- Email: [email protected]
Hepatocellular carcinoma in the developing world
Hepatocellular
Carcinoma 1. Olufemi
There some able
has recently forms of cancer in large part to
munodeficiency cies into the
world
syndrome of medicine
most
of these
which cases. main
proportionately Despite this, the big killers
that
in
yielded Africa noma
cases
some
prove Semin Saunders
are
evidence, to further
increase in This is attributof acquired im-
(AIDS)-related malignanand it is interesting that
seen
in the
developing
world,
leads
with the number of AIDS some more traditional cancers rein these areas of the world, except
countries
definitive
excellent results in reducing and the developing world, (HCC) is the leading cause
ing some clearly view describes known etiologic available ployed
been an observable the world over. the introduction
interventions disease hepatocellular of cancer
established etiologic the current status factors in the various suggests stem the
on survival in these Oncol 28:/79-187.
options incidence populations. Copyright
factors. of each areas
have burden. death,
In carcihav-
This reof these and, using
that may of HCC
be and
emim-
0
by
W.B.
2001
Company.
H
EPATOCELLULAR CARCINOMA (HCC) accounts for between 60% and 90% of all primary liver malignancies depending on the population studied. The remaining fraction of liver cancers comprises primary tumors deriving from other cell types, as well as secondary metastatic tumors. EPIDEMIOLOGY
The annual incidence rates for HCC vary from three to seven cases per 100,000 population in America and most of Europe, to up to 35 or more cases per 100,000 population in parts of Africa. Recent reports indicate a rise in the number of cases in the United States and this increase was greater among black than white meni as well as more pronounced among younger people. HCC was the number 1 cancer killer among adult males in Ibadan, Nigeria by 1975.2 At present, its frequency is second to that of prostate cancer among adult male cancer cases recorded in the Ibadan Cancer Registry, but the absolute number of cases is actually on the increase.3 HCC represented 8.32% of all carcinomas and 5.56% of all cancers in Zaire in 1992.4 The highest incidence is found in black Africans, with variable spread in the eastern, western, and southern regions of the continent. Southeast Asia, China, and the Far East also share in this Semmors in Oncology, Vol 28. No 2 (April),
200 I: pp I79- I87
in the Developing
World
Ogunbiyi
ravaging problem. The lowest incidence is found among whites in North and South Africa. In most populations, the incidence increases with age, with a peak in the fifth and sixth decades and a tendency to decrease in the elderly. In high-incidence areas, there is a marked shift towards the younger age groups, with peaks in Africa occurring in the third through fifth decades of life. The early onset in such places is attributed to exposure to environmental carcinogens especially hepatitis B virus (HBV), aflatoxin, and hepatitis C virus (HCV) at or soon after birth. Males tend to be more commonly affected, with a male to female ratio that varies between 4 and 8: 1. Chronic HBV infection and the presence of androgen receptors in HCC cells have been sug gested as reasons for the male preponderance.5 The three major etiologic associations for HCC are infections by the hepatitis viruses B, C, and D, as well as aflatoxin exposure (especially aflatoxin Bl [AFBl]) and cirrhosis. The relative contribution of these factors to the prevalence of HCC varies between cases occurring in high- versus lowincidence areas for the disease. Other conditions that may predispose to the development of HCC include neonatal hepatitis, biliary atresia, and some familial conditions, especially the Byler-type familial cholestatic cirrhosis.6 HCC has been reported in congenital hepatic fibrosis,7 situs inversus, and neurofibromatosis as well. In some cases, this occurrence was probably due to chance. No specific reports on these factors have been made from Africa, but their occurrence cannot be ruled out. The tumor may appear grossly as either a unifocal large mass, multifocal masses widely distributed in the liver, 01: a diffusely infiltrative cancer that sometimes involves the entire liver surface.
From the Department lb&m,
of Pathology,
University
College Hospital,
Nigeria.
Address reprint requests to 1. Olufemi Ogunbiyi, MBBS, FWACP (Lab. Med.), Department of Pathology, P.M.B. 5017, G.P.O., University College Hospital, Ibadan, Nigeria. Email: ogunbiyi~skannet.com. Q 2001 by WB. Saunders Company 0093~7754/0l/2802~0008$35.00/0 Copyright
doi:10.1053/sonc.2001.21963
179
J. OLUFEMI
180
Okuda et a19 described two major growth patterns, expanding and spreading (or infiltrative), while Nakashima and Koj iro 10 described four variations: infiltrative, expansive nodular, mixed infiltrative and expansive, and diffuse. There is some overlap between these two systems. Cirrhosis is commonly associated and the presence or absence of cirrhosis has been linked with etiologic factors, biochemical findings, and prognosis in some studies of HCC. For example, HCV and current or previous HBV infections were found more commonly in cirrhotic than noncirrhotic patients with HCC, while extrahepatic extension of HCC was more common in noncirrhotic patients. 11 The high prevalence of HCC in cirrhosis was associated with multiple risk factors in a study in Italy.12 It has also been shown that a significant difference exists in the number of genetic changes seen in HCC cases arising in macronodular cirrhosis as distinct from those arising in noncirrhotic livers. Specifically, a significant copy number loss of 4qll -q23 was identified in tumors larger than 3 cm in diameter.13 This review is an attempt to summarize the situation in Africa and the developing world, which essentially encompasses Southeast Asia and South America. Figure 1 is a histogram showing incidence figures for HCC across the continents of Africa, South America, and Southeast Asia.‘4 Thailand has the highest annual incidence rate, while in Africa HCC is most common in Mali. Not all countries are represented in this collection.
Si@ppWe Philippines KU&t KOBI Japan (Osaka) Israel (all Jews) India (Aggregate) W
RISK FACTORS While the major risk factors for HCC in the United States are infection with HCV or HBV,
Kong
China (Shangai) China (Qidong) Puerto Rico Peu (Ttujiilo) Peru (Lima) ECWBdOr casta mx Celomtia Brad
(Porta Alegre)
zIlnki+we
l.Eumpean)
Zmbabee
(AUcam) Uganda Mali
France. La Reunion Al&a
-A0
Incidence
AGE As stated earlier, the peak age incidence in most parts of Africa is in the third through fifth decades. Additionally, cases occur in the second decade in several regions. In a 1982 review of 585 rural southern African black males with HCC, Kew and Geddes noted that the mean age of patients was 35 years and that 40% were less than 30 years of age. In fact, the ages of patients ranged from 18 to 70 years.15 It had earlier been observed that the highincidence geographic areas are characterized by a shift of the age-incidence profile towards the younger age groups, suggesting that early exposure to carcinogenic agents was responsib1e.l”
OGUNBIYI
Fig South
Histogram I. America, and
20
(per
40
100,000
shows southeast
the
population)
incidence Asia.
