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Childhood Leukemias
Mehmet Tevfik DORAK, MD, PhD
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Leukemia is a malignancy of the hematopoietic system characterized by diffuse replacement of the bone marrow by neoplastic cells. In acute leukemias, the immature hematopoietic cells are increased in the blood, and chronic leukemias are characterized by an excess of well-differentiated blood cells. In children, the vast majority of leukemias are of the acute type, whereas in adults, chronic leukemias are more common 1. Leukemias are the most common childhood malignancies, accounting for just above 30% of all cancer diagnoses in children under 15 years of age 2-4. In this age group, approximately 75% of leukemias are classified as acute lymphoblastic leukemia (ALL) 2; 4. The prefix 'acute' is superfluous but persists in the universal acronym ALL. The second most frequent leukemia type in childhood is acute myeloid leukemia (AML), and the second most common cancer in childhood is central nervous system tumors 2; 4; 5.
Immature hematopoietic cells giving rise to ALL are not easy to distinguish morphologically. The modern classification of acute leukemias relies on the changes in the expression of cell surface antigens as a precursor cell differentiates. Using monoclonal antibodies, cell surface antigens (called clusters of differentiation (CD)) can be identified in cell populations; leukemias can be accurately classified by this means (immunophenotyping) 6; 7. By immunophenotyping, it is possible to classify ALL into the major categories of 'common - CD10+ B-cell precursor' (around 50%), 'pre-B' (around 25%), 'T' (around 15%), 'null' (around 9%) and 'B' cell ALL (around 1%) 8. All forms other than T-ALL are considered to be derived from some stage of B-precursor cell, and 'null' ALL is sometimes referred to as 'early B-precursor' ALL. Etiology of childhood ALL is not known. The undisputed fact is the multigenic, multifactorial and multistep nature of its development 9-11. A few recognized risk factors account for a small proportion of cases. The genetic abnormalities associated with the disease and the recognized epidemiological risk factors provide some clues to the etiology of childhood ALL.
Genetic background
Childhood ALL is not an inherited disease 12; 13. A genetic background in childhood ALL is, however, suggested by a tendency to cluster in families that experience an excess incidence of leukemia or cancer 13-17, increased risk for the siblings of a patients with childhood leukemia (one in five siblings develop leukemia) 18; 19, and a high degree of concordance among twins 20-24, although not in all studies 25. There is, however, evidence for intrauterine single cell origin, with twin-to-twin transmission, of concordant leukemia in twins 22; 23; 26. This is a more likely cause for concordance than genetic factors. It has recently been shown that leukemia may indeed arise in utero 27-29. Several molecular studies found the same clonotypical MLL or TEL rearrangement in patients' blood samples taken at birth. This was shown for patients with infant leukemia and for those with cALL. These results provide unequivocal evidence for prenatal initiation of acute leukemia in most patients.
Acquired genetic changes
Cytogenetic or molecular biological techniques have revealed a number of clonal chromosomal changes in childhood ALL 30-33. A major group of these changes consists of alterations in the number of chromosomes as a feature of genomic instability as in any malignancy. Alterations in ploidy is common in childhood ALL and have prognostic significance, patients with hyperdiploidy having better prognosis 9; 33-36. Among the specific genetic changes, chromosomal translocations are common in childhood ALL. The t(12;21) translocation, barely detectable when searched by conventional cytogenetic techniques, is the most frequent genetic lesion occurring in childhood ALL 37. Certain translocations have a negative influence on prognosis, particularly in cases of t(9;22) or t(4;11); whereas, t(12;21) confers a better prognosis 9; 31; 33; 36. During the production of a translocation, the chromosome is broken and the gene at this site may be disrupted. The broken gene comes to lie adjacent to another gene as the partner chromosomes fuse. This reorganization can lead to the production of a fusion protein which can contribute to the development of leukemia. An example of this is the TEL-AML1 fusion protein resulting from t(12;21) 9; 32; 37. Among infants with ALL, translocations involving 11q23 / MLL occur in about 85% of cases 10. Also more frequently detected by molecular analysis is deletions on chromosome 6q 38; 39. This chromosomal change is present in 32% of (adult) ALL cases.
