

Acute Leukemia

In the United States, leukemias are the most common childhood cancer, representing approximately 31% of all cancer cases occurring in children under the age of 15 years. 3 Acute lymphoblastic leukemia (ALL) represents approximately 75% of all leukemias within this age group, whereas acute myeloid leukemia (AML) accounts for 20%. Childhood ALL is characterized by a sharp peak in the annual incidence occurring between the ages of 2 and 3 years, with a subsequent decrease in the rate occurring by 8 to 10 years of age. Leukemia occurs at a much higher rate in Caucasian children compared to African-American children (4.6 vs. 2.8 per 100,000), with an approximate threefold higher incidence in Caucasians during the early childhood peak. In the United States, the annual incidence of acute leukemia in children has demonstrated a very modest but consistent increase in annual incidence, which has led to ongoing speculation regarding the significance, if any, of this observed trend. 4, 5

Although childhood leukemias have been the subject of numerous epidemiologic investigations, the etiology of most cases remains unknown. 6 There are a number of genetic conditions associated with risk, including Down syndrome, neurofibromatosis, Shwachman syndrome, Bloom’s syndrome, and ataxia-telangiectasia. Factors that are generally agreed to infer an increased risk for childhood ALL include male gender, age 2 to 5 years, Caucasian race, higher socioeconomic status, in utero radiation exposure, and postnatal exposure to radiation (i.e., therapeutic doses, atomic bomb exposure). There are a number of other less well-characterized factors that have been reported to be associated with risk of childhood ALL such as increased birth weight, maternal history of fetal loss, older maternal age, and selected environmental exposures. Recent investigations have provided evidence against a role for environmental factors such as low-frequency electromagnetic fields and indoor radon. 7, 8 Hypotheses have been proposed for a potential etiologic role to postnatal infections—specifically, exposure to common infectious agents in susceptible populations. 9, 10

With respect to childhood AML, risk factors include Hispanic race and exposure to chemotherapeutic agents (specifically, alkylating agents or DNA topoisomerase-II inhibitors). Genetic conditions including Down syndrome, neurofibromatosis, Shwachman syndrome, Bloom’s syndrome, familial monosomy 7, and Fanconi’s anemia are also associated with an increased risk for myeloid leukemia during childhood. 11 Several recent studies have identified an association between maternal alcohol consumption during pregnancy and increased risk of childhood AML, as well as exposures of parents and children to pesticides and specific solvents. 12– 14 However, these environmental exposures require confirmation within populations where the exposure assessment is of high quality.

Central Nervous System Tumors

Central nervous system (CNS) malignancies are the second most common malignancy in childhood and the most common form of solid tumor. 3 Approximately 17% of all pediatric cancers arise in the CNS, of which 90% are located with the brain. In contrast to CNS tumors occurring in adults, pediatric CNS tumors have a relatively high rate of occurrence within the cerebellum and brain stem. Histologically, 52% of CNS tumors are astrocytomas, 21% medulloblastoma/primitive neuroctodermal tumor (PNET), 15% other gliomas, and 9% ependymomas. The incidence of CNS tumors are higher in males versus females and higher in Caucasians compared to African Americans. In contrast to the age-specific pattern for childhood leukemia, CNS tumors do not demonstrate a marked variation in age. The incidence of childhood brain tumors has been reported to be increasing over the past several decades and is thus the topic of considerable speculation. 4 Assessment of the secular trends in CNS tumors suggests that improvements in diagnostic technology may account for some of the observed increases. 15

Review of the literature reveals that currently there are no known risk factors that account for a substantial proportion of CNS tumors in children. 16– 19 Factors known to be associated with an increased risk of CNS tumors include male gender (medulloblastoma/PNET, ependymomas), ionizing radiation (therapeutic doses), and genetic conditions such as neurofibromatosis, tuberous sclerosis, nevoid basal cell syndrome, Turcot syndrome, and Li-Fraumeni syndrome. Exposure to N-nitroso compounds, primarily through dietary intake of cured meats, has been actively pursued as an etiologic risk factor in childhood brain tumors, with results suggestive of an increased risk. More recently, interest has increased in the potential role of polyomaviruses (i.e., simian virus 40, JC, BK) in the etiology of childhood brain tumors, but further investigation is necessary to elucidate the possible association and mechanisms. 20– 23


