Br. J. Cancer (1977) 36, 793

PRIMARY CANCER OF THE LIVER IN KENYAN CHILDREN

H. M. CAMERON* AND G. P. WARIWICKtFromt the Department of Pathcology, University of Nf`airobi, Kenya

Receive(d 31 December 1976 Accepte(d 15 -JIly 1977

Summary.-In 9 years in Kenya, 34 examples of primary liver cancer were diagnosedin patients in the first two decades of life. This represents 4.7O% of all liver cancersduring this period. The larger proportion (29) were hepatocellular carcinoma. In thesecond decade, there was a notable association with macronodular cirrhosis. Analogywith experimental work suggests that cells in mitotic cycle may be more vulnerableto the effect of environmental carcinogens.

Five examples of hepatoblastoma were identified at ages from 2 months to 14years; none showed the features of "mixed" tumours. The ratio of hepatoblastomato hepatocellular carcinoma was the reverse of that found in other large series ofjuvenile hepatic tumours.The histopathological features of these tumours are described and problems of

their classification are discussed.

IT has been said that there is a "strangeabsence" of primary cancer of the liverin children in parts of the world in whichit is common in adults (Edmondson, 1956;Fraumeni, Miller and Hill, 1968). Sincethese areas, which include Africa southof the Sahara, are mostly in countrieswith recently developed and inadequatemedical resources, one should be cautiousabout accepting comparisons with moregenerously endowed communities. How-ever, the statement is not altogethersupported by the small number of papersfrom sub-Saharan Africa in which relevantdata are given (Table I). Davies (1955)thought that the apparent dearth ofjuvenile cases was probably the result of"lack of observation or reporting", andthis appears to be confirmed by Anthony'slater finding in Uganda (1973) of 11examples of liver cell carcinoma in theunder-twenties. As one might expect, evenlarger numbers have been reported fromsouthern Africa, notably Lourenco Marques(Prates, 1961). In Kenya, although liver

cancer apparently does not reach the veryhigh incidence found in Mozambique(Torres, Purchase and van der Watt,1970), it comes fifth in the table ofrelative frequency ratios (Linsell, 1967).Investigation of liver disease in early lifemay reasonably be expected to yield someclues to aetiological factors and, with thisin mind, we have reviewed liver diseasein Kenya in patients in the first twodecades of life (Bowry and Cameron,1976). This revealed a considerable num-ber of cases of primary cancer of the liver.

MATERIALS AND METHODS

Kenya has a population of almost 11million (1969 census). The histopathologicallaboratory of the University of Nairobiprovides a diagnostic service for almost thethe entire country (a small proportion ofspecimens is dealt with at the Nairobihospital, the Aga Khan Hospital, Nairobiand the Provincial Hospital at Kisumu).Provision of medical services (and particu-larly, availability of sophisticated investi-

Present addresses: * Department of Pathology, Uniiversity of Edinburgh.t Iinternatioinal Union against Cancer, Box 400, 1211 Geneva.

7H. M. CAMERON AND G. P. WARWICK

Cases of Primary Liver Cancer Reported from AfricanCentres

CountryUgandaUgandaS. Africa

(Natal)Mozambique

(LourenqoMarques)

Rhodesia

UgandaKenya

gations such as biopsy) is limited and uneven.Necropsies are performed regularly at theteaching centre, the Kenyatta NationalHospital; elsewhere, they are carried outinfrequently, and the tissues are submittedto the laboratory in Nairobi for diagnosis.We reviewed all examples of liver disease atages 0-20 years diagnosed histologically onbiopsy or necropsy material received at thislaboratory over the years 1965-1973 inclu-sive. All tumours of the liver were re-examined microscopically.Two main histological forms of primary