Inherited genetic changes
In addition to the acquired genetic abnormalities, a number of inherited genetic syndromes are associated with childhood leukemia, although they lead to a small number of cases 3; 10; 40. The best-known ones causing ALL are Down’s syndrome, neurofibromatosis, Shwachman syndrome, Bloom syndrome and ataxia-telangiectasia. Children with Down’s syndrome are estimated to have an approximate 10- to 15-fold increased risk for the development of acute leukemia (ALL or AML), the most common subtype being M7 (megakaryoblastic) variant of AML 41; 42. The familial occurrence of leukemia mentioned above also suggests a genetic component in the etiology.
Childhood ALL is a heterogeneous disease. Significant geographic variations in its incidence exist, with rates ranging from 9 to 47 per million 2. Rates are highest in Costa Rica, low among US blacks, and lowest in Kuwait 2; 43. There are variations in the incidence among whites, with rates being higher in New Zealand and Australia than in Europe. In England and Wales, there seems to be geographical clustering 44; 45. This may be due to environmental exposures, infectious agents or unknown factors. The incidence of childhood ALL (below the age of 15 years) is approximately 30% higher among boys and male gender is a poor prognostic factor 36; 46-50. In the case of T-cell disease, the male:female ratio is nearly 4:1 51, and in infant leukemia there is a female predominance 3.
The distribution of childhood ALL in age groups is not homogeneous. A peak in incidence occurs between the ages of two and five years but only in common ALL 40; 43; 52; 53. The age peak is absent in many developing countries 3, leading some to postulate that it may reflect environmental exposures associated with modernization 54. In Africa, ALL is relatively rare before the age of five years 3 although this may be due to under registration. The absence of the age peak in other subtypes of childhood ALL underlines the importance of taking the heterogeneity of the disease into account in epidemiological studies. A number of epidemiological risk factors have been identified in childhood ALL (Table 1). Some of these are discussed below.
Table 1. Risk factors for childhood ALL identified in epidemiological studies
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Male sex
Down's syndrome and other genetic disorders
Sibling with leukemia, brain tumor or Down's syndrome
Middle and upper socioeconomic class
Miscarriage(s) in the maternal reproductive history
Advanced maternal and paternal age
Parental smoking
Parental or household exposure to pesticides
Parental history of autoimmune disorders
High birth weight
Being the first-born or the only child
Delayed exposure to common childhood infections
Prenatal ionizing (diagnostic) radiation exposure
Nitrous oxide administration during delivery
Post-natal use of chloramphenicol
Electromagnetic field exposure (?)
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Data compiled from Refs 3; 10; 55-57
See also the SEER childhood leukemia report (Table I.5) and Table 1 in Linet, 2003.
The speculation that the peak incidence of ALL in early childhood may reflect socio-economic factors prompted epidemiological studies to investigate this possibility. The epidemiological data have generally shown a consistently increased risk of ALL in children of the middle and upper socio-economic classes 58; 59 but there is also evidence against this 53; 60; 61. Although socio-economic status can be confounded with race, personal habits, life style, access to medical care, maternal age, occupational exposures and parental education, there are also several etiologic hypotheses that attempt to explain this phenomenon, including delayed exposure to infectious agents associated with smaller families, less crowding, and later interaction with other children 3; 61-65.
Maternal reproductive history
Since noted in the Oxford survey of childhood malignancies by Stewart et al in 1958 66, numerous studies have examined the association between miscarriages in maternal reproductive history and childhood leukemia 61; 67-73. Prior fetal loss appears to be one of the most consistent risk factors for childhood ALL in different populations such as UK 66, USA 68; 69; 73, Holland 70, and Germany 61. Only one study has found a lower risk associated with prior fetal loss in a Chinese population 71. One study failed to find any association in ALL 74, and another one in infant leukemia 75. It is particularly important that the ongoing US Children's Cancer Group case-control study has so far reported only the maternal history of fetal loss as a risk factor for childhood ALL 73; 76. In that study, this association is significant only for those patients diagnosed before four years of age and most significant in those patients diagnosed before two years of age. In the latter group, one previous fetal loss is associated with a five-fold increased risk (P < 0.001), whereas, two or more fetal losses are associated with a relative risk [RR] of 24.8 (P < 0.001) 73. About a third of patients’ mothers have a history of spontaneous abortions. The same study reported a similar association also for childhood AML diagnosed before two years of age 73.
