Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991), pp. 962-972

CONFERENCE REPORT

Hepatocellular Carcinoma A Worldwide Problem and the Major Risk Factors ROSA GIOVANNA SIMONETTI, MD, CALOGERO CAMMA, MD, FELICE FIORELLO, MD, FLAVIA POLITI, MD, GENNARO D'AMICO, MD, and LUIGI PAGLIARO

Male sex, age, cirrhosis, and HB~Ag are the major risk factors for hepatocellular carcinoma (HCC). The geographic distribution of HCC is highly uneven, such that three distinct incidence areas are recognized. To clarify the reason(s)for this geographic Variability of HCC, the risk factors in each incidence area were assessed. In parallel with the geographic distribution of HCC, HBsAg prevalence was highest in both HCC patients and in general population in Africa and Asia, where mothers of HCC patients are frequently HB~Ag-positive, suggesting that hepatitis B virus hyperendemicity and perinatal infection account for the high HCC incidence in these areas. Cirrhosis, which is found on autopsy in 80% of the cases of HCC patients worldwide, is the most prevalent risk factor for HCC in areas where hepatitis B virus infection is less common. However, HBsAg carriage adds to the HCC risk carried by cirrhosis and explains the higher incidence of HCC in cirrhoticsfrom Africa and Asia as well as elsewhere. Available data suggest that chronic HCV infection is a risk factor for cirrhosis and HCC. HBV vaccination should decrease HCC incidence rates worldwide; however, HCC prevention in regions where HB~Ag carriage is infrequent may also require prevention of the other causes of cirrhosis in order for HCC rates to decline. KEY WORDS: HCC; risk factors; geographic distribution; box plot.

This presentation is aimed at providing an overview of the epidemiological data dealing with risk factors (RFs) for HCC. The search for pertinent papers was performed using the Medline data base reference lists of published articles and reviews, the volumes of the series "Cancer incidence in 5 continents" (1970, 1976, i982, 1987) (1-4) and those of WHO Annual Statistics, 1988 (5). Published and unpublished data from our own department were analyzed also.

Manuscript received January 10, 1990; revised manuscript received February 13, 1991; accepted February 13, 1991. From the Divisione di Medicina Generale, and Clinica Medica "R," Ospedale "V. CERVELLO," Palermo, Italy. Presented at the Proceedings of the International Meeting on Normal and Neoplastic Growth in Hepatology, Bail, Italy, June 1989. Address for reprint requests: Dr. Rosa Giovanna Simonetti, Divisione di Medicina Interna, Ospedale Cervello, Via Trabucco 180, 90146 Palermo, Italy.

962

In order to highlight the distribution of RFs in different HCC incidence areas or subsets of patients, a visual display called a box plot was used (6). The box includes the middle 50% of a series of data; the horizontal bar inside the box represents the median. The upper and lower ends of the box (hinges) represent the approximate upper and lower quartiles of the data distribution. Extreme data are connected to the ends of the box by vertical bars (Figure 1). The statistical significance of differences between variables was assessed by the Student's t test when appropriate. WORLDWIDE INCIDENCE OF HCC

HCC is one of the most common cancers in males. Its worldwide annual incidence has been estimated to be 250,000 to 1,000,000 (7, 8) with a male-female ratio of about 4 or 5:1 (8, 9). Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)

0163-2116/91/0700-0962506.50/09 1991PlenumPublishingCorporation

HEPATOCELLULAR CARCINOMA EXTREME

10080-

40-

(14)

(14)

80-

UPPER HINGE

r

(7)

100

i

I

X 60 IIJ r LOWER HINGE

ILl

.J 4 0 -

2020-

EXTREME

0

O.

Fig 1. The box plot. The upper and lower hinges represent the approximate upper and lower quartiles, respectively.

L O W ( L ) INTERMEDIATE (I.) HIGH (H.) INCIDENCE AREAS (...)