liver cancer are found in children:1. A tumour which is indistinguishable

from adult hepatocellular carcinoma;2. An embryonic tumour analogous to the

nephroblastoma. Willis (1962) uses hepato-blastoma for all such embryonic tumours,and he sub-divides them into "embryonichepatomas" which contain only embryonicliver tissue, "mixed tumours", which includebone or cartilage, and the rare "rhabdomyo-blastic mixed tumours".We did not see any examples with mesen-

chymal elements, and for the purposes of thispaper we confined ourselves to the two maincategories: hepatocellular carcinoma andhepatoblastoma. Even on this simple classifi-cation, allocation of occasional tumours isuncertain and arbitrary, and the sole criterionmay be whether the tumour cells are recogniz-ably of parenchymal type or not (Shorter etal.,1960).

RESULTS

Thirty-four examples of primary livercancer were identified. During this 9-year

Total6390

120

526

Cases ofprimary liver

cancer in children03

17

107

90

263716

3

1134

Age range(yrs)

0-19

0-19

0-20(7< 10)

0-20

0-200-20

period, the total number of cancers in allsites and at all ages diagnosed histologic-ally was 12,674; of these 716 (5.6%) wereprimary hepatic neoplasms. The 34juvenile examples made up 4-7% of allliver cancers. Of these 29 were hepato-cellular carcinoma and 5 hepatoblastoma.

Hepatocellular carcinomaDetails of the 29 cases are shown in

Table II. Two occurred below the age of10 years and the younger one (Case 1)was only 2 months old (Fig. 1). In this,the tumour cells, although mostly small,bore a close resemblance to hepaticparenchymal cells and in some parts werearranged in trabeculae. The remainingcases in the two decades showed the rangeof features commonly seen in tumours ofadults (Figs. 2 and 3). Attempts atformation of ducts and acini were seen insome; in Case 19 (Fig. 4) parts resembledcholangiocarcinoma; it was clear from itsmajor component, however, that it wasessentially hepatocellular. Haemopoiesiswas present in the tumour in Cases 1 and4, and in both tumour and the neighbour-ing parenchyma in Case 13 (Fig. 5).In two cases (11 and 12) there was associ-ated hepatic schistosomiasis.

In 12 specimens there was sufficientnon-neoplastic liver for histological assess-

ment, and 8 of these showed macronodularcirrhosis. All 8 patients were between theages of 12 and 20 years.

TABLE I.-Juvenile

AuthorDavies (1955)Steiner and Davies

(1957)Wainwright (1961)

Prates (1961)

Gelfand, Castle andBuchanan (1972)

Anthony (1973)Cameron and Warwick

(this paper)

794

LIVER CANCER IN KENYAN CHILDREN

TABLE II.-Hepatocellular Carcinoma in Age Group 0-20 YearsCase Age (yrs) Sex Tribe Cirrhosis* Nature of specimen

1 2/12 F - - Necropsy2 9 F Meru I Open biopsy3 12 M Kikuyu I Needle biopsy4 12 F Tugen - Necropsy5 12 M Kamba + Needle & necropsy6 12 M Luhya I Open7 12 M Kikuyu I Open8 13 M Luo I. Open9 13 M Kamba' I Needle

10 13 M Kikuyu - Needle & necropsy11 14 F Luo + Open12 15 F Kikuyu - Necropsy13 15 M Kikuyu + Open-14 15 M Kikuyu' I Needle15 15 M Luhya I Open16' 16 M Marakwet I Open17 16 F Luo I Needle18 16 F Kikuyu + Open19 16 F Elgeyo + Necropsy20 18 M Kikuyu I Needle21 18 M Kamba I Needle22 18 M Luo I Needle23 19 M Kikuyu I Needle24 19 M Kamba + Necropsy25 20 M Duruma I Open26 20 F Kikuyu I Needle27 20 M Meru + Necropsy28 20 M Somali I Necropsy29 20 M Kikuyu + Necropsy

4+ -Cirrhosis.-=No evidence of cirrhosis.I= Insufficient for assessment.

