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Turkish Journal of Cancer
2002, Volume 32, Number 1, Page(s) 05-11
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Evaluation of risk factors in children with acute lymphoblastic leukemia
PELİN ZORLU1, GÜL ERGÖR2, TAHSİN TEZİÇ1, FERİDE DURU1, ULYA ERTEM1
1Dr. Sami Ulus Childrens' Hospital, 2Department of Public Health, Hacettepe University Medical School, Ankara-Turkey
Keywords: Acute lymphoblastic leukemia, risk factors, childhood, epidemiology
Summary
The aim of the present study was to investigate the influence of some possible risk factors in development of ALL. A hundred and sixteen children diagnosed as ALL over a three year period in our institute were involved in the study. Their ages ranged between 1 and 14 years (7.35±3.8). Four hundred children without any malignant or chronic disorders served as the control group. Male sex, increased paternal age (over 40 years), presence of malignant disorders among close relatives, pesticide exposure and birthweight over 4 kg seemed to be the factors associated with increased risk of ALL in children.
  • Top
  • Summary
  • Introduction
  • Methods
  • Results
  • Disscussion
  • References
  • Introduction
    Childhood leukemia comprises 35% of all malignancies in children under 15 years of age. Acute lymphoblastic leukemia (ALL) accounts for approximately 75-80% of childhood leukemia with an incidence of 0.004%, that shows a peak between 3-5 years of age [1,2]. However, geographic variation has been reported [1-4]. Male preponderance has been described especially in the pubertal ages. Variable demographic, prenatal, perinatal, genetic and environmental factors have been suggested to contribute to the development of childhood ALL. Included, these are; increased paternal or maternal age, maternal use of oral contraceptives, in-utero viral infections, living in proximity to high voltage power lines or exposure to electromagnetic fields, parental occupational exposures, socioeconomic status, higher birthweight, male sex, in-utero ionizing radiation exposure, having a sibling, especially a monozygotic twin with leukemia, and history of maternal fetal loss [2,5-8]. Definitive links between several of these risk factors such as exposure to ionizing radiation, male sex, having a sibling or twin with leukemia, and childhood ALL have been well established [9-15]. However, the etiology remains undetermined in majority of patients; therefore, further case-control studies are warranted. Here, we investigated the association of some demographic, genetic, prenatal, perinatal and environmental factors with the development of childhood ALL in a case-control study.
  • Top
  • Introduction
  • Methods
  • Results
  • Disscussion
  • References
  • Material and Methods
    One hundred and sixteen children diagnosed to have ALL, between December 1993 and December 1996, in the Department of Pediatric Oncology of Dr. Sami Ulus Childrens’ Hospital were involved in the study. Sixty-six of them were male and the remaining were female with a mean age of 7.35±3.8 years (range: 1-14 years). The majority of the patients were of low socioeconomic status. Seventy-nine percent of the patients are still alive, whereas 37% either died or were lost to follow-up. The control group consisted of four hundred children between the ages of 1-14 years without any malignant, hematologic or chronic disorders, who were seen in the outpatient clinics for mild infectious diseases. Data including age, sex, birthweight, history of breast- feeding, intrauterine exposure to infectious agents, medications, ionizing radiation, maternal and paternal age, maternal smoking during pregnancy, paternal occupation, history of malignant disorders among the family members and close relatives of the patients, exposure to pesticides and electromagnetic fields, living in proximity to high power voltage lines were all obtained for the patients and the control group either by inquiry to the parents or from the medical records of the patients not in follow-up. The results were analysed by the "Epi-Info" computer program, chi-square and Fisher's exact chi-square tests and by estimating Odd's ratio if necessary.
  • Top
  • Introduction
  • Methods
  • Results
  • Disscussion
  • References
  • Results
    Male to female ratio in patients was 1.32. Mean age was 7.35±3.8 in the patients and 5.35±3.5 in controls. Since the difference between the mean age in the patients and the control subjects was statistically significant (p <0.0002), age adjusted Odd's ratio was calculated to compare the parameters between the two groups. The socioeconomical status of the patients and the control group did not show a significant difference, with approximately 75% belonging to lower socioeconomical status. The most common parental occupation in patients with ALL was farming (40%), whereas farming comprised of only 10% of parental occupation in the control group. Tradesman's calling was the most common (45%) parental occupation in the control group. The maternal education status was significantly lower in the ALL group than that in the control group. Fifty-eight percent of children with ALL were from rural areas whereas only 10% of the control group were living in rural areas. The estimated risk for development of ALL was 1.6 times higher in girls than the boys (p:0.023). The distribution of prenatal, perinatal and genetic risk factors in the children with ALL and the controls are shown in table 1.