(W)
of
HCC
Males;
(0)
in Africa, females.
and alcoholic cirrhosis,‘7 in parts of Africa and Southeast Asia, dietary exposure to aflatoxin is of particular significance in addition to infection by the hepatotropic viruses.ls-zi However, the exact mechanism of interaction between the viruses and aflatoxin in the pathogenesis of HCC is still poorly understood, although the presence of aflatoxin metabolites has been shown to influence the body’s interaction with HBV. AfIatoxin Aflatoxin plays a significant role among cases of HCC in Africa and Southeast Asia. Oettle prob-
LIVER
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WORLD
ably was first to present evidence that a high incidence of HCC was associated with a greater moldiness of foodstuffs? Coady demonstrated significant aflatoxin contamination of staple foods in Ethiopia as far back as 1965,23 and Bababunmi et al demonstrated significant mycotoxin contamination of Nigerian food supplies in 1978.24 Recent epidemiologic studies of specific populations have provided estimates of population exposures and show values ranging from 10 to 200 rig/kg body weight per day in sub-Saharan Africa and Southeast Asia, to less than 3 rig/kg body weight per day in the United Statesz5 Diallo et al found detectable levels of AFBl adduct in more than 90% of serum samples tested from Guinea, West Africa.26 In that cohort, 14.7% of people were positive for hepatitis B surface antigen (HbsAg, a marker of current infection with the virus) and 8% had antibodies to HCV. In comparative analysis, this population probably has the highest level of contamination in the world. Pooled data from Africa, Southeast Asia, Europe, and the United States clearly demonstrate high serum levels of aflatoxin adducts in Africa and Southeast Asia.27 These measurements were obtained by the use of recently described dosimetric methods. Prospective studies confirmed a link between adduct levels and increased risk of developing HCC in China. 28~9 In Nigeria, Olubuyide et al reported “pathologic” levels of aflatoxins in serum of 9% of a normal population,sO as well as higher “pathologic” levels in patients with WCC than in matched controls.s* Exposure has been shown to occur in the perinatal period, since aflatoxin Ml was detected in breast milk of women from the Gambia, West Africa.s2 Susceptibility to HCC is believed to be associated with genetic variation in the enzymatic detoxification of AFB1,33 and Kirby et al34 showed a difference in the in vitro metabolism of this chemical by normal and tumorous liver tissue. Further proof of association was the finding that significant aflatoxin-albumin adducts were associated with various cytogenetic alterations in individuals from the Gambia.35 Additionally, in areas with high aflatoxin exposure, there is an association with a specific mutation in the p.53 tumor-suppressor gene, with a G-+T transversion at codon 249, which results in the amino acid substitution of serine for arginine.36-39
0 ther Toxins Idiopathic hemochromatosis leads to cirrhosis and occurs mostly in males, only rarely affecting females. It is linked to an autosomal-recessive inheritance, as well as the human leukocyte antigen (HLA)-A3 and -B14 major histocompatibility complex (MHC) antigens. HCC develops in about 20% of cases and occurs irrespective of therapy for iron removal.40 The major work on iron overload in Africa done by Strachan in 1929 was recently revisited and indicates an increased risk of death from HCC in patients with excessive tissue iron stores.41 In patients with iron overload, iron-free foci within liver nodules had been shown to be preneoplastic, and it was suggested that the finding of iron-free foci in the initial biopsies from these patients should lead to screening for HCC.42 Hepatitis
B Virus
By far the most important environmental factors in HCC in the developing world are probably HBV and HCV. The development of HCC is the most important consequence of infection with these viruses, and HBV accounts for up to 80% of all cases of liver cancer, being second only to tobacco among human carcinogens.43 The risk of developing HCC varies among carriers of the virus however. In a study comparing carriers from Africa (Senegal, West Africa) and China (Haimen City), two countries with a similar prevalence of chronic HBV infection, Evans et al found the risk of HCC to vary among HBV-positive subjects.44 In the group with the lesser number of HCC cases developing, viral DNA levels in the serum had depreciated faster over time. However, even when HbsAg is lost from the serum, persistent HBV DNA is found in the liver cells45 and chronic HBV infection is often associated with major structural genetic changes in both the viral and the host DNA46-48 that possibly lead to hepatocarcinogenesis. While the global estimate of HBV carriers keeps rising,49 about 13% of cases are found in Africa.50 The main points of evidence for an etiologic role for HBV in HCC cases can be summarized as follows: (1) HBV carrier rates match tumor incidence rates; (2) there is a greater risk of malignancy in cirrhosis due to HBV; (3) liver cell dysplasia is seen commonly in chronic HBV; (4) HBV antigens are present in tumor-bearing patients;
182
and (5) there is HBV DNA integration in tumor cells5i In high-incidence areas, transmission is from mother to infant at or soon after birth, and this is associated with a high incidence of liver cell carcinoma in early life. Transmission seems to occur more readily in males. In some countries, especially the Gambia, West Africa, inclusion of HBV vaccine in the expanded program of immunization has substantially reduced the incidence and prevalence of HCC. An earlier experience was reported in Taiwan, where the prevalence of HbsAg declined from 10% to less than 1% within a loyear period.52 Kew and Geddesis noted 62% HBV positivity among male miners with HCC in rural southern Africa in 1982. Several studies of HCC patients from various regions of the African continent have shown a significant association between HBV infection and the development of HCC with HbsAg positivity, mostly in the range of 75% to 90% in cases of HCC seen.ss-s6 Most recently, Abe et al57 found that HBV was the most prevalent virus among HCC cases in Korea (82%), and among Japanese Americans in Hawaii (50%) as against HCV prevalence in Japan (61.5%), Spain (60%), and the United States (41.5%). Hepatitis C Virus HCV infection is known to be associated with various liver disorders, including steatohepatitis, chronic (including granulomatous) hepatitis, cirrhosis, and HCC. Patients with HCV-associated HCC are generally older than those with HBVassociated HCC,ss and this was also the case in Nigeria.59 Different viral types of HCV produce different forms of disease, with some inducing chronic liver disease for up to 20 years without the development of cirrhosis, while others are associated with the development of HCC.60 In one study of 70 patients with HCC, HCV RNA was found in 62% of patients, the prevalence of antibody to HCV was 63%, and HCV was more prevalent than HBV in HCC patients.61 Similar figures are quoted from Europe and the United States, but the picture in the developing countries is different. What is probably most important about HCV-associated HCC is that facts emerging regarding the biology of HCV indicate that the incidence of HCC is 2.7 times higher than that associated with HBV in-
J. OLUFEMI
OGIJNBIYI
fection and the incubation period until HCC is detected is shorter.‘jl This suggests a more aggressive virus than was originally thought. A recent study in India found HCV to be second to HBV in the causation of chronic liver disease.63 In a prospective study of chronic liver disease patients in Ife, Nigeria, 4% of patients were noted to be positive for anti-HCV antibodies, and all had HCC.64 In Nigeria, the range is between 5% and 12% of blood donors (P.O. Olatunji, Ilorin, Nigeria, personal communication, 1999), while a study in Ibadan, Nigeria, showed a prevalence of about 19% among HCC patients.59 Another important finding is that the latency period between HCV infection and the development of HCC is relatively long. HCV-positive patients followed longitudinally in Spain showed a long interval between exposure and the development of cirrhosis and HCC.65 The exact role of HCV, and therefore the burden of disease in chronic liver disease patients (including HCC patients), is not known for most of Africa and the developing countries where screening for HCV is not routinely performed. It is urgent that work be done to establish the burden of HCV in these nations and to plan adequate intervention. Hepatitis
D Virus
The delta virus is believed to coinfect or superinfect along with HBV and is capable of producing chronic hepatitis. The exact role of HDV in developing nations is not fully characterized. One study from Nigeria found HDV antigen in the sera of 6.5% of HbsAg-positive patients with chronic active liver disease.66 The other African study published in the English literature was performed on sub-Saharan African immigrants to Spain; serum samples from these subjects did not test positive for markers of HDV.67 It seems that more work needs to be done in Africa with respect to determining the status of HDV among patients with chronic liver disease and HCC.
