Preneoplastic Lesions as Early Indicators of Neoplastic Development

  • P. Bannasch
  • U. R. Jahn
  • H. Zerban


In human pathology, the terms “preneoplasia” and “precancer” have traditionally been used as synonyms indicating a pathological condition carrying increased risk for the development of malignant neoplasia (cancer). In addition to definite proliferative lesions such as nodular hyperplasia, papilloma, or carcinoma in situ, dysplastic lesions have been considered potential prestages of cancer and have, hence, been widely involved in the early diagnosis of neoplasia (Carter 1984, and this volume; Koss 1979, and this volume). However, investigations in several animal models and some studies in man revealed that characteristic changes in the biochemical and morphological phenotype of focal cell populations, which initially deviate only slightly from the normal differentiated state, precede the appearance of both benign and malignant neoplasms in a number of tissues by weeks and months or even years (Bannasch 1986; Sirica 1989). This holds especially true for epithelial tissues endowed with a low cell turnover under normal conditions, such as the hepatic parenchyma (Bannasch et al. 1989a; Symposium 1989), exocrine pancreatic parenchyma (Longnecker and Millar 1990; Woutersen et al. 1991), and renal tubular system (Bannasch and Zerban 1990; Dietrich and Swenberg 1991), but it also relates to some epithelial tissues with a high cell turnover like the colonic mucosa (Mayer et al. 1987; Barrow et al. 1990) and bronchial mucosa (Gusterson 1984) (Table 1). Based on these findings, preneoplasia may be defined as phenotypically altered cell populations which have no obvious neoplastic nature but indicate an increased risk for the development of benign or malignant neoplasia in the respective tissue (Bannasch 1986).


Glycogen Phosphorylase Preneoplastic Lesion Renal Oncocytoma Malignant Neoplasia Peliosis Hepatis 
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  1. Altmann HW (1978) Pathology of human liver tumors. In: Remmer H, Bolt H, Bannasch P, Popper H (eds) Primary liver tumors. MTP Press, Lancaster, pp 53–71Google Scholar
  2. Baba M, Yamamoto R, Fishi H, Tatsuta M, Wada A (1989) Role of glucose-6-phosphate dehydrogenase on enhanced proliferation of pre-neoplastic and neoplastic cells in rat liver induced by N-nitrosomorpholine. Int J Cancer 43:892–895PubMedCrossRefGoogle Scholar
  3. Balâzs M (1976) Licht-und elektronenmikroskopische Untersuchungen in einem Fall von primärem Leberkarzinom im Säuglingsalter. Zentralbl Allg Pathol 120:3–13PubMedGoogle Scholar
  4. Bannasch P (1968) The cytoplasm of hepatocytes during carcinogenesis. Electron and light microscopic investigations of the nitrosomorpholine-intoxicated rat liver. Recent Results Cancer Res 19:1–100Google Scholar
  5. Bannasch P (1984) Sequential cellular changes during chemical carcinogenesis. J Cancer Res Clin Oncol 108:11–22PubMedCrossRefGoogle Scholar
  6. Bannasch P (1986) Preneoplastic lesions as end points in carcinogenicity testing. I. Hepatic preneoplasia. II. Preneoplasia in various non-hepatic tissues. Carcinogenesis 7:689–695, 849–852Google Scholar
  7. Bannasch P (1988) Phenotypic cellular changes as indicators of stages during neoplastic development. In: Iversen OH (ed) Theories of carcinogenesis. Hemisphere, Washington, pp 231–249Google Scholar
  8. Bannasch P (1990) Pathobiology of chemical hepatocarcinogenesis: recent progress and perspectives. I. Cytomorphological changes and cell proliferation. II. Metabolic and molecular changes. J Gastroenterol Hepatol 5:149–159, 310–320PubMedCrossRefGoogle Scholar
  9. Bannasch P, Klinge O (1971) Hepatozelluläre Glykogenose und Hepatombildung beim Menschen. Virchows Arch [A] 352:157–164Google Scholar