The connection between reproductive failure and childhood leukemia is further supported by the reports that survivors of threatened abortions are at a higher risk to develop childhood leukemia 66; 70. Prior fetal loss suggests a number of potential mechanisms, including chronic environmental exposures and/or a genetic predisposition with varying effects on the fetus ranging from nonviability to damage to a single cell lineage. Several lines of evidence support the genetic theory: childhood rhabdomyosarcoma and maternal reproductive history of stillbirth(s) show a similar association 77; selective early mortality of twin fetuses or neonates who would otherwise have developed a clinical cancer, an effect particularly notable in males 78; increased incidence of cancer, leukemia and lymphoma in the families of women experiencing spontaneous recurrent abortions 79; increased HLA-DR sharing between parents in both leukemia (ALL or AML) 80-85 and recurrent spontaneous abortions 86-90 or reproductive failure 91; 92; in rats the growth-retardation complex (grc) is involved in both fetal development and susceptibility to post-natal malignancies 93-100. The grc complex is part of the rat major histocompatibility complex (MHC).
Parental age
Advanced maternal age has been associated with childhood ALL in a number of studies even after adjustment for associations with Down’s syndrome 48; 67; 69; 101; 102. The Chinese study which did disagree with other studies on the association of recurrent fetal loss with childhood ALL, also disagreed about the effect of the maternal age 71 together with a Swedish study 103. Advanced paternal age has been identified as a risk factor in some studies 69, and as a possible risk factor in another 104.
Parental smoking
Maternal smoking during pregnancy with the index child is associated with increased risk in a dose-related manner 105-109. Others reported no elevated risk with maternal smoking 61; 70; 71; 110; 111. Recent progress in toxicology and molecular pharmacogenetics suggested plausible mechanisms for the possible effect of smoking on the fetus. Cigarette smoke contains many leukemogenic compounds including benzene 112 and animal experiments showed the carcinogenic effect of transplacental cigarette smoke 113. The main carcinogens in cigarette smoke are polycyclic aromatic hydrocarbons (PAHs) which are activated mainly by the xenobiotic enzyme CYP1A1 114. In experimental models, genetically-determined differences in CYP1A1 activity correlate with susceptibility to chemically-induced leukemia 115. This enzyme is present in the fetal liver and is activated by maternal cigarette smoking in the placenta 114. Since smoking has a leukemogenic effect in adults 116, and the metabolic pathways involved in this process are active in the fetus, maternal cigarette smoking may be a serious risk factor for childhood leukemia. Paternal smoking before conception also increases the risk for childhood ALL among offspring of non-smoking mothers 117.
Parental occupational exposures
Results of animal studies support the hypothesis of a relation between a number of chemical exposures and leukemia risk, particularly pesticides 118; 119. Many pesticides, including household insecticides and agricultural herbicides and fungicides contain organophosphate 120. Household exposure to insecticides is associated with childhood leukemia 121. A significant association was also found for pesticide use in gardens (odds ratio [OR] = 2.5) 122. One study which examined the risk specifically for childhood ALL, found an increased risk associated with maternal occupational exposure to pesticides (OR = 3.5) 71. There seems to be an agreement in the overall results of pesticide association studies that they are a risk factor for childhood leukemia 123. While the xenobiotic enzyme CYP1A1 is involved in the activation of procarcinogens, GSTM1 and GSTT1 inactivate the carcinogens including those in cigarette smoke, pesticides and solvents 124-126. It is important that a high frequency of combined null genotype for GST-M1/T1 has been reported in black children with ALL 127. If lacking the enzymes inactivating the notorious chemicals is a risk factor for childhood ALL, the epidemiological observations may soon be confirmed by molecular studies specifically designed to investigate this possibility. This finding, however, is restricted to the black patients with childhood ALL at the moment and has not been confirmed by another study.
Parental history of autoimmune disorders
A possible link between leukemia, especially CLL, and autoimmune disorders has been suspected for a long time 128; 129. History of autoimmunity in the family is increased in childhood ALL 130. More specifically, an increased co-occurrence of multiple sclerosis and leukemia in families has been reported 131; 132. Maternal multiple sclerosis increases the RR four-fold for childhood ALL, while paternal multiple sclerosis does not make a difference in the risk 132. In this context, it is important to note that leukemic cells in some cases of virus-induced adult T-cell leukemia seem to have derived from T cells autoreactive to HLA-DR / DQ molecules 133. Since many common viruses mimic common HLA epitopes as an immune evasion mechanisms 134-137, similar virus-induced autoimmune reactions may be relevant in the development of childhood ALL 138.