Cirrhosis Cirrhosis may occur in association with many etiologic factors, including chronic alcohol abuse, metabolic disorders, and, possibly other toxins, with all of these causes probably following the pathway of injury, regeneration, and cirrhosis. However, the majority of cases of cirrhosis follow infection with the hepatitis viruses B, C, and D.
LIVER
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Cirrhosis is associated with an increased rate of cell loss and replacement, which enhances the efficiency of many carcinogens and the probability of viral DNA integration. The stage of cirrhosis influences the development of HCC, which generally occurs only in advanced cases. In an Italian multicenter study of cirrhosis, it was found that the highest prevalences of HCC occurred with HBV infection, with or without alcohol abuse, and in HCV cirrhosis with or without alcohol abuse.67 The morphology of cirrhosis found to be associated with the presence of HCC is nearly always mixed or macronodular and not micronodular. The macronodular pattern is associated both with long duration of the disease and with its etiology. The characteristic finding in cirrhosis due to HBV infection is a macronodular (so-called incomplete septal or posthepatitic) cirrhosis pattern, also called Miyakis’ type B by Japanese workers. This finding may be expectedly extended to HDV and HCV, except that HCV may be associated with steatosis in 70% of cases.68 Cirrhosis is a common theme in African HCC. The frequency of association with HCC varies between 60% and 90% in African series. Kew and Geddesis reported that cirrhosis was present in the nontumourus liver tissue at necropsy in 60% of patients. In Ethiopia, Pavlica and Samuel found that 94.7% of HCC cases had cirrhosis of the liver, of which 75% were of the postnecrotic type.69 In most adults, cirrhosis is of the posthepatitic type, and in fact even in children, cirrhosis associated with HCC is predominantly of the posthepatitic type. MORPHOLOGY
OF AFRICAN
CASES
The morphology of tumors is not distinctly dif, ferent between developing countries and the de, veloped nations, and in Africa most authors adhere to the traditional three patterns of nodular, massive, and spreading forms. Any of these three patterns may cause enlargement of the liver up to about 3 kg. When there is associated cirrhosis, the liver may be normal in weight or even become reduced in size. Occasionally, there is a greenish pigmentation because of bile retention. Tumor nodules may become necrotic as a result of ischemia, and may rupture, producing infarction in the liver. This is a common finding in Africa and Asia. A third of patients seen in Zaria, Nigeria, for example, presented acutely in the hospital in hy-
povolemic shock following rupture of tumor nodules.70 Histologically, the appearance is determined by the degree of differentiation and depends on a combination of the following features: (1) the structural pattern; (2) the degree of differentiation; and (3) other cytologic variations such as bile production, fatty change, cytoplasmic hyaline, and pleomorphism. Therefore, one may find a trabecular growth pattern (most common) or an acinar (pseudoglandular) pattern of growth. The stroma is variable and may be desmoplastic. Various ale terations such as steatosis and inflammatory cellular infiltration may be seen as well. The distinctive good-prognosis variant called “fibrolamellar carcinoma” is not usually seen in the setting of chronic viral infection. The fibrolamellar variant of HCC occurs in younger patients, without a sex predilection, arises in noncirrhotic livers, and has an extended duration of symptoms. The histology is that of large polygonal tumor cells with deeply eosinophilic granular cytoplasm, diffuse fibrous stroma, and an increased number of mitochondria at ultrastructural examination. HCC
IN INFANCY
AND
CHILDHOOD
Cancer in children is currently a topical issue especially because of possible genetic predisposition. A more important consideration for Africa and the developing world is the toll this will have on survival, since about 40% of most of these populations are aged less than 15 years, thus producing social and economic stresses on both the society at large, as well as the immediate family of the afflicted children. In these environments, the prognosis for cancer remains poor due to late presentation, prohibitive cost of procuring chemotherapy/radiotherapy, and the inadequacy of follow-up. Cancer was sho,wn to account for 8.7% of deaths and to be the fourth leading cause of death in children at the University College Hospital, Ibadan in 1992.71 In comparing these findings with an earlier report, HCC maintained a prevalence figure of 1.2% with a suggestion of an increase in the absolute number of cases. A few reports on childhood cancer have addressed the problem of HCC. The etiologic factors in childhood HCC in Africa, as in other parts, are much the same as in adults, ie, HBV, aflatoxin with possibly other toxins, and HCV.i5,z4 Reference
184
J. OLUFEMI
OVWdl Years Reviewed
country Algeria Ewt Malawi Malawi
I986- I995 I980- I989 (Blantyre)
l987- I985 I983- I992
Nigeria
198% I992
South Africa Blacks
1988-1991 1988-1991
Whites Uganda
I992- I995 I990- I994
(blacks)
Total Data from Parkin
-
1991-1995 1991-1995
Mali Namibia
Zimbabwe
RF (%)
NO. Male
o-4
-
-
2
0.15
I
4 2
0.7 I .7 -
3 2
-
-
-
-
-
-
-
-
-
-
2
0.5
2
35 6
I .4 0.7
I9 4
2 3
0.6 I .4
I 2
56
Age Group 5-9
34
2 I
3 2 5
(rr) IO-14
_
NO.
