Document 5Dbk6vZe31v3j9v8JN6JVbkz0

Clinical Epidemiology of Leukemia B y JOSEPH F. FRAUMEJSRI., 1s STUDIES OF LEuKExwEhxsIs, the contribution of epidemiology is greatest when it interacts-with the clinic or the laboratory. This paper reviews recent clinical-epidemiologic developments, with a range of information fro single cases to large populations, which have provided some insight into eti logic factors in leukemia. PATTERSS OF OCCCXRESCE Demographic patterns have suggested leads to the etiology of leukemia. The .sharp age peak for leukemia at 3 4 years which occurs among LY.S.\vhite echildren, but not among the U.S. nonwhites or in Japan, appears to be sp - cific or acute lymphocytic leukemiall An additional, smaller, peak at adoles, cence is due to acute myeloid leukemia.'* Although the mechanisms under!\ Ing these age variations are uncertain, the patterns suggest the influence cjf 'nost factors: genetic susceptibility in early childhood and hornional changes In adolescence. The relatively low frequency of leukemia in Japan2 and other Oriental countriesa1 may be ascribed to the near absence of chronic lympllb cytic leukemia. The deficiency may result from a lack of genetic susceptibilit)-, as suggested by 1' preliminaq- study of Japanese immigrants to the C.S. who =: have shown. as yet. no increase in mortalit). from thu disease.:"j These de- : ~ scriptive studies support the notion that leukemia is a heterogeneous complex of diseases. Although an enviionmental leukemogen such as radiation Cdfi induce many (but not all) forms of leukemia, the demographic patterns of each cell t\pe of leukemia are s&ciently dissimilar to suggest etiologic differences between them. .I recent don-nturn in leukemia mort&@ has been reported for the U.% - white populaticq especially in young children.z Whether or not the trend 1s due to diminished exposure to an environmental leukemogen, such as more cautious use of medical x-rays which followed recognition of the hazads, should be clarified by study of leukemia patterns by cell type in the future. Even a cytologic type of leukemia may consist of etiologically distinct entities. as is suggested by recent studies cf chronic myelogenous leukenlia which ~ 1 ~ 1 . ciinical-epidemiologic differences behveen patients with and nithout the Phi..tielpiria chromosome.s3 TE EssmoxxnT Racliutmn Radiahon in sui?iciently hizh doses is h o \ m to cause chronic nyeiogenous Ieukernia and acute leukemia. This evidence has been obtzined rn- fiom the iolicnv-up studies of patients recei\ing partid-body radiation for.treabent JOGEPFI F FR+CX=X @. \I D.: lid,Ern/& Studrer Srctfon, EpdRntdogU 6mnch. S c t i o i d Ccncer Inmute, Bcthcsda, J f d - was no e "31 of anhclosing spondylitis,l' and survivors of the atomic blasts in Hiroshima :ia and Xagasaki, where 20 years later the rates for acute leukemia are still es- ce~sive.A~mong the various groups esposed to radiation, the highest risk of ukemia has been found among patients with polycythemia vera ~ 4 1 0ha\fe n treated with s-ray, radioactive phosphorus, or both.ss llvhetlier or not e frequency of leukemia ( 16 per cent within 10-15 years) can be ascribed radiation damage aloneM should be clarified by a prospective study in gressW The exceptional risk of leukemia may result from the interaction radiation with a disease which is intrinsically susceptible, on the basis of its eloproliferative character or its recentlv described chromosomal aneu- p l o i d ~ . ' ~The mechanism may be similar io the process by which chronic yelogenous leukemia "converts" to acute leukemia.5' Preconceptional diagnostic irradiation of parents was reported recently to crease the risk of leukemia among children conceived after exiposure; a reective case-control study of 319 children showed a relative risk of 1.6 1.3, respectively, following radiation-eqosure of future mothers or fas.33 In mntrast, a prospective study of 17,700 children by the Atomic Bomb - Commission (-4BCC) showed no increase in leukemia after much \Tosure cf their parents to preconceptional radiation." Furthermore, was no excess of chromosomal abnormalities-an indes of radiation t-among children conceived at various intervals since the mothers or s were eyposed to the atomic b1ast.l In a similar manner, retrospective s have shown a relation between maternal preconceptional irradiation d Donx's q-ndrome" cC or other trisomies5Gin the oEsprmg, whereas no such es were observed in the ABCC follow-up.". The lack of consistency and city of effect suggests that the associabon between preconceptional raon and leuhernia is not causal, but results from some aspect of the underng state which required radiologic esamination.56 61 , - Several retrospective and p r o s m e studies have indicated that diasnostic &tion during pregnancy may as much as double the risk of childhood Ho\vever. the