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ChildhoodRobert W. Miller, M.D.*
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Though low compared with the incidence of some adult cancers, cancer is second only to accidents as the leading cause of death among children. Recent incidence rates (1990-91) of cancer among children under age 15 in this country were 14.4 per 100,000 among whites and 11.8 among blacks (Ries et al., 1994). More than 40 percent of all childhood cancers occur in the very young--age four and under (Robison LL, 1993). More encouraging is the fact that five-year relative survival rates for many of the childhood cancers increased dramatically in this country from the 1960s to the 1970s (Ries et al., 1990; Miller and McKay, 1984). For example, the five-year survival rate for acute lymphocytic leukemia in children increased from 1 percent to almost 75 percent. Incidence of childhood cancer varies greatly throughout the world, depending on the type. Acute lymphocytic leukemia accounts for about 78 percent of all childhood leukemia in this country, whereas acute myelomonocytic leukemia (AMML) accounts for only 4 percent. In Ankara, Turkey, almost half of all childhood leukemias are AMML. In tropical Africa, leukemia is rare, but Burkitt's lymphoma, a cancer of the lymph system, accounts for more than half of childhood cancers. There are also varying age trends for the childhood leukemias. Among U.S. whites, Western Europeans, and, more recently, Japanese, there is a peak in leukemia incidence at about age four (Miller, 1989a). Among black children in the United States, there is little, if any, peak. The major childhood cancers in this country are the following: Acute Leukemias Acute leukemias are the most frequent, with acute lymphocytic leukemia (ALL) accounting for most. The incidence is higher among boys than among girls. About 90 percent of acute lymphocytic and more than 80 percent of acute nonlymphocytic leukemia cases in children have been linked with chromosome disorders (Poplack, 1993; Grier and Weinstein, 1993). Ionizing radiation--energetic rays that cause molecules to gain or lose electrons--can cause leukemia. When warnings about radiation were widely publicized to the medical community in the mid-1950s, safety procedures for diagnostic X-rays were tightened, use became more conservative, and, by the 1960s, leukemia incidence had fallen among all groups under age 75 (Fraumeni and Miller, 1967). Some anticancer drugs and at least one industrial solvent, benzene, can cause leukemia in adults, but drugs, other than cancer chemotherapy, have rarely been implicated in childhood leukemia, and chemical pollutants not at all (Miller, 1989). Central Nervous System Cancers of the central nervous system (the brain and spinal cord), the second most frequent cancer of childhood, account for about a fifth of cancers in children under age 15, and tend to occur in the first ten years of life. A number of genetic disorders are linked with excess risk for developing these cancers, including neurofibromatosis (Hope and Mulvihill, 1981) and the Li-Fraumeni family cancer syndrome (Li et al., 1988). Radiotherapy for ringworm of the scalp in more than 10,000 Israeli children was followed by an excess of brain cancer, with a relative risk of 6.9 when compared with the controls (Ron et al., 1988). Lymphomas Cancers of the lymph system are the third most common childhood cancer. Hodgkin's disease, which accounts for about half of all lymphomas, is rare in early childhood, peaking in frequency at age 25-29 and then, again, late in life. The one known exception is among the Japanese, who do not exhibit the early peak first described by MacMahon in 1966. The non-Hodgkin's lymphomas (NHL) are also more common among boys and occasionally cluster in families as do Hodgkin's disease cases. They are linked with several rare, genetically determined, immune system diseases. Further evidence for the link of NHL with immune system disorders comes from the observations that persons who receive kidney transplants, and have thus been deliberately immunosuppressed, have a 150-fold increased risk of NHL (Hoover, 1977). Among persons with AIDS, the increased risk of NHL is close to 200-fold (Coté, 1995). Burkitt's lymphoma, a form of non-Hodgkin's lymphoma common among African children, has been linked to malaria and Epstein-Barr virus (EBV) through the detection of raised levels of EBV antibodies (de Thé, 1985). The same unusual cell type accounts for one-third of NHL in U.S. children, but apparently has different cellular origins or pathogenesis from the disease in Africa (Magrath, 1989). Evidence of EBV infection is uncommon. Bone Cancers These account for about 5 percent of