The geographic distribution is highly uneven; hence, three geographic areas having different incidence rates have been categorized (Tables 1 and 2). In several countries, the incidence appears to have increased in the last century, as reported by Saracci and Repetto (26); a reevaluation of the available data is shown in Tables 3 and 4. MAJOR RISK FACTORS OF HCC

Male gender, increasing age, cirrhosis, and chronic HBsAg carriage are well-recognized RFs for HCC. Aflatoxin has been suggested as a further RF; however, the available data on the relationship between aflatoxin intake and HCC are sparse and somewhat conflicting (30, 31). The geographic variability of HCC incidence suggests that one (or more) strong RF is most prevalent

No OF STUDIES

Fig 2. Male sex in HCC pts. References: low--17, 18, 32-36; intermediate--21-24, 37-47; high--9, 48-60.

in the areas of higher incidence, but not in areas where the incidence of HCC is less. Male Gender. More than 80% of the cases of HCC occur in males. No substantial difference between areas with low or high incidence in this male prevalence is evident (Figure 2). Therefore, the hypothesis is that RF associated with male gender cannot account for the geographic variability of HCC incidence. Age. The mean age of HCC cases is greater in low and intermediate incidence areas than it is in high incidence areas. There also are differences within areas of high incidence, African patients being younger than those from Asia (Figure 3). This

TABLE 1. WORLDWIDE HCC DISTRIBUTION: DEATH RATES (MALES, AGE STANDARDIZED TO WORLD POPULATION)* (HCC/100,000/YR) Low?

Mauritius Mexico Switzerland Holland USA UK Canada Yugoslavia Australia Norway Spain West Germany Hungary (Szabolcs) Denmark Chile Argentina Sweden India (Bombay)

Intermediate?

0.2 0.5 1.5 1.6 1.8 1.9 2.0 2.0 0.8-3.1 2.6 3.1 3.4 3.5 3.6 3.8 4.7 4.7 4.9

Austria Singapore Seychelles Italy Sao Tome France Poland Alaska Greece:~ Bulgaria Johannesburg Japan South Africa (Durban)

Hight

5.1 5.5 6.1 7.1 7.4 7.8 7.9 11.0 12.0 12.0 13.7 19.2 20.0

China (Tianjin) Senegal Japan (Nagasaki) New Zealand Hong Kong South Africa (Natal) Bulawayo (Rhodesia) Singapore (Chinese) Japan (Osaka) China (Shanghai) Taiwan Mozambique (Maputo) Korea

23.1 25.6 25.8 26.6 28.4 28.4 31.2 31.6 31.9 34.4 80.0 106.7 100-150

*Sources of data: references 1, 2, 10-14. ?Incidence areas: low death rate 20/100,000/yr. ~Data from Greece are conflicting, ranging from 1 to 23.3 (5, 15). Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)

963

SIMONETTI ET AL C6)

80

C12)

C13)

-+-

6 0 84

(11)

100'

(6)

(11)

80-

(15)

(11)

(14

7-

r.,

>'~ 4 0 -

(a 60O "r a, a, 40"

UJ 0 < 20-

U 20-

O" LOW(L.)

INTERMEDIATE (I.) HIGH (H.) INCIDENCE

AREAS

LOW ( L . )

(..-) No OF STUDIES

INTERMEDIATE (I.) INCIDENCE

Fig 3. Age o f H C C pts. Student's t test: L. vs I., 1.21, p = N.S. (0.24); I. vs H., 6.89, p = 1 • 10-7. References: low--16, 17, 32, 33, 35; intermediate--21-23, 37, 38, 41-45, 61, 62; high--9, 48, 52-55, 58, 59, 63-66, 67..

[]

AREAS

AUTOPTIC DATA

[ ~ ] CLINICAL (.,.)

finding suggests that RFs for HCC arise at an earlier age or are more rapidly carcinogenic in highincidence areas, especially in Africa, than in lowincidence areas. Cirrhosis. The prevalence of cirrhosis in HCC cases is about 80% in each of the three incidence areas in various autopsy studies (Figure 4). On the other hand, clinical studies showed a significantly smaller proportion of cirrhosis in HCC cases from high-incidence areas (Figure 4), suggesting that in these regions the cirrhosis underlying the HCC is well compensated and therefore undiagnosed before death (79). In contrast to the almost unchanging autopsy prevalence of cirrhosis in HCC cases, the proportion of cirrhotics developing HCC is higher in high-incidence areas, as shown in Table 5 and has changed over time: in Japan, the prevalence of HCC in autopsied cases of cirrhosis increased from

HIGH (H.)