    Although, increased birthweight, malignant disease among close relatives and increased paternal age were found to be significantly associated with development of ALL, maternal age did not seem to influence its development. There was 3.3 and 3.99 fold increased risk of ALL in children with increased paternal age (over 40 years) and in children with birthweight over 4 kg, respectively.

    Maternal smoking during pregnancy, fetal loss, plural gravidity did not seem to be significant factors in development of ALL in our study group. In contrast, there was a significant relationship between the development of ALL and the occurrence of maternal febrile illnesses with rash, physical trauma during gestation, and the use of various medications (Table 2).

    Among several environmental factors, pesticide exposure was found to be associated with increased risk of ALL (p <0.05), whereas no relationship was detected between development of ALL and living in proximity to higher voltage power lines and also with habit of watching television too close (Table 3). There was history of maternal diagnostic X-ray exposure (dental in one, and extremity in the other) during pregnancy in two patients with ALL whereas none of the subjects in the control group had prenatal X-ray exposure. Therefore, no conclusion was yielded in the present study regarding the hazards of ionizing radiation in the development of ALL.

    Table 1: Distribution of paternal age and birthweight in ALL and control groups

    Table 2: The distribution of maternal factors in children with ALL and control group

    Table 3: Distribution of environmental factors in the ALL and control groups

  • Top
  • Introduction
  • Methods
  • Results
  • Disscussion
  • References
  • Discussion
    It has been shown that the incidence of ALL is higher among boys than girls [2]. The male preponderance is particularly significant in T cell ALL with an increasing male to female ratio of 4/1. Young et al [2] have demonstrated that the incidence of ALL was 1.4 times higher in boys than girls among children of age 14 years. Consistent with the established data the risk for development of ALL was found to be 1.6 times higher among boys than girls in this study.

    Genetic factors are presumed to play a significant role in development of acute leukemia including ALL. Some inborn chromosomal defects have been shown to be associated with high risk of ALL such as trisomy 21 Down Syndrome [16-18]. When a sibling of a child develops ALL, the risk of the disease in that child has been found to be 2-4 times higher than the risk in normal population [13]. The concordance of acute leukemia in identical twins has been estimated to be 20-25%. These findings suggest that leukemogenesis originates in utero and blood born metastases may also occur from one twin to the other. On the other hand, shared environmental exposures to leukomogens may play a role in the increased incidence of leukemia between siblings and other family members. Families with constitutional p53 abnormalities have been noted to have children with both AML and ALL [19]. Based on the above data, we investigated whether the incidence of the malignant disorders among close relatives of children with ALL was higher than those in controls and showed that it was 5.36 fold increased in ALL group.

    There have been conflicting results in the literature about the influence of increased maternal and paternal age in the development of ALL [3]. In the present study, although no relationship was detected between the maternal age and the risk of ALL, increased paternal age (over 40 years old) has been shown to be associated with 3.5 fold increased risk.

    The association of higher birth weight and the risk of the development of ALL is an area of controversy as well [5,7]. Daling et al [5] have reported an increased incidence of ALL among children between the ages of 2-4 years whose birthweight was higher than normal, however, beyond the age of 4 years such an association disappeared. In contrast, Mc Mohan et al [6] have found no association between the risk of ALL and the birth weight of children. In this study, the risk of ALL was found to be 3.9 fold increased in children born with a weight over 4 kg. However, no significant effect of birth weight on different age groups was detected as shown by Daling et al.