  10. Bannasch P, Zerban H (1990) Animal models and renal carcinogenesis. In: Eble JN (ed) Contemporary issues in surgical pathology. Tumors and tumor-like conditions of the kidneys and ureters. Livingstone, Edinburgh, pp 1–34Google Scholar
  11. Bannasch P, Zerban H (1992) Predictive value of hepatic preneoplastic lesions as indicators of carcinogenic response. IARC Sci Publ (in press)Google Scholar
  12. Bannasch P, Krech R, Zerban H (1978a) Morphogenese und Mikromorphologie epithelialer Nierentumoren bei Nitrosomorpholin-vergifteten Ratten. II. Tubuläre Glykogenose und die Genese von klar-oder acidophilzelligen Tumoren. Z Krebsforsch 92:63–86Google Scholar
  13. Bannasch P, Krech R, Zerban H (1978b) Morphogenese und Mikromorphologie epithelialer Nierentumoren bei Nitrosomorpholin-vergifteten Ratten. III. Onkocytentubuli und Onkocytome. Z Krebsforsch 92:87–104CrossRefGoogle Scholar
  14. Bannasch P, Hacker HJ, Klimek F, Mayer D (1984) Hepatocellular glycogenosis and related pattern of enzymatic changes during hepatocarcinogenesis. Adv Enzyme Regul 22: 97–121PubMedCrossRefGoogle Scholar
  15. Bannasch P, Benner U, Enzmann H, Hacker HJ (1985a) Tigroid cell foci and neoplastic nodules in the liver of rats treated with a single dose of aflatoxin B1. Carcinogenesis 6:1641–1648CrossRefGoogle Scholar
  16. Bannasch P, Moore MA, Hacker HJ, Klimek F, Mayer D, Enzmann H, Zerban H (1985b) Potential significance of phenotypic instability in focal and nodular liver lesions induced by hepatocarcinogens. In: Brunner H, Thaler H (eds) Hepatology: a Festschrift for Hans Popper. Raven, New York, pp 191–209Google Scholar
  17. Bannasch P, Enzmann H, Hacker HJ, Weber E, Zerban H (1989a) Comparative pathobiology of hepatic preneoplasia. In: Bannasch P, Keppler D, Weber G (eds) Liver cell carcinoma. Kluwer, Dordrecht, pp 53–73Google Scholar
  18. Bannasch P, Enzmann H, Klimek F, Weber E, Zerban H (1989b) Significance of sequential cellular changes inside and outside foci of altered hepatocytes during hepatocarcinogenesis. Toxicol Pathol 17:617–629Google Scholar
  19. Bannasch P, Hacker HJ, Klimek F, Mayer D, Stumpf H, Zerban H (1991) Cytochemical, microbiochemical and molecular genetic analysis of chemical carcinogenesis. Prog Histochem Cytochem 23:45–60PubMedGoogle Scholar
  20. Barrow BJ, O’Riordan MA, Stellato TA, Calkins BM, Pretlow TP (1990) Enzyme-altered foci in colons of carcinogen-treated rats. Cancer Res 50:1911–1916PubMedGoogle Scholar
  21. Brözel U (1989) Hepatozelluläre Tumoren bei angeborener Glykogenspeicherkrankheit. Thesis, University of HeidelbergGoogle Scholar
  22. Cain H, Kraus B (1977) Entwicklungsstörungen der Leber und Leberkarzinom im Säuglings-und Kindesalter. Dtsch Med Wochenschr 102:505–509PubMedCrossRefGoogle Scholar
  23. Carter RL (ed) (1984) Precancerous states. Oxford University Press, LondonGoogle Scholar
  24. Dietrich DR, Swenberg JA (1991) Preneoplastic lesions in rodent kidney induced spontaneously or by non-genotoxic carcinogens. Mutat Res 248:239–260PubMedCrossRefGoogle Scholar
  25. Enzmann H, Bannasch P (1987) Potential significance of phenotypic heterogeneity of focal lesions at different stages in hepatocarcinogenesis. Carcinogenesis 8:1607–1612PubMedCrossRefGoogle Scholar
  26. Farber E, Sarma DSR (1987) Hepatocarcinogenesis: a dynamic cellular perspective. Lab Invest 56:4–22PubMedGoogle Scholar
  27. Fischer G, Hartmann H, Droese M, Schauer A, Bock KW (1986) Histochemical and immunohistochemical detection of putative preneoplastic liver foci in women after long-term use of oral contraceptives. Virchows Arch [B] 50:321–337CrossRefGoogle Scholar