DATA

No OF STUDIES

Fig 4. Cirrhosis in HCC patients: autopsy data and data based on clinical diagnosis. Autopsy data references: low--17, 68, 69; intermediate--20-23, 68-72; high--67-69, 73. Data based on clinical diagnosis--Student's t test: L. vs I., 0.69, p = N.S. (0.49); I. vs H., 2.05, p = 0.04. References: low 28, 33, 68, 74-76; intermediate--11, 16, 24, 26, 28, 37, 39, 41-43, 45-47, 61; high--9, 28, 48, 49, 51, 63, 65, 67, 77, 78.

about 50% in 1958-1961 to about 70% in 1980-1983, paralleling the increasing incidence of HCC (28). The variable tendency for cirrhosis to develop HCC accounts for the lack of a geographic relationship between the death rate for cirrhosis and the HCC incidence in an area (Figure 5). Altogether, these findings suggest that cirrhosis is a RF for HCC worldwide. The stronger and possibly earlier risk of HCC in cirrhotics seen in highincidence areas depends on the differing etiologies (or type) of cirrhosis seen in each area.

TABLE 2. WORLDWIDE HCC DISTRIBUTION:AUTOPSYDATA (MALES AND FEMALES), HCC/100 AUTOPSIES Low?

USSR Finland Denmark Switzerland USA, Boston England USA Chicago Massachusetts Los Angeles Scotland Sweden

Intermediate?

0.28 0.29 0.34 0.40 0.43 0.53 0.58 0.60 0.96 1.00 1.36

Italy, Modena Trieste Florence France Thailand Japan Japan

High? 1,33

1.33 1.40 1.40 1.40

South Africa Japan, Tokushima Nigeria Hong Kong Taiwan

4.0 5.1 5.8 6.8 25.4

2.40 2.90 3.61

*Sources of data: references 16-25. tlncidence areas: low death rate 20/100,000/yr.

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Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)

HEPATOCELLULAR CARCINOMA TABLE 3. TIME VARIATIONOF HCC INCIDENCE IN VARIOUS COUNTRIES: DEATH RATES* (HCC/100,000/YR) 1970

West Germany Hungary (Szabolcs) Brazil (Sao Paulo) Finland Sweden India (Bombay) Israel (Born Africa or Asia) Miyagi New Zealand (Maori) Singapore (Chinese) Japan (Osaka) Mozambique

0.9 1.2 2.5 0.5 2.8 1.3 7.5 98.2t

1976

1987

5.6 0.9 1.4 2.1 2.9 1.4 4.3 1.8 7.7 34.2 1.5 150.0~:

2.9 3.5 3.6 4.0 4.7 4.9 7.4 11.2 11.2 31.6 31.9

ul

(15)

50"

HBsAg. The prevalence of HBsAg in HCC cases has increased progressively and significantly from 21.7% in areas where HCC is rare to 67.4% in African and Asian areas where the rate is high (Figure 6); similarly the proportion of HBsAg carriers in the general population in high-risk areas is increased (Figure 6). These findings document the fact that HBsAg hyperendemicity is the most likely reason that accounts for the high incidence of HCC seen in African and Asian regions.

3o, o

20-

z,~ 10-

%u

w a

O. LOW ( L . )

Boston (Massachusetts Hospital) (17)

Japan (28) Europe (29) Glasgow (19) Germany (16) Paris (19) Italy (Modena) (20) Italy (Florence) (22)

*Reference numbers are in parentheses. Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)

0.13 0.17 0.33 0.96 0.0 0.14 0.37 0.46 0.59 0.60 2.58 4.80 0.13 0.18 0.21 0.60 1.0 0.26 0.82 0.60 2.50 0.70 1.50 0.30 2.56

HIGH (H.)

AREAS

No OF STUDIES

Fig 5. Death rates from cirrhosis in areas with different HCC incidence. Student's t test: L. vs I., 0.81, p = N.S. (0.42). eTaiwan, Hong Kong, New Zealand, South Africa, South Asia. References: low 5; intermediate--5; high 5, 70, 80, 81.

The relative risk (RR) of HCC in HBsAg carriers is increased about 10- to 28-fold in case-control studies enrolling controls from the general population or patients with nonhepatic diseases (43, 47, 49, 56-59, 64, 91). A lower figure not greater than three was obtained in our own studies examining HCC incidence in Italy (most of whom were cirrhotic)

(41, 42, 45). In longitudinal studies, the RR ranged from a value of 30 in Japan (92) to a value of 106 in Taiwan

TABLE 4. TIME VARIATION OF H C C INCIDENCE IN VARIOUS COUNTRIES: AUTOPSY DATA (HCC/100 AUTOPSIES)

Before-1900 1918-1953 1954-1963 1964-1973 1894-1910 1911-1920 1921-1930 1931-1940 1941-1950 1951-1960 1958-1959 1982 1900-1912 1920-1932 1938-1950 1949-1963 1959-1967 1951-1960 1961-1970 1959 1966 1937-1955 1956-1965 1958-1962 1978-1982

INTERMEDIATE(L) INCIDENCE

(10)

100-

Los Angeles (18)*

(5)

0'l- 4 0 n,, r,,

(.--)

*Only countries with variation larger than 1.0/100,000/yr are reported. Sources of data: references 1, 3, 4, 12. t1966 (12). 21976 (27).

