Medical and Pediatric Oncology 4:99-103 ( 1 978)
Hepatocellular Carcinoma in a Young Woman With Prolonged Exposure to Oral Contraceptives Perry N. Gattanell,
MD,
Marjorie Perloff,
MD,
and James F. Holland,
MD
Department of Neoplastic Diseases, Mount Sinai School of Medicine, New York
A case of hepatocellular carcinoma in a young female is presented in which the apparent etiology was the use of oral contraceptives for 5% years. Sequential therapeutic trials with intraarterial 5-fluorouracil, intraarterial adriamycin, and intravenous 1,3 bis[ 2-chloroethyl] -1-nitrosourea (BCNU) were unsuccessful. The adverse effects of oral contraceptives on the structure and function of hepatic tissue are reviewed. Key words: hepatoma, birth control pills, intraarterial chemotherapy
INTRODUCTION
Only within the last few years have the adverse effects of oral contraceptives on liver tissue become apparent. These appear t o be a spectrum of abnormalities ranging from benign conditions, including cholestatic jaundice, peliosis hepatis, focal nodular hyperplasia, and adenomas, to malignant hepatocellular carcinomas. The widespread use of such agents continues. It remains to be determined whether there will be a higher incidence of malignant hepatic tumors with increasingly long follow-up and awareness of this potential (although as yet unproven) hazard. CASE REPORT
A 28-year-old white secretary was well until she developed epigastric pain in May 1975. Initial diagnostic evaluation was performed at another medical center, where a liver scan showed several focal filling defects. Hepatic arteriogram revealed tumor involvement of the entire right lobe and a poorly visualized left lobe. An open liver biopsy confirmed the diagnosis of hepatocellular carcinoma. There was a striking resemblance of the tumor cells to normal hepatocytes. The tumor was multinodular and composed of cords separated by sinusoid-like vascular spaces. Occasionally, dilated blood-filled vascular lakes were seen. The tumor cells were the same size as the normal hepatocytes, tumor cytoplasm
Address reprint requests to Dr. Marjorie Perloff, Department of Neoplastic Diseases, Mount Sinai School of Medicine, 100th Street and Fifth Avenue, New York NY 10029.
0098-1532/78/0402-0099$01.40 0 1978 Alan R. Liss, Inc
100
Gattanell, Perloff, a n d Holland
being more compact and without lipofuscin pigment. The tumor nuclei were larger and more hyperchromatic than normal. Two mitotic figures were seen per high-power field. (Figs. 1-2). Medical history was nonrevealing except for the fact that the patient had been taking Norinyl 1 t 50 on a regular basis from age 22% to 25, stopped for several months, then restarted and continued for the three years preceding the development of the present illness. Her total calculated dose from April 1969 to May 1975 was 1,365 mg of norethindrone, the 17-alpha-ethinyl-substitutedderivative of 19-nortestosterone, and 68 mg of mestranol, the 3-methyl ether of ethinylestradiol. There was no history of hepatitis or alcoholism. On physical examination she was cachectic but not jaundiced. There were no spider angiomata or dilated venous plexi. Pertinent findings were limited to the abdomen. There was visible abdominal fullness and a firm, tender nonnodular liver with a 16 cm span in the right axillary line. The left lobe was palpable 9 cm below the left costal margin. Neither ascites nor peripheral edema was present. There was no asterixis. Pertinent laboratory data included a hemoglobin of 10.8 gm%, WBC of 6,80O/d with a normal differential, and a platelet count of 548,000/~1.The bilirubin was 0.4 mg/dl, SCOT 71 milliunits/dl (normal 15-50 milliunits/dl), SGPT 41 milliunits/dl (normal 6-53 milliunits/dl), alkaline phosphatase 406 milliunits/dl (normal 30-90 milliunits/dl), albumin 4.3 gm/dl, and total protein 7.3 gm/dl. The prothrombin time was 12.8 seconds with a control of 12.4 seconds. Alpha-fetoprotein, antimitochondrial antibody, smooth muscle antibody, antinuclear antibody, and carcinoembryonic antigen were all negative. A catheter was placed percutaneously into the common hepatic artery via the right femoral artery. The patient was treated with intrarterial 5-fluorouracil (Hoffman LaRoche),
Fig. 1. Low-power view of the open biopsy specimen in which dilated vascular channels are present (Hand E X 10).