Birth weight and birth order
Like all other associations, there are studies for and against the suggestion that high birth weight may be a risk factor for childhood ALL. The majority of the studies have reported that there is a higher risk for ALL in children who weigh more than 3,500 to 4,500 g (depending on the study) at birth 69; 71; 75; 139-142. In a population-based cohort study, a steady increase with increasing birth weight in ALL risk was noted 104. The same study showed that high birth weight increases the risk also for childhood AML. The following biological scenario has been constructed to explain this association 143. Birth weight is correlated positively with circulating levels of insulin-like growth factor-1 (IGF-1). IGF-1 is important in blood formation and regulation. It stimulates the growth of both myeloid and lymphoid cells in culture. Since infants who develop leukemia are likely to have had at least one transforming event occurred in utero 62; 144, it has been hypothesized that high levels of IGF-1 may produce a larger baby while contributing to leukemogenesis. This hypothesis remains to be tested. (Note added in 2008: One recent study on birth weight and childhood cancer association found that heavier babies have higher risk for childhood ALL but in boys only in the North of England (Dorak, 2007) but see also Milne, 2007 & McNally, 2007).
Being firstborn or the only child was one of the first identified risk factors for childhood leukemia 66; 67; 101; 145. Some of the later studies supported this earlier finding 146; 147, whereas some could not find evidence in favor of it 60; 71; 104; 140. Because of a negative confounding effect, when maternal age is taken into account, the decreasing risk with increasing birth order 67; 101; 145 becomes more accentuated 148. No association between birth order and infant leukemia risk was found 75. One study did not find any change in the risk for childhood ALL with birth order but noted that larger intervals (greater than five years) between the birth of the proband and the preceding sibling conferred an increased risk (OR = 1.86) 69. It has been speculated that birth order may be a surrogate measure for timing of exposure to infectious agents 149. This suggests that increased birth order reflects lower ages for exposure to infection 148 which would support the delayed exposure to infection hypothesis of leukemia development.
There may be another explanation for these observations. The strong association of childhood ALL with a history of abortion(s) may be a confounding factor. It is not only being the first child but also being the only child, which is associated with a high risk, and longer than 5 years interval between the proband and the preceding sibling is another risk factor. Thus, the firstborn association may be a reflection of the most consistent risk factor identified so far, i.e., reproductive failure in the same families. It is important that if reproductive failure is a confounder, in those families experiencing fetal losses, the family size will be small with one or two children. Childhood ALL is not the only cancer which has an association with being firstborn or small family size. The same has been observed in testis cancer and the increased risk for testicular cancer among boys from small families could be explained by the association between family size and birth order 150. Generally lacking distinction between the firstborn and the only child in previous studies makes it difficult to distinguish these possibilities using the available data. It would be interesting to see if the birth order effect was the same if it was sought only in the families with no reproductive problems.
Prenatal and postnatal radiation
Although accounting for a small proportion of cases, prenatal (obstetric) exposures to diagnostic radiation is considered to be a causal risk factor for childhood ALL 3; 10; 151. In general, the increase in the risk is in the range of 1.4 to 1.7 66; 67; 108; 151-157. In contrast to the increased risk related to diagnostic radiation, no elevated risk of leukemia was observed in children exposed in utero to atomic bomb radiation 158. Further evidence supporting a leukemogenic effect of diagnostic X-rays in utero is the increase in the risk with the number of exposures 151.
Postnatal diagnostic radiation is not a risk factor for childhood ALL 159. Therapeutic radiation for the treatment of both malignant and benign conditions 160; 161 and exposure to the atomic blasts of children in Japan 162; 163 are associated with elevated risk. There have been inconsistent observations on the clusters of childhood leukemia around nuclear power facilities, the most popular one being the Sellafield report 164. A general consensus seems to have been reached that there is not firm evidence to believe that the external doses are high enough to cause increases in childhood ALL 165-168.
Electromagnetic fields
A possible connection between non-ionizing radiation in the form of electromagnetic field (EMF) exposure and childhood cancer, including ALL, was first reported in 1979 169. The results of the following studies have been most inconsistent and most of them suffered from small numbers of patients in different categories of exposures. This issue is another one in the epidemiology of childhood ALL, and in fact in all cancers, which remains inconclusive. The overall data cannot be said to be pointing towards a definitive etiological link with EMF exposure 10; 166; 170-174. The main problem is that an apparent biological justification is missing even though there are reported associations.