Age Group
Female
o-4
-
--
I
I
I 1
I
--
l I
---
2
----
-
I3 2
I6 2
-
-
I 2
I I
---
23
22
6
(rr) IO-14
---
3
5-9
OGUNBIYI
-
-
4 I
I2 I l l
5
I7
et al.75
has been made to early exposure to aflatoxins in childhood.32 Using the polymerase chain reace tion technique, it was possible to demonstrate HBV DNA in liver tissue of 67% of children with HCC but with negative results of serologic testing for HBV markers.?* Williams et al reported four cases of HCC occurring in infancy and childhood in Nigeria. The patients ranged in age from 4 months to 10 years. The authors noted the rarity of coexisting cirrhosis in these cases, as well as the absence of abdominal pain at presentation, features that characterize adult cases of HCC.73 There was solo involvement of the right lobe of the liver in two of four cases, both lobes in one of four, and the left lobe in one of four. The prognosis was deemed to be poor, as the average life span from diagnosis was 4 months. In another study from the same environment, 12 cases of HCC occurring in children were reviewed. The mean age at diagnosis was 8.7 years (range, 3 to 14), and massive hepatomegaly was a presenting symptom in 25% (Akinyinka 00, et al, unpublished data, June 1990). Table 1 lists the relative frequency of HCC in children in some African countries.74 The highest relative ratio frequency is found in Malawi (Blantyre).75 The male to female ratio in children is about 2:l. The majority of cases occur in the loto 14-year age group in both sexes, which might
suggest equal environmental exposure to possible causative agents. In most African countries, the sex ratio at birth is in favor of males, so that the distribution of disease in children may not have significant sexual bias as has been suggested in adults. CONCLUSION HCC is an important form of cancer in Africa and the developing world. It is the leading cause of cancer death in most of these countries, despite the recent scourge of acquired immunodeficiency syndrome-associated cancers worldwide. The sex ratio is significantly in favor of males, this being less prominent in children. The etiologic factors involved are aflatoxin and the hepatitis viruses-B more so than C and D. Alcohol appears to be a less important cause of HCC in these areas. Other toxins may be important, but have not yet been conclusively researched. Education about food preservation and storage, as well as early vaccination against HBV, have led to decreases in incidence and long-term complications in those places embracing such procedures. Vigilance and more extensive research into the roles of HCV, HDV, and other toxins will further stem the incidence of HCC and improve on survival in these populations.
LIVER
CANCER
IN THE DEVELOPING
WORLD
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20. Shank RG, Bhamarapravati N, Gordon JE, et al: Dietary aflatoxins and human liver cancer. IV. Incidence of primary liver cancer in two municipal populations of Thailand. Food Cosmet Toxic01 10:171-179, 1972 21. van Rensburg SJ, van der Watt JJ, Purchase IFH, et al: Primary liver cancer rate and aflatoxin intake in a high cancer area. S Afr Med J 48:2508a-d, 1974 22. Oettle AC: The aetiology of primary carcinoma of the liver in Africa: A critical appraisal of previous ideas with an outline of the mycotoxin hypothesis. S Afr Med J 39:817-825, 1965 23. Schoental R, Coady A: The hepatotoxicity of some Ethiopian and East African plants, including some used in traditional medicines. East Afr Med J 45:577-580, 1968 24. Bababunmi EA, Uwaifo AO, Bassir 0: Hepatocarcinogens in Nigerian foodstuffs. World Rev Nutr Diet 28:188-209, 1978 25. Some Naturally Occurring Substances: Food Items and Constituents, Heterocyclic Aromatic Amines and Mycotoxins. IARC Monograph on Eva1 Carcinog Risks Hum, ~0156. Lyon, France, IARC, 1996 26. Diallo MS, Sylla A, Sidibe K, et al: Prevalence of exposure to aflatoxin and hepatitis B and C viruses in Guinea, West Africa. Nat Toxins 3:6-9, 1995 27. Montesano R, Hainaut I’, Wild Cl’: Hepatocellular carcinoma: From gene to public health. J Nat1 Cancer Inst 89: 1844-1851, 1997 28. Qian GS, Ross RK, Yu MC, et al: A follow-up study of urinary markers of a&toxin exposure and liver cancer risk in Shanghai, People’s Republic of China. Cancer Epidemiol Biomarkers Prev 3:3-10, 1994 29. Wang JS, Qian GS, Zarba A, et al: Temporal patterns of aflatoxin-albumin adducts in hepatitis B surface antigen-positive and antigen-negative residents of Daxin, Qidong County, People’s Republic of China. Cancer Epidemiol Biomarkers Prev 5253-261, 1996 30. Olubuyide IO, Maxwell SM, Akinyinka 00, et al: HbsAg and aflatoxins in sera of rural (Igbo-Ora) and urban (Ibadan) populations in Nigeria. Afr J Med Med Sci 22:77-80, 1993 31. Olubuyide IO, Maxwell SM, Hood H, et al: HbsAg, aflatoxins and primary hepatocellular carcinoma. Air J Med Med Sci 22~89-91, 1993 32. Zarba A, Wild CP, Hall J, et al: Aflatoxin Ml in human breast milk from the Gambia, West Africa, quantified by combined monoclonal antibody immunoaffinity chromatography and HPLC. Carcinogenesis 13:891-894, 1992 33. McGlynn KA, Rosvold EA, Lustbader ED, et al: Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin Bl. Proc Nat1 Acad Sci U S A 92:2384-2387, 1995 34. Kirby GM, Wolf CR, Neal GE, et al: In vitro metabo, lism of aflatoxin Bl by normal and tumourous liver tissue from Thailand. Carcinogenesis 14:2613-2620, 1993 35. Miele M, Donato F, Hall AJ, et al: Aflatoxin exposure and cytogenetic alterations in individuals from the Gambia, West Africa. Mutat Res 349:209-217, 1996 36. Hollstein MC, Wild CP, Bleicher F, et al: P53 mutations and aflatoxin Bl exposure in hepatocellular carcinoma patients from Thailand. Int J Cancer 53:51-55, 1993