(9)

(14)

(7)

(18)

(9)

(27)

80r

< 60~ .I-

Im]

40,,

i11i

20~

0 LOW (L.) []CARRIERS

INTERMEDIATE (I.) HIGH (H.) I N C I D E N C E AREAS IN GENERAL POPULATION

D

HCC CASES

(...)

No OF STUDIES

Fig 6. HB~Ag in HCC cases and in general population. Carriers in general population--Student's t test: L. vs. I., 2.25, p = 0.05; L. vs H., 6.68, p = 0.0001; I. vs H., 3.91, p = 0.001. References: l o w - - l l , 16, 82; intermediate--8, 15, 16, 82; high--ll, 13, 82, 83. HCC cases---Student's t test: L. vs I., 3.35, p = 0.002; L. vs H., 8.08, p = 1 x 10-7; I. vs H., 4.85, p = 1 • 10 -4. References: low--8, 11, 14, 16, 32, 33, 35, 56; intermediate--ll, 16, 23, 34, 37-39, 41-43, 45-47, 61, 84, 85; high--9, 11, 14, 28, 48-53, 55, 57-59, 63-66, 86-90.

965

SIMONETTI ET AL TABLE 5. PREVALENCE OF H C C IN CIRRHOSIS: AUTOPSY DATA, HCC/100 CIRRHOSIS

Low*

USA (62)t Boston (62) Boston (69) Chicago (69)

Intermediate*

2.2 3.4 5.0 5.0

France (62) France (19) Italy (20) Italy (21) Sweden (75) Italy (22) Japan (69) Japan (69) Japan (28)

High*

6.4 7.0 11.0 12.6 15.0 17.0 26.3 40.9 73.0

Uganda (69) Malaysia(Chinese) (70) South Africa (69) Malaysia(Senoi) (70)

17.0 43.0 44.0 55.0

*Incidence areas: low death rate 20/ 100,000/yr. ?References, (13); it is of interest that in the Taiwan data the RR of HCC was 481 in patients with "known cirrhosis" and 101 in those without cirrhosis (93). This finding points out how methodological differences (retrospective or prospective studies; selection of patients; underlying cirrhosis) can result in a variable RR; however, conditions inherent to HBsAg carriage (age of infection) in itself or cofactors (ariatoxin, others) probably play a role in HCC risk. Relationship between Cirrhosis and HBsAg. The presence of cirrhosis strongly increases the HCC risk carried by a HB~Ag carrier, as shown by the Taiwan data reported above. Similarly, HB~Ag positivity increases the HCC risk in cirrhotics in general, regardless of geographic location, as suggested by the higher prevalence of HB~Ag in patients with cirrhosis associated to HCC than in patients with cirrhosis alone in several cross-sectional studies. Data from two representative Italian studies are shown in Figure 7. Further evidence for the increased risk of HCC in HB~Ag-positive cirrhosis is provided by longitudi-

//•PAGLIARO ET AL

V I L L A ET

TABLE 6. DEVELOPMENT OF HCC IN PATIENTS WITH HBs-POSITIVE OR -NEGATIVE CIRRHOSIS: LONGITUDINAL STUDIES

5(1

,~

40

nal studies. Representative data from Japan (94) and from Italy (95, 96) are reported in Table 6. The value of Obata's data has been questioned (32), because they do not take into account the male prevalence in HCC patients. This objection cannot be ascribed to the study of D'Amico, however, in which the role of HBsAg as an independent RF of HCC was confirmed by multivariate analysis including gender as a variable in two separate large sets of cirrhotics (Table 7). Yet another longitudinal study from UK (32) found that male gender, increasing age, and non-UK origin, but not HBsAg, were independent RFs for HCC in cirrhosis. This result was probably due to the low prevalence of HBsAg in the study cohort (47 of 613 patients), exemplifying that in a region where HBV circulation is low, cirrhosis p e r s e is the main RF for HCC. Cirrhosis of any etiology is a risk factor for HCC, although with a variable penetrance (69, 97). Alcohol abuse--the most important RF for cirrhosis in developed countries--does not add to the risk of HCC experienced by cirrhotics. This fact can be

(28)

D'Amico et al Obata et al (94)*

[]