Hepatocellular Carcinoma and Oral Contraceptives
101
Fig. 2. Large hyperchromatic nuclei and mitotic cells are readily apparent. (Hand E X 40).
25 mg/kg/24 h , by continuous infusion in a regimen planned t o be similar t o that reported by Ansfield et al. (1). By the 42nd hour the patient became confused and agitated, and dislodged the catheter. A diagnosis of prehepatic coma was made. On the fourth day of precoma she was given a single dose of adriamycin (Adria Laboratories), 30 mg/m2 as an intravenous bolus. Her confusion lasted a total of 5 days. On day 17, a percutaneous catheter was reinstated in the hepatic artery and adriamycin as an intraarterial infusion at a dose of 1 mg/m2/h X 100 h was initiated. She received two courses at four-week intervals without incident and with only minimal regression in the extent of parenchymal liver involvement on liver scan. A third course was terminated after 72 h because of hepatic precoma from which she again recovered. A final attempt at chemotherapy employing BCNU (1,3 bis[2-chloroethyl] -1nitrosourea) at a dose of 75 mg/m2 intravenously was undertaken. This was repeated 1 month later without objective response. The patient died in hepatic coma complicated by aspiration pneumonia 8 months after the diagnosis was made. Permission for autopsy was not obtained. Of note is that she never became jaundiced or developed ascites, nor did the bilirubin ever rise above 2 mg/dl.
DISCUSSION
Awareness of the adverse effects of oral contraceptives on the structure and function of hepatic tissue has been growing steadily since the early 1960s. Schaffner (2) reported the interference of oral contraceptives with bile secretion, thus delaying the excretion of bile or bromsulphalein, in up to 40% of patients taking these pills. Paulsen and Winkler
102
Cattanell, Perloff, and Holland
(3) believe that these agents may be responsible for dilation of periportal liver sinusoids similar to the vascular abnormalities of peliosis hepatis (4). Since the late 1960s an increased incidence of benign hepatic adenomas has been noted in young women, but investigations looking for a specific etiology were not undertaken (5-7). The first report of a possible association between oral contraceptives and liver tumors was made by h u m and associates (8) in 1973 with their description of seven cases of benign hepatic adenomas in young females taking oral contraceptives for various periods of time. Coinciding with or shortly following Baum’s observations there was a rush of similar case reports (9-14) and one editorial (1 5). The possible carcinogenic potential of oral contraceptives on liver tissue was not considered, and in a recent editorial (1 6) such a possibility was not even mentioned. However, there is a large body of data, in both rodents and man, on the development of hepatocellular carcinoma following exposure to androgenic anabolic steroids. Johnson et al. (17) reported four cases of hepatocellular cancer in patients with aplastic anemia treated with either oxymetholone or methyl-testosterone, both 17alpha-alkyl anabolic androgenic steroids. The duration of treatment was 40-89 months, leading the authors to speculate that the effects of the anabolic steroids may be both dose- and time-related. Of interest is the report by Ishak and Glunz (18) describing a case of probably oxymetholoneinduced hepatocellular cancer which regressed following cessation of the androgen. Laboratory data, obtained from mice strains with a high likelihood of developing spontaneous hepatocellular cancers, indicate that increases in the androgenic environment can increase the incidence of spontaneous hepatocellular cancer while castration of males can decrease the incidence threefold (1 9). In 1974, a case was reported of a young female who developed hepatocellular carcinoma after being treated for three years for