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37. Coursaget P, Depril N, Chabaud M, et al: High prevalence of mutations at codon 249 of the p53 gene in hepatocellular carcinomas from Senegal. Br J Cancer 67:1395-1397, 1993 38. Hainaut P, Soussi T, Shomer B, et al: Database of p53 gene somatic mutations in human tumours and cell lines: Updated compilation and future prospects. Nucleic Acids Res 25:151-157, 1997 39. Bressac B, Kew M, Wands J, et al: Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350:429-431, 1991 40. Purtilo DT, Gottleib LS: Cirrhosis and hepatoma occurring at Boston City Hospital (1917~1968). Cancer 32:458-462, 1973 41. Gordeuk VR, McLaren CE, MacPhail AP, et al: Asso, ciations of iron overload in Africa with hepatocellular carcinoma and tuberculosis. Strachan’s 1929 thesis revisited. Blood 87:3470-3476, 1996 42. Deugnier YM, Charalambous P, Le Quilleuc D, et al: Preneoplastic significance of hepatic iron-free foci in genetic heamochromatosis. Hepatology 181363-1369, 1993 43. Beasley RF’: Hepatitis B virus: The major aetiology of hepatocellular carcinoma. Cancer 61:1942-1956, 1988 44. Evans AA, O’Connell AI’, Pugh JC, et al: Geographic variation in viral load among hepatitis B carriers with differing risks of hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev 7~559.565, 1998 45. Fong TL, Di Bisceglie AM, Gerber MA, et al: Persistence of hepatitis B virus DNA in the liver after loss of HbsAg in chronic hepatitis B. Hepatology 18:1313-1318, 1993 46. Zhou YZ, Slagle BL, Donehower LA, et al: Structural analysis of a hepatitis B virus genome integrated into chromosome 17p of a human hepatocellular carcinoma. Virology 62: 4224-423 1, 1988 47. Slagle BL, Zhou YZ, Butel JS: Hepatitis B virus integration event in human chromosome 17p near the ~53 gene identifies the region of the chromosome commonly deleted in virus-positive hepatocellular carcinomas. Cancer Res 51:49-54, 1991 48. Meyer M, Weidon KH, Hofschneider PH, et al: Chromosome 17:7 translocation is associated with a hepatitis B virus DNA integration in human hepatocellular carcinoma DNA. Hepatology 15:665-671, 1992 49. Maynard JE: Hepatitis B: Global importance and need for control. Vaccine 820, 1990 (suppl) 50. Oon CJ: Prevention and control of hepatitis B. Med Digest 10:14-21, 1984 51. Brechot C, Pourcel C, Louise A, et al: Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature 2X6:533-535, 1980 52. Chang MH: Hepatocellular carcinoma in children. ChungHua Min Kuo Hsiao Erh Ko I Hsueh Hui Tsa Chih 39366-370, 1998 53. Vogel CL, Anthony PP, Mody N, et al: Hepatitis-associated antigen in Ugandan patients with hepatocellular carcinoma. Lancet 2:621-624, 1970 54. Kew MC, Desmyter J, Bradborne AF, et al: Hepatitis-B virus infection in southern African blacks with hepatocellular carcinoma. J Nat1 Cancer Inst 62:517-520, 1979 55. Gashua W, Mohammed I: Hepatitis B viral markers in
J. OLUFEMI
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Nigerian patients with primary liver carcinoma. Trop Geog Med 43:64-67, 1991 56. Enwezor CJ: Sixty cases of primary hepatocellular carcinoma in one year: A preliminary appraisal. Int Surg 77:277279, 1992 57. Abe K, Edamoto Y, Park YN, et al: In situ detection of hepatitis B, C, and G virus nucleic acids in human hepatocellular carcinoma tissues from different geographic regions. Hepatology 28568-572, 1998 58. Petry W, Heintges T, Hensel F, et al: Hepatocellular carcinoma in Germany. Epidemiology, etiology, clinical aspects, and prognosis in 100 consecutive patients of a university clinic. Z Gastroenterol 35:1059-1067, 1997 59. Olubuyide IO, Aliyu B, Olaleye OA, et al: Hepatitis B and C virus and hepatocellular carcinoma. Tram R Sot Trop Med Hyg 91:38-41, 1997 60. Sacco R, Randone A, Flichman D, et al: The prevalence of hepatitis C virus types in patients of the same geographic area, according to the source of infection and liver disease. Clin Diagn Virol 8:189-194, 1997 61. Ruiz J, Sangro B, Cuende )I, et al: Hepatitis B and C viral infections in patients with hepatocellular carcinoma. Hepatology 16637-641, 1992 62. Nakashima T, Okuda K, Kijoro M, et al: Pathology of HCC in Japan; 232 consecutive cases autopsied in 10 years. Cancer 51863-877, 1983 63. Berry N, Chakravarti A, Kar P, et al: Association of hepatitis C virus and hepatitis B virus in chronic liver disease. Indian J Med Res 108:255-259, 1998 64. Ojo OS, Thursz M, Thomas HC, et al: Hepatitis B virus markers, hepatitis D virus antigen and hepatitis C virus antibodies in Nigerian patients with chronic liver disease. East Afr Med J 72~719-721, 1995 65. Castells L, Vargas V, Gonzalez A, et al: Long interval between HCV infection and development of hepatocellular carcinoma. Liver 15:159-163, 1995 66. Ojo OS, Akonai AK, Thursz M, et al: Hepatitis D virus antigen in HbsAg positive chronic liver disease in Nigeria. East Afr Med J 75:329-331, 1998 67. Lopez-Velez R, Turrientes C, Gutienez C, et al: Prevalence of hepatitis B, C, and D markers in subsaharan African migrants. J Clin Gastroenterol 25:650-652, 1997 68. De Bat C, Stroffolini T, Gaeta GB, et al: Pathologic factors in cirrhosis with and without hepatocellular carcinoma: A multicenter Italian study. Hepatology 20:12251230, 1994 69. Bach N, Thung SN, Schaffner F: The histological features of chronic hepatitis C and autoimmune chronic hepatitis: A comparative analysis. Hepatology 15:572-577, 1992 70. Pavlica D, Samuel I: Primary carcinoma of the liver in Ethiopia: A study of 38 cases proved at post-mortem examination. Br J Cancer 24:22-29, 1970 71. Muhammad I, Mabogunje 0: Spontaneous rupture of primary hepatocellular carcinoma in Zaria, Nigeria. J R Co11 Surg Edinb 36:117-120, 1991 72. Akang EEU, Asinobi AO, Fatunde OJ, et al: Childhood mortality in Ibadan: An autopsy study. Nigeria J Paediatr 19(2):30-36, 1992 73. Pontisso P, Morsica G, Ruvoletto MG, et al: Latent hepatitis B virus infection in childhood hepatocellular carcinoma. Cancer 69~2731-2735, 1992
LIVER
CANCER
IN THE
DEVELOPING
WORLD
74. Trevisanl F, D’Intino FE, Caraceni P, et al: Etiologic factors and clinical presentation of hepatocellular carcinoma. Differences between cirrhotic and noncirrhotic Italian patients. Cancer 75~2220.2232, 1995 75. Williams OA, Edington GM, Obakponovwe PC: Hep-
187
atocellular carcinoma in infancy and childhood in Ibadan, Western Nigeria. Br J Cancer 21:474-482, 1967 76. Parkin DM, Kramarova E, Draper GJ, et al (eds): International Incidence of Childhood Cancer, vol II. IARC Scientific Publications No. 144, Lyon, France, IARC, 1999
Carcinoma 1. Olufemi
There some able
has recently forms of cancer in large part to
munodeficiency cies into the
world
syndrome of medicine
most
of these
which cases. main
proportionately Despite this, the big killers
that
in
yielded Africa noma
cases
some
prove Semin Saunders
are
evidence, to further
increase in This is attributof acquired im-
(AIDS)-related malignanand it is interesting that
seen
in the
developing
world,
leads
with the number of AIDS some more traditional cancers rein these areas of the world, except
countries
definitive
excellent results in reducing and the developing world, (HCC) is the leading cause
ing some clearly view describes known etiologic available ployed
been an observable the world over. the introduction
interventions disease hepatocellular of cancer
established etiologic the current status factors in the various suggests stem the
on survival in these Oncol 28:/79-187.
options incidence populations. Copyright
factors. of each areas
have burden. death,
In carcihav-
This reof these and, using
that may of HCC
be and
emim-
0
by
W.B.
2001
Company.
