CONTRACEPTION TEE RISK OF LIVER NEOPLASIA IN RELATION TO COMBINED ORAL CONTRACEPTIVE USE
Lynn Rosenberg, Sc.D.
Slone Epidemiology Unit Boston University School of Medicine 1371 Beacon Street Brookline, MA 02146
ABSTRACT Benign liver tumors occurring in young women were rarely reported in the medical literature before the introduction of oral contraceptives in the early 1960s. Subsequently, there were numerous case reports from the U.S. and other countries of liver tumors in women who used combined oral contraceptives. These reports, coupled with data from two U.S. case-control studies, indicate that the risk of hepatocellular adenoma increases sharply with increasing duration of oral contraceptive use. Case reports suggest that there may be a similar effect on the risk of focal nodular hyperplasia, but this is not established because there have been no case-control studies of the lesion. The incidence of benign liver disease attributable to oral contraceptive use in the U.S. is small because of the very low incidence of the disease. There have also been numerous case reports of malignant liver tumors in young women who used oral contraceptives. Seven case-control studies have been conducted -- two in Great Britain, two in the U.S., one in Italy, one in several developing countries (conducted by the World Health Organization (WHO)), and one in South Africa. Data from the first five studies, all conducted in low risk populations, indicated an association of hepatocellular carcinoma (largely in the absence of liver cirrhosis) with oral contraceptive use. Because of small numbers estimates were unstable, but the risk did not appear to be increased appreciably for durations of use less than about five years. For longer durations, the risk appeared increased by five- t:o tenfold OK more. There was little evidence of hepatitis B infection in the cases, but systematic determinations were not carried out. An increased risk of cholangiocarcinoma was not established, but few of these lesions were studied. Because the incidence of primary liver cancer in Northern Europe and the U.S. is low, the incidence attributable to oral contraceptive use is also likely to be low. The WHO study was carried out in eight countries, most of which have a high incidence of liver cancer and a high prevalence of a predisposing factor, hepatitis B infection. Similarly, the South African study was carried out among black women, and virtually all of
JUNE 1991 VOL. 43 NO. 6
CONTRACEPTION
the cases had serological evidence of hepatitis B infection. Both studies indicated no association of short-term oral contraceptive use with risk of hepatocellular carcinoma, and the WHO study indicated a lack of association with cholangiocarcinoma. The prevalence of longterm use was too low for informative analysis. Future studies will be needed to assess whether long durations of oral contraceptive use increase the risk of liver cancer in countries in which both hepatitis B infection and liver cancer are common. INTRODUCTION In 1978 the World Health organization (WHO) issued a report on steroid contraception and the risk of neoplasia (1). It was concluded that the risk of hepatocellular adenoma was markedly increased among Because the women who used oral contraceptives for prolonged periods. tumor is very rare, however, the incidence in users was estimated to be The present paper reviews human studies on use of combined oral small. contraceptive preparations in relation to liver neoplasia, with an emphasis on studies published after the 1978 WHO report.
BENIGN LIVER TUMORS In 1973 Baum et al. (2) raised concern about the effect of steroid hormones on the risk of liver neoplasia when they published a description of seven cases of hepatocellular adenoma in U.S. women who This report was followed by numerous had used oral contraceptives. others, from the U.S. and other countries, of hepatocellular adenomas Before the and focal nodular hyperplasias in oral contraceptive users. advent of oral contraceptives in the early 196Os, there had been few reports of these lesions. et The largest case series, reported by Vana et al. (3) and Nime al. (4), resulted from a national survey of liver tumors in persons 1545 years of age conducted in 749 U.S. hospitals from 1970 to 1975. There was a striking difference in the distribution of tumors in men whereas there were similar numbers of malignant tumors (166 and women: in women, 151 in men), there were many more benign tumors in women than A high proportion of women with in men (212 and 15, respectively). hepatic cell adenoma or focal nodular neoplasia whose contraceptive The distribution by history was known had used oral contraceptives. age of cases of hepatic cell adenoma showed a peak at age 26-30, and the authors suggested that this distribution paralleled the ageFor focal specific prevalence of oral contraceptive use in U.S. women. there was also an increase in the number of cases nodular hyperplasia, up to age 26-30, and this was followed by a plateau. The case reports have been reviewed by Klatskin (5,) and by Prentice and 'Thomas (6). In the main, two types of benign liver tumor were reported -- hepatic cell adenoma and focal nodular neoplasia. (Some of the latter had been called hamartomas, but a panel of reclassified them as hepatocellular adenomas or, more pathologists often, focal nodular hyperplasias) (4). A high proportion of the reported cases were oral contraceptive users. Other findings were an absence of cirrhosis; an association between tumor size and oral