childhood cancers. The incidence of osteosarcoma, the most common bone cancer, peaks in late adolescence--perhaps related to a period of rapid bone growth (Miller, 1981). It usually develops in the weight-bearing bones of the legs and pelvis, particularly in the bone areas where the most growth takes place. While osteosarcoma tends to develop in some genetically caused bone lesions, Ewing's sarcoma does not. Ewing's sarcoma accounts for about 45 percent of bone cancers in U.S. white children, but is rare in non-white children. Because Ewing's sarcoma is seen so rarely among non-white children, there is no doubt that genetics plays a part in its development in whites. Soft Tissue Sarcomas Of the soft tissue sarcomas, rhabdomyosarcoma is the most common. These cancers show two distinct age peaks--one before age five, the other in the teens (Li and Fraumeni, 1969a). Rhabdomyosarcomas of the head, neck, and genitourinary system form the first peak, and there is some suspicion that these cancers form before birth. There are several genetic disorders that predispose to sarcomas, some of which also occur as components of family cancer syndromes (Li et al., 1988). Retinoblastoma Retinoblastoma constitutes only 2.5 percent of childhood cancers, and about 90 percent of these children survive. Forty percent of retinoblastomas are hereditary, predominantly bilateral, and occur earlier than the nonfamilial variety, with the peak incidence occurring shortly after birth (Knudson, 1989). In the 1960s, a few cases were found with a partial deletion of the long arm of chromosome 13, thus localizing the gene for the neoplasm. Because it shares the same gene locus, osteosarcoma occurs excessively as a double primary with retinoblastoma. The gene has recently been cloned and, through the use of DNA probes, children with a high probability of developing retinoblastoma can be identified and screened for early detection, which usually leads to a cure through surgery. When the genes from both chromosomes 13 are deleted or inactivated, they can no longer control normal growth of the retina, and neoplasia develops. Such genes, which suppress a cancer, are called tumor-suppressor genes (Knudson, 1989). Studies of this rare cancer have unlocked the mechanism of a number of common cancers, including breast, colon, and certain forms of lung cancer. High rates for this cancer have been reported in India, Pakistan, Latin American countries, and, to a lesser extent, Israel (Parkin et al., 1988). Wilms' Tumor Wilms' tumor, which accounts for 6 percent of childhood cancer, is a renal neoplasm with a peak incidence under five years of age. There are multiple gene loci for this cancer. An association with a rare birth defect, congenital absence of the iris of the eye, led to microscopic visualization of a partial deletion of the short arm of chromosome 11. This deletion helped locate a tumor-suppressor gene for both Wilms' tumor and the eye defect. A second gene for Wilms' tumor, associated with an overgrowth (Beckwith-Wiedemann) syndrome is at a separate locus on chromosome 11, and a third, in a family with a large aggregation of the neoplasm, is at an as yet unidentified locus, not on chromosome 11 (Coppes, 1994). Wilm's tumor has a five-year relative survival rate of 89 percent (Ries et al., 1994) and shows little variation in frequency worldwide, except among the Japanese and other Asians, who have half the usual rate (Parkin et al., 1988), as if they have a less mutable Wilms' tumor gene. Neuroblastoma Neuroblastoma accounts for 8 percent of childhood cancer. It is a tumor of the peripheral nervous system which arises during intrauterine life and usually becomes clinically manifest in infancy (Miller et al., 1968). There is evidence that microscopic nests of neuroblastoma cells present in the adrenal glands in late fetal life normally disappear with maturation of the fetus, and are gone by the third month of life. Rarely, when they persist, they develop into clinically detectable tumors with a five-year survival rate of 55 percent (Miller et al., 1992). The tumor-suppressor gene for this neoplasm has been localized to chromosome 1. Neuroblastoma is virtually absent in much of East Africa, perhaps because of a maternal influence, beginning in utero, that causes regression of the microscopic nests of neuroblastoma cells, as described above (Miller, 1990). From these rare cancers of childhood it was possible to recognize a previously unknown class of cancer genes that are involved in a broad array of cancer in people of all ages. New methods for screening, diagnosis, prevention, and treatment may now be devised. |
* From the Clinical Epidemiology Branch, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland
