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LIVER-CELL CARCINOMA AFTER LONG-TERM ŒSTROGEN-LIKE DRUGS
270 incidence of C.H.D. whereas countries with a high standard of living have a high incidence of c.H.D.6 This may be because a high standard of living is equated with a low level of physical exercise. While individual methods of improving physical fitness - e.g., jogging-are associated with some problems and even dangers, 6, the side-effects of improved physical fitness are entirely beneficial. These benefits include control or improvement of some of the factors associated with a high risk of C.H.D., loss of body-fat, and improvement in emotional stability, and in efficiency and performance at work whether this work is physical or mental.7 These other benefits would almost be sufficient reason by themselves for advocating exercise, but it is interesting that, in West Germany, the unemotional financial men of life insurance, who look at statistics and not at people, are beginning to suggest the use of cardiac reconditioning as a preventive measure against C.H.D.,8,9 and they are unlikely to accept as fact " a big lie often and loudly repeated ". Fitness as a means of reducing C.H.D. may as yet be an unproven hypothesis, but " it is a question of probabilities and with every fresh study that is completed the odds on exercise having protective value against C.H.D. are
shortening." 10 Department of Anaesthetics, Royal Infirmary, Edinburgh. 1. 2. 3.
4.
5. 6. 7. 8. 9. 10.
E. LL. LLOYD.
LIVER-CELL CARCINOMA AFTER LONG-TERM ŒSTROGEN-LIKE DRUGS
SIR,-Your leader on liver tumours (Dec. 29, p. 1481) prompts us
following
review of the interaction between female sex hormones and the liver reveals no mention of the possibility of hepatocellular carcinoma developing after administration of these drugs. Nevertheless, histological changes in the liver are known to follow administration of non-steroidal drugs with oestrogenic activity or of oral contraceptives.’-9 Therefore it is very tempting to suggest a possible association between cestrogens or drugs with oestrogen activity and the development of hepatocellular carcinoma, rather as long-term administration of androgenic/anabolic steroids was followed by hepatocellular carcinoma.The widespread use of oral contraceptives calls for careful study of this possible association. N. C. THALASSINOS C. LYMBERATOS Medical Professorial Unit,
Evangelismos Hospital,
and steroid report the
to
case.
For 3 years before her only pregnancy a woman aged 30 had been treated for infertility with varying doses of drugs with oestrogen activity, which were continued during the first 30 weeks of her pregnancy. For 3 months before conception she was on clomiphene. 10 days after a normal delivery she had high fever with chills and right subcostal pain. Examination revealed a liver enlarged to about 5 cm., hard and painful to palpation; the spleen was palpable to about 2 cm. A liver scan was compatible with a large space-occupying lesion in the middle of the organ. At laparotomy liver carcinoma was diagnosed and biopsy specimens taken from three sites were reported as follows:
" Increased fibrosis surrounding portal spaces with hyperplastic bile canaliculi. In this connective tissue, atypical carcinomatous cells (isolated or in clumps) containing little protoplasm and sizeable nuclei with increased chromatin and large nucleoli were present. Some of these atypical cells contained abundant waterclear protoplasm giving a positive RAS reaction and a nucleus pushed at the edge of the cell. Among these carcinomatous cells, a few hepatic trabecu1ae, with hepatic cells showing signs of regeneration, were observed." The patient was started on 5-fluorouracil and and was discharged from the hospital.
prednisone,
2.
3. 4. 5. 6. 7. 8. 9.
J. HADJIOANNOU C. GARDIKAS.
Athens, Greece. 1.
Sanne, H. Acta med. scand. 1973, suppl. 551. Fox, S. M., Naughton, J. P. Prev. Med. 1972, 1, 92. Morris, J. N., Heady, J., Raffle, P., Roberts, C., Park, F. J. Lancet, 1953, ii, 1053, 1111. Morris, J. N., Chave, S. P. W., Adam, C., Sirey, C., Epstein, L., Sheehan, D. J. ibid. 1973, i, 333. Brown, J., Bourke, G. J., Gearty, G. F. Wld Rev. Nutr. Diet. 1970, 12, 1. Corrigan, A. B., Fitch, K. D. Med. J. Aust. 1972, ii, 363. Cooper, K. H. New Aerobics. New York, 1970. Raab, W. R., Gilman, L. B. Am. J. Cardiol. 1964, 13, 670. Dick, F. W. Personal communication. Bannister, R. Br. med. J. 1972, iv, 711.