infertility with preparations containing variable estrogen activity (20). Subsequently, Meyer et al. ( 2 1) described an 18-year-old who developed a hepatoblastoma after taking oral contraceptives for 15 months. A recent report describes a patient with hepatocellular carcinoma developing in both lobes after 11 years of birth control pills (22). In the most extensive series to date, Mays et al. (23) report nine benign and four malignant hepatic tumors in women taking birth control pills. With the inclusion of the present report there are now eight published cases of hepatocellular carcinoma in women of childbearing age treated with oral contraceptives, and a much larger number with benign hepatic adenomas. Birth control pills contain both estrogens and progestational agents. The estrogen components, mestranol or ethinyl estradiol, are 17-alpha-alkyl-substituted steroids, while the progestational compounds are derivatives of either progesterone or 19-nortestosterone - the latter also being a 17-alpha-alkyl-substitutedsteroid. Both the 19-nortestosterone derivatives and the estrogen compounds are metabolized in the liver by either hydroxylation, glucuronidation, or by formation of sulfoconjugates. The development of benign hepatic adenomas in women taking birth control pills, usually for extensive periods of time, is well established. Edmondson (24,25) believes that the estrogen component is responsible and attributes a minor role to the progestational agent (26). His data show that in 1,451 total months of birth control pill use by his patients who developed hepatic adenomas, mestranol was the estrogen component in 92.6%. His conclusions of mestranol’s importance have recently been questioned, since there was not an adequate sampling of contraceptives containing ethinyl estradiol(27). In an attempt to relate the hepatic carcinogenicity of androgens to oral contraceptives, Gross et al. (28) suggested that the progestational agents derived from 19- nortestoterone have androgenic activity and thus are highly suspect. Modulation of the androgenic activity by the estrogenic component may be a complex interaction yielding a final end-
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103
point through a spectrum of minor and benign hepatic changes into a final phase of malignant transformation. ACKNOWLEDGMENTS
This work was supported in part by grant No. 5 PO 1 CA 15936-03, awarded by the National Cancer Institute, Department of Health, Education, and Welfare. REFERENCES 1. Ansfield FH, Ramirez G, Skibba JL, Boyan GT, Davis HL, Wistamen GW: Intrahepatic arterial infusion with 5-fluorouracil. Cancer 28:1147-1151, 1971. 2. Schaffner F: The effect of oral contraceptives on the liver. JAMA 198:1019-1023, 1966. 3. Paulsen H, Winkler K: Liver disease with periportal sinusoidal dilatation. Digestion 8:441, 1973. 4. Yanoff M, Rawson AJ: Peliosis hepatis. Arch Path 77:159-165, 1964. 5. Albritton DB, Tomplins RK, Langmie NP: Hepatic cell adenoma. A report of 4 cases. Ann Surg 180:14-19, 1974. 6. Matsey AJ, Gamble NG: Clinical experience with hepatic adenomas. Surg Gynecol Obst 134:41541 8,1972. 7. Scarer CG: Spontaneous rupture of hepatic adenoma. Brit J Surgery 56:633, 1969. 8. Baum JK, Bookstein JJ, Haltz F, Klein EW: Possible association between benign hepatomas and oral contraceptives. Lancet 2:926-29, 1973. 9. Tountas C, Paraskevas C, Deligeorgi H: Benign hepatoma and oral contraceptives. Lancet 1 : 13.511352,1974. 10. Contostavlos DL: Hepatomas and oral contraceptives. Lancet 2: 1200, 1973. 11. Kelso DR: Benign hepatomas and oral contraceptives. Lancet 2:315-316, 1973. 12. Knapp WA, Ruckner BH: Hepatoma and oral contraceptives. Lancet 1:270-271, 1974. 13. Harvath E, Kovacs K, Ross R: Benign hepatoma in a young woman on contraceptive steroids. Lancet 1:357-358,1974. 14. Berg JW, Ketelaar RS, Rose EF, Vernon RG: Hepatoma and oral Contraceptives. Lancet 2:348350,1974. 