The third most common form of childhood cancer in the United States is the lymphomas, accounting for 15% of all childhood malignancies. 3 The pediatric lymphomas are comprised of two prominent forms including Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL), with annual rates (per million population) of 6.5 and 8.4, respectively. Pediatric Hodgkin’s disease is comprised of histologically distinct subgroups including nodular sclerosis (70%), mixed cellularity (16%), lymphocytic predominance (7%), and lymphocytic depletion (< 2%). The frequency of mixed cellularity and nodular sclerosis subtypes are age and gender dependent, with both forms increasing with older age at diagnosis. NHL represent a heterogenesis group of tumors with Burkitt and Burkitt-like tumors predominating in children diagnosed between the ages of 5 to 14 years. Moreover, in contrast to Hodgkin’s disease, NHL varies less by age. Males and Caucasians have a higher incidence of NHL.

Risk of pediatric Hodgkin’s disease is associated with a positive family history of Hodgkin’s disease among siblings and particularly among monozygotic twins. Epstein-Barr virus (EBV) infections have been documented to be associated with Hodgkin’s disease (primarily of mixed cellularity subtype) with detection of EBV genomic material within the Reed-Sternberg cells. 24, 25 Based on epidemiologic observations in young adults with Hodgkin’s (primarily the nodular sclerosis subtype), there is also speculation of an infectious etiology given the reported associations with socioeconomic status and social contacts. Similarly, there is limited information relating to risk factors for childhood NHL with only immunodeficiency, either congenital or acquired, and EBV (within “African-type” Burkitt’s lymphoma) as established associations. 26


In the United States, it is estimated that approximately 700 children are diagnosed annually with tumors of the sympathetic nervous system, of which approximately 650 are neuroblastoma. 3 Neuroblastoma, most commonly occurring in the adrenal gland, is predominantly a tumor of infancy with 16% of children diagnosed within the first month of life and 41% diagnosed within the first 3 months of life. There are no appreciable differences in the occurrence of neuroblastoma according to sex or race.

Research stimulated by Japanese investigators has demonstrated that neuroblastoma can be detected preclinically through urinary screening of catecholamine metabolites (homovanillic acid and vanillylmandelic acid). 27 Results from population-based screening at 3 weeks and 6 months of age has shown that the incidence of neuroblastoma is increased two-fold; thus, a large proportion of tumors spontaneous regress and do not come to clinical diagnosis. 28

Little is known about the etiology of neuroblastoma. Clinical and biologic characteristics, such as the very early age at onset, spontaneous regression, amplification of the myc-n oncogene, hyperdiploidy, and loss of heterozygosity on 1p, have generated a great deal of interest in the etiology of neuroblastoma. 29 The relatively limited number of epidemiologic studies conducted have provided some suggestions of risk associated with maternal use of medications, hormones, tobacco, and alcohol during the index pregnancy, birth characteristics (i.e., increased birth weight), and a variety of parental occupations. 30


Although retinoblastoma accounts for only 3% of all childhood cancers (approximately 300 cases annually in the United States), it does comprise 11% of all malignancies occurring within the first year of life. 3 As seen in neuroblastoma, retinoblastoma is a tumor of infancy, with 63% diagnosed within the first 2 years and 95% within the first 5 years. Bilateral retinoblastoma is associated with younger age at diagnosis, with bilateral disease occurring in 42% of children less than 1 year old, 21% of those 1 year of age, and only 9% of those 2 or more years of age. The annual incidence rate of retinoblastoma is similar for males versus females and Caucasians compared to Afrian Americans.

Based on the observed age-specific incidence patterns for children with the hereditary and nonhereditary forms of retinoblastoma, the concept of tumor suppressor genes was proposed and validated. 31 Thus, the identification of the retinoblastoma gene at 13q23. 32 Each child of a parent with familial bilateral retinoblastoma has a 50% risk of inheriting the retinoblastoma gene, of whom 90% will develop retinoblastoma. 33 The etiology of the nonhereditary form of retinoblastoma (sporadic retinoblastoma) is not known.