FIG. 1. Case 1: Hepatocellular carcinoma ina girl of 2 months. Trabecular arrange-ment of tumour cells of parenchymal type.Cirrhosis absent. H. and E. x 275.

HepatoblastomaIn all 5 cases (Table III) the tumour

was made up of sheets of uniform smallcells with scanty lightly basophilic cyto-plasm and a relatively large nucleus53

(Fig. 6). The&chromatin of the latter was"open" and granular, and there was aprominent nuclear membrane. Mitoticactivity-lvaried, being very high in Case 30and low in Case 31. In only one case(Case 32) was there an attempt at ductformation. Haemopoiesis was seen withinthe t'umour in' Case 32, but was not aprominent feature. The diagnosis in Case30 was difficult because the biopsyspecimen was very small, but the presenceof bile in tumour'cells confirmed thatthey were of hepatic type.

Case'34 w'as the most difficult to sub-stantiate 'and is therefore presented ingreater detail. This was a 14-year-oldSomali boy who had been troubled byepigastric pain "for years". He experienceddysphagia and had occasional haematem-eses. On admission to Meru Hospital, hewas extremely anaemic and emaciatedbut was not jaundiced. He was in a stateof shock, and vomited dark brown fluid.

795

H. M. CAMERON AND G. P. WARWICK

FIG. 2.-Case 7: Hepatocellular carcinoma in a boy of 12 years. H. and E. x 450.

.'IG. H.-Uase is: niepatocellular carcinoma-clear-cell type in a girl of 16 years. The liver was cirrhotic.H. and E. x 450.

Attempts to counteract this with bloodtransfusion were unsuccessful, and he died12 h after admission.At necropsy, a pale liver was found

containing 5 or 6 round tumour masses

4-5 cm in diameter. Both lobes wereaffected. Otherwise the liver was normaland there was no cirrhosis. The spleenwas enlarged but in other respects normal.No other tumour was found in a full post-

796

ILI- -3 d

LIVER CANCER IN KENYAN CHILDREN 797

r iu.-,%--/ase ao: -nepatoceiiuiar carcinoma in a girl o0 16 years. Parts of the tumour have a ductular structureand resemble cholangiocarcinoma. The liver was cirrhotic. H. and E. x 450.

FIG. 5.-Case 13: Hepatocellular carcinoma in a boy of 13 years. There is extramedullary haemopoiesis.The liver was cirrhotic. H. and E. X 450.

1'To- A

H. M. CAMERON AND G. P. WARWICK

TABLE III.-Hepatoblastoma in Age Groups0-20 Years

Case3031323334

Age (yrs)2/129/1225

17

SexMFMMM

TribeKalenjinMeruKipsigisKambaSomali

Nature ofspecimenNeedleOpenOpenOpenNecropsy

mortem examination. On histological ex-amination, some shrinkage artefact wasseen as a result of postmortem autolysis,but preservation of cells was good. Thetumour was composed of uniform smallcells with deeply staining, granular nuclei(Fig. 7). They were arranged in large"packets" but had no trabecular orductular pattern. There was no cirrhosisof the non-neoplastic liver.

DISCUSSIONHistologyMost hepatocellular carcinomas, whether

in adults or children, are sufficiently welldifferentiated to be easily recognized.Similarly, the typical embryonic hepato-blastoma poses little diagnostic problem,particularly when it is of "mixed" type.

When there is no "foreign" mesenchymalelement, distinction from hepatocellularcarcinoma may,be arbitrary and subjective.Edmondson (1956) found every grade oftransition between the two, and Willis(1962) acknowledged that some tumoursin older children are difficult to classify.The distinction between the two tumoursmay not be entirely academic, since it islikely that the factors which produce atruly embryonic tumour differ from thosewhich give rise to a carcinoma of adulttype. Some workers have attempted tomake more elaborate classifications (Ishakand Glunz, 1967; Kasai and Watanabe,1970) but our experience, in keeping withthe findings of Edmondson (1956) Willis(1962) and Sinniah, Campbell and Cole-batch (1974), is that there is a "grey zone"between the occasional poorly differen-tiated hepatocellular carcinoma and thepurely epithelial hepatoblastoma. It isunsatisfactory to have no more objectivecriterion than the degree to which tumourcells resemble hepatic parenchyma, butwe find that for practical diagnosticpurposes there is often no other.