15. Editorial: Liver tumor and steroid hormones, Lancet 2:1481, 1973. 16. Editorial: Oral contraceptives and the liver. Brit J Med 4:430-431, 1974. 17. Johnson FL, Feagler JR, Lerner KG, Majerus PW, Hartmann JR, Siegal M, Thomas ED: Association of androgenic anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 2:1273-1276,1972. 18. Ishak KG, Glunz PR: Hepatoblastoma and hepatocarcinoma in infancy and childhood. Cancer 20:396-422,1967. 19. Johnson FL: Androgenic anabolic steroids and hepatocellular carcinoma. In: Peters RL (ed): “Hepatocellular Carcinoma.” New York: John Wiley, 1976, p 95-103. 20. Thalassinos NC, Lymberatos C, Hadjioannou J , Gardikas C: Liver cell carcinoma after long-term estrogen-like drugs. Lancet 1: 270, 1974. 21. Meyer P, LiVolsi VA, Cornog JL: Hepatoblastoma associated with an oral contraceptive. Lancet 2: 1387,1974. 22. Glassberg A, Rosenbaum E: Oral contraceptives and malignant hepatoma. Lancet 1:479, 1976. 23. Mays ET, Christopherson NM, Mahr NM, Williams HC: Hepatic changes in young women ingesting contraceptive steroids. JAMA 235:730-732, 1976. 24. Edmondson HA, Henderson R, Benton B: Liver cell adenoma associated with use of oral contraceptives. N Eng J Med 294:470, 1976. 25. Edmondson HA, Henderson BE, Benton B: Letters to the editor. N Eng J Med 294:1064, 1976. 26. Metreau SM, Ohumeaux D, Berthelot P: Oral contraceptives and the liver. Digestion 7:318-335, 1972. 27. Barnes AC, Sorenson TIA, Evrard JR: Letters to the editor. N Eng J Med 294:1061, 1976. 28. Gross G, Arnold OH, Brittinger G: Peliosis hepatis after long-term administration of oxymetholone (letter). Lancet 1:874, 1974.
Hepatocellular Carcinoma in a Young Woman With Prolonged Exposure to Oral Contraceptives Perry N. Gattanell,
MD,
Marjorie Perloff,
MD,
and James F. Holland,
MD
Department of Neoplastic Diseases, Mount Sinai School of Medicine, New York
A case of hepatocellular carcinoma in a young female is presented in which the apparent etiology was the use of oral contraceptives for 5% years. Sequential therapeutic trials with intraarterial 5-fluorouracil, intraarterial adriamycin, and intravenous 1,3 bis[ 2-chloroethyl] -1-nitrosourea (BCNU) were unsuccessful. The adverse effects of oral contraceptives on the structure and function of hepatic tissue are reviewed. Key words: hepatoma, birth control pills, intraarterial chemotherapy
INTRODUCTION
Only within the last few years have the adverse effects of oral contraceptives on liver tissue become apparent. These appear t o be a spectrum of abnormalities ranging from benign conditions, including cholestatic jaundice, peliosis hepatis, focal nodular hyperplasia, and adenomas, to malignant hepatocellular carcinomas. The widespread use of such agents continues. It remains to be determined whether there will be a higher incidence of malignant hepatic tumors with increasingly long follow-up and awareness of this potential (although as yet unproven) hazard. CASE REPORT
A 28-year-old white secretary was well until she developed epigastric pain in May 1975. Initial diagnostic evaluation was performed at another medical center, where a liver scan showed several focal filling defects. Hepatic arteriogram revealed tumor involvement of the entire right lobe and a poorly visualized left lobe. An open liver biopsy confirmed the diagnosis of hepatocellular carcinoma. There was a striking resemblance of the tumor cells to normal hepatocytes. The tumor was multinodular and composed of cords separated by sinusoid-like vascular spaces. Occasionally, dilated blood-filled vascular lakes were seen. The tumor cells were the same size as the normal hepatocytes, tumor cytoplasm
Address reprint requests to Dr. Marjorie Perloff, Department of Neoplastic Diseases, Mount Sinai School of Medicine, 100th Street and Fifth Avenue, New York NY 10029.