644
JUNE 1991 VOL. 43 NO. 6
CONTRACEPTION
contraceptive use; in some patients, regression of the tumors after cessation of use; and in some patients, recurrence of tumors with continuation of use. While both hepatic cell adenomas and focal nodular neoplasias also occurred in men (with the latter tumor being more common), they occurred much more rarely than in women. Finally, both hepatocellular adenomas and focal nodular hyperplasias are highly vascular and they showed more peliosis (blood filled spaces and cysts), thrombosis, and scarring in users than nonusers. It was suggested that oral contraceptive use might lead to hemorrhage and thereby to increased detection of these tumors; on the other hand, some tumors were diagnosed in the absence of hemorrhage. Two U.S. case-control studies of hepatic cell adenoma have been published. Edmondson et al. (7) conducted telephone interviews of 34 of 42 eligible women who had undergone surgery for hepatic cell adenomas during 1955 to 1976 in Los Angeles. They also interviewed age-matched friend controls for 34 of the cases. Use of oral contraceptives for a year or less was reported by 18% of cases and 44% of controls, while use for at least 85 months was reported by 38% of cases and 6% of controls. The risk ratio increased from 1.3 for 13-36 months of use, to 5.0 for 61-84 months, 7.5 for 85-108 months, and 25 for 109+ months. The cases had more commonly used mestranol-containing preparations then the controls. In 1979 Rooks et al. (8) reported on a larger study. Of 89 eligible cases of hepatocellular adenoma in women aged 16-50 reported from 1960 to 1976 to the Armed Forces Institute of Pathology, 79 were interviewed in person. Up to three age-matched neighbor controls were obtained for each of 76 cases. Oral contraceptive histories were taken with the aid of calendars for recording milestones such as marriages and births, and of photographs of oral contraceptive pills and packets. Only 9% of cases as compared with 55% of controls had used oral contraceptives for less than 13 months, and 25% and 3%, respectively, had used them for 85 or more months. The relative risk estimate increased markedly with increasing duration of use, and the estimate was reported to be 503 for 85+ months of use. Similar results were obtained for subjects diagnosed before 1973 when the report of Bawn et al. (2) appeared and for subjects diagnosed after 1973, suggesting that reporting bias did not explain the association. In contrast to the study of Edmondson (7), there was no excess of mestranol use in the cases. However, users of pills with high estrogen "potency" appeared to have a higher risk than those who used lower potency preparations, and the risk also appeared higher in women over 30. Because the earliest oral contraceptives marketed had higher doses of estrogen, users of higher potency pills might have tended to be older, and these women might also have had an opportunity to use oral contraceptives longer than younger women. Thus, the results according to age and to potency of the oral contraceptive may have been confounded by the duration of use. Based on the case reports and case-control studies, there is strong evidence that oral contraceptive use greatly increases the risk of hepatic cell adenoma. Despite methodologic limitations, relative risks of the magnitude reported in the case-control studies are
JUNE 1991 VOL. 43 NO. 6
645
unlikely to be explained by an unidentified bias. Although an association with focal nodular hyperplasia is also suggested by the data from case reports, it has not been established. Whether or not combined oral contraceptive use increases the risk of focal nodular hyperplasia, the increased risk of benign liver tumors attributable to use of these agents is small because of the rarity of the tumors. In 1978, the WHO Scientific Group on Steroid Contraception and the Risk of Neoplasia estimated the attributable risk of hepatocellular adenoma to be no more than 3 per 100,000 users under 30 years of age; it was not possible to estimate the attributable risk for older women (1). MALIGNANT
LIVER
TUMORS
Hepatocellular carcinomas account for 75% or more of primary liver cancers; most of the remainder are cholangiocarcinomas (carcinomas of the intrahepatic bile duct) (9). There have been case reports of areas of hepatocellular malignancy occurring with hepatic cell adenoma or focal nodular hyperplasia in women who used oral contraceptives (5,6). This has been taken to be evidence of transition from benign to malignant tumor. There have also been numerous case reports of liver cancers, primarily ordinary hepatocellular carcinomas but other histologic types as well, occurring in women who used oral contraceptives. These reports were recently reviewed by Prentice and Thomas (6). In most cases, there was no evidence of alcoholic cirrhosis or of hepatitis B virus, which are common causes of liver cancer. Two large case series have been published, neither of which suggested an association between oral contraceptive use and liver cancer. The first series, which also included benign tumors and has been described above, consisted of liver tumors which were identified in 1970-1975 in 749 hospitals in the U.S. (3,4). Among a total of 317 malignant liver tumors in persons aged 15-45 years, 166 occurred in women and 151 in men; the ratio of female to male cases was close to l:l, in contrast to benign tumors which occurred overwhelmingly in women. The proportion of women with malignant tumors who had used oral contraceptives did not seem unusually high, but there was no comparison group. The number of cases of malignant liver cancer rose steadily with increasing age, in contrast to benign tumors which peaked at ages 26-30, ages at which oral contraceptive use is most common. Thus, while these reports provided evidence to suggest an association of benign liver tumors with oral contraceptive use, there was no such With hindsight, it evidence for an association with malignant disease. may be that there was insufficient long-term oral contraceptive use at that time for an effect to have occurred (see discussion of casecontrol studies below). The second large case series comprised 128 cases of hepatocellular carcinoma reported to the U.S. Armed Forces Institute of Pathology from 1953-1980 (10). The age-distribution of the cases was bimodal, with a peak at age 23 and another in the mid 60s. Alcoholism and hepatitis B infection were less common in cases under age 40 than in older cases. Similarly, cirrhosis was less common in younger than older cases: three of 48 cases under age 40 (6%) had evidence of cirrhosis, compared
646
JUNE1991VOL.43NO.6
CONTRACEPTION with 31 of 80 cases (39%) in older women. Fibrolamella carcinoma is a tumor thought to occur mainly in young women. Similar proportions of young women with fibrolamella carcinoma and with other histologic types had used oral contraceptives, which the authors interpreted as a lack of association of oral contraceptive use with any particular tumor type. Seven case-control studies of oral contraceptives and liver cancer have been conducted (Table I). Five were in populations at relatively low risk of liver cancer (11-15): two in the United States (11,14) two in Great Britain (12,13), one in Italy (15). Two were conducted in populations at higher risk, one in several developing countries (the WHO collaborative study (16)), and one in South Africa (17). The first five studies were quite small. Table Case-control
studies
af oral
I
contraceptives
NUllbl?r First
author,
country
year
Type
Hepatocellular
US
Henderson, 1983(11)
of cancer
carcinoma Neuberger,
1986
(12)
Hepatocellular
UK
carcinoma Forman,
1986
(13)
Hepatocellular
UK
Hepatocellular
US
(14)
UHO,
1989
1989
(15)
RR calculated
1,333
2 8 yr
4.4b
L 8 yr
20.lb
t 8 yr
0.9
11 45
L 5 yr
20b not
5
t 5 yr
21
145
> 5 yr
8.3b
36
266
> 2 yr
0.24
30
234
z. 2 yr
1.28
56
302
> 2 yr
0.49
46
92
> 8 yr
1.5
cancer
carcinoma
Hepatocettular carcincma
Crude
26
1
diagnosed S. Africaf
2 5 yr
Undetermined
Clinically
(17)
22
I 5 yr
Cholangiocarcinoma
1990
13.5arb
11
10
countriese
Kew,
Relative risk
2
Hepatocellular
Eight
(16)
of of cases controlsexposure
Cholangiocarcinuna
Liver
Italy
Measure
NUlbT
of
9
carcinoma
La Vecchia,
cancer
147
Cholangiocarcinoma 1989
Liver
19
carcinoma
Palmer,
and
from data
given
determinedC not determi"edd
in paper.
p < .05. 1 of 2 cases None
used
Chile, Black
and
oral
China, ruse"
none
of 5 controls
contraceptives Colombia,
used
oral
contraceptives
for Z 5 yrs.
for z 5 yrs.
Israel,
Kenya,
Nigeria,
Philippines,
Thailand.
only.
JUNE 1991 VOL. 43 NO. 6
647
CONTRACEPTION
The first study, described in 1983 by Henderson et al. (ll), was a case-control study of hepatocellular carcinoma in Los Angeles. Of 12 cases in women 18-39 years reported to a population-based registry in 1975-1980, information was obtained on 11. In three instances the case herself was interviewed, and for the remainder information was obtained from the physician or relatives. For each case, two controls matched to the case on age, race, and neighborhood were interviewed. Ten of the 11 cases (91%) had used oral contraceptives, and the eleventh had received multiple "hormone" injections. Among the 22 controls, 13 (59%) had used oral contraceptives. The mean duration of use was 64 months among case users and 27 months among control users, and a test for trend for statistically significant (p
Lynn Rosenberg, Sc.D.