magnitude of the association is similar to that o h vith preconceptional radiation, suggesting the influence of as yet nnown confounding variables. This interpretation is strengthened by the same k of specificip, since iii utero esposure is associated uith equally increased es for each childhood neoplasm other than leukemia.jO - llthough a dose-response relation is characteristic of radiogenic leukemia,:$ o recent studies suggest a paradosical occurrence under certain cirmm- ces. IYhereas an excess of leukemia w a s found in a limited sample of ceiving castrating doses of pelvic irradiation for rnetropthia hemorno increase in risk was observed among women who received much of radiation for treatment of cenical cancer.e These findings, if suggest that under condhons of intense localized irradiation, the ow c ~ I l smay have less capacity for transformation than when more li!$tly . Fmtber cla.rScatiun awaits completion of a foTIor-up study of a large cf women who receir-ed ovarian w o n for benign gynecoio$c . Chemicals vealed the development of leukemia in three instances, although only one had characteristics indicative of a causal relation between drug e?rposure and leukemia." Another patient in this study group, however, subsequently developed leukemia and w a s reported separately.1 Other case reports linking chlotam. phenicol toxicity to leukemias and to chromosomal aberrationssmil have enhanced the possibility that this drug has leukemogenic potential. Since r a d i a t i ~ n b, ~enzene,sj and chloramphenicol have the capacity to depress the bone-marrow and damage chromosomes, other agents with these chilncteris. tics should be evaluated for Ieukemogenic actisit).. t'irtrscs Despite the discovery that several leukemias in laboratory animals are vir& induced. there is as yet no epidemiologic substantiation of the hypothesis that human leukemia is transmitted by infectious agents.2c.5s.GEvidence is lachng 'to incriminate "vertical" transmission of an agent (from one generation to the next). as demonstrated for murine leukemia; for esample. no excess of leu- kemia was found among offspring of mothers who were leukemic during prepmcy,`lJS and the breast-feeding e1;perience of leukemic childr6n was similar to that of q control g ~ u p".Ho~ri~zontal" (contagious I spread of leu- kemia has been suggested by anecdotal reports of ``clusters.''but most statistical studies ivhich detect epidemicity of a low order have implicated random vari- ation as the basis for the clustering of cases-with respect to the time and place in nhich the leukemia developed or the patient was -4- though the use of one technic in different populations has indicated weak clustering of leukemia among young children within variable time and space distances,2s the effect may be due to a methodologic bias or demographic shifts.z-;z Furthermore: the risk of leukemia is not increased in children re- ceiving neonatal eschange transfusions,1**i~n~sponses of leukemic patients.56 in the masters of Ieukemic dogs?: in certain seasons2"or in other situations that might reffed the infectious spread of disease. .particular agent recently incriminated in chiIdhood Ieukemia is simian- \inis 40, which is oncogenic in laboratory animals and was contained in many e x $ -lots of polio \accine.'A -4report from hnstralia indicated that I e u h z n e chil&en received &cant&- more polio vaccine (presumed to contain S t ' 4 i than did a control p u p , \liith no such difference in 0 t . k i p M n n i z a t i o n ~ . ~ ~ ~ Howeh-er, comparison of the leukemia mortality esprience of 3 groups of 6-to S-year-old children reeking polio vaccine duxins the L`S.mass vaccination program of 195showed no differences a.mrding to the dose-k.eI of SV-~O lvhich rontaml.nated certzin l0ts.2~Furthermore. among a group of newbarns (the age & mn\imum bmsceptibilify to oncogenic agents! &it -ka&ertedy received 'mt-hs of polio vaccine containi~ghi& doses oi S\`40. m e have itable D is0rdcTS soaatioii. Since a togenetic study 0: an autosomal rec rs indicate that esre is less convincing follow-up survey of chloramphenicol re;bough only one had 1g e.uposure and leusequently developed rfi linking chloramyrations6.7' have en.lit potential. Since ncip to depress the & these characteris- ry animals are virally the hypothesis that Evidence is lacking )ne generation to the .le, no excess of leuere leukemic. during .Jiqmic children V:~S ;ious) spread of leu- ..'