HCC W,TH CI..HOS,S

D

C,...OS,S

HCC .O C,.RHOS.S

[]

.ON .E.AT.C CHRON. D I S E A S E

(-..) No OF C A S E S

Fig 7. HBsAgprevalence in HCC cases and appropriate controls in Italy. References: Pagliaroet al (42) and Villa et al (39). 966

Patients (N) Enrollment Mean follow-up (months) HBsAg +ve (N) With HCC (N) HBsAg +ve HB~Ag-ve

115 1973-1977 34.6 30 7 p = 0.019 5

First study (95)

Second study (96)

1155 494 1974-1980 1981-1984 25.4 -+ 25 178 26 64

54 --_26 68 11 34

*References. Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)

HEPATOCELLULAR CARCINOMA TABLE 7. HCC INDEPENDENTRFs IN PATIENTSWITH CIRRHOSIS(Cox's MODEL;4 VARIABLES) Set I (95)* RR

Male sex Age (>50) HBsAg +ve Alcohol

3.6 3 • 10-6 3.6 2 x 10-6 1.3 0.04 Not significant

RR

P

2.9 4.9 3.0

0.004 0.003 0.003

C9)

I

Set l l ( 9 6 ) t

P

C9)

80

60 ev

II 0" 40

IDIII I

m 0 < 20'

"1,155 patients; HBsAg unknown in 150. ( ) = references. t494 patients; HB~Ag known in all. HBsAg positive

inferred by the low alcohol intake and the low prevalence of alcoholic cirrhosis in most areas having high HCC incidence. Moreover, several studies have shown that in cross-sectional and longitudinal studies the proportion of HCC is similar in alcoholic and nonalcoholic cirrhosis (Figure 8, Table 7). Relationship between Age and HBsAg. The mean age in HBsAg-positive HCC patients is lower than in HBsAg negative individuals (Figure 9), although the difference does not reach the level of statistical significance. This difference is greatest in Africa. This finding may account for the lower age of HCC found in Africa and to a lesser degree in Asian countries, where many HCC cases are HBsAgpositive. It is of some interest that mothers of HCC cases from these areas are more frequently HBsAgpositive than are the mothers of controls (Table 8), suggesting that offspring who are infected at birth are highly Susceptible to the subsequent development of HCC and do so at a younger age. HCV Infection. The role of HCV infection as an independent RF for HCC and cirrhosis is under evaluation at present. A substantial Proportion of patients with either disease are anti-HCV-positive

~ ..I

60-"

ETAL

eDATA FROM AFRICA (...)

No OF STUDIES

Fig 9. Age in HBsAg positive or negative HCC patients: Student's t test: HBsAg +ve vs. HBsAg - v e , 1.14, p = N.S. (0.26). References: HBsAg + v e - - l l , 33, 35, 43, 46, 50, 57, 59; HB~Ag - v e - - - l l , 33, 35, 43, 46, 50, 57, 59.

by the ELISA test (98-100) and immunoblotting (101). The available data suggest geographic variability in the prevalence of anti-HCV in HCC patients, with figures as high as 65-76% (98-100, 102) in Europe and Japan, lower (29-37%) figures in sub-Saharan Africa (103, 104), Korea (105), and variable figures from the United States (106, 107). A large case-control study (101) in our department suggests that HCC risk is increased in antiHCV positive cirrhosis [odds ratio 1.7 (95% CI 1.09-2.7)]. Overall, these data show a causative role for the sequence cirrhosis-HCC, more evident in countries with low-intermediate HCC incidence and HB~Ag prevalence. Furthermore, the decreasing prevalence of HB~Ag in individuals with HCC in Japan (28) and Sicily (data from our department, Figure 10), while the rate of HCC remains constant, might suggest the hypothesis of a corresponding increase in HCV-related HCC.

V I L L A ET A L

~ /

---~----

TABLE 8. HBsAg IN MOTHERSOF HCC PATIENTSAND CONTROLS FROM HIGH-INCIDENCEAREAS HCC patients

D

HCC W|TH C|RRHOS|S

N t . . c , No c, (..1 No OF CASES

.os,s

HBsAg negative

D

C|R'~"~OS|S

W .ON-HE A.,C CHRON. DISEASE

Fig 8. Alcohol abuse in HCC cases and appropriate controls in Italy. References: Pagliaro et al (42) and Villa et al (39). Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)

