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Histochemical and immunohistochemical detection of putative preneoplastic liver foci in women after long-term use of oral contraceptives

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Virchows Archiv B

Summary

Localized areas with altered enzyme patterns were observed in liver tissue surrounding focal nodular hyperplasia in women after long-term use of oral contraceptives. These localized lesions were of three different types. Type I lesions were characterized by glycogen storage, a reduction in ATPase and an increase inγ-glutamyltranspeptidase (γ-GT) and UDP-glucuronyltransferase (UDP-GT) detected immunohistochemically. Type II lesions, which were morphologically very similar to small hyperplastic nodules, showed only a decreased ATPase reaction. Type III lesions showed an increase inγ-GT (detected histochemically) and a slight reduction in ATPase. The results indicated that in human liver from patients given oral contraceptives long-term, localized lesions with altered enzyme patterns may occur which are very similar to those observed in animal models during experimental hepatic carcinogenesis.

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References

  • Adlercreutz H, Tenhunen R (1970) Some aspects of the interaction between natural and synthetic female sex hormones and the liver. Am J Med 49:630–648

    Article  PubMed  CAS  Google Scholar 

  • Altmann HW (1978) Pathology of human liver tumors. In: Remmer H, Bolt H, Bannasch P, Popper H (eds) Primary liver tumors. Proceedings of the 25th Falk Symposium, Titisee 1977. MTP Press, Lancaster, pp 53–71

    Google Scholar 

  • Altmann HW (1984) Neubildungen der Leber. Verh Dtsch Krebsges 5:423–435

    Google Scholar 

  • Balazs M, Gergely R, Winkler G (1977) Primäres Leberkarzinom nach mehrjähriger Anwendung eines oralen Kontrazeptivums und Schwangerschaft. Dtsch Med Wochenschr 102:1472–1474

    Article  PubMed  CAS  Google Scholar 

  • Bannasch P, Klinge O (1971) Hepatocelluläre Glykogenose und Hepatombildung beim Menschen. Virchows Arch [Pathol Anat] 352:157–164

    CAS  Google Scholar 

  • Bannasch P, Papenburg J, Ross W (1972) Cytomorphologische und morphometrische Studien der Hepatocarcinogenese. I. Reversible und irreversible Veränderungen am Cytoplasma der Leberparenchymzellen bei Nitrosomorpholin-vergifteten Ratten. Z Krebsforsch 77:108–133

    Article  CAS  Google Scholar 

  • Baum JK, Holtz F, Bookstein JJ et al. (1973) Possible association between benign hepatomas and oral contraceptives. Lancet II: 926–929

    Article  Google Scholar 

  • Bock KW, Lilienblum W (1985) Immunochemical studies on a 3-methylcholanthrene-inducible UDP-glucuronyltransferase of rat liver. In: Matern S, Bock KW, Gerok W (eds) Advances in glucuronide conjugation. MTP Press, Lancaster, pp 51–59

    Google Scholar 

  • Cohen GM, Gibby EM, Mehta R (1981) Routes of conjugation in normal and cancerous tissue from human lung. Nature 291:662–664

    Article  PubMed  CAS  Google Scholar 

  • Cohen GM, Grafstrom RC, Gibby EM, Smith L, Autrup H, Harris CC (1983) Metabolism of benzo(a)pyrene and 1-naphthol in cultured human tumorous and nontumorous colon. Cancer Res 43:1312–1315

    PubMed  CAS  Google Scholar 

  • Davis M, Portmann B, Searle M, Wright R, Williams R (1975) Histological evidence of carcinoma in a hepatic tumour associated with oral contraceptives. Br Med J 4:496–498

    PubMed  CAS  Google Scholar 

  • El Etreby MF (1980) Influence of contraceptive steroids on tumor development in experimental animals and man. A short review. In: Genazzani E, Dicarno F, Mainwaring WJP (eds) Proceedings of the Satellite Symposium on Pharmacological Modulation of Steroid Action, Turin 1978. Raven Press, New York, p 239

    Google Scholar 

  • Enomoto K, Farber E (1982) Kinetics of phenotypic maturation of remodeling of hyperplastic nodules during liver carcinogenesis. Cancer Res 42:2330–2335

    PubMed  CAS  Google Scholar 

  • Enomoto K, Ying ThS, Griffin MJ, Farber E (1981) Immunohistochemical study of epoxide hydrolase during experimental liver carcinogenesis. Cancer Res 41:3281–3287

