etiology of childhood leukemia: a possible alternative to the greaves hypothesis

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Page 1: Etiology of childhood leukemia: A possible alternative to the Greaves hypothesis

Leukemia Research Vol. 14, No. l 1/12, pp. 937439, 1990. 0145-2126/90 $3.130 + .00 Printed in Great Britain. Pergamon Press ptc

OPEN FORUM

ETIOLOGY OF CHILDHOOD LEUKEMIA: A POSSIBLE ALTERNATIVE TO THE GREAVES HYPOTHESIS

ALICE STEWART

Department of Social Medicine, University of Birmingham, Birmingham B15 2TJ, U.K.

(Received 3 July 1990. Accepted 14 July 1990)

Abstract--Whenever a country has experienced a significant decrease in infant mortality there has always been a concomitant increase in childhood cases of acute lymphoblastic leukemia (ALL). According to Greaves, this increase is the result of a new type of leukemia, which was first seen in Britain between 1920 and 1940. An alternative hypothesis is proposed which assumes that, for childhood cases of ALL, infections are competing causes of death and for juvenile myeloid leukemia (JML) the principal competitor is the sudden infant death syndrome (SIDS). The SIDS association is the result of JML originating in undifferentiated (erythro-myeloid) stem cells and having faulty erythropoiesis as a side effect. With this congenital anomaly as part of the disease process, the low oxygen pressures of deep sleep may be sufficient to cause sudden death from tissue anoxia.

Key words: Competing causes of death; faulty erythropoiesis; sudden infant death.

ACCORDING to the Greaves hypothesis, childhood cases of acute lymphoblastic leukemia (ALL) are commonly the result of two independent spontaneous mutations, the first arising in utero or shortly there- after, and the second, after an average latency of three years, precipitates overt disease [1, 2]. Other facets of this hypothesis are as follows: (1) ALL is the major subtype of paediatric cancer in developed countries because lymphocyte progenitors are rela- tively prone to mutation by virtue of their high pro- liferation rate during early development; (2) delay in the normal pattern of exposure of the immune system to infection, which is characteristic of developed countries, has deleterious consequences which make it possible for common infections to increase the frequency of the second mutation; (3) the emergence of common ALL (as identified by the 2-4-year-old peak in mortality figures for ALL) between 1920 and 1940 for U.K. and U.S.A. white children, later for Japanese and later still for U.S.A. black children, is in large part a real increase in incidence, i.e. ALL is a "modern" disease provoked by an unusual pattern

Abbreviations: ALL, acute lymphoblastic leukemia; JML, juvenile myeloid leukemia; SIDS, sudden infant death syndrome; HbF, fetal haemoglobin; RES, reticulo- endothelial system.

Correspondence to: Dr A. M. Stewart, Health Services Research Centre, Department of Social Medicine, Uni- versity of Birmingham, Edgbaston, Birmingham B15 2TJ, U.K.

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of common infections; and (4) a suggestion, several years ago, that the 2-4-year-old peak of A LL mor- tality was merely the result of modern drugs reducing the number of infection deaths of preleukemic chil- dren [3] is not acceptable because it leaves unex- plained the fact that a similar large increase for infants with ALL was not recorded.

The first person to realize that, between 1920 and 1940, mortality statistics had begun to "reveal a marked discontinuity in the risk of death from leu- kemia in early childhood" was Hewitt [4]. In a review of 1930-1953 deaths in England and Wales, he drew attention to the fact that, by the end of this period, "the death rate for lymphatic leukemia among 2- year-olds was more than three times as great as among infants of 0 to 12 months". He went on to say that "this abrupt, upward change in mortality has no parallel in any other cause of death for which statistics are available. It is quite different from the age-gradi- ent for other malignant diseases or for non-neoplastic diseases of the blood and blood-forming organs. This phenomenon appears to affect boys more than girls, and to have become more important during recent years."

During the period covered by Hewitt 's review of official statistics, there was both a decrease in the infection death rate and an increase in leukemia mortality. Each change was having a dispropor- tionate effect on infection sensitive age groups (under 10 and over 60 years), but whereas the increase in

Page 2: Etiology of childhood leukemia: A possible alternative to the Greaves hypothesis

938 A. STEWART

childhood leukemia was exclusively due to lymphatic cases, the increase in adult leukemias was largely the result of myeloid cases [5]. Furthermore, although infants were benefiting more from the falling infec- tion death rate than older children, it was children between 2 and 4 years who were bearing the brunt of the rising leukemia death rate.

