Studies on the role of oral contraceptive use in the etiology of benign and malignant liver tumors.
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Humans are remarkably resistant to many carcinogens that readily produce liver tumours in rodents, particularly the rat. The neoplastic process has been extensively studied in animal experiments, but little is known so far of how it evolves in humans. Few drugs have been shown to cause liver tumours in humans, and the risk appears to be low. The best-known examples are C17-alkylated or ethinylated gonadal sex steroids. Oral contraceptives have now been in use by millions for thirty years, but only a few hundred cases at most of liver cell adenoma have been observed. The role of these substances in liver cell carcinoma remains controversial, and the evidence is weaker still in relation to focal nodular hyperplasia and other tumour-like conditions. Anabolic-androgenic steroids stand out as the major cause of peliosis, but liver cell tumours induced by them seem to be adenomas and not carcinomas as originally suggested. The effect that both oral contraceptives and anabolic-androgenic steroids have on liver vasculature is of great clinical importance as the most important complication of liver tumours is rupture, leading to life-threatening haemorrhage. For this reason, liver tumours arising in users of these drugs should be removed whenever feasible. Thorium dioxide will remain a risk factor for the development of angiosarcoma, liver cell carcinoma and bile duct carcinoma for some time yet, and the number of patients who have been exposed is high--tens of thousands at least. The evidence of a carcinogenic role for many other drugs is anecdotal or weak. Neoplasia in the liver seems to be the least important side-effect of drugs in clinical use.
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Our study of more than 250 women with hepatic tumors, accessioned in our tumor registry at the University of Louisville, disclosed three types of tumor: FNH , HCA, and HCC. The ingestion of sundry kinds of sex steroids by the majority of these women, chiefly for purposes of preventing conception, warrants the suspicion that such hormones induced these different types of hepatic tumors. Publications by others reporting similar hepatic tumors in men using male sex steroids lends support to this hypothesis. Rupture of the hepatic tumor and consequent hemorrhage, producing hemoperitoneum, is a major risk factor. Other presenting symptoms are pain and palpable mass. Symptomatic women using OCs should be subjected to a CT or technetium hepatic scan as an initial screening assessment. Because of the imminent possibility of rupture, large turgid vascular tumors should be resected without biopsy. Biopsy-proved HCC should also be removed surgically. All other tumors, including small multiple tumors, will usually regress when exogenous sex steroids are withdrawn and pregnancy avoided. Other significant hepatic changes observed in this study are peliosis hepatis, periportal sinusoidal dilation, and vascular lesions. The branches of the hepatic artery and the tributaries of the portal vein show combinations of intimal and smooth muscle proliferation, vascular thickening, occlusive intimal thickening, and, at times, obstructing thrombosis. Similar smooth muscle proliferation in the afferent vessels of the livers of animals treated with sex steroids suggests that there is a cause and effect relationship in women using OCs.
The risk of liver cancer in relation to use of oral contraceptives was evaluated in a hospital-based case-control study conducted in five US cities from 1977 to 1985. Twelve new cases of liver cancer were identified in women aged 19-54 years; five controls selected from among patients hospitalized for acute conditions unrelated to oral contraceptive use were matched to each case on age (five-year categories), date of interview (three-year categories), and geographic location of the hospital. Among nine cases classified as having hepatocellular carcinoma, eight (89%) had used oral contraceptives; only 16 (36%) of 45 matched controls had used oral contraceptives. Among three other cases (two with cholangiocarcinomas and one with liver cancer of undetermined type), all had used oral contraceptives, compared with four of 15 matched controls. The results confirm the strong positive association between oral contraceptive use and hepatocellular carcinoma observed in earlier studies. Such an association is consistent with evidence that oral contraceptive use is associated with benign hepatic tumors in young women. However, the number of cases of liver cancer in the United States that are attributable to oral contraceptive use is probably small, because liver cancer is extremely rare in the United States.
Follow-up by computed tomography (CT) was quite useful in a woman with an oral-contraceptive-associated benign hepatic cell adenoma. Follow-up by CT without therapy (except to stop the oral contraceptives) was sufficient to show spontaneous regression of the lesion.
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We report a case of intrahepatic biliary cystadenoma in a young woman who had no prior history of liver disease and who had taken oral contraceptives for one year. A 27-year-old woman was admitted to our hospital with a firm epigastric mass. At laparotomy, a large cystic mass was resected from the left hepatic lobe, and diagnosed as biliary cystadenoma. In the tumor tissue, the estrogen receptor content was 14.0 fmol/mg cytosol protein, which was much higher than the 3.0 fmol/mg cytosol protein in the surrounding liver tissue. This is the first case of biliary cystadenoma in which the estrogen receptor content was increased.
The clinicopathological features of 50 patients with hepatocellular carcinoma arising in a non-cirrhotic liver are described and compared with those of 100 patients in whom the tumour arose as a complication of cirrhosis. The non-cirrhotic patients were significantly younger, more often female and had a less strong association with serum markers of hepatitis B virus infection. Liver function tests and serum AFP were less often abnormal and survival was significantly better than in the cirrhotic group. The different aetiological factors, clinical features and prognosis of hepatocellular carcinoma arising in the non-cirrhotic liver compared to the more common form of hepatocellular carcinoma which complicates cirrhosis justifies detailed investigation by liver biopsy and other techniques.
The case is presented of a female patient who developed two pill-associated tumors in the liver, a liver cell adenoma in the right lobe and focal nodular hyperplasia in the left lobe. The pathological, clinical and prognostic features are discussed.
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