    PubMed  CAS  Google Scholar 

  • Fabian W, Höer PW, März E, Blum U (1979) Gutartige Lebertumoren und Ovulationshemmer. Med Klin 74:662–666

    PubMed  CAS  Google Scholar 

  • Farber E (1976) Hyperplastic areas, hyperplastic nodules, and hyperbasophilic areas as putative precursor lesions. Cancer Res 36:2532–2533

    PubMed  CAS  Google Scholar 

  • Farber E (1980) The sequential analysis of liver cancer induction. Biochim Biophys Acta 605:149–166

    PubMed  CAS  Google Scholar 

  • Farber E (1984) Chemical carcinogenesis: a current biological perspective. Commentary. Carcinogenesis 5:1–5

    Article  CAS  Google Scholar 

  • Farber E, Cameron R (1980) The sequential analysis of cancer development. Adv Cancer Res 31:125–226

    PubMed  CAS  Google Scholar 

  • Fechner RE (1977) Benign hepatic lesions and orally administered contraceptives. A report of seven cases and a critical analysis of the literature. Hum Pathol 8:255–268

    Article  PubMed  CAS  Google Scholar 

  • Fischer G, Ullrich D, Katz N, Bock KW, Schauer A (1983 a) Immunohistochemical and biochemical detection of uridine-diphosphate-glucuronyltransferase (UDP-GT) activity in putative preneoplastic liver foci. Virchows Arch [Cell Pathol] 42:193–200

    CAS  Google Scholar 

  • Fischer G, Schauer A, Bock KW, Ullrich D, Katz N (1983 b) Immunohistochemical demonstration of increased UDP-glucuronyltransferase in putative preneoplastic liver foci. Naturwissenschaften 70:153

    Article  PubMed  CAS  Google Scholar 

  • Fischer G, Altmannsberger M, Schauer A, Katz N (1983c) Early stages of chemically induced liver carcinogenesis by oral administration of the antihistaminic methapyrilene hydrochloride. J Cancer Res Clin Oncol 106:53–57

    Article  PubMed  CAS  Google Scholar 

  • Fischer G, Ullrich A, Lilienblum W, Bock KW, Schauer A, Katz N (1983 d) Quantitativhistochemische und biochemische Untersuchungen zur methapyrileninduzierten Lebercarcinogenese der Ratte. Verh Dtsch Ges Pathol 67:637

    Google Scholar 

  • Fischer G, Bock KW, Katz N, Schauer A (1984) Alteration of drug metabolizing enzymes in preneoplastic liver foci by induction-promotion models. Verh Dtsch Krebsges 5:450

    Google Scholar 

  • Fischer G, Ullrich D, Bock KW (1985) Effects of N-nitrosomorpholine and phenobarbital on UDP-glucuronyltransferase in putative preneoplastic foci of rat liver. Carcinogenesis 6:605–609

    Article  PubMed  CAS  Google Scholar 

  • Foster JH, Berman MM (1977) Solid liver tumors. Major problems in clinical surgery, vol XXII. Saunders, Philadelphia London Toronto

    Google Scholar 

  • Gibby EM, Mehta R, Ellison M, Cohen GM (1981) Conjugation pathways in human bronchial carcinoma cell lines. Biochem Pharmacol 30:3333–3336

    Article  PubMed  CAS  Google Scholar 

  • Goldfarb S (1976) Sex hormones and hepatic neoplasia. Cancer Res 36:2584–2588

    PubMed  CAS  Google Scholar 

  • Gräf KJ, Meyer zum Büschenfelde KH (1980) Leberzelltumorinduktion durch orale Kontrazeptiva. Dtsch Med Wochenschr 105:61–65

    Article  PubMed  Google Scholar 

  • Heine WD (1981) Experimentelle und menschliche hepatozelluläre Lebertumoren und ihre Vorstufen — Histologische, enzymhistochemische und zellkinetische Charakteristika. In: Zelder O, Röher HD, Fischer M, Bode JC (eds) Experimentelle und klinische Hepatologie. Schattauer, Stuttgart New York (3. Arbeitstagung Experimentelle und Klinische Hepatologie, Marburg/Lahn 1980)

  • Helling TS, Wood WG (1982) Oral contraceptives and cancer of the liver: a review with two additional cases. Am J Gastroenterol 77:504–508