FIG. 6. Uase 31: lepatoblastoma in a 9-month-old girl. H. and E. x 450.

798

LIVER CANCER IN KENYAN CHILDREN

FIG. 7.-Case 34: Hepatoblastoma in a boy of 14 years. H. and E. x 450.

It has been said that extra-medullaryhaemopoiesis is a feature of hepato-blastoma (Misugi et al., 1967) and Shi0dt(1970) takes this as favouring the embry-onic nature of the tumour. We found it in1 of our 5 cases but also in 3 hepatocellularcarcinomas, and therefore of no diagnostichelp. This is hardly surprising, particularlyin young anaemic children.

AgeThe ages of the 34 cases of primary

cancer of the liver ranged from 2 monthsto 20 years. Comparison of age distribu-tion with other series is difficult because:(a) the numbers in any series are small;(b) available statistics (Doll, Muir andWaterhouse, 1970) do not distinguishbetween hepatocellular carcinoma andhepatoblastoma; (c) in countries likeKenya, with a scattered population ofabout 11 million, the provision of medicalservices is uneven, and it is likely thatmany cases of neoplasia go undiagnosed;and (d) the available data do not permitany realistic assessment of populationfrequencies.

Hepatoblastoma.-Most hepatoblas-tomas are identified in the first two yearsof life (Fraumeni et al., 1968; Misugi etal., 1967; Ishak and Glunz, 1967; Keeling,19711 and in the series of Misugi et al.(1967) there was a clear separation of their19 examples of embryonal tumours fromthe 5 "hepatomas". The former were allless than 3 years of age and the latter weremore than 6, no tumours being found inthe intervening years. Similarly Ishakand Glunz (1967) described 35 hepato-blastomas, all in children aged less than40 months; of their 12 hepatocarcinomas,only one was less than 5 years. Neverthe-less, distinction by age is not alwaysclear-cut: occasional examples of hepato-cellular carcinoma occur in the youngerage group, and some cases of hepato-blastoma are found after the age of 3.Milman and Grayzel (1951) describe a"mixed" tumour in a boy of 6, and Willis'(1962) oldest case was 7 years old. In -aseries of 16 cases (Sinniah et al., 1974) 3were aged between 6 and 10 years. Weagree with Ishak and Glunz (1967) indoubting whether some examples of

799

H. M. CAMERON AND G. P. WARWICK

"mixed" tumours reported in adults arerelated to hepatoblastoma, but since thisis an embryonic tumour, one mightexpect to find, as with nephroblastoma,occasional examples in adults (Barnett,Erickson and Halpert, 1958); some, indeedhave been described in elderly patients(Alexander, 1961; Carter, 1969).Of the present group of 5 hepatoblas-

tomas, 3 occurred within the first 2 yearsof life, and one was 5 years. The last was14 years old, and required careful scrutiny,both because of the age and because itwas multinodular. The latter feature doesnot exclude the diagnosis (Bigelow andWright, 1953; Shorter et al., 1960; Ishakand Glunz, 1967) and the histologicalresemblance to the other 4 cases persuadedus it was a hepatoblastoma.

Hepatocellular carcinoma.-We foundtwo examples of hepatocellular carcinomain the first decade, one at 2 months. Thelatter patient had a distended abdomenand a large hard liver since birth, and thiswas thought to be a congenital neoplasmsimilar to that described by Wilbur,Wood and Willett (1944). McDougal andGatzimos (1957) present 5 cases of hepato-cellular carcinoma in patients below theage of 5 years, and 2 of these were less thanone year old; in the series of 11 cases byShorter et al. (1960), 4 were less than 10years old and 2 of these were in the firstyear of life.