Slone Epidemiology Unit Boston University School of Medicine 1371 Beacon Street Brookline, MA 02146
ABSTRACT Benign liver tumors occurring in young women were rarely reported in the medical literature before the introduction of oral contraceptives in the early 1960s. Subsequently, there were numerous case reports from the U.S. and other countries of liver tumors in women who used combined oral contraceptives. These reports, coupled with data from two U.S. case-control studies, indicate that the risk of hepatocellular adenoma increases sharply with increasing duration of oral contraceptive use. Case reports suggest that there may be a similar effect on the risk of focal nodular hyperplasia, but this is not established because there have been no case-control studies of the lesion. The incidence of benign liver disease attributable to oral contraceptive use in the U.S. is small because of the very low incidence of the disease. There have also been numerous case reports of malignant liver tumors in young women who used oral contraceptives. Seven case-control studies have been conducted -- two in Great Britain, two in the U.S., one in Italy, one in several developing countries (conducted by the World Health Organization (WHO)), and one in South Africa. Data from the first five studies, all conducted in low risk populations, indicated an association of hepatocellular carcinoma (largely in the absence of liver cirrhosis) with oral contraceptive use. Because of small numbers estimates were unstable, but the risk did not appear to be increased appreciably for durations of use less than about five years. For longer durations, the risk appeared increased by five- t:o tenfold OK more. There was little evidence of hepatitis B infection in the cases, but systematic determinations were not carried out. An increased risk of cholangiocarcinoma was not established, but few of these lesions were studied. Because the incidence of primary liver cancer in Northern Europe and the U.S. is low, the incidence attributable to oral contraceptive use is also likely to be low. The WHO study was carried out in eight countries, most of which have a high incidence of liver cancer and a high prevalence of a predisposing factor, hepatitis B infection. Similarly, the South African study was carried out among black women, and virtually all of
JUNE 1991 VOL. 43 NO. 6
CONTRACEPTION
the cases had serological evidence of hepatitis B infection. Both studies indicated no association of short-term oral contraceptive use with risk of hepatocellular carcinoma, and the WHO study indicated a lack of association with cholangiocarcinoma. The prevalence of longterm use was too low for informative analysis. Future studies will be needed to assess whether long durations of oral contraceptive use increase the risk of liver cancer in countries in which both hepatitis B infection and liver cancer are common. INTRODUCTION In 1978 the World Health organization (WHO) issued a report on steroid contraception and the risk of neoplasia (1). It was concluded that the risk of hepatocellular adenoma was markedly increased among Because the women who used oral contraceptives for prolonged periods. tumor is very rare, however, the incidence in users was estimated to be The present paper reviews human studies on use of combined oral small. contraceptive preparations in relation to liver neoplasia, with an emphasis on studies published after the 1978 WHO report.
BENIGN LIVER TUMORS In 1973 Baum et al. (2) raised concern about the effect of steroid hormones on the risk of liver neoplasia when they published a description of seven cases of hepatocellular adenoma in U.S. women who This report was followed by numerous had used oral contraceptives. others, from the U.S. and other countries, of hepatocellular adenomas Before the and focal nodular hyperplasias in oral contraceptive users. advent of oral contraceptives in the early 196Os, there had been few reports of these lesions. et The largest case series, reported by Vana et al. (3) and Nime al. (4), resulted from a national survey of liver tumors in persons 1545 years of age conducted in 749 U.S. hospitals from 1970 to 1975. There was a striking difference in the distribution of tumors in men whereas there were similar numbers of malignant tumors (166 and women: in women, 151 in men), there were many more benign tumors in women than A high proportion of women with in men (212 and 15, respectively). hepatic cell adenoma or focal nodular neoplasia whose contraceptive The distribution by history was known had used oral contraceptives. age of cases of hepatic cell adenoma showed a peak at age 26-30, and the authors suggested that this distribution paralleled the ageFor focal specific prevalence of oral contraceptive use in U.S. women. there was also an increase in the number of cases nodular hyperplasia, up to age 26-30, and this was followed by a plateau. The case reports have been reviewed by Klatskin (5,) and by Prentice and 'Thomas (6). In the main, two types of benign liver tumor were reported -- hepatic cell adenoma and focal nodular neoplasia. (Some of the latter had been called hamartomas, but a panel of reclassified them as hepatocellular adenomas or, more pathologists often, focal nodular hyperplasias) (4). A high proportion of the reported cases were oral contraceptive users. Other findings were an absence of cirrhosis; an association between tumor size and oral