H
EPATOCELLULAR CARCINOMA (HCC) accounts for between 60% and 90% of all primary liver malignancies depending on the population studied. The remaining fraction of liver cancers comprises primary tumors deriving from other cell types, as well as secondary metastatic tumors. EPIDEMIOLOGY
The annual incidence rates for HCC vary from three to seven cases per 100,000 population in America and most of Europe, to up to 35 or more cases per 100,000 population in parts of Africa. Recent reports indicate a rise in the number of cases in the United States and this increase was greater among black than white meni as well as more pronounced among younger people. HCC was the number 1 cancer killer among adult males in Ibadan, Nigeria by 1975.2 At present, its frequency is second to that of prostate cancer among adult male cancer cases recorded in the Ibadan Cancer Registry, but the absolute number of cases is actually on the increase.3 HCC represented 8.32% of all carcinomas and 5.56% of all cancers in Zaire in 1992.4 The highest incidence is found in black Africans, with variable spread in the eastern, western, and southern regions of the continent. Southeast Asia, China, and the Far East also share in this Semmors in Oncology, Vol 28. No 2 (April),
200 I: pp I79- I87
in the Developing
World
Ogunbiyi
ravaging problem. The lowest incidence is found among whites in North and South Africa. In most populations, the incidence increases with age, with a peak in the fifth and sixth decades and a tendency to decrease in the elderly. In high-incidence areas, there is a marked shift towards the younger age groups, with peaks in Africa occurring in the third through fifth decades of life. The early onset in such places is attributed to exposure to environmental carcinogens especially hepatitis B virus (HBV), aflatoxin, and hepatitis C virus (HCV) at or soon after birth. Males tend to be more commonly affected, with a male to female ratio that varies between 4 and 8: 1. Chronic HBV infection and the presence of androgen receptors in HCC cells have been sug gested as reasons for the male preponderance.5 The three major etiologic associations for HCC are infections by the hepatitis viruses B, C, and D, as well as aflatoxin exposure (especially aflatoxin Bl [AFBl]) and cirrhosis. The relative contribution of these factors to the prevalence of HCC varies between cases occurring in high- versus lowincidence areas for the disease. Other conditions that may predispose to the development of HCC include neonatal hepatitis, biliary atresia, and some familial conditions, especially the Byler-type familial cholestatic cirrhosis.6 HCC has been reported in congenital hepatic fibrosis,7 situs inversus, and neurofibromatosis as well. In some cases, this occurrence was probably due to chance. No specific reports on these factors have been made from Africa, but their occurrence cannot be ruled out. The tumor may appear grossly as either a unifocal large mass, multifocal masses widely distributed in the liver, 01: a diffusely infiltrative cancer that sometimes involves the entire liver surface.
From the Department lb&m,
of Pathology,
University
College Hospital,
Nigeria.
Address reprint requests to 1. Olufemi Ogunbiyi, MBBS, FWACP (Lab. Med.), Department of Pathology, P.M.B. 5017, G.P.O., University College Hospital, Ibadan, Nigeria. Email: ogunbiyi~skannet.com. Q 2001 by WB. Saunders Company 0093~7754/0l/2802~0008$35.00/0 Copyright
doi:10.1053/sonc.2001.21963
179
J. OLUFEMI
180
Okuda et a19 described two major growth patterns, expanding and spreading (or infiltrative), while Nakashima and Koj iro 10 described four variations: infiltrative, expansive nodular, mixed infiltrative and expansive, and diffuse. There is some overlap between these two systems. Cirrhosis is commonly associated and the presence or absence of cirrhosis has been linked with etiologic factors, biochemical findings, and prognosis in some studies of HCC. For example, HCV and current or previous HBV infections were found more commonly in cirrhotic than noncirrhotic patients with HCC, while extrahepatic extension of HCC was more common in noncirrhotic patients. 11 The high prevalence of HCC in cirrhosis was associated with multiple risk factors in a study in Italy.12 It has also been shown that a significant difference exists in the number of genetic changes seen in HCC cases arising in macronodular cirrhosis as distinct from those arising in noncirrhotic livers. Specifically, a significant copy number loss of 4qll -q23 was identified in tumors larger than 3 cm in diameter.13 This review is an attempt to summarize the situation in Africa and the developing world, which essentially encompasses Southeast Asia and South America. Figure 1 is a histogram showing incidence figures for HCC across the continents of Africa, South America, and Southeast Asia.‘4 Thailand has the highest annual incidence rate, while in Africa HCC is most common in Mali. Not all countries are represented in this collection.
Si@ppWe Philippines KU&t KOBI Japan (Osaka) Israel (all Jews) India (Aggregate) W
RISK FACTORS While the major risk factors for HCC in the United States are infection with HCV or HBV,
Kong
China (Shangai) China (Qidong) Puerto Rico Peu (Ttujiilo) Peru (Lima) ECWBdOr casta mx Celomtia Brad
(Porta Alegre)
zIlnki+we
l.Eumpean)
Zmbabee
(AUcam) Uganda Mali
France. La Reunion Al&a
-A0
Incidence
AGE As stated earlier, the peak age incidence in most parts of Africa is in the third through fifth decades. Additionally, cases occur in the second decade in several regions. In a 1982 review of 585 rural southern African black males with HCC, Kew and Geddes noted that the mean age of patients was 35 years and that 40% were less than 30 years of age. In fact, the ages of patients ranged from 18 to 70 years.15 It had earlier been observed that the highincidence geographic areas are characterized by a shift of the age-incidence profile towards the younger age groups, suggesting that early exposure to carcinogenic agents was responsib1e.l”
OGUNBIYI
Fig South
Histogram I. America, and
20
(per
40
100,000
shows southeast
the
population)
incidence Asia.
(W)
of
HCC
Males;
(0)
in Africa, females.