  28. Fischer G, Ruschenburg J, Eigenbrodt E, Katz N (1987) Decrease in glucokinase and glucose-6-phosphatase and increase in hexokinase in putative preneoplastic lesions of rat liver. J Cancer Res Clin Oncol 113:430–436PubMedCrossRefGoogle Scholar
  29. Goldsworthy TL, Hanigan HM, Pitot HC (1986) Models of hepatocarcinogenesis in the rat — contrasts and comparisons. CRC Crit Rev Toxicol 17:61–89CrossRefGoogle Scholar
  30. Gusterson BA (1984) Precancerous changes in the lungs and the potential of cells to have modulated phenotypes. In: Carter RL (ed) Precancerous states. Oxford University Press, London, pp 161–184Google Scholar
  31. Hacker HJ, Moore MA, Mayer D, Bannasch P (1982) Correlative histochemistry of some enzymes of carbohydrate metabolism in preneoplastic and neoplastic lesions in the rat liver. Carcinogenesis 3:1265–1272PubMedCrossRefGoogle Scholar
  32. Harada T, Maronpot RR, Morris RW, Boorman GA (1989) Observations on altered hepatocellular foci in National Toxicology Program two-year carcinogenicity studies in rats. Toxicol Pathol 17:690–708PubMedGoogle Scholar
  33. 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, pp 13–24Google Scholar
  34. Karhunen PJ, Pentillä A (1987) Preneoplastic lesions of human liver. Hepatogastroenterology 34:10–15PubMedGoogle Scholar
  35. Kaufmann WK, MacKenzie SA, Kaufman DG (1985) Quantitative relationship between hepatocytic neoplasms and islands of cellular alteration during hepatocarcinogenesis in the male F344 rat. Am J Pathol 119:171–174PubMedGoogle Scholar
  36. Kaufmann WK, Rahija RJ, MacKenzie SA, Kaufman DG (1987) Cell cycle-dependent initiation of hepatocarcinogenesis in rats by (±) 7r, 8t-dihydroxy-9t, 10t-epoxy-7,8,9,10tetrahydrobenzo(a)pyrene. Cancer Res 47:3771–3775PubMedGoogle Scholar
  37. Klimek F, Mayer D, Bannasch P (1984) Biochemical microanalysis of glycogen content and glucose-6-phosphate dehydrogenase activity in focal lesions of the rat liver induced by N-nitrosomorpholine. Carcinogenesis 5:265–268PubMedCrossRefGoogle Scholar
  38. Koss LG (1979) Diagnostic cytology and its histopathologic bases, 3rd edn. Lippincott, PhiladelphiaGoogle Scholar
  39. Kraupp-Grasl B, Huber W, Putz B, Gerbracht U, Schulte-Hermann R (1990) Tumor promotion by the peroxisome proliferator nafenopin involving a specific subtype of altered foci in rat liver. Cancer Res 50:3701–3708PubMedGoogle Scholar
  40. Krech R, Zerban H, Bannasch P (1981) Mitochondrial anomalies in renal oncocytes induced in rat by N-nitrosomorpholine. Eur J Cell Biol 25:331–339PubMedGoogle Scholar
  41. Longnecker DS, Millar PM (1990) Tumours of the pancreas. IARC Sci Publ 99:199–240Google Scholar
  42. Mayer D, Trocheris V, Hacker HJ, Viallard V, Murat JC, Bannasch P (1987) Sequential histochemical and morphometric studies on preneoplastic and neoplastic lesions induced in rat colon by 1,2-dimethylhydrazine. Carcinogenesis 8:155–161PubMedCrossRefGoogle Scholar
  43. Mayer D, Klimek F, Hacker HJ, Seelmann-Eggebert G, Bannasch P (1989) Carbohydrate metabolism in hepatic preneoplasia. In: Bannasch P, Keppler D, Weber G (eds) Liver cell carcinoma. Kluwer, Dordrecht, pp 321–337Google Scholar
  44. Moore MA, Kitagawa T (1986) Hepatocarcinogenesis in the rat; the effect of the promoters and carcinogens in vivo and in vitro. Int Rev Cytol 101:125–173PubMedCrossRefGoogle Scholar
  45. Moore MA, Mayer D, Bannasch P (1982) The dose-dependence and sequential appearance of putative preneoplastic populations induced in the rat liver by stop experiments with N-nitrosomorpholine. Carcinogenesis 3:1429–1436PubMedCrossRefGoogle Scholar
  46. Moore MA, Nakamura T, Shirai T, Ito N (1986) Immunohistochemical demonstration of increased glucose-6-phosphate dehydrogenase in preneoplastic and neoplastic lesions induced by propylnitrosamine in F344 rats and Syrian hamsters. Jpn J Cancer Res 77:131–138PubMedGoogle Scholar