644
JUNE 1991 VOL. 43 NO. 6
CONTRACEPTION
contraceptive use; in some patients, regression of the tumors after cessation of use; and in some patients, recurrence of tumors with continuation of use. While both hepatic cell adenomas and focal nodular neoplasias also occurred in men (with the latter tumor being more common), they occurred much more rarely than in women. Finally, both hepatocellular adenomas and focal nodular hyperplasias are highly vascular and they showed more peliosis (blood filled spaces and cysts), thrombosis, and scarring in users than nonusers. It was suggested that oral contraceptive use might lead to hemorrhage and thereby to increased detection of these tumors; on the other hand, some tumors were diagnosed in the absence of hemorrhage. Two U.S. case-control studies of hepatic cell adenoma have been published. Edmondson et al. (7) conducted telephone interviews of 34 of 42 eligible women who had undergone surgery for hepatic cell adenomas during 1955 to 1976 in Los Angeles. They also interviewed age-matched friend controls for 34 of the cases. Use of oral contraceptives for a year or less was reported by 18% of cases and 44% of controls, while use for at least 85 months was reported by 38% of cases and 6% of controls. The risk ratio increased from 1.3 for 13-36 months of use, to 5.0 for 61-84 months, 7.5 for 85-108 months, and 25 for 109+ months. The cases had more commonly used mestranol-containing preparations then the controls. In 1979 Rooks et al. (8) reported on a larger study. Of 89 eligible cases of hepatocellular adenoma in women aged 16-50 reported from 1960 to 1976 to the Armed Forces Institute of Pathology, 79 were interviewed in person. Up to three age-matched neighbor controls were obtained for each of 76 cases. Oral contraceptive histories were taken with the aid of calendars for recording milestones such as marriages and births, and of photographs of oral contraceptive pills and packets. Only 9% of cases as compared with 55% of controls had used oral contraceptives for less than 13 months, and 25% and 3%, respectively, had used them for 85 or more months. The relative risk estimate increased markedly with increasing duration of use, and the estimate was reported to be 503 for 85+ months of use. Similar results were obtained for subjects diagnosed before 1973 when the report of Bawn et al. (2) appeared and for subjects diagnosed after 1973, suggesting that reporting bias did not explain the association. In contrast to the study of Edmondson (7), there was no excess of mestranol use in the cases. However, users of pills with high estrogen "potency" appeared to have a higher risk than those who used lower potency preparations, and the risk also appeared higher in women over 30. Because the earliest oral contraceptives marketed had higher doses of estrogen, users of higher potency pills might have tended to be older, and these women might also have had an opportunity to use oral contraceptives longer than younger women. Thus, the results according to age and to potency of the oral contraceptive may have been confounded by the duration of use. Based on the case reports and case-control studies, there is strong evidence that oral contraceptive use greatly increases the risk of hepatic cell adenoma. Despite methodologic limitations, relative risks of the magnitude reported in the case-control studies are
JUNE 1991 VOL. 43 NO. 6
645
unlikely to be explained by an unidentified bias. Although an association with focal nodular hyperplasia is also suggested by the data from case reports, it has not been established. Whether or not combined oral contraceptive use increases the risk of focal nodular hyperplasia, the increased risk of benign liver tumors attributable to use of these agents is small because of the rarity of the tumors. In 1978, the WHO Scientific Group on Steroid Contraception and the Risk of Neoplasia estimated the attributable risk of hepatocellular adenoma to be no more than 3 per 100,000 users under 30 years of age; it was not possible to estimate the attributable risk for older women (1). MALIGNANT
LIVER
TUMORS