Larouze et al (108) N % HBsAg Beasley (93) N % HBsAg Chang et al (109) N % HBsAg

28 78.6

HCC Control Controls mothers mothers

28 57

28 71.4

28 14.3

14 100

49 100

14 86

49 35

48 75

44 100

28 93

44 50

967

SIMONETTI ET AL

35I

30

25

,~ 2 o

~242 ~ /

[.:-:.:-:,:.:,:,7.:.! r.'.','.'.'.':.'.'.l

i:i:i:i:i:i:!:?:i::

r .'.'.'.'.'.'.'.'.'.1 :.:-:.:.:.:-:.:.:-

:.:.:.:.:.:.:.:.1.:

:.:.:-:.:+:.:.:.

r .'.'.'.','.'.'.'.'.l

ti:!:i:i:i:;:~:!!!!l/ 1973' 1980

/

1981'1988

(.-) No OF HCC CASES

Fig 10. Prevalence variation of HBsAg in patients admitted ofr HCC at the Department of Medicine, Hospital V. Cervello, Palermo. Reference: 46.

DISCUSSION Only the major RFs of HCC were dealt with in this overview. Other RFs, like anabolic or sex steroids (110-115) and perhaps plant-derived or chemical agents (116) have not been considered, because their impact on HCC epidemiology is doubtful or very Small and the data available are difficult to interpret. The worldwide distribution of the major RFs for HCC was assessed relative to their prevalence in each of three distinct incidence areas. Visual dis: play and statistical methods were used to highlight the differences between geographic areas or subsets of patients. In high-incidence areas, HBsAg prevalence in the general population and in HCC cases is significantly higher, and the mean age of HCC cases is significantly lower than in other regions. African cases were the youngest~ The male gender preponderance was about 80% worldwide. The prevalence of cirrhosis was the same in the three areas based upon available autopsy data, but lower in high-incidence areas in clinical studies, possibly reflecting the development of HCC at an earlier, latent compensated stage of disease. Altogether, these observations highlight the geographic differences in HBsAg prevalence as the major determinant of geographic HCC variability and of the high incidence of the tumor in several African and Asian regions, most often complicating a cirrhotic process. The lower age of HCC development in these countrieS may be due to the frequent occurrence of perinatal HBV infection. However, other factors, such as aflatoxin (30), malnutrition (117), and other infections, may also 968

play a role in Africa, where HCC under age 40 frequently occurs even in HB~Ag-negative subjects. Cirrhosis, which had an almost invariable 80% prevalence in autopsied cases of HCC worldwide, emerges as the most important RF for HCC in lowand intermediate-incidence areas, where HBV carriage rates are low. However, the risk of HCC carried by cirrhosis is variable, presumably depending on the etiology and morphological character (macro- or micronodular) of the cirrhosis. HB~Ag positivity is one of the factors that increases the risk for HCC in cirrhosis, as shown by the vast majority of cross-sectional or longitudinal studies. The etiologic role of HCV infection cannot be fully evaluated as yet. The very high prevalence of anti-HCV in patients with HCC and in cirrhosis emphasizes the etiological role of chronic HCV infection for both diseases. Further studies from different geographic areas and more direct markers of HCV infection are needed for sound conclusions. Both ~B~Ag and cirrhosis are more frequent in males, therefore contributing at least in part to (albeit not fully accounting for) the male preponderance in HCC. This male-female ratio is high also in HBsAg,negative HCC, although a lower male predominance in HCC cases without cirrhosis has been reported as part of a few studies (9, 74, 75) but not others (21, 24, 42, 44, 46, 61). Several studies have suggested a role for endocrine factors (I 18-121). Brechot et al detected integrated HBV-DNA in the liver of 85-100% of HBsAg-negative patients having HCC associated with cirrhosis of both nonalcoholic or alcoholic origin (122, 123), suggesting a predominant role for HBV infection even in HB~Ag-negative HCC cases. However, these data have been substantiated by some but not all laboratories (124-126) examining this issue. In conclusion, the epidemiological data available concerning HCC point to HBV vaccination as the most efficient measure currently available likely to reduce the HCC mortality in high-incidence areas and hence worldwide. A strategy aiming at preventing cirrhosis of any etiology (HBV or HCV infection, alcohol, others) may be required to prevent HCC in the case of low and intermediate incidence.

ACKNOWLEDGMENTS W e are indebted to Mrs. Clara Profeta and Mrs. Rossella Lo Verde for skilled secretarial assistance in the preparation of the manuscript. Digestive Diseases and Sciences, Vol. 36, No. 7 (July 1991)

HEPATOCELLULAR

CARCINOMA

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