SexThe series of 29 hepatocellular carci-

nomas shows the mnarked male predomi-nance (20:9) which is well recognized inadult cases. The numbers of hepatoblas-toma are too small to show whether thisis a regular feature.

Geographical variationThis survey has been carried out in a

country with limited medical facilitieswhich militate against early investigationand all too often preclude follow-up.Any comparison with more sophisticatedcentres is therefore hazardous, particularly

when dealing with lesions as uncommon aschildhood neoplasms of the liver. One canhowever make some valid observations.

1. Our 34 cases were collected over aperiod of 9 years. This can be comparedwith figures from some major centres: 11cases in 53 years at the Mayo Clinic(Shorter et al., 1960); 24 cases in 18 yearsat the Children's Hospital, Columbus,Ohio (Misugi et al., 1967); 47 from theRegistries of Pediatric and Hepatic Path-ology at the Armed Forces Institute ofPathology over a period of more than 40years (Ishak and Glunz, 1967); 46 since1926 at Great Ormond Street, London(Keeling, 1971); 30 in 22 years at theHospital for Sick Children, Toronto (Einand Stephens, 1974) and 20 in 22 years atthe Royal Children's Hospital, Melbourne(Sinniah et al., 1974).

2. In five large series (Ishak and Glunz,1967; Misugi et al., 1967; Kasai andWatanabe, 1970; Keeling, 1971; and Einand Stephens, 1974), hepatoblastomas out-number hepatocellular carcinomas by 169to 38. The proportions are reversed in theKenyan series, there being 29 hepato-cellular carcinomas and 5 hepatoblastomas.One might postulate that the incidence ofhepatoblastoma, like that of nephro-blastoma, is unlikely to show muchgeographical variation. The proportionateincrease in hepatocellular carcinoma wouldthen point to the existence of some localcarcinogenic factors. The fact that 11cases occurred in patients below the ageof 15 years indicates that such influencesstart early in life.

3. In neighbouring Uganda, the propor-tion of liver cancers found at age 20 or less(4.2% Anthony, personal communica-tion) is similar to the 4-7% found in Kenya,and this confirms that the "strangeabsence" of juvenile cases (Edmondson,1956) is an illusion as far as these high-frequency areas are concerned.

Pathogenesis of hepatocellular carcinomaIt seems that cirrhosis is seldom

associated with hepatocellular carcinomain very young children in the first decade

800

LIVER CANCER IN KENYAN CHILDREN

of life, although individual examples havebeen reported (Jones, 1960). However, inthis series, the association is a notablefeature after the age of 10; macronodularcirrhosis was found in 8/12 in which therewas adequate tissue for assessment.The precise role of cirrhosis in hepatic

carcinogenesis is uncertain, but the con-stant high association with hepatocellularcarcinoma seen in all parts of the worldsuggests an important clue to the patho-genesis of the tumour. It is not known,however, whether the association is coinci-dental or causative, whether the cirrhoticliver is intrinsically prone to neoplasiaor simply more vulnerable to the actionof environmental carcinogens. Epidemio-logical and experimental work suggestsan important role for such carcinogens.In areas where liver cancer is common,both viruses and chemical substanceshave been proposed as possible oncogenicagents.