    PubMed  CAS  Google Scholar 

  • Hirota N, Hamazaki M, Williams GM (1982) Resistance to iron accumulation and presence of hepatitis B surface antigen in preneoplastic and neoplastic lesions in human hemochromatotic livers. Hepatogastroenterol 29:49–51

    CAS  Google Scholar 

  • Ishak KG, Rabin L (1975) Benign tumors of the liver. Med Clin N Am 59:995–1013

    PubMed  CAS  Google Scholar 

  • Ishak KG (1979) Hepatic neoplasms associated with contraceptive and anabolic steroids in carcinogenic hormones. In: Lingemann C (ed) Recent results in cancer research. Springer, Berlin Heidelberg New York, pp 73–128

    Google Scholar 

  • Kalengayi MMR, Ronchi G, Desmet VJ (1975) Histochemistry of gamma-glutamyl transpeptidase in rat liver during aflatoxin B1-induced carcinogenesis. J Natl Cancer Inst 55:579–588

    PubMed  CAS  Google Scholar 

  • Kalengayi MMR, Desmet VJ (1978) Gamma-glutamyl transferase as oncofetal marker of experimental hepatocarcinogenesis in the rat. Scand J Immunol [Suppl] 8:547–556

    CAS  Google Scholar 

  • Kerlin P, Davis GL, McGill DB, Weiland LH, Adson MA, Sheedy II PF (1983) Hepatic adenoma and focal nodular hyperplasia: clinical, pathologic, and radiologic features. Gastroenterol 84:994–1002

    CAS  Google Scholar 

  • Klatskin G (1977) Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterol 73:386–394

    CAS  Google Scholar 

  • Kondo Y, Niwa Y, Akikusa B, Takazawa H, Okabayashi A (1983) A histopathologic study of early hepatocellular carcinoma. Cancer 52:687–692

    Article  PubMed  CAS  Google Scholar 

  • Lang W (1984) Geographische Pathologie und Epidemiologie der Neubildungen in der Leber. Verh Dtsch Krebsges 5:437–4142

    Google Scholar 

  • Mays ET, Christopherson WM, Mahr MM, Williams HC (1976) Hepatic changes in young women ingesting contraceptive steroids. JAMA 235:730–732

    Article  PubMed  CAS  Google Scholar 

  • Mori H, Tanaka T, Sugie S, Takahashi M (1982) Adenoma with multiple hyperplastic nodules in noncirrhotic liver possibly related to long-term administration of a hypolipidemic drug. Acta Pathol Jpn 32:671–675

    PubMed  CAS  Google Scholar 

  • O’Sullivan JP, Rosswick RP (1976) Oral contraceptives and malignant hepatic tumors. Lancet 1:1124–1125

    PubMed  CAS  Google Scholar 

  • Palmer PE, Christopherson WM, Wolfe HJ (1977) Alpha1-antitrypsin, protein marker in oral contraceptive-associated hepatic tumors. Am J Clin Pathol 68:736–739

    PubMed  CAS  Google Scholar 

  • Philips MJ, Langer B, Stone R, Fisher MM, Ritchie S (1973) Benign liver cell tumors. Classification and ultrastructural pathology. Cancer 32:463–470

    Google Scholar 

  • Pitot HC, Sirica AE (1980) The stages of initiation and promotion in hepatocarcinogenesis. Biochim Biophys Acta 605:191–215

    PubMed  CAS  Google Scholar 

  • Pitot HC, Barsness L, Goldsworthy T, Kitagawa T (1978) Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine. Nature 271:456–458

    Article  PubMed  CAS  Google Scholar 

  • Rutenburg AM, Kim H, Fischbein JW, Hanker JS, Wasserkrug HL, Seligman A (1969) Histochemical and ultrastructural demonstration of γ-glutamyl transpeptidase activity. J Histochem Cytochem 17:517–526

    PubMed  CAS  Google Scholar 

  • Schaffner F (1966) The effect of oral contraceptives on the liver. JAMA 198:1019–1023

    Article  PubMed  CAS  Google Scholar 

  • Schauer A, Kunze E (1968) Enzymhistochemische und autoradiographische Untersuchungen während der Cancerisierung der Rattenleber mit Diäthylnitrosamin. Z Krebsforsch 70:252–266