and alcoholic cirrhosis,‘7 in parts of Africa and Southeast Asia, dietary exposure to aflatoxin is of particular significance in addition to infection by the hepatotropic viruses.ls-zi However, the exact mechanism of interaction between the viruses and aflatoxin in the pathogenesis of HCC is still poorly understood, although the presence of aflatoxin metabolites has been shown to influence the body’s interaction with HBV. AfIatoxin Aflatoxin plays a significant role among cases of HCC in Africa and Southeast Asia. Oettle prob-
LIVER
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IN THE DEVELOPING
181
WORLD
ably was first to present evidence that a high incidence of HCC was associated with a greater moldiness of foodstuffs? Coady demonstrated significant aflatoxin contamination of staple foods in Ethiopia as far back as 1965,23 and Bababunmi et al demonstrated significant mycotoxin contamination of Nigerian food supplies in 1978.24 Recent epidemiologic studies of specific populations have provided estimates of population exposures and show values ranging from 10 to 200 rig/kg body weight per day in sub-Saharan Africa and Southeast Asia, to less than 3 rig/kg body weight per day in the United Statesz5 Diallo et al found detectable levels of AFBl adduct in more than 90% of serum samples tested from Guinea, West Africa.26 In that cohort, 14.7% of people were positive for hepatitis B surface antigen (HbsAg, a marker of current infection with the virus) and 8% had antibodies to HCV. In comparative analysis, this population probably has the highest level of contamination in the world. Pooled data from Africa, Southeast Asia, Europe, and the United States clearly demonstrate high serum levels of aflatoxin adducts in Africa and Southeast Asia.27 These measurements were obtained by the use of recently described dosimetric methods. Prospective studies confirmed a link between adduct levels and increased risk of developing HCC in China. 28~9 In Nigeria, Olubuyide et al reported “pathologic” levels of aflatoxins in serum of 9% of a normal population,sO as well as higher “pathologic” levels in patients with WCC than in matched controls.s* Exposure has been shown to occur in the perinatal period, since aflatoxin Ml was detected in breast milk of women from the Gambia, West Africa.s2 Susceptibility to HCC is believed to be associated with genetic variation in the enzymatic detoxification of AFB1,33 and Kirby et al34 showed a difference in the in vitro metabolism of this chemical by normal and tumorous liver tissue. Further proof of association was the finding that significant aflatoxin-albumin adducts were associated with various cytogenetic alterations in individuals from the Gambia.35 Additionally, in areas with high aflatoxin exposure, there is an association with a specific mutation in the p.53 tumor-suppressor gene, with a G-+T transversion at codon 249, which results in the amino acid substitution of serine for arginine.36-39
0 ther Toxins Idiopathic hemochromatosis leads to cirrhosis and occurs mostly in males, only rarely affecting females. It is linked to an autosomal-recessive inheritance, as well as the human leukocyte antigen (HLA)-A3 and -B14 major histocompatibility complex (MHC) antigens. HCC develops in about 20% of cases and occurs irrespective of therapy for iron removal.40 The major work on iron overload in Africa done by Strachan in 1929 was recently revisited and indicates an increased risk of death from HCC in patients with excessive tissue iron stores.41 In patients with iron overload, iron-free foci within liver nodules had been shown to be preneoplastic, and it was suggested that the finding of iron-free foci in the initial biopsies from these patients should lead to screening for HCC.42 Hepatitis
B Virus
By far the most important environmental factors in HCC in the developing world are probably HBV and HCV. The development of HCC is the most important consequence of infection with these viruses, and HBV accounts for up to 80% of all cases of liver cancer, being second only to tobacco among human carcinogens.43 The risk of developing HCC varies among carriers of the virus however. In a study comparing carriers from Africa (Senegal, West Africa) and China (Haimen City), two countries with a similar prevalence of chronic HBV infection, Evans et al found the risk of HCC to vary among HBV-positive subjects.44 In the group with the lesser number of HCC cases developing, viral DNA levels in the serum had depreciated faster over time. However, even when HbsAg is lost from the serum, persistent HBV DNA is found in the liver cells45 and chronic HBV infection is often associated with major structural genetic changes in both the viral and the host DNA46-48 that possibly lead to hepatocarcinogenesis. While the global estimate of HBV carriers keeps rising,49 about 13% of cases are found in Africa.50 The main points of evidence for an etiologic role for HBV in HCC cases can be summarized as follows: (1) HBV carrier rates match tumor incidence rates; (2) there is a greater risk of malignancy in cirrhosis due to HBV; (3) liver cell dysplasia is seen commonly in chronic HBV; (4) HBV antigens are present in tumor-bearing patients;
182
and (5) there is HBV DNA integration in tumor cells5i In high-incidence areas, transmission is from mother to infant at or soon after birth, and this is associated with a high incidence of liver cell carcinoma in early life. Transmission seems to occur more readily in males. In some countries, especially the Gambia, West Africa, inclusion of HBV vaccine in the expanded program of immunization has substantially reduced the incidence and prevalence of HCC. An earlier experience was reported in Taiwan, where the prevalence of HbsAg declined from 10% to less than 1% within a loyear period.52 Kew and Geddesis noted 62% HBV positivity among male miners with HCC in rural southern Africa in 1982. Several studies of HCC patients from various regions of the African continent have shown a significant association between HBV infection and the development of HCC with HbsAg positivity, mostly in the range of 75% to 90% in cases of HCC seen.ss-s6 Most recently, Abe et al57 found that HBV was the most prevalent virus among HCC cases in Korea (82%), and among Japanese Americans in Hawaii (50%) as against HCV prevalence in Japan (61.5%), Spain (60%), and the United States (41.5%). Hepatitis C Virus HCV infection is known to be associated with various liver disorders, including steatohepatitis, chronic (including granulomatous) hepatitis, cirrhosis, and HCC. Patients with HCV-associated HCC are generally older than those with HBVassociated HCC,ss and this was also the case in Nigeria.59 Different viral types of HCV produce different forms of disease, with some inducing chronic liver disease for up to 20 years without the development of cirrhosis, while others are associated with the development of HCC.60 In one study of 70 patients with HCC, HCV RNA was found in 62% of patients, the prevalence of antibody to HCV was 63%, and HCV was more prevalent than HBV in HCC patients.61 Similar figures are quoted from Europe and the United States, but the picture in the developing countries is different. What is probably most important about HCV-associated HCC is that facts emerging regarding the biology of HCV indicate that the incidence of HCC is 2.7 times higher than that associated with HBV in-
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OGIJNBIYI
fection and the incubation period until HCC is detected is shorter.‘jl This suggests a more aggressive virus than was originally thought. A recent study in India found HCV to be second to HBV in the causation of chronic liver disease.63 In a prospective study of chronic liver disease patients in Ife, Nigeria, 4% of patients were noted to be positive for anti-HCV antibodies, and all had HCC.64 In Nigeria, the range is between 5% and 12% of blood donors (P.O. Olatunji, Ilorin, Nigeria, personal communication, 1999), while a study in Ibadan, Nigeria, showed a prevalence of about 19% among HCC patients.59 Another important finding is that the latency period between HCV infection and the development of HCC is relatively long. HCV-positive patients followed longitudinally in Spain showed a long interval between exposure and the development of cirrhosis and HCC.65 The exact role of HCV, and therefore the burden of disease in chronic liver disease patients (including HCC patients), is not known for most of Africa and the developing countries where screening for HCV is not routinely performed. It is urgent that work be done to establish the burden of HCV in these nations and to plan adequate intervention. Hepatitis
D Virus
The delta virus is believed to coinfect or superinfect along with HBV and is capable of producing chronic hepatitis. The exact role of HDV in developing nations is not fully characterized. One study from Nigeria found HDV antigen in the sera of 6.5% of HbsAg-positive patients with chronic active liver disease.66 The other African study published in the English literature was performed on sub-Saharan African immigrants to Spain; serum samples from these subjects did not test positive for markers of HDV.67 It seems that more work needs to be done in Africa with respect to determining the status of HDV among patients with chronic liver disease and HCC.
Cirrhosis Cirrhosis may occur in association with many etiologic factors, including chronic alcohol abuse, metabolic disorders, and, possibly other toxins, with all of these causes probably following the pathway of injury, regeneration, and cirrhosis. However, the majority of cases of cirrhosis follow infection with the hepatitis viruses B, C, and D.
