Oral-Contraceptive-Associated Liver Tumours: Occurrence of Malignancy and Difficulties in Diagnosis

Neuberger, James; Nunnerley, H.B.; Davis, Michael R.; Portmann, Bernard; Laws, J. W.; Williams, Roger

doi:10.1016/s0140-6736(80)90776-x

Cited by 106 publications

(32 citation statements)

References 7 publications

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“…Nevertheless, some authors reported an increase in incidence of hepatocellular carcinomas in women using hormonal contraceptives for prolonged periods. [1][2][3] This was supported by long-term animal studies, which demonstrate an enhancement of hepatocarcinogenesis by various synthetic estrogens, eg, ethinyl estradiol and diethylstilbestrol. 4 -7 The mechanisms of estrogen carcinogenesis are quite complex: They include nongenotoxic, ie, proliferative effects via direct mitogenic action, as well as by enhancement of the effects of epidermal growth factor (EGF), hepatocyte growth factor (HGF), and transforming growth factor ␣ (TGF␣) on hepatocytes.…”

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confidence: 92%

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Klotz

Hacker

Klingmüller

et al. 2000

The American Journal of Pathology

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The mechanisms of hepatocarcinogenesis by certain synthetic estrogens seem to involve both nongenotoxic and indirect genotoxic effects. However, the natural estrogen estradiol did not exert any carcinogenic effects in established experimental protocols. To elucidate specific long-term effects of natural estrogens on hepatocytes, small pieces of ovarian tissue were transplanted via the portal vein into the livers of ovariectomized female rats. One week, 3 weeks, and 3 months after transplantation the transplants were found to proliferate and to secrete estradiol. Three weeks after transplantation the hepatocytes of the liver acini downstream of the stimulated transplants already showed a remarkable loss of glycogen, distinct cytoplasmic amphophilia, enlargement of their nuclei, a strong increase in the number and size of peroxisomes, an increase in proliferative activity and apoptotic elimination, and changes in the activity of certain key enzymes of energy metabolism. All hepatocellular alterations could be inhibited by the estrogen receptor antagonist toremifene and are, therefore, attributed to specific effects of estradiol produced by the transplants. The observed alterations resemble in some respects amphophilic preneoplastic liver foci, which particularly occur after long-term administration of nongenotoxic hepatocarcinogens, including the adrenal steroid hormone dehydroepiandrosterone. In a preliminary experiment three of six animals exhibited a hepatocellular carcinoma, and another animal developed a hepatocellular adenoma 18 months after intrahepatic ovarian tissue transplantation. A causal relationship between the use of oral contraceptive steroids and the development of hepatocellular adenomas in humans is now accepted, whereas a definite relationship between oral contraceptive use and malignant liver tumors has not yet been established. Nevertheless, some authors reported an increase in incidence of hepatocellular carcinomas in women using hormonal contraceptives for prolonged periods. [1][2][3] This was supported by long-term animal studies, which demonstrate an enhancement of hepatocarcinogenesis by various synthetic estrogens, eg, ethinyl estradiol and diethylstilbestrol. 4 -7 The mechanisms of estrogen carcinogenesis are quite complex: They include nongenotoxic, ie, proliferative effects via direct mitogenic action, as well as by enhancement of the effects of epidermal growth factor (EGF), hepatocyte growth factor (HGF), and transforming growth factor ␣ (TGF␣) on hepatocytes. 8 -10 Furthermore, genotoxic effects like the formation of DNA adducts and the generation of reactive intermediates (quinones) and free radicals, causing lipid peroxidation, have been identified. 11,12 Interestingly, the natural estrogen estradiol exerts stimulating effects on hepatocyte proliferation, whereas no carcinogenic effect of estradiol has been demonstrated so far. 13 Some of the carcinogenic effects of ethinyl estradiol can be inhibited by simultaneous application of estrogen receptor antagonists like tamoxifen, ...