Wilms’ Tumor

Approximately 6% of all childhood cancers arise in the kidney (annual incidence rate of 7.9 per million population). 3 In the United States, approximately 91% of the 550 renal tumors diagnosed are Wilms’ tumors, with the remaining consisting of rhabdoid tumors and clear cell sarcoma of the kidney. The vast majority of Wilms’ tumors occur within the first 5 years of life. Females have a somewhat higher incidence of Wilms’ tumor compared to males, and Afrian-American children have a higher incidence compared to Caucasian children. It is notable that the rate of Wilms’ tumor is substantially lower in Asians.

In contrast to many of the less common childhood malignancies, Wilms’ tumor has been relatively extensively studied from an epidemiologic perspective. 3, 16, 34 The only established associations include race and presence of congenital and genetic conditions including aniridia, genitourinary anomalies, WAGR syndrome (Wilms’ tumor, aniridia, genitourinary abnormalities, mental retardation), Beckwith-Wiedemann syndrome, Perlman syndrome, Denys-Drash syndrome, and Simpson-Golabi-Behmenl syndrome. 35 Some studies have reported increased risks associated with paternal occupations including welders and mechanics. A variety of other risk factors have been observed, but the evidence is limited or inconsistent, including increased birth weight, parental exposure to pesticides, in utero radiation exposure, maternal pregnancy factors such as consumption of coffee and tea, hair dye use, medication use, and occupational exposures.

Bone Tumors

With an annual incidence rate of 8.7 per million population, malignant bone tumors account for approximately 6% of all cancers in children and young adults under the age of 20 years in the United States. 3 The age-specific incidence of bone tumors is characterized by very low rates before the age of 5 years, followed by increasing rates that peak around 13 to 15 years of age. Of the estimated 650 to 700 bone tumors diagnosed each year, approximately 400 are osteosarcomas and 200 Ewing’s sarcoma. Among children, 56% of bone tumors are osteosarcoma, whereas 34% are Ewing’s sarcoma. The primary site for osteosarcoma is in the long bones of the lower extremities (78%), which differs from the most common primary site for Ewing’s sarcoma, which is the central axis (45%). For both osteosarcoma and Ewing’s sarcoma, the incidence rates are generally comparable for males and females. Incidence rates for osteosarcoma are higher among African Americans compared to Caucasians. In contrast, the incidence of Ewing’s sarcoma is approximately six times higher in Caucasians compared to African Americans.

Known risk factors for bone tumors during childhood and adolescence include exposure to radiation/chemotherapy for the treatment of other childhood malignancies, and genetic conditions including hereditary retinoblastoma and Li-Fraumeni syndrome. 36– 39 Because of the peak incidence that coincides with the pubertal growth spurt, several investigations have assessed a potential association with stature and/or growth velocity during pubertal development with limited or inconsistent findings. 40, 41


In the United States, there are approximately 850 to 900 children and young adults diagnosed annually with soft-tissue sarcoma including approximately 350 cases of rhabdomyosarcoma, which represents 50% of soft-tissue sarcomas under the age of 15 years and 60% of those under 5 years of age. 3 Approximately 75% of rhabdomyosarcomas are embryonal histology (annual incidence of 3.0 per million), whereas alveolar histology is less common (annual incidence of 0.7 per million). African Americans have a slightly higher incidence of soft-tissue sarcomas, whereas males have a somewhat higher incidence compared to females.

Assessment of risk factors has, by and large, been confined to children with rhabdomyosarcoma. 16 A higher frequency of congenital anomalies has been reported among rhabdomyosarcoma cases as have genetic conditions including Li-Fraumeni syndrome and neurofibromatosis type 1. 42, 43 Limited information suggests potential association with lower socioeconomic status, in utero x-ray exposure, and parental use of recreational drugs during pregnancy.


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Bookshelf ID: NBK20819


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