LIVER
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WORLD
Cirrhosis is associated with an increased rate of cell loss and replacement, which enhances the efficiency of many carcinogens and the probability of viral DNA integration. The stage of cirrhosis influences the development of HCC, which generally occurs only in advanced cases. In an Italian multicenter study of cirrhosis, it was found that the highest prevalences of HCC occurred with HBV infection, with or without alcohol abuse, and in HCV cirrhosis with or without alcohol abuse.67 The morphology of cirrhosis found to be associated with the presence of HCC is nearly always mixed or macronodular and not micronodular. The macronodular pattern is associated both with long duration of the disease and with its etiology. The characteristic finding in cirrhosis due to HBV infection is a macronodular (so-called incomplete septal or posthepatitic) cirrhosis pattern, also called Miyakis’ type B by Japanese workers. This finding may be expectedly extended to HDV and HCV, except that HCV may be associated with steatosis in 70% of cases.68 Cirrhosis is a common theme in African HCC. The frequency of association with HCC varies between 60% and 90% in African series. Kew and Geddesis reported that cirrhosis was present in the nontumourus liver tissue at necropsy in 60% of patients. In Ethiopia, Pavlica and Samuel found that 94.7% of HCC cases had cirrhosis of the liver, of which 75% were of the postnecrotic type.69 In most adults, cirrhosis is of the posthepatitic type, and in fact even in children, cirrhosis associated with HCC is predominantly of the posthepatitic type. MORPHOLOGY
OF AFRICAN
CASES
The morphology of tumors is not distinctly dif, ferent between developing countries and the de, veloped nations, and in Africa most authors adhere to the traditional three patterns of nodular, massive, and spreading forms. Any of these three patterns may cause enlargement of the liver up to about 3 kg. When there is associated cirrhosis, the liver may be normal in weight or even become reduced in size. Occasionally, there is a greenish pigmentation because of bile retention. Tumor nodules may become necrotic as a result of ischemia, and may rupture, producing infarction in the liver. This is a common finding in Africa and Asia. A third of patients seen in Zaria, Nigeria, for example, presented acutely in the hospital in hy-
povolemic shock following rupture of tumor nodules.70 Histologically, the appearance is determined by the degree of differentiation and depends on a combination of the following features: (1) the structural pattern; (2) the degree of differentiation; and (3) other cytologic variations such as bile production, fatty change, cytoplasmic hyaline, and pleomorphism. Therefore, one may find a trabecular growth pattern (most common) or an acinar (pseudoglandular) pattern of growth. The stroma is variable and may be desmoplastic. Various ale terations such as steatosis and inflammatory cellular infiltration may be seen as well. The distinctive good-prognosis variant called “fibrolamellar carcinoma” is not usually seen in the setting of chronic viral infection. The fibrolamellar variant of HCC occurs in younger patients, without a sex predilection, arises in noncirrhotic livers, and has an extended duration of symptoms. The histology is that of large polygonal tumor cells with deeply eosinophilic granular cytoplasm, diffuse fibrous stroma, and an increased number of mitochondria at ultrastructural examination. HCC
IN INFANCY
AND
CHILDHOOD
Cancer in children is currently a topical issue especially because of possible genetic predisposition. A more important consideration for Africa and the developing world is the toll this will have on survival, since about 40% of most of these populations are aged less than 15 years, thus producing social and economic stresses on both the society at large, as well as the immediate family of the afflicted children. In these environments, the prognosis for cancer remains poor due to late presentation, prohibitive cost of procuring chemotherapy/radiotherapy, and the inadequacy of follow-up. Cancer was sho,wn to account for 8.7% of deaths and to be the fourth leading cause of death in children at the University College Hospital, Ibadan in 1992.71 In comparing these findings with an earlier report, HCC maintained a prevalence figure of 1.2% with a suggestion of an increase in the absolute number of cases. A few reports on childhood cancer have addressed the problem of HCC. The etiologic factors in childhood HCC in Africa, as in other parts, are much the same as in adults, ie, HBV, aflatoxin with possibly other toxins, and HCV.i5,z4 Reference
184
J. OLUFEMI
OVWdl Years Reviewed
country Algeria Ewt Malawi Malawi
I986- I995 I980- I989 (Blantyre)
l987- I985 I983- I992
Nigeria
198% I992
South Africa Blacks
1988-1991 1988-1991
Whites Uganda
I992- I995 I990- I994
(blacks)
Total Data from Parkin
-
1991-1995 1991-1995
Mali Namibia
Zimbabwe
RF (%)
NO. Male
o-4
-
-
2
0.15
I
4 2
0.7 I .7 -
3 2
-
-
-
-
-
-
-
-
-
-
2
0.5
2
35 6
I .4 0.7
I9 4
2 3
0.6 I .4
I 2
56
Age Group 5-9
34
2 I
3 2 5
(rr) IO-14
_
NO.
Age Group
Female
o-4
-
--
I
I
I 1
I
--
l I
---
2
----
-
I3 2
I6 2
-
-
I 2
I I
---
23
22
6
(rr) IO-14
---
3
5-9
OGUNBIYI
-
-
4 I
I2 I l l
5
I7
et al.75
has been made to early exposure to aflatoxins in childhood.32 Using the polymerase chain reace tion technique, it was possible to demonstrate HBV DNA in liver tissue of 67% of children with HCC but with negative results of serologic testing for HBV markers.?* Williams et al reported four cases of HCC occurring in infancy and childhood in Nigeria. The patients ranged in age from 4 months to 10 years. The authors noted the rarity of coexisting cirrhosis in these cases, as well as the absence of abdominal pain at presentation, features that characterize adult cases of HCC.73 There was solo involvement of the right lobe of the liver in two of four cases, both lobes in one of four, and the left lobe in one of four. The prognosis was deemed to be poor, as the average life span from diagnosis was 4 months. In another study from the same environment, 12 cases of HCC occurring in children were reviewed. The mean age at diagnosis was 8.7 years (range, 3 to 14), and massive hepatomegaly was a presenting symptom in 25% (Akinyinka 00, et al, unpublished data, June 1990). Table 1 lists the relative frequency of HCC in children in some African countries.74 The highest relative ratio frequency is found in Malawi (Blantyre).75 The male to female ratio in children is about 2:l. The majority of cases occur in the loto 14-year age group in both sexes, which might
suggest equal environmental exposure to possible causative agents. In most African countries, the sex ratio at birth is in favor of males, so that the distribution of disease in children may not have significant sexual bias as has been suggested in adults. CONCLUSION HCC is an important form of cancer in Africa and the developing world. It is the leading cause of cancer death in most of these countries, despite the recent scourge of acquired immunodeficiency syndrome-associated cancers worldwide. The sex ratio is significantly in favor of males, this being less prominent in children. The etiologic factors involved are aflatoxin and the hepatitis viruses-B more so than C and D. Alcohol appears to be a less important cause of HCC in these areas. Other toxins may be important, but have not yet been conclusively researched. Education about food preservation and storage, as well as early vaccination against HBV, have led to decreases in incidence and long-term complications in those places embracing such procedures. Vigilance and more extensive research into the roles of HCV, HDV, and other toxins will further stem the incidence of HCC and improve on survival in these populations.
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