In Africa south of the Sahara, thehepatitis B surface antigen (HBsAg) isfound widely in the African population(Parker, Muiruri and Preston, 1971;Bagshawe and Nganda, 1973; Lowenthalet al., 1973). It is not only associated withviral hepatitis, but is found in a largeproportion of cases with chronic hepatitisand cirrhosis (Anthony et al., 1972; Kewet al., 1974), The proportion of positivesin adult hepatocellular carcinoma varieswidely in different series: from 1.3% to65% (Bagshawe, 1975). It has been sug-gested that the hepatitis B virus may"set the scene" for liver cancer byproducing cirrhosis or, alternatively, thatit may itself on occasions be oncogenic.Much attention has been paid recently

to the possibility that chemical carcino-gens in the environment may be respon-sible for the frequency of liver cancerin Africa. Aflatoxin B1 has repeatedlybeen identified in food, and surveys shownot only that man does ingest thiscarcinogen, but that there is a correlationbetween the intake of aflatoxin and theincidence of liver-cell cancer (Peers andLinsell, 1973; van Rensburg et al., 1975).

Aflatoxin has been identified in humanmilk (Burton, 1971) and experimentalstudies show that it can be transferredto offspring in maternal milk, and resultin tumours in later life (Mohr and Althoff,1971; Grice, Moodie and Smith, 1973).The very high degree of association of

hepatocellular carcinoma with cirrhosisshould not be taken as evidence that thelatter is itself premalignant. A sizeableproportion of tumours develop in theabsence of cirrhosis, and this appears toinclude those occurring in very youngchildren. Experimental evidence shows noparallel relationship between the cirrho-genic and the carcinogenic effects ofchemicals. Some agents such as carbontetrachloride are strongly cirrhogenic butare weak carcinogens (Warwick, 1971a).With others (including aflatoxin B1) thereverse is true (Wogan and Newberne,1967). Thus, although evidence from mansuggests a central role for cirrhosis inhepatic carcinogenesis, much experimentalwork contradicts this.A more important factor may be the

intensity of mitotic activity in the liverat the time of administration of a carci-nogen. Newborn and young animals areoften highly sensitive to hepatocarcino-gens (Della Porta and Terracini, 1969).The same is true of adult animals whoselivers are regenerating following partialhepatectomy (Craddock and Frei, 1974;Warwick, 1971b) or chemical damage(Craddock, 1 976). It would seem that cellsin cycle are more vulnerable to the actionof hepatocarcinogens. If so, this could berelevant to human liver cell cancer in twocircumstances: (a) when exposure occursin early life, during active liver growth(if environmental carcinogens were respon-sible for the tumours seen in this studythey must have been encountered veryearly); (b) in adults whose livers show anabnormally high level of regenerativeactivity resulting from diverse liver dis-eases. On this basis one might postulatethat the association between cirrhosisand liver cancer is accounted for by theregenerative activity which is a notable

801

802 H. M. CAMERON AND G. P. WARWICK

feature of cirrhosis, but which it shareswith other diseases in which hepatic cellsdie.

We wish to thank Dr Say van der Werfof Meru Hospital, who kindly supplied uswith details of the autopsy on Case 34.

REFERENCESALEXANDER, M. K. (1961) A Mixed Tumour of the

Liver in an Adult. J. Path. Bact., 82, 217.ANTHONY, P. P. (1973) Primary Carcinoma of the

Liver: a Study of 282 Cases in Ugandan Africans.J. Path., 110, 37.

ANTHONY, P. P., VOGEL, C. L., SADIKALI, F.,BARKER, L. F. & PETERSON, M. R. (1972) Hepatitis-associated Antigen and Antibody in Uganda.Brit. med. J., i, 403.

BAGSHAWE, A. F. (1975) Hepatocellular Carcinoma.In: Modern Trends in Gastroenterology, Ed. A. E.Read. London: Butterworths. p. 115

BAGSHAWE, A. F. & NGANDA, T. N. (1973) Hepatitis-B Antigen in a Rural Community in Kenya.Trans. R. Soc. trop. Med. Hyg., 67, 663.

BARNETT, W. H., ERICKSON, E. E. & HALPERT, B.(1958) Embryonic Tumor of the Liver in anAdult. Cancer, N.Y., 11, 306.

BIGELOW, N. H. & WRIGHT, A. W. (1953) PrimaryCarcinoma of the Liver in Infancy and Childhood.Cancer, N.Y., 6, 170.