    Spontaneous fetal loss particularly prior to the birth of a child has been shown by a number of investigators to be with 2 fold increased leukemia risk in that child [3]. No such relationship was demonstrated in this study. Furthermore, history of maternal smoking during pregnancy also did not seem to influence the development of ALL. In contrast to our results, Stjernfeldt et al [20] have reported two fold increased risk of leukemia in children with history of maternal smoking during gestation; however, some other investigators have not confirmed this finding [21,22].

    Large epidemiological studies have documented that ionizing radiation under certain conditions of exposure induces human cancers including leukemia [11,15]. In a study by the American National Academy of Science [12] prenatal exposure to ionizing irradiation during the first trimester was found to be associated with five fold increased risk of childhood cancers and when the exposure occurred beyond the first trimester, the risk has been shown to be increased 1.5 folds.

    Several investigators have reported that intrauterine exposure to 0.3 - 0.8 cGy radiation was associated with significantly increased risk of ALL [10,12]. Since the effect of ionizing radiation on development of cancer is well-established, large measures are taken to avoid exposure to radiation, and nowadays ionizing radiation is underrepresented as a risk factor among leukemia cases. Thus, in this study a history of diagnostic X-ray during gestation was present in only two cases. Consequently, no conclusive statement could be yielded regarding the relationship between in-utero exposure to radiation and the risk of ALL.

    The role of viral infections in the pathogenesis of leukemia has frequently been brought to the attention. Although it has not been confirmed in humans, many viruses have been shown to induce leukemogenesis in animals. The Ebstein Barr virus (EBV) infection has been shown to contribute, at least partially to development of African Burkitt Lymphoma and ALL with L3 morphology. In immunocompromised individuals this virus has been shown to cause lymphoproliferative disorders, and in its most aggressive form, EBV infections can result in chromosomal breaks, translocation and malignant transformation to a monoclonal proliferation [23]. In our study group, we tried to identify if there was an association between in-utero exposure to viral agents and risk of ALL. Indeed, we have found significantly higher incidence of history of acute febrile infections with rash during gestation in the ALL group than in controls. Not only maternal febrile infections but also the incidence of physical trauma and medication usage during gestation were found to be increased in the ALL group when compared to controls. However, this finding may represent a recall bias due to the possibility of mothers of leukemic children to remember such gestational events much more than those mothers in the control group. When the effect of breast-feeding was analysed, we did not find a difference in the incidence of being devoid of breast-feeding between the groups with ALL and controls as shown by Shu et al [7] in 1995.

    The effects of paternal occupation and exposure to some chemicals including pesticides on the development of childhood cancers have also been studied. Contaminations in drinking water, food additives, pesticides in environment can expose children particularly living in rural area [3]. In the present study, the finding of higher incidence of living in rural area and having paternal occupation of farming in the ALL group may suggest an association between pesticide exposure and risk of ALL. However, a selection bias may also be considered.

    Exposure to electromagnetic fields has been shown to induce chromosomal breaks and lymphoblastic transformation in experimental studies [8,14,24]. However, the results of clinical studies are conflicting. Measurement of exposure is difficult, given that electromagnetic field not only exists near high voltage power lines, but is also generated by several equipments including computers, television monitors and cellular phones. We compared the rates of living proximity to high voltage power lines and habit of watching television too close among ALL and control groups, but did not show a significant difference. Although a similar method was also used in several previous studies, we believe that more sensitive and reliable methods would be more informative.

    In conclusion, our present study suggests that sex, paternal age, existence of malignant disorder among close relatives, higher birth weight, and exposure to pesticides is associated with increased risk of ALL in children.

  • Top
  • Introduction
  • Methods
  • Results
  • Discussion
  • References
  • References

    1) Poplack DG. Acute Lymphoblastic Leukemia. In: Pizzo PH, Poplack GD, editors. Principles and Practice of Paediatric Oncology. 2nd ed. Philadelphia: JB Lippincot Company. 1993:431-81.