0098-1532/78/0402-0099$01.40 0 1978 Alan R. Liss, Inc
100
Gattanell, Perloff, a n d Holland
being more compact and without lipofuscin pigment. The tumor nuclei were larger and more hyperchromatic than normal. Two mitotic figures were seen per high-power field. (Figs. 1-2). Medical history was nonrevealing except for the fact that the patient had been taking Norinyl 1 t 50 on a regular basis from age 22% to 25, stopped for several months, then restarted and continued for the three years preceding the development of the present illness. Her total calculated dose from April 1969 to May 1975 was 1,365 mg of norethindrone, the 17-alpha-ethinyl-substitutedderivative of 19-nortestosterone, and 68 mg of mestranol, the 3-methyl ether of ethinylestradiol. There was no history of hepatitis or alcoholism. On physical examination she was cachectic but not jaundiced. There were no spider angiomata or dilated venous plexi. Pertinent findings were limited to the abdomen. There was visible abdominal fullness and a firm, tender nonnodular liver with a 16 cm span in the right axillary line. The left lobe was palpable 9 cm below the left costal margin. Neither ascites nor peripheral edema was present. There was no asterixis. Pertinent laboratory data included a hemoglobin of 10.8 gm%, WBC of 6,80O/d with a normal differential, and a platelet count of 548,000/~1.The bilirubin was 0.4 mg/dl, SCOT 71 milliunits/dl (normal 15-50 milliunits/dl), SGPT 41 milliunits/dl (normal 6-53 milliunits/dl), alkaline phosphatase 406 milliunits/dl (normal 30-90 milliunits/dl), albumin 4.3 gm/dl, and total protein 7.3 gm/dl. The prothrombin time was 12.8 seconds with a control of 12.4 seconds. Alpha-fetoprotein, antimitochondrial antibody, smooth muscle antibody, antinuclear antibody, and carcinoembryonic antigen were all negative. A catheter was placed percutaneously into the common hepatic artery via the right femoral artery. The patient was treated with intrarterial 5-fluorouracil (Hoffman LaRoche),
Fig. 1. Low-power view of the open biopsy specimen in which dilated vascular channels are present (Hand E X 10).
Hepatocellular Carcinoma and Oral Contraceptives
101
Fig. 2. Large hyperchromatic nuclei and mitotic cells are readily apparent. (Hand E X 40).
25 mg/kg/24 h , by continuous infusion in a regimen planned t o be similar t o that reported by Ansfield et al. (1). By the 42nd hour the patient became confused and agitated, and dislodged the catheter. A diagnosis of prehepatic coma was made. On the fourth day of precoma she was given a single dose of adriamycin (Adria Laboratories), 30 mg/m2 as an intravenous bolus. Her confusion lasted a total of 5 days. On day 17, a percutaneous catheter was reinstated in the hepatic artery and adriamycin as an intraarterial infusion at a dose of 1 mg/m2/h X 100 h was initiated. She received two courses at four-week intervals without incident and with only minimal regression in the extent of parenchymal liver involvement on liver scan. A third course was terminated after 72 h because of hepatic precoma from which she again recovered. A final attempt at chemotherapy employing BCNU (1,3 bis[2-chloroethyl] -1nitrosourea) at a dose of 75 mg/m2 intravenously was undertaken. This was repeated 1 month later without objective response. The patient died in hepatic coma complicated by aspiration pneumonia 8 months after the diagnosis was made. Permission for autopsy was not obtained. Of note is that she never became jaundiced or developed ascites, nor did the bilirubin ever rise above 2 mg/dl.