BowRY, T. & CAMERON, H. M. (1976) Liver Diseasein Early Life in Kenya. Proc. R. Soc. trop. Med.Hyg., 70, 439.

BURTON, B. T. (1971) Nutrition Research Notesfrom Niamid. Nutrition Notes, p. 5.

CARTER, R. (1969) Hepatoblastoma in the Adult.Cancer, N. Y., 23, 191.

CRADDOCK, V. M. (1976) In: Liver Cell Cancer, Ed.H. M. Cameron, C. A. Linsell and G. P. Warwick.Amsterdam: Biochemical Press, V. B. p. 153.

CRADDOCK, V. M. & FREI, J. V. (1974) Induction ofLiver Cell Adenomata in the Rat by a SingleTreatment with N-methyl-N-nitrosourea given atVarious Times after Partial Hepatectomy. Br. J.Cancer, 30, 503.

DAVIES, J. N. P. (1955) Human Implications.Primary Carcinoma of the Liver in Africans. J.natn. Cancer Inst., 15 (Suppl.), 1637.

DELLA PORTA, G. & TERRACINI, B. (1969) ChemicalCarcinogbnesis in Infant Animals. Tumor Res.,11, 334.

DOLL, R., MUIR, C. & WATERHOUSE, J. (1970) CancerIncidence in Five Continents. Vol. 2. U.I.C.C.Berlin: Springer-Verlag. p. 85.

EDMONDSON, H. A. (1956) Differential Diagnosis ofTumors and Tumor-like Lesions of Liver inInfancy and Childhood. J. Dis. Child., 91, 168.

EIN, S. H. & STEPHENS, C. A. (1974) MalignantLiver Tumours in Children. J. Pediat. Surg., 9,491.

FRAUMENI, J. F., MILLER, R. W. & HILL, J. A.(1968) Primary Carcinoma of the Liver in Child-hood. J. natn. Cancer In8t., 40, 1087.

GELFAND, M., CASTLE, W. M. & BUCHANAN, W. M.(1972) Primary Carcinoma of the Liver (Hepa-toma) in Rhodesia. S. Afr. med. J., 46, 527.

GRICE, H. C., MOODIE, C. A. & SMITH, D. C. (1973)

The Carcinogenic Potential of Aflatoxin or itsMetabolites in Rats from Dams Fed AflatoxinPre- and Post-partum. Cancer Res., 33, 262.

ISHAK, K. G. & GLUNZ, P. R. (1967) Hepatoblas-toma and Hepatocarcinoma in Infancy andChildhood. Cancer, N. Y., 20, 396.

JONES, E. (1960) Primary Carcinoma of the Liverwith Associated Cirrhosis in Infants and Children.Archs Path., 70, 19/5.

KASAI, M. & WATANABE, I. (1970) HistologicalClassification of Liver Cell Carcinoma in Infancyand Childhood and its Clinical Evaluation. AStudy of 70 Cases Collected in Japan. Cancer,N.Y., 25, 551.

KEELING, J. W. (1971) Liver Tumours in Infancyand Childhood. J. Path., 103, 69.

KEW, M. C., GEDDES, E. W., MACNAB, G. M. &BERSOHN, I. (1974) Hepatitis-B Antigen andCirrhosis in Bantu Patients with Primary LiverCancer. Cancer, N. Y., 34, 539.

LINSELL, C. A. (1967) Cancer in Kenya. In: Cancerin Africa. Ed. P. Clifford, C. A. Linsell and G. L.Timms. Nairobi: E. Afr. Pub. Hse. p7.

LOWENTHAL, M., BANATVALA, J. E., CHRY-STIE, I.L., JONES, I. G., NAG, J., MOHELSKY, V. &HUTT, M. S. R. (1973) Australia Antigen in LiverDisease in Zambia. Trop. geogr. Med., 25, 39.