Hepatocellular carcinomas account for 75% or more of primary liver cancers; most of the remainder are cholangiocarcinomas (carcinomas of the intrahepatic bile duct) (9). There have been case reports of areas of hepatocellular malignancy occurring with hepatic cell adenoma or focal nodular hyperplasia in women who used oral contraceptives (5,6). This has been taken to be evidence of transition from benign to malignant tumor. There have also been numerous case reports of liver cancers, primarily ordinary hepatocellular carcinomas but other histologic types as well, occurring in women who used oral contraceptives. These reports were recently reviewed by Prentice and Thomas (6). In most cases, there was no evidence of alcoholic cirrhosis or of hepatitis B virus, which are common causes of liver cancer. Two large case series have been published, neither of which suggested an association between oral contraceptive use and liver cancer. The first series, which also included benign tumors and has been described above, consisted of liver tumors which were identified in 1970-1975 in 749 hospitals in the U.S. (3,4). Among a total of 317 malignant liver tumors in persons aged 15-45 years, 166 occurred in women and 151 in men; the ratio of female to male cases was close to l:l, in contrast to benign tumors which occurred overwhelmingly in women. The proportion of women with malignant tumors who had used oral contraceptives did not seem unusually high, but there was no comparison group. The number of cases of malignant liver cancer rose steadily with increasing age, in contrast to benign tumors which peaked at ages 26-30, ages at which oral contraceptive use is most common. Thus, while these reports provided evidence to suggest an association of benign liver tumors with oral contraceptive use, there was no such With hindsight, it evidence for an association with malignant disease. may be that there was insufficient long-term oral contraceptive use at that time for an effect to have occurred (see discussion of casecontrol studies below). The second large case series comprised 128 cases of hepatocellular carcinoma reported to the U.S. Armed Forces Institute of Pathology from 1953-1980 (10). The age-distribution of the cases was bimodal, with a peak at age 23 and another in the mid 60s. Alcoholism and hepatitis B infection were less common in cases under age 40 than in older cases. Similarly, cirrhosis was less common in younger than older cases: three of 48 cases under age 40 (6%) had evidence of cirrhosis, compared
646
JUNE1991VOL.43NO.6
CONTRACEPTION with 31 of 80 cases (39%) in older women. Fibrolamella carcinoma is a tumor thought to occur mainly in young women. Similar proportions of young women with fibrolamella carcinoma and with other histologic types had used oral contraceptives, which the authors interpreted as a lack of association of oral contraceptive use with any particular tumor type. Seven case-control studies of oral contraceptives and liver cancer have been conducted (Table I). Five were in populations at relatively low risk of liver cancer (11-15): two in the United States (11,14) two in Great Britain (12,13), one in Italy (15). Two were conducted in populations at higher risk, one in several developing countries (the WHO collaborative study (16)), and one in South Africa (17). The first five studies were quite small. Table Case-control
studies
af oral
I
contraceptives
NUllbl?r First
author,
country
year
Type
Hepatocellular
US
Henderson, 1983(11)
of cancer
carcinoma Neuberger,
1986
(12)
Hepatocellular
UK
carcinoma Forman,
1986
(13)
Hepatocellular
UK
Hepatocellular
US
(14)
UHO,
1989
1989
(15)
RR calculated
1,333
2 8 yr
4.4b
L 8 yr
20.lb
t 8 yr
0.9
11 45
L 5 yr
20b not
5
t 5 yr
21
145
> 5 yr
8.3b
36
266
> 2 yr
0.24
30
234
z. 2 yr
1.28
56
302
> 2 yr
0.49
46
92
> 8 yr
1.5
cancer
carcinoma
Hepatocettular carcincma
Crude
26
1
diagnosed S. Africaf
2 5 yr
Undetermined
Clinically
(17)
22
I 5 yr
Cholangiocarcinoma
1990
13.5arb
11
10
countriese
Kew,
Relative risk
2
Hepatocellular
Eight
(16)
of of cases controlsexposure
Cholangiocarcinuna
Liver
Italy
Measure
NUlbT
of
9
carcinoma
La Vecchia,
cancer
147
Cholangiocarcinoma 1989
Liver
19
carcinoma
Palmer,
and
from data
given
determinedC not determi"edd
in paper.
p < .05. 1 of 2 cases None
used
Chile, Black
and
oral
China, ruse"
none
of 5 controls
contraceptives Colombia,
used
oral
contraceptives
for Z 5 yrs.
for z 5 yrs.
Israel,
Kenya,
Nigeria,
Philippines,
Thailand.
only.
JUNE 1991 VOL. 43 NO. 6
647
CONTRACEPTION
The first study, described in 1983 by Henderson et al. (ll), was a case-control study of hepatocellular carcinoma in Los Angeles. Of 12 cases in women 18-39 years reported to a population-based registry in 1975-1980, information was obtained on 11. In three instances the case herself was interviewed, and for the remainder information was obtained from the physician or relatives. For each case, two controls matched to the case on age, race, and neighborhood were interviewed. Ten of the 11 cases (91%) had used oral contraceptives, and the eleventh had received multiple "hormone" injections. Among the 22 controls, 13 (59%) had used oral contraceptives. The mean duration of use was 64 months among case users and 27 months among control users, and a test for trend for statistically significant (p