.but most statistical :&Wed random vari;xct to the time and u.as born.2"2"."' -11, has indicated weak iable time and space bias or demographic :-eaed in children re)f leukemic patients."" or in other situaticx QJXIC.4.L EPIDEMIOLOGY OF LEUKEMIA 233 &d of leukemia or other cancers in the first eight years of life (unpublished The recent discovery that patients with infectious mononucleosis acquired tibodies to the EB virus derived from Burkitt-lymphoma cell lines1" has tion that this virus induces both infectious mononucleosis and eoplasia. Epidemiologic studies are in progress to evaluate a ible relation between the two diseases, including a follow-up survey of veterans who contracted mononucleosis during 11-orld IVar II.59 This will also assess the relation of leukemia and other cancers to infectious tis, a disease which also harbors the EB virus;" and which has been minishing the risk of cancer.jg . Since the study of leukemia clusters or "viral-like" patterns has made little progress in detecting leukemogenic agents, more promising as subjects for laboratory research would appear to be those groups of individuals whose host aracteristics confer an exceptional risk of leukemia. ritable Disorders THE HOST The mentyfoId or greater increase of leukemia among persons with Down's a:' in which the characteristic chromosomal defect ( Gtrisomy ) remeiotic nondisjunction prior to conception, suggests that extra chro- mosomes ianeuplaidy 1play a role in leukemogenesis. More tenuous is the re- lation of leukemia to other congenital chromosomal defects, perha2s since many of these disorders are rare, highly lethal, and/or poorly recognized. Since the risk of leukemia in mongolism is increased at all ages &d appears es- pecially great during neonatal life,G+the frequency of leukemia in other conditions should be estimated more precisely when technics are developed to rmit the diagnosis of such defects early in life and improve the survival of ted children. However, compilation of case reports'*- suggests that other s of aneuploidy-Gnefelter's syndrome ('DTor variants 1 in 4 patients D-trisomy sgdrome in 2 newborn infants7eS2- are related to leukemia. ugh follow-up stud>-of more affected cMdren is ceeded to establish an ociation. Since aneuploidy may occur in phenotypicalIy normal persons, study of leukemic patients in remission might be more productive antecedent defects. In such a study based on examination of blood ceUs of 2.5 leukemic children without somatic anomalies, Borges et a17 3 with aneuploidy (LC,probably SIT, and F-trisomy)and one \vi& n g a t d Y. Other investigators have reported yezygotic chromosomal normalities in 3 of 52 persons of all apes with chronic my&, menom leu% and 2 af I S patients n-i& acnre ieukemia.G ptibdity to leukemia is strongly suggested in 3 diseases. all inherit4 an autosomal recessive pattern n-hich show increased chromosomal break- , in 3 patients with Fanconi's syndrome of aplastic anemia and multiple an9malies.6.3' Atasia-telangiectasia, which has an immune-deficiency state and appears to predispose to lymphoma {see below), has been reported in 3 children with acute leukemia,3'.39 including 2, sibs nith the lymphatic tYpe.:;" Despite the small number of cases, the type-specific nature of the acute leukemia in each condition would appear to extend the evidence for heterogeneity in leukemia and suggests distinct host-related pathogenic -mechanisms for variom forms of acute leukemia. \\-hereas conzenital cytogenetic defects predispose to various leukemias, review'6 of case studies suggests that lymphoma occurs disproportionately among the genetic syndromes associated with immune deficiency, such as ataxiatelangiectasia, Wiskott-Aldrich syndrome, and ses-linked agammaglobulinemia. Epidemiologic support for the relation of immune deficiency to lymphoma was provided recently by a study of the British Medical Research Council; among 176 persons with hypogammaglobulinemia (all presumed to be geneticallyinduced) followed over variable periods of time, 6 subsequently developed Iymphoreticular neoplasm^.^^ It remains to be determined whether or not other congenital disorders, not associated with chromosomal or immunologic defects, are related to an increased risk of leukemia. One possibility would be osteogenesis imperfecta, which has been reported with acute lymphatic leukemia in 2 sibs.'g Indn-idual case reports of childhood leukemia with achondroplasia,25Marfan's s!mdronie,;o Dppel-Feil syndrome,;P and a variant of the Ellis-~anCreveld syndrome.z7sug- gests a general relation bemeen leukemia and genetically-determined dseases of the skeletal system. Such a relation, if estab!ished, would edend the spectruxi oi hematologic disorders which have been observed with congenital syn- dromes involving skeletal abnormality.15 Oflicr Ecidence of a Genetic Influence There is increasing - aiderice, beyond the conccrrence of leukemia with heritable disorders, that genetic factors may influence leukemogenesis. In childhood, the contribution of inheritance may be estimated by the concord- ance rate of 20 per cent among identicd firins, whiie no concordance occu.?