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confidence: 92%

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Klotz

Hacker

Klingmüller

et al. 2000

The American Journal of Pathology

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“…However, more recently Tao (43) in Canada showed-based on a biopsy study in three patients with HCC and nine patients with adenoma, all taking oral contraceptives -that adenoma would regress before dysplastic foci developed in adenomas, and that it takes at least 8 yr for dysplastic foci to emerge. Neuberger et al (44) compared seven cases of contraceptive-associated HCC with seven cases of HCC in noncirrhotic livers in patients who had not used oral contraceptives. Distinct differences were present between the tumors in Pill-users and non-users; in the former a-fetoprotein (AFP) was not elevated, vascularity was greater and survival was longer.…”

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confidence: 99%

Hepatocellular Carcinoma: Recent Progress

1992

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HCC is not a major killer among malignant diseases in Western countries, and until recently few Western hepatologists were interested in this cancer. After the demonstration of an etiologic role for HBV infection in hepatocarcinogenesis, interest surged even in lowincidence countries, particularly among molecular biologists and oncologists. A large body of literature now exists dealing with molecular mechanism in HBVrelated human HCC and hepadnavirus-induced HCC in animals. The recent identification and cloning of hepatitis C virus (HCV) has focused interest on chronic C hepatitis which, under the name of non-A, non-B (NANB) hepatitis, had for some time been suspected as another etiological factor for HCC in certain areas of the world. It did not take long before well-documented evidence linked HCV to HCC. Imaging diagnosis of small-mass lesions in the liver has progressed remarkably in recent years, as emphasized in a previous review in this JOURNAL (1). In countries where detection and resection of small HCCs in cirrhotic livers are common practice, pathologists are discussing how to differentiate large, benign, hyperplastic nodules; adenomatous hyperplastic nodules with potential to transform; and early HCC lesions histopathologically. Radiologists are attempting to make similar diagnostic distinction by imaging alone with limited success. This review attempts to update the recent progress made in the basic study of HCC. EPIDEMIOLOGY AND ETIOLOGYAccording to Muiioz and Bosch (2), no clear indication of a change has appeared in the incidence rate of HCC in developed Western countries in the past 20 yr or so as far as cancer registry data are concerned. However, in Japan, incidence of HCC began to increase about 20 yr ago; the increase was accounted for by non-HBV-related cases, and an etiologic role of chronic NANB hepatitis was suspected in the early 1980s (3). All cancer registries in Japan have clearly shown significant increases in HCC because of non-HBV-related cases. HBsAgpositive patients accounted for more than 40% of all HCC cases in the early 1970s, when testing was by the immunoprecipitation techniques. This figure is currently less than 20% as tested by the much more sensitive methods (4). At the autopsy table, the numbers of patients with HCC and of those with cirrhosis alone were about the same in early 1960s, but HCC now far exceeds cirrhosis in number. The frequency of complicating HCC among all cirrhotic livers autopsied used to be 20% to 40% and is currently about 80% (5). A similar trend of increase has been observed among autopsies in northern Italy (6) and the United States (7). A number of studies in Japan have shown that the frequency with which HCC develops in cirrhotic patients during follow-up is more than 6%/yr (8) among all cirrhotic patients. In a recent study in northern Italy, HCC developed in 29 (7%) of 417 patients with cirrhosis (62% viral) during follow-up periods averaging 33 mo (9).Shortly after the identification of HCV by the group at Chiron Laboratories and the developmen...

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“…The studies comparing the features of he patocellular carcinoma in users and nonus ers have shown few differences: trends to ward a more protracted course and a lower alpha-fetoprotein among users might be con firmed in larger studies [38,39]. There are, however, major characteristics of hepatocel lular carcinoma occurring in young women, regardless of oral contraceptive use.…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

“…There are, however, major characteristics of hepatocel lular carcinoma occurring in young women, regardless of oral contraceptive use. that dif ferentiate them from those arising in women above 45 years or in men: (a) association with hepatitis B virus, cirrhosis or chronic active hepatitis is commonly lacking [33]; (b) the fibrolamellär variant of hepatocellu lar carcinoma accounts for 10-50% of the cases; this type of hepatocellular carcinoma is characterized by a slower growth and a belter prognosis than the classical trabecular type [33,38,39], It is not clear, at present, whether oral contraceptives increase the in cidence of a particular type of hepatocellular carcinoma.…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%