DISCUSSION
Awareness of the adverse effects of oral contraceptives on the structure and function of hepatic tissue has been growing steadily since the early 1960s. Schaffner (2) reported the interference of oral contraceptives with bile secretion, thus delaying the excretion of bile or bromsulphalein, in up to 40% of patients taking these pills. Paulsen and Winkler
102
Cattanell, Perloff, and Holland
(3) believe that these agents may be responsible for dilation of periportal liver sinusoids similar to the vascular abnormalities of peliosis hepatis (4). Since the late 1960s an increased incidence of benign hepatic adenomas has been noted in young women, but investigations looking for a specific etiology were not undertaken (5-7). The first report of a possible association between oral contraceptives and liver tumors was made by h u m and associates (8) in 1973 with their description of seven cases of benign hepatic adenomas in young females taking oral contraceptives for various periods of time. Coinciding with or shortly following Baum’s observations there was a rush of similar case reports (9-14) and one editorial (1 5). The possible carcinogenic potential of oral contraceptives on liver tissue was not considered, and in a recent editorial (1 6) such a possibility was not even mentioned. However, there is a large body of data, in both rodents and man, on the development of hepatocellular carcinoma following exposure to androgenic anabolic steroids. Johnson et al. (17) reported four cases of hepatocellular cancer in patients with aplastic anemia treated with either oxymetholone or methyl-testosterone, both 17alpha-alkyl anabolic androgenic steroids. The duration of treatment was 40-89 months, leading the authors to speculate that the effects of the anabolic steroids may be both dose- and time-related. Of interest is the report by Ishak and Glunz (18) describing a case of probably oxymetholoneinduced hepatocellular cancer which regressed following cessation of the androgen. Laboratory data, obtained from mice strains with a high likelihood of developing spontaneous hepatocellular cancers, indicate that increases in the androgenic environment can increase the incidence of spontaneous hepatocellular cancer while castration of males can decrease the incidence threefold (1 9). In 1974, a case was reported of a young female who developed hepatocellular carcinoma after being treated for three years for infertility with preparations containing variable estrogen activity (20). Subsequently, Meyer et al. ( 2 1) described an 18-year-old who developed a hepatoblastoma after taking oral contraceptives for 15 months. A recent report describes a patient with hepatocellular carcinoma developing in both lobes after 11 years of birth control pills (22). In the most extensive series to date, Mays et al. (23) report nine benign and four malignant hepatic tumors in women taking birth control pills. With the inclusion of the present report there are now eight published cases of hepatocellular carcinoma in women of childbearing age treated with oral contraceptives, and a much larger number with benign hepatic adenomas. Birth control pills contain both estrogens and progestational agents. The estrogen components, mestranol or ethinyl estradiol, are 17-alpha-alkyl-substituted steroids, while the progestational compounds are derivatives of either progesterone or 19-nortestosterone - the latter also being a 17-alpha-alkyl-substitutedsteroid. Both the 19-nortestosterone derivatives and the estrogen compounds are metabolized in the liver by either hydroxylation, glucuronidation, or by formation of sulfoconjugates. The development of benign hepatic adenomas in women taking birth control pills, usually for extensive periods of time, is well established. Edmondson (24,25) believes that the estrogen component is responsible and attributes a minor role to the progestational agent (26). His data show that in 1,451 total months of birth control pill use by his patients who developed hepatic adenomas, mestranol was the estrogen component in 92.6%. His conclusions of mestranol’s importance have recently been questioned, since there was not an adequate sampling of contraceptives containing ethinyl estradiol(27). In an attempt to relate the hepatic carcinogenicity of androgens to oral contraceptives, Gross et al. (28) suggested that the progestational agents derived from 19- nortestoterone have androgenic activity and thus are highly suspect. Modulation of the androgenic activity by the estrogenic component may be a complex interaction yielding a final end-