~ed for fraternal twins.:' Recently con6rmed,0' this finding suggests that leu- kemogenic mechanisms may be clarified by laboratory study of undected identical twins of children diagnosed with leukemia. Genetic factors probably account also for the-fourfold increased risk of leukemia among sibs of leukemic children,g"-although the idhence of environmental factors cannot be excluded. Recent case reports inciude f d e s io vibich 3 or more young sibs developed acute Iqmpboc)-tic le-xa 2 sets of infant sibs had chronic myelogenous leukemia in the absence of the Philaddphk chromosome.u) and 3 c h i i h n related- as musks showed a myeloproliferative disorder rffernbling myelo- genous ag- l eepuildaenmkio@IogFaicmili'al' aggreg3tion af 1eukemXamong adults, u7Me ' ' tion, is strongly sugested bp-case studies 0i W e s IT& a hi& 5 e q y q Q speciiic ianns of l e u k e a ~ m, ost often the chronic $m@oqtir: va.r. jety.'8 multiple ano,ncy state and orted in 3 chilnphatic type.:3v the acute leu.r heterogeneity inisms for van- :leukemias, reionately among >uch as atasiamglobulinemia. lymphoma was zouncil; among be geneticallyndy developed .1 disorders, not lated to an in,?sis imperfecta, bs,Z9 Individual s1' spdroi_n-e,;O ~ n & o m e , -s*ug- dried diseases stend the speccongenital ?TI- ISICAL EPIDEIIIOLOGY OF L E U K E I I U 255 erited diseases (previously noted 1 which predispose to kemia and l>mphoma suggest that, even in the absence of genetic syn- ms may be subject to the influence of recessive genes. possibility is of mamages supported by occur among a6rresct ecnotussitunsd,y-l_JfrwomhcJhapreavne, awlehderepaarbeonutatl 4 per con- pairs with leukemia at various ages.*i In this country, reported infrequently in case studies-? aggregations kemia involving 3 or more and a cluster of onic lymphocytic leukemia in 3 adult sibs (unpublished obsemation) , igli Risk Disorders of Adults 4 number of conditions of an "acquired" nature appear to predispose to leuh putative mechanisms are more obscure than rders. In contrast to the epidemiologic survey of polp- emia vera which ascribed a heightened risk of leukemia to the radioactive as therapy,%a follow-up study of h>perthyioid pacent increase of all forms of leukemia regardless of t with radioacti1.e iodne.:' In addition, pernlcious znernia has been c m y a small increased risk of mFelogenous leukemia,' and case suggest that leukemia can evolve from certain forms of refracton l3 Chromosomal aberrations obsened in the megaloblastic". and re- role in the increased susceptibility to leukernla. sms also appear to occur e s c e s s i ~ ~ liyn particuk terized by immunologic deficiency and/ or I>mphoid eactivity. "-4cquired" as we11 as congenital forms of h>-poyammaslobu!a show a high risk of such tumors.53 In addition. among 202 patients adult celiac disease or idiopathic steatorrhea, 14 developed 1)mphomas ding 10 with reticulum cell sarcoma involving the gastrointestinal 3E -1study of 58 patients foHowed with Sjogren's syndrome revealed tlut urn cell sarcoma occnrred in 3 cases, and Waidenstrom's macroglobu- ports on the follow-up sun-e? of hyperthyroid psshould clarify the suggestion derived from a c u e senes that iong-standyperthyroidism predisposes to I y m p h ~ r n a .F~in~ally, case reports have ronmentally-triggered conditions. Lynphoreticular scessively in hydantoin-induced l>mphadeno- 1 homotransplantation associated uith immunousual proportion of reticuIllm cell sarcomas after and Sj6gren.s syndrome w,n=~stst i 3 t as ma! types of I>mphomahalve &Act etiopa&ogenic evant even when the neoplasm is Enassociated d?; of patientr witL ieukmk and !-.-r=ph,m~5t.r;` 0'1 a sigi5cant maease m the risk of fcr&r cancers. By f a t &e %est s occurred for cancers of the skin which had a c o n s e r ~ a t i \ - e I T - ~ S ~ a i e d 1+-- - . inia appears to be reflected in .:enera1 population. as \vel1 as ,oplasm. .e human leukemia. The;.: ;s 2 in risk during childhood ioiJuterine radiation. The posji,jch &agnostic radiation was \\-ith radiation merely an in2s ma\- enhance the leukemo.e very high rate of leukemia Benzene is the only chemical , the basis of striking occupa- '1 directed to chloramphenicol .ukemia in laboraton- animals, m a n leukemia has not been to detect an infectious spread. iced if the asents are: (1) not logenic viruses, (2:, too evan''trisger" mechnnislns are de?mi3 clusters has made little ients, an apparently more en- M utilize p q i s of iiiclividu.:!s disorders associated n-ith #.>-. k e d , whereas inherited cy~:.fiy to the lFmphomas. Genetic 1s in leukemia. some oi n-kch 'XOmojJTZd an2 ~ X X T I ~ ~ O I C + ned risk of leukemia and Ilm:itzRy-induced con&tions. The -1 in the origin o i reticn- reqLecy d dl& CZU tl-pe in .;n-ig imm<lnol;lJppie5<'Iznk x < ICAL EPIDEMIOLOGY OF LEUxE;ESfM 257 REFERENCES Awa A. .i.,Bloom, A. D., Toshtda, SI. blortality from cancer and other causes S . , and Archer, P. 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