  47. Mori H, Tanaka T, Sugie S, Takahashi M, Williams GM (1982) DNA content of liver cell nuclei of N-2-fluorenylacetamide-induced altered foci and neoplasms in rats and human hyperplastic foci. JNCI 69:1277–1282PubMedGoogle Scholar
  48. Nogueira E, Bannasch P (1988) Cellular origin of rat renal oncocytoma. Lab Invest 59:337–343PubMedGoogle Scholar
  49. Nogueira E, Klimek F, Weber E, Bannasch P (1989) Origin of rat renal clear cell tumors from the collecting duct. Virchows Arch [3] 57:275–283CrossRefGoogle Scholar
  50. Ortmann M, Vierbuchen M, Koller G, Fischer R (1988) Renal oncocytoma. I. Cytochrome C oxidase in normal and neoplastic renal tissue as detected by immunohistochemistry — a valuable aid to distinguish oncocytomas from renal cell carcinomas. Virchows Arch [B] 56:165–173CrossRefGoogle Scholar
  51. Schaff Z, Lapis K, Henson DE (1986) Liver. In: Henson DE, Albores-Saavedra J (eds) The pathology of incipient neoplasia. Saunders, Philadelphia, pp 167–202Google Scholar
  52. Seelmann-Eggebert G, Mayer D, Mecke D, Bannasch P (1987) Expression and regulation of glycogen phosphorylase in preneoplastic and neoplastic hepatic lesions in rats. Virchows Arch [B] 53:44–51CrossRefGoogle Scholar
  53. Shapiro P, Ikeda RM, Ruebner BH, Coonors MH, Halsted CC, Abildgaard CF (1977) Multiple hepatic tumors and peliosis hepatis in Fanconi’s anemia treated with androgens. Am J Dis Child 131:1104–1106PubMedGoogle Scholar
  54. Sirica AE (1989) Preneoplasia and precancerous lesions. In: Sirica AE (ed) The pathobiology of neoplasia. Plenum, New York, pp 199–215Google Scholar
  55. Störkel S, Pannen B, Thoenes W, Steart PV, Wagner S, Drenckhahn D (1988) Intercalated cells as a probable source for the development of renal oncocytoma. Virchows Arch [B] 56:185–189CrossRefGoogle Scholar
  56. Symposium (1989) Significance of foci of cellular alteration in the rat liver. Toxicol Pathol 17:557–735Google Scholar
  57. Tatematsu M, Nagamine Y, Farber E (1983) Redifferentiation as a basis for remodeling of carcinogen-induced hepatocyte nodules to normal appearing liver. Cancer Res 433:5049–5058Google Scholar
  58. Watanabe K, Williams GM (1978) Enhancement of rat hepatocellular-altered foci by the liver tumor promoter phenobarbital: evidence that foci are precursors of neoplasms and that the promoter acts on carcinogen-induced lesions. JNCI 61:1311–1314PubMedGoogle Scholar
  59. Weber E (1989) Dosisabhängigkeit der Sequenz zellulärer Veränderungen bei der NNitrosomorpholin-induzierten Hepatokarzinogenese in der Ratte. Thesis, University of DarmstadtGoogle Scholar
  60. Weber E, Moore MA, Bannasch P (1988) Enzyme histochemical and morphological phenotype of amphophilic foci and amphophilic/tigroid cell adenomas in rat liver after combined treatment with dehydroepiandrosterone and N-nitrosomorpholine. Carcinogenesis 9:1049–1054PubMedCrossRefGoogle Scholar
  61. Woutersen RA, van Garderen-Hoetmer A, Lamers CBHW, Scherer E (1991) Early indicators of exocrine pancreas carcinogenesis produced by non-genotoxic agents. Mutat Res 248:291–302PubMedCrossRefGoogle Scholar
  62. Zerban H, Nogueira E, Riedasch G, Bannasch P (1987) Renal oncocytoma: origin from the collecting duct. Virchows Arch [B] 52:375–387CrossRefGoogle Scholar
  63. Zerban H, Rabes HM, Bannasch P (1989) Sequential changes in growth kinetics and cellular phenotype during hepatocarcinogenesis. J Cancer Res Clin Oncol 115:329–334PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • P. Bannasch
  • U. R. Jahn
  • H. Zerban

There are no affiliations available

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