hormones
Hepatocellular carcinoma is known to be associated with long-term administration of androgenic/anabolic steroids 1; oestrogens and oestrogenic agents have been reported as having a carcinogenic potential in organs such as vagina2 and breast,3and there have been reports of benign liver-cell neoplasms in women on oral contraceptives. 4,5Extensive
Johnson, F. L., Feagler, J. R., Lerner, K. G., Majerus, P. W., Siegel, M., Hartmann, J. R., Thomas, E. D. Lancet, 1972, ii, 1273. Black, M. N., Leis, H. P., Jr. N.Y. St. J. Med. 1972, 72, 1601. Herbst, A. L., Kurman, R. J., Scully, R. E. Obstet. Gynec. 1972, 40, 287. Contostavlos, D. L. Lancet, 1973, ii, 1200. Baum, J. K., Holtz, F., Bookstein, J. J., Klein, E. W. ibid. p. 926. Adlercreutz, H., Tenhunen, R. Am. J. Med. 1970, 49, 630. Adlercreutz, H., Svanborg, A., Anberg, A. ibid. 1967, 42, 335. Larsson-Cohen, U., Stenram, U. Acta med. scand. 1967, 181, 257. Perez, V., Gorosdisch, S., De Martire, J., Nicholson, R., Di Paola, G. Science, 1969, 165, 805.
HEPATOMAS AND ORAL CONTRACEPTIVES
SIR,-An association of hepatic adenomas, with or without peliosis hepatis, and oral contraceptives has been proposed by Dr Baum and her colleagues1 as well as Dr Contostavlos.2 Another patient with findings nearly identical to those described has come to our attention. A 33-year-old White woman who had been taking ’Ortho Novum’ (norethindrone with mestranol) daily for several years presented with severe right-upper-quadrant abdominal pain of sudden onset. Acute cholecystitis was diagnosed and abdominal exploration was performed late the same day. Operation, however, revealed a hxmorrhagic mass in the right lobe of the liver that measured 16 x 17 X 5 cm. A right hepatectomy that included the haemorrhagic and a cholecystectomy were performed. Grossly the lesion appeared well circumscribed from adjacent normal liver parenchyma and seemed largely composed of dilated blood sinuses and interposed islands
mass
of
tan
tissue. Focal
areas
of necrosis
were
identified.
Microscopically the mass was composed of sheets of relatively uniform slightly hyperplastic hepatocytes; no portal areas were seen. The necrotic areas were partly organised and often adjacent to the large blood sinuses. There was some compression of the surrounding normal liver. The final diagnosis was hepatic-cell adenoma with necrosis into which haemorrhage had occurred (peliosis hepatis). Postoperatively the patient developed recurrent hepaticbed bleeding, a right subphrenic abscess, recurrent right pleural effusions, and bronchopneumonia. In spite of intensive therapy she died. Permission for necropsy was not granted. This case adds further support to the suspicion that oral contraceptives may be associated with the development of hepatic adenomas. Later these neoplasms may become focally necrotic and large vascular sinuses are presumably
shortening." 10 Department of Anaesthetics, Royal Infirmary, Edinburgh. 1. 2. 3.
4.
5. 6. 7. 8. 9. 10.
E. LL. LLOYD.
LIVER-CELL CARCINOMA AFTER LONG-TERM ŒSTROGEN-LIKE DRUGS
SIR,-Your leader on liver tumours (Dec. 29, p. 1481) prompts us
following
review of the interaction between female sex hormones and the liver reveals no mention of the possibility of hepatocellular carcinoma developing after administration of these drugs. Nevertheless, histological changes in the liver are known to follow administration of non-steroidal drugs with oestrogenic activity or of oral contraceptives.’-9 Therefore it is very tempting to suggest a possible association between cestrogens or drugs with oestrogen activity and the development of hepatocellular carcinoma, rather as long-term administration of androgenic/anabolic steroids was followed by hepatocellular carcinoma.The widespread use of oral contraceptives calls for careful study of this possible association. N. C. THALASSINOS C. LYMBERATOS Medical Professorial Unit,
Evangelismos Hospital,
and steroid report the
to
case.
For 3 years before her only pregnancy a woman aged 30 had been treated for infertility with varying doses of drugs with oestrogen activity, which were continued during the first 30 weeks of her pregnancy. For 3 months before conception she was on clomiphene. 10 days after a normal delivery she had high fever with chills and right subcostal pain. Examination revealed a liver enlarged to about 5 cm., hard and painful to palpation; the spleen was palpable to about 2 cm. A liver scan was compatible with a large space-occupying lesion in the middle of the organ. At laparotomy liver carcinoma was diagnosed and biopsy specimens taken from three sites were reported as follows:
" Increased fibrosis surrounding portal spaces with hyperplastic bile canaliculi. In this connective tissue, atypical carcinomatous cells (isolated or in clumps) containing little protoplasm and sizeable nuclei with increased chromatin and large nucleoli were present. Some of these atypical cells contained abundant waterclear protoplasm giving a positive RAS reaction and a nucleus pushed at the edge of the cell. Among these carcinomatous cells, a few hepatic trabecu1ae, with hepatic cells showing signs of regeneration, were observed." The patient was started on 5-fluorouracil and and was discharged from the hospital.
prednisone,
2.