In the interval since 1955 we have learnt that preleukemia may be a cause of sudden death as well as infection deaths 16, 7]; that abnormally high levels of fetal haemoglobin are typical of juvenile myeloid leukemia (JML) [8], and that childhood cancers may have prezygotic as well as early embryonic origins [ 9, 10]. Therefore, before assuming that ALL is a new disease, the following possibilities should be considered: for every cancer mutation in a lym- phocyte progenitor of a newly formed zygote there is an equal probability of the same type of mutation in an erythro-myeloid stem cell. In both situations there is a high risk of faulty maturation of immu- noglobulins (with serious consequences for the immune system), and in the second situation there is also a risk of faulty erythropoiesis. Therefore, in cases of JML there is both difficulty in switching from passive to active immunity and difficulty in replacing fetal with adult haemoglobin. As a result of these developmental anomalies there was a time when rival causes of death were suppressing both types of leukemia, but today the disease with the longer latency (ALL) has considerably less chance of being suppressed than the disease with the shorter latency (JML).

This hypothesis has two requirements: among SIDS cases there should be some deaths from tissue anoxia, and in the age range most affected by SIDS (1-6 months), calendar months of birth and death of leukemia cases should exhibit mirror image dif- ferences in the northern and southern hemispheres [6]. Faulty erythropoiesis explains why JML is the only variant of leukemia which has not increased in frequency since antibiotics became generally avail- able, and faulty maturation of immunoglobulins explains why childhood leukemias have associations with several infection related factors [11].

This alternative to the Greaves hypothesis assumes that there is immune system resistance to neoplastic as well as infective diseases which puts RES neo- plasms on a special footing vis ~ vis infections, and allows indigenous infections to play unusual roles when these neoplasms have in utero origins. For example, in places where early development of an exceptionally high level of immunological com- petence is a condition of survival--as it is in areas of holoendemic malaria--unusually localized forms of

RES neoplasms (either Burkitt tumour or cholo- roma) will be commoner than leukemia (either A L L or JML).

Furthermore, any change in the "immunity criti- cality" will cause qhanges in the relative frequency of the localized and diffuse neoplasms. Therefore , as already suggested by Ramot and Magrath, a recent switch from Burkitt tumour to A LL in the Gaza Strip was probably a direct consequence of a dramatic decrease in infant deaths in a malaria-infested region [121.

The Greaves hypothesis also assumes that there is reciprocity between Burkitt tumour and ALL [1,2], but there remains a difference between the present attempt to account for the early peak of A LL mor- tality and the Greaves explanation. This difference is the result of Greaves seeing infections as promoters of ALL, and the alternative hypothesis seeing them as events which have a much wider range of immune system effects. In this wider role it would be possible for infections to be promoters of RES neoplasms, but they would also be competing causes of death and events which influenced the overall frequency of leukemias and lymphomas and the relative frequency of the localized and diffuse neoplasms. Finally, as competing causes of death there would be differences between JML and A L L which--given the possibility of antibiotic intervention--would produce an early peak of ALL mortality in national statistics.

R E F E R E N C E S

1. Greaves M. F. (1988) Speculations on the cause of childhood acute lymphoblastic leukaemia. Leukemia 3, 120.

2. Greaves M. F. (1989) Etiology of childhood acute lymphoblastic leukaemia: A soluble problem? In U. C.L.A. Symposium on Cellular Biology. New Series 108 (Gale R. P. & Hielzer S. D., Eds). Alan Liss, New York.

3. Stewart A. M. & Kneale G. W. (1969) The role of local infections in the recognition of haemopoietic neo- plasms. Nature 223, 741.

4. Hewitt D. (1955) Some features of leukaemia mortality. Br. J. Prey. Soc. Med. 9, 81.

5. Stewart A. M. (1972) Epidemiology of acute (and chronic) leukaemias. In Clinics in Haematology (Roath S., Ed.), p. 3. W. B. Saunders, London.

6. Stewart A. M. (1975) Infant leukaemias and cot deaths. Br. Med. J. ii, 605.

7. Kneale G. W. (1971) The excess sensitivity of pre- leukaemics to pneumonia: A model situation for study- ing the interaction of an infectious disease with cancer. Br. J. Prey. Soc. Med. 25, 152.

8. Weatherall D. J., Edwards J. A. & Donahue W. T. A. (1968) Haemoglobin and red cell enzyme changes in juvenile myeloid leukaemia. Br. Med. J. i, 679.

9. Gardner M. J., Snee M. P., Hall A. J., Powell C. A., Downes S. & Terrell J. D. (1990) Results of a case-

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control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. Br. Med. J. 300, 423.

10. Knox E. G., Marshall T. & Barling R. T. (1984) Leukaemia and childhood cancer in twins. J. Epid. & Comm. Health 38, 12.

11. Knox E. G., Stewart A., Gilman E. & Kneale G. W.

(1988) Background radiation and childhood cancer. J. Soc. Radiol. Prot. 8, 9.

12. Ramot B. & Magrath I. (1982) Hypothesis: the environment is a major determinant of the immu- nological sub-type of lymphoma and acute lym- phoblastic leukaemia in children. Br. J. Haemat. 50, 183.