Medications
Among the medications reported to have been associated with an elevated risk for childhood ALL are post-natal use of chloramphenicol 175 and nitrous oxide during delivery 103.
Infections
There is no proven association of leukemia with childhood infections. Conversely, there has been some speculation that the occurrence of infections in childhood is in some way protective for later development of ALL 147. Because of the association of several animal leukemias with viruses, a viral connection in human leukemia has been frequently considered 176-178. Identification of Epstein-Barr virus (EBV) as the major cause of specific subtypes of Burkitt's lymphoma and Hodgkin's disease, particularly paediatric Hodgkin's disease 178-180, and the recent involvement of the human T-cell leukemia virus type I (HTLV-1) in adult T-cell leukemia (ATL) have given further momentum to the presumptions that childhood ALL may be a virus-related disease 10. Various reports investigated several infectious agents as possible etiological agents for childhood leukemia. Among these various animal retroviruses 181; 182, pre-natal influenza 183-186, chickenpox 187 / varicella 188, enteroviruses 189; post-natal infection with Mycoplasma pneumoniae 190, adenovirus 138; 191; 192 and EBV 193-195 can be mentioned. An increased frequency of an influenza-like illness prior to the diagnosis of childhood ALL has also been reported 196. Most of these suggestions were based on single case reports or questionnaire-based case-control studies that may have suffered from recall bias. Biological plausibility of a suggested association has also been an important issue. In summary, there is no firm evidence available at this time that consistently associates childhood ALL with either prenatal or postnatal infection. Two viruses, however, have been thought to be relevant as a result of sero-epidemiological studies. These are adenovirus and EBV and deserve further comment.
Lower titres of antibody to adenovirus indicate either absence of infection or persistent infection 197. This has been shown in two independent studies for adenovirus in children with leukemia 191; 192. If this is taken as an indication of persistent infection with adenovirus in leukemic children, then, one has to justify a biological role for adenovirus in the development of leukemia. An interaction between a specific HLA type and specific adenovirus types has been postulated as a promoter in the clonal evolution of childhood B-lineage ALL 138 (Dorak, 1996). Promotion of pre-existing mutant clones that have arisen spontaneously to overt malignancy may have a precedent in the form of low-grade gastric B-cell lymphoma associated with Helicobacter pylori 198. This tumor occurs in the presence of the bacteria and regresses with the elimination of the bacteria. The adenovirus model makes use of the B-cell tropism and the well-known immunoevasive features of adenovirus 197; 199-201, as well as the extensive molecular mimicry between adenoviruses and HLA-DR53 137. It remains to be a speculation in the absence of experimental data. PCR studies have shown that adenovirus may cause fetal infection that was otherwise unrecognized 202. Thus, unless ruled out, it remains a possibility that adenovirus may take part in the development of childhood ALL. (Note added in 2008: No direct data have been generated to support the adenovirus hypothesis proposed by Dorak with the exception of limited data on the increased frequency of adenoviral sequences in leukemia cells (Fernandez-Soria, 2002) but that study suffered from a contamination problem. Most recently, adenovirus DNA was detected in Guthrie cards of childhood ALL cases more frequently than healthy children (Gustafsson, 2007) although the authors do not seem to be aware of the previously published hypothesis on this connection (Dorak, 1996)).
In another study, which did not investigate adenovirus-specific antibodies, antibodies to EBV were found more frequently in leukemic children under the age of 6 years than in age-matched control subjects 195. Although this study conflicts with an earlier one 192, since B lymphocytes are a major target also for EBV 197; 201; 203, and EBV mimics the same epitope of HLA-DR53 as adenoviruses do 137, a similar scenario can be valid for EBV.