    2) Young JL Jr, Miller RW. Incidence of malignant tumours in U.S. children. J Pediatr 1975;86:254-7.

    3) Neglia J, Robinson L. Epidemiology of the childhood leukemias. Pediatr Clin North Am 1988;35:675-92.

    4) Kersey JH, Sabad A, Gajl-Peczalska K, et al. Acute lymphoblastic leukemic cells with T (thymus-derived) lymphocyte markers. Science 1973;182:1355-6.

    5) Daling JR, Starzyk P, Olshan AF, et al. Birth weight and the incidence of childhood cancer. J Natl Cancer Inst 1984;72:1039-41.

    6) McMohan B, Newil VA. Birth characteristics of children dying of malignant neoplasms. J Natl Cancer Inst 1962;28:231-44.

    7) Shu XO, Clemens J, Zeng W, et al. Infant breastfeeding and the risk of childhood lymphoma and leukemia. Int J Epidemiol 1995;24:27-32.

    8) Savitz DA, Wachtel H, Darnes FA, et al. Case control study of childhood cancer and exposure to 60 Hz magnetic fields and childhood leukemia. Pediatrics 1991;88:630-5.

    9) Bizzozzero OJ Jr, Johnson KG, Ciocco A. Radiation-related leukemia in Hiroshima and Nagasaki, 1946-64: 1. Distribution, incidence and appearance in time. N Engl J Med 1966;274:1095-101.

    10) Brill AB, Tomonaga M, Hessel RM. Leukemia in man following exposure to ionising radiation. Ann Intern Med 1962;56:590-609.

    11) Jablon S, Kato H. Childhood cancer in relation to prenatal exposure to atomic bomb radiation. Lancet 1970;2:100-3.

    12) National Academy of Sciences: Biological effects of atomic radiation. Washington DC, National Research Council, 1980.

    13) Cocco P, Rapollo M, Tonghetta R. Analyses of risk factors in a cluster of childhood acute lymphoblastic leukemia. Arch Environ Health 1996;51:242-4

    14) Hatch EE, Linet MS, Kleinerman RA, et al. Association between childhood acute lymphoblastic leukemia and use of electrical appliance during pregnancy and childhood. Epidemiology 1998;9:234-45.

    15) Black D. New evidence on childhood leukemia and nuclear establishment. Br Med J 1987;294:591-2.

    16) Miller RW. Neoplasia and Down’s Syndrome. Ann NY Acad Sci 1970;171:637-44.

    17) Sawitsky A, Bloom D, German J. Chromosomal breakage and acute leukemia in congenital telangiectatic erythema and stunted growth. Ann Intern Med 1966;65:487-95.

    18) Dosik H, Hsu LY, Todaro GL, et al. Leukemia in Fanconi’s Anemia: cytogenetic tumour virus susceptibility studies. Blood 1970;36:341-52.

    19) Gunz FW, Veale AMO. Leukemia in close relatives - accident or predisposition. J Nat Cancer Inst 42:517-42.

    20) Stjernfeldt M, Berglund K, Lindsten J, et al. Maternal smoking during pregnancy and risk of childhood cancer. Lancet 1986;1:1350-2.

    21) Buckley JD, Hobbie WC, Ruccjone K, et al. Maternal smoking during pregnancy and the risk of childhood cancer. Lancet 1986;2:519-20.

    22) Dahlquist G, Wall S. Maternal smoking during and the risk of childhood cancer. Lancet 1986;2:519.

    23) Nonoyama M, Kawai Y, Huang CH. Epstein Barr Virus DNA in Hodgkin Disease, American Burkitt Lymphoma, and other human tumours. Cancer Res 1974;34:1156-60.

    24) Sol M, Michaelson DVM. Household magnetic field and childhood leukemia: a critical analysis. Pediatrics 1991;88:630–5.

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  • Introduction
  • Methods
  • Results
  • Discussion
  • References
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