    Article  PubMed  CAS  Google Scholar 

  • Schuppler J, Günzel P (1979) Liver tumors and steroid hormones in rats and mice. Arch Toxicol [Suppl] 2:181–195

    Google Scholar 

  • Shar SR, Kew MC (1982) Oral contraceptives and hepatocellular carcinoma. Cancer 49:407–410

    Article  PubMed  CAS  Google Scholar 

  • Squire RA, Levitt M (1975) Report of a workshop on classification of specific hepatocellular lesions in rats. Cancer Res 35:3214–3223

    PubMed  CAS  Google Scholar 

  • Stewart HL, Williams GM, Keysser CH, Lombard LS, Montali RJ (1980) Histologic typing of liver tumors of the rat. J Natl Cancer Inst 64:176–206

    Google Scholar 

  • Stromeyer FW, Ishak KG (1981) Nodular transformation (nodular “regenerative” hyperplasia) of the liver. A clinicopathologic study of 30 cases. Hum Pathol 12:60–71

    Article  PubMed  CAS  Google Scholar 

  • Tatematsu M, Nagamine Y, Farber E (1983) Redifferentiation as a basis for remodeling of carcinogen-induced hepatocyte nodules to normal appearing liver. Cancer Res 43:5049–5058

    PubMed  CAS  Google Scholar 

  • Taylor CR, Burns J (1974) The demonstration of plasma cells and other immunoglobulin cells in formalin-fixed, paraffin-embedded tissues using peroxydase-labeled antibody. J Clin Pathol 27:14–20

    Article  PubMed  CAS  Google Scholar 

  • Thalassinos NC, Lymberatos C, Hadjioannou J, Gardikas C (1974) Liver cell carcinoma after long-term oestrogen-like drugs. Lancet I: 270

    Article  Google Scholar 

  • Thomas DB (1978) Role of exogenous female hormones in altering the risk of benign and malignant neoplasms in humans. Cancer Res 38:3991–4000

    PubMed  CAS  Google Scholar 

  • Thung SN, Gerber MA (1981) Enzyme pattern and marker antigens in nodular “regenerative” hyperplasia of the liver. Cancer 47:1796–1799

    Article  PubMed  CAS  Google Scholar 

  • Tsuda H, Lee G, Farber E (1980) Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens. Cancer Res 40:1157–1164

    PubMed  CAS  Google Scholar 

  • Uchida T, Miyata H, Shikata T (1981) Human hepatocellular carcinoma and putative precancerous disorders. Arch Pathol Lab Med 105:180–186

    PubMed  CAS  Google Scholar 

  • Wachstein M, Meisel E (1957) Histochemistry of hepatic phosphatases at a physiologic pH. Am J Clin Pathol 27:13–23

    PubMed  CAS  Google Scholar 

  • Wanless IR, Medline A (1982) Role of estrogens as promoters of hepatic neoplasia. Lab Invest 46:313–320

    PubMed  CAS  Google Scholar 

  • Ying TS, Sarma DSR, Farber E (1981) Role of acute hepatic necrosis in the induction of early steps in liver carcinogenesis by diethylnitrosamine. Cancer Res 41:2096–2102

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Zentrum Pathologie, Universität Göttingen, Robert-Koch-Straße 40, D-3400, Göttingen, Federal Republic of Germany

    G. Fischer, M. Droese & A. Schauer

  2. Zentrum Innere Medizin, Universität Göttingen, Robert-Koch-Straße 40, D-3400, Göttingen, Federal Republic of Germany

    H. Hartmann

  3. Zentrum Pharmakologie, Universität Göttingen, Kreuzbergring 57, D-3400, Göttingen, Federal Republic of Germany

    K. W. Bock

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  1. G. Fischer
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  2. H. Hartmann
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  3. M. Droese
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  4. A. Schauer
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  5. K. W. Bock
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Supported by the Bundesministerium für Forschung und Technologie, UC-Teilprojekt CMT 18 (A.S., G.F.) and the Deutsche Forschungsgemeinschaft (K.W.B.)

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Fischer, G., Hartmann, H., Droese, M. et al. Histochemical and immunohistochemical detection of putative preneoplastic liver foci in women after long-term use of oral contraceptives. Virchows Archiv B Cell Pathol 50, 321–337 (1986). https://doi.org/10.1007/BF02889911

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  • DOI: https://doi.org/10.1007/BF02889911

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