Infection related hypotheses
In the late 1980s, Greaves suggested that the most common form of childhood ALL, common ALL, which is responsible for the age peak, may be due to two separate genetic events 62; 144. The first event is thought to be a spontaneous mutation in a B cell precursor and occurs in utero. This transformed B cell precursor clone will proliferate when exposed to a later antigenic challenge. The second stage is influenced by external agents which results in an expansion of the transformed B cell clone into clinically overt ALL. Older children who have delayed exposures to specific agents may experience more vigorous B-cell proliferation, resulting in an increased probability of the second genetic event leading to leukemia. In essence, this hypothesis says that the childhood ALL peak may be due to delayed antigenic challenge from common infections contracted after the usual exposure period in infancy. Under his hypothesis, either non-specific antigenic challenge or infection modulate the late-stage malignant events leading to common ALL in the childhood peak. This hypothesis proposes that immunological isolation in infancy increases the risk of common ALL arising in the childhood peak. Greaves suggests that no specific infectious agent is involved but reduced antigenic challenge in infancy can lead to increased proliferation of a preleukemic clone when a later infection occurs. There are biological and epidemiological data providing indirect support for this broad hypothesis. The epidemiological data, reviewed by Greaves and Alexander 64, indicate that risk of common ALL increases by higher socio-economic status, isolation, and other community characteristics suggestive of abnormal patterns of infection during infancy. Delayed exposure to a common infection can indeed behave differently from the earlier exposure, and may lead to a different pathological condition. The precedent of this model is paralytic poliomyelitis 204; 205. A similar model has also been proposed for the development of Hodgkin’s disease 205-207, multiple sclerosis 208, and atopic diseases 209. In the case of atopic diseases, isolation as an infant as opposed to going to a child care center, small family size, and higher socio-economic status are predictors of a higher risk of allergies in childhood 209.
Kinlen hypothesized in 1988 that common ALL may be a rare response to an unidentified mild or subclinical infection, the transmission of which is facilitated when large numbers of people come together, particularly from a variety of origins 63. He considered the clusters of leukemia surrounding nuclear installations as a result of massive migration into previously remote and unpopulated areas 210; 211. He suggests that the influx of individuals into an isolated community produces conditions in which leukemia is more likely to occur. Isolated communities newly exposed to migrants from elsewhere could experience an unusual exposure to some hypothetical infectious agent(s) to which no (herd) immunity exists 212. The novel mix of infectious agents met by families in these new environments may cause some immune dysregulation in susceptible children. Kinlen suggests that isolated communities may be too small to maintain common infections in endemic form and may experience miniepidemics 63; 210; 213. The study of clusters and clusterings of childhood ALL 45 suggests an etiological role for one or more agent(s). The agent must be common or even ubiquitous because, for example, it is present in each instance of population mixing which form the basis of this hypothesis 65. There is also evidence that population density is correlated with childhood ALL risk which may be indicative of a viral involvement 214.
Another model, called the aberrant response model, relies heavily on earlier hypotheses of Kinlen and Greaves but is more general than either of them 45. It states that a substantial proportion of childhood ALL cases arise as a rare host response to certain patterns of exposure to common infectious agents. The model does not attempt to define biological mechanisms, and is consistent with Greaves’s hypothesis for the childhood peak but extends to all childhood ALL. Under the model, a specific but yet unknown transmissible agent is causally associated with childhood ALL. For children diagnosed in the childhood peak, primary infection may occur shortly before diagnosis while for other ages, attention has focused on gestational / neonatal exposure leading to persistent infection. In this situation too, exposure close to diagnosis may be involved. Thus, the unknown agent is expected to be able to establish persistent infection.
(Note added in 2008: The latest UKCCS paper unambiguously reports a correlation between increased infections in infancy and childhood ALL (earlier onset) (Roman, 2007; see also Dorak, 2007). The authors acknowledge that these findings do not support the original (Greaves) hypothesis that a deficit of exposure to infectious agents is associated with an increased risk of ALL development (i.e., delayed infection hypothesis) but interpret the data as supporting the hypothesis that a dysregulated immune response to infection in the first few months of life promotes transition to overt ALL later in childhood (Roman, 2007). The original hypothesis was that delayed common infections would cause an abnormal or dysregulated immune response and that would trigger ALL development (Greaves 1988; 1993; 2006)).
In summary, the infection-related hypotheses propose delayed exposure to a childhood infection(s). The agent must be common in childhood, should also infect adults and should be able to establish persistent infection. The two infections mentioned above, adenovirus and EBV, meet these criteria. A recent study found a converse association between EBV seropositivity and childhood leukemia 215. The adenovirus link has been neither tested nor challenged.
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Original Publication in 2000; last edited on 17 August 2009
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