3. 4. 5. 6. 7. 8. 9.
J. HADJIOANNOU C. GARDIKAS.
Athens, Greece. 1.
Sanne, H. Acta med. scand. 1973, suppl. 551. Fox, S. M., Naughton, J. P. Prev. Med. 1972, 1, 92. Morris, J. N., Heady, J., Raffle, P., Roberts, C., Park, F. J. Lancet, 1953, ii, 1053, 1111. Morris, J. N., Chave, S. P. W., Adam, C., Sirey, C., Epstein, L., Sheehan, D. J. ibid. 1973, i, 333. Brown, J., Bourke, G. J., Gearty, G. F. Wld Rev. Nutr. Diet. 1970, 12, 1. Corrigan, A. B., Fitch, K. D. Med. J. Aust. 1972, ii, 363. Cooper, K. H. New Aerobics. New York, 1970. Raab, W. R., Gilman, L. B. Am. J. Cardiol. 1964, 13, 670. Dick, F. W. Personal communication. Bannister, R. Br. med. J. 1972, iv, 711.
hormones
Hepatocellular carcinoma is known to be associated with long-term administration of androgenic/anabolic steroids 1; oestrogens and oestrogenic agents have been reported as having a carcinogenic potential in organs such as vagina2 and breast,3and there have been reports of benign liver-cell neoplasms in women on oral contraceptives. 4,5Extensive
Johnson, F. L., Feagler, J. R., Lerner, K. G., Majerus, P. W., Siegel, M., Hartmann, J. R., Thomas, E. D. Lancet, 1972, ii, 1273. Black, M. N., Leis, H. P., Jr. N.Y. St. J. Med. 1972, 72, 1601. Herbst, A. L., Kurman, R. J., Scully, R. E. Obstet. Gynec. 1972, 40, 287. Contostavlos, D. L. Lancet, 1973, ii, 1200. Baum, J. K., Holtz, F., Bookstein, J. J., Klein, E. W. ibid. p. 926. Adlercreutz, H., Tenhunen, R. Am. J. Med. 1970, 49, 630. Adlercreutz, H., Svanborg, A., Anberg, A. ibid. 1967, 42, 335. Larsson-Cohen, U., Stenram, U. Acta med. scand. 1967, 181, 257. Perez, V., Gorosdisch, S., De Martire, J., Nicholson, R., Di Paola, G. Science, 1969, 165, 805.
HEPATOMAS AND ORAL CONTRACEPTIVES
SIR,-An association of hepatic adenomas, with or without peliosis hepatis, and oral contraceptives has been proposed by Dr Baum and her colleagues1 as well as Dr Contostavlos.2 Another patient with findings nearly identical to those described has come to our attention. A 33-year-old White woman who had been taking ’Ortho Novum’ (norethindrone with mestranol) daily for several years presented with severe right-upper-quadrant abdominal pain of sudden onset. Acute cholecystitis was diagnosed and abdominal exploration was performed late the same day. Operation, however, revealed a hxmorrhagic mass in the right lobe of the liver that measured 16 x 17 X 5 cm. A right hepatectomy that included the haemorrhagic and a cholecystectomy were performed. Grossly the lesion appeared well circumscribed from adjacent normal liver parenchyma and seemed largely composed of dilated blood sinuses and interposed islands
mass
of
tan
tissue. Focal
areas
of necrosis
were
identified.
Microscopically the mass was composed of sheets of relatively uniform slightly hyperplastic hepatocytes; no portal areas were seen. The necrotic areas were partly organised and often adjacent to the large blood sinuses. There was some compression of the surrounding normal liver. The final diagnosis was hepatic-cell adenoma with necrosis into which haemorrhage had occurred (peliosis hepatis). Postoperatively the patient developed recurrent hepaticbed bleeding, a right subphrenic abscess, recurrent right pleural effusions, and bronchopneumonia. In spite of intensive therapy she died. Permission for necropsy was not granted. This case adds further support to the suspicion that oral contraceptives may be associated with the development of hepatic adenomas. Later these neoplasms may become focally necrotic and large vascular sinuses are presumably