McDOUGAL, R. A. & GATZIMOS, C. D. (1957) PrimaryCarcinoma of the Liver in Infants and Children.Cancer, N.Y., 10, 678.

MILMAN, D. H. & GRAYZEL, D. M. (1951) MixedTumor of the Liver. Am. J. Dis. Child., 81,408.

MIsuGI, K., OKAJIMA, H., MISUGI, N. & NEWTON,W. A. (1967) Classification of Primary MalignantTumors of the Liver in Infancy and Childhood.Cancer, N.Y., 20, 1760.

MOHR, U. & ALTHOFF, J. (1971) Carcinogenic Acti-vity of Aliphatic Nitrosamines via the Mother'sMilk in the Offspring of Syrian Golden Hamsters.Proc. exp. Biol. Med., 136, 1007.

PARKER, A. M., MUIRURI, K. L. & PRESTON, J. K.(1971) Hepatitis-associated Antigen in BloodDonors in Kenya. E. Afr. med. J., 48, 470.

PEERS, F. G. & LINSELL, C. A. (1973) DietaryAflatoxins and Liver Cancer: a Population BasedStudy in Kenya. Br. J. Cancer, 27, 473.

PRATES, M. D. (1961) Cancer and Cirrhosis of theLiver in the Portuguese East African with SpecialReference to the Specific Age and Sex Rates inLouren,o Marques. Acta Un. int. Cancr., 17,718.

SCHIeDT, T. (1970) Hepatoblastoma and Hepato-carcinoma in Infancy and Childhood. Acta path.microbiol. scand., 212, 181.

SHORTER, R. G., BAGGENSTOSS, A. H., LOGAN, G. B.& HALLENBECK, G. A. (1960) Primary Carcinomaof the Liver in Infancy and Childhood. Pediatrics,25, 191.

SINNIAH, D., CAMPBELL, P. E. & COLEBATCH, J. H.(1974) Primary Hepatic Cancer in Infancy andChildhood. In: Progress in Pediatric Surgery.Vol. 7. Ed. P. P. Rickam, W. Ch. Heoker and J.Prevot. Munich: Urban and Schwarzenberg. p. 141.

STEINER, P. E. & DAVIES, J. N. P. (1957) Cirrhosisand Primary Liver Carcinoma in Uganda Africans.Br. J. Cancer, 11, 523.

TORRES, I. O., PURCHASE, I. F. H. & VAN DERWATT, J. J. (1970) The Aetiology of PrimaryLiver Cancer in the Bantu. J. Path., 102, 163.

LIVER CANCER IN KENYAN CHILRDEN 803

VAN RENSBURG, S. J., KIRSIPUU, A., PEREIRACOUTINHO, L. P. & VAN DER WATT, J. J. (1975)Circumstances Associated with the Contaminationof Food by Aflatoxin in a High Primary LiverCancer Area. S. Afr. med. J., 49, 877.

WAINWRIGHT, J. (1961) Malignant Hepatoma inthe African in Natal. Acta Un. int. Cancer, 17, 677.

WARWICK, G. P. (1971a) Metabolism of LiverCarcinogens and Other Factors InfluencingLiver Cancer Induction. In: Liver Cancer Lyon:I.A.R.C. Pubs. No. 1.

WARWICK, G. P. (1971b) The Effect of the CellCycle on Carcinogenesis. Fed. Proc., 30, 1760.

WILBUR, D. L., WOOD, D. A. & WILLETT, F. M.(1944) Primary Carcinoma of the Liver. Ann.intern. Med., 20, 453.

WILLIS, R. A. (1962) The Pathology of the Tumour8 ofChildren. Edinburgh: Oliver & Boyd. p. 59.

WOGAN, G. W. & NEWBERNE, P. M. (1967) Dose-response Characteristics of Aflatoxin B1 Carcino-genesis in the Rat. Cancer Re8., 27, 2370.