Hepatocellular Carcinoma a n d Oral Contraceptives
103
point through a spectrum of minor and benign hepatic changes into a final phase of malignant transformation. ACKNOWLEDGMENTS
This work was supported in part by grant No. 5 PO 1 CA 15936-03, awarded by the National Cancer Institute, Department of Health, Education, and Welfare. REFERENCES 1. Ansfield FH, Ramirez G, Skibba JL, Boyan GT, Davis HL, Wistamen GW: Intrahepatic arterial infusion with 5-fluorouracil. Cancer 28:1147-1151, 1971. 2. Schaffner F: The effect of oral contraceptives on the liver. JAMA 198:1019-1023, 1966. 3. Paulsen H, Winkler K: Liver disease with periportal sinusoidal dilatation. Digestion 8:441, 1973. 4. Yanoff M, Rawson AJ: Peliosis hepatis. Arch Path 77:159-165, 1964. 5. Albritton DB, Tomplins RK, Langmie NP: Hepatic cell adenoma. A report of 4 cases. Ann Surg 180:14-19, 1974. 6. Matsey AJ, Gamble NG: Clinical experience with hepatic adenomas. Surg Gynecol Obst 134:41541 8,1972. 7. Scarer CG: Spontaneous rupture of hepatic adenoma. Brit J Surgery 56:633, 1969. 8. Baum JK, Bookstein JJ, Haltz F, Klein EW: Possible association between benign hepatomas and oral contraceptives. Lancet 2:926-29, 1973. 9. Tountas C, Paraskevas C, Deligeorgi H: Benign hepatoma and oral contraceptives. Lancet 1 : 13.511352,1974. 10. Contostavlos DL: Hepatomas and oral contraceptives. Lancet 2: 1200, 1973. 11. Kelso DR: Benign hepatomas and oral contraceptives. Lancet 2:315-316, 1973. 12. Knapp WA, Ruckner BH: Hepatoma and oral contraceptives. Lancet 1:270-271, 1974. 13. Harvath E, Kovacs K, Ross R: Benign hepatoma in a young woman on contraceptive steroids. Lancet 1:357-358,1974. 14. Berg JW, Ketelaar RS, Rose EF, Vernon RG: Hepatoma and oral Contraceptives. Lancet 2:348350,1974. 15. Editorial: Liver tumor and steroid hormones, Lancet 2:1481, 1973. 16. Editorial: Oral contraceptives and the liver. Brit J Med 4:430-431, 1974. 17. Johnson FL, Feagler JR, Lerner KG, Majerus PW, Hartmann JR, Siegal M, Thomas ED: Association of androgenic anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 2:1273-1276,1972. 18. Ishak KG, Glunz PR: Hepatoblastoma and hepatocarcinoma in infancy and childhood. Cancer 20:396-422,1967. 19. Johnson FL: Androgenic anabolic steroids and hepatocellular carcinoma. In: Peters RL (ed): “Hepatocellular Carcinoma.” New York: John Wiley, 1976, p 95-103. 20. Thalassinos NC, Lymberatos C, Hadjioannou J , Gardikas C: Liver cell carcinoma after long-term estrogen-like drugs. Lancet 1: 270, 1974. 21. Meyer P, LiVolsi VA, Cornog JL: Hepatoblastoma associated with an oral contraceptive. Lancet 2: 1387,1974. 22. Glassberg A, Rosenbaum E: Oral contraceptives and malignant hepatoma. Lancet 1:479, 1976. 23. Mays ET, Christopherson NM, Mahr NM, Williams HC: Hepatic changes in young women ingesting contraceptive steroids. JAMA 235:730-732, 1976. 24. Edmondson HA, Henderson R, Benton B: Liver cell adenoma associated with use of oral contraceptives. N Eng J Med 294:470, 1976. 25. Edmondson HA, Henderson BE, Benton B: Letters to the editor. N Eng J Med 294:1064, 1976. 26. Metreau SM, Ohumeaux D, Berthelot P: Oral contraceptives and the liver. Digestion 7:318-335, 1972. 27. Barnes AC, Sorenson TIA, Evrard JR: Letters to the editor. N Eng J Med 294:1061, 1976. 28. Gross G, Arnold OH, Brittinger G: Peliosis hepatis after long-term administration of oxymetholone (letter). Lancet 1:874, 1974.
