Pathology of Human Bronchioloalveolar Carcinoma and Its Relationship to the Ovine Disease

  • J.-F. Mornex
  • F. Thivolet
  • M. De Las Heras
  • C. Leroux
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 275)


Lung cancer is a leading cause of cancer with a poor prognosis. Bronchioloalveolar carcinoma (BAC) is a rare tumor that has always intrigued physicians. Since the last World Health Organization classification the pathology has been clarified; BAC per se is an adenocarcinoma with a pure bronchioloalveolar growth pattern and appears as an in situ alveolar adenocarcinoma. More usually BAC is a clinically recognizable entity presenting as multi-focal nodules evolving towards pneumonia associated with pulmonary shunting. Pathology is that of a multifocal mixed adenocarcinoma: bronchioloalveolar and papillar. Whatever the stage, survival is better than in other forms of non-small cell lung cancer (NSCLC). The true frequency of BAC is unknown, although it is a rare form of lung cancer; smoking cannot be excluded as a risk factor. It appears that p53 and ras genes are less often mutated than in other lung adenocarcinomas, suggesting that the cellular mechanisms involved are different. Ovine pulmonary adenocarcinoma (OPA) presents with the same symptoms as BAC in humans and is caused by a betaretrovirus — Jaagsiekte sheep retrovirus. Very early on, clinical and histological similarities with human BAC were stressed. A recent series of OPA described, according to the third edition of the WHO classification for human lung cancer, mixed adenocarcinoma, BAC and papillary and/or acinar carcinoma. An immunohistochemical study suggested that some human pulmonary tumors (including BAC) may be associated with a Jaagsiekte sheep retrovirus-related retrovirus, but so far no molecular study has confirmed this observation. Thus, OPA is an exquisite model of carcinogenesis for human lung adenocarcinomas.


Bronchioloalveolar Carcinoma FHIT Gene FHIT Protein Acinar Adenocarcinoma Murine Mammary Tumor Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Auerbach O, Garfinkel L (1991) The changing pattern of lung carcinoma. Cancer 68:1973–7PubMedCrossRefGoogle Scholar
  2. Barsky SH, Cameron R, Osann KE, Tomita D, Holmes EC (1994) Rising incidence of bronchioloalveolar lung carcinoma and its unique clinicopathologic features. Cancer 73:1163–70PubMedCrossRefGoogle Scholar
  3. Barsky SH, Grossman DA, Ho J, Holmes EC (1994) The multifocality of bronchioloalveolar lung carcinoma: evidence and implications of a multiclonal origin. Mod Pathol 7:633–40PubMedGoogle Scholar
  4. Bonne C (1939) morphological resemblance of pulmonary adenomatosis (jaaksiekte) in sheep and certain cases of cancer of the lung in man. Am J Cancer 35:491–501Google Scholar
  5. Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y (2001) The new World Health Organization classification of lung tumours. Eur Respir J 18:1059–68PubMedCrossRefGoogle Scholar
  6. Breathnach OS, Ishibe N, Williams J, Linnoila RI, Caporaso N, Johnson BE (1999) Clinical features of patients with stage IIIB and IV bronchioloalveolar carcinoma of the lung. Cancer 86:1165–73PubMedCrossRefGoogle Scholar
  7. Breathnach OS, Kwiatkowski DJ, Finkelstein DM, Godleski J, Sugarbaker DJ, Johnson BE, Mentzer S (2001) Bronchioloalveolar carcinoma of the lung: recurrences and survival in patients with stage I disease. J Thorac Cardiovasc Surg 121:42–7PubMedCrossRefGoogle Scholar
  8. Caamano J, Ruggeri B, Momiki S, Sickler A, Zhang SY, Klein-Szanto AJ (1991) Detection of p53 in primary lung tumor s and nonsmall cell lung carcinoma cell lines. Am J Pathol 139:839–45PubMedGoogle Scholar
  9. Crawford L (1983) The 53,000-dalton cellular protein and its role in transformation. Int Rev Exp Pathol 25:1–50PubMedGoogle Scholar
  10. De las Heras M, Barsky SH,Hasleton P,Wagner M, Larson E, Egan J, Ortin A, Gimenez-Mas JA, Palmarini M, Sharp JM (2000) Evidence for a protein related immunologically to the jaagsiekte sheep retrovirus in some human lung tumours. Eur Respir J 16:330-2PubMedCrossRefGoogle Scholar
  11. Denissenko MF, Chen JX, Tang MS, Pfeifer GP (1997) Cytosine methylation determines hot spots of DNA damage in the human P53 gene. Proc Natl Acad Sci USA 94:3893–8PubMedCrossRefGoogle Scholar
  12. Denissenko MF, Pao A, Tang M, Pfeifer GP (1996) Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 274:430–2PubMedCrossRefGoogle Scholar
  13. Etienne B, Bertocchi M, Gamondes JP, Wiesendanger T, Brune J, Mornex JF (1997) Successful double-lung transplantation for bronchioalveolar carcinoma. Chest 112:1423–4PubMedCrossRefGoogle Scholar
  14. Falk RT, Pickle LW, Fontham ET, Greenberg SD, Jacobs HL, Correa P, Fraumeni JF Jr (1992) Epidemiology of bronchioloalveolar carcinoma. Cancer Epidemiol Biomarkers Prev 1:339–44PubMedGoogle Scholar
  15. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–67PubMedCrossRefGoogle Scholar
  16. Fong KM, Biesterveld EJ, Virmani A, Wistuba I, Sekido Y, Bader SA, Ahmadian M, Ong ST, Rassool FV, Zimmerman PV, Giaccone G, Gazdar AF, Minna JD (1997) FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res 57:2256–67PubMedGoogle Scholar
  17. Fong KM, Sekido Y, Minna JD (1999) Molecular pathogenesis of lung cancer. J Thorac Cardiovasc Surg 118:1136–52PubMedCrossRefGoogle Scholar
  18. Galy P, Marcq M (1973) le carcinome bronchiolo-alvéolaire. Rev Fr Mal Respir 1:665–682Google Scholar
  19. Garver RI Jr, Zorn GL, Wu X, McGiffin DC, Young KR JR, Pinkard NB (1999) Recurrence of bronchioloalveolar carcinoma in transplanted lungs. N Engl J Med 340:1071–4PubMedCrossRefGoogle Scholar
  20. Gazzeri S, Brambilla E, Caron de Fromentel C, Gouyer V, Moro D, Perron P, Berger F, Brambilla C (1994) p53 genetic abnormalities and myc activation in human lung carcinoma. Int J Cancer 58:24–32PubMedCrossRefGoogle Scholar
  21. Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54:4855–78PubMedGoogle Scholar
  22. Hainaut P, Pfeifer GP (2001) Patterns of p53 G→T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke. Carcinogenesis 22:367–74PubMedCrossRefGoogle Scholar
  23. Hernandez-Boussard TM, Hainaut P (1998) A specific spectrum of p53 mutations in lung cancer from smokers: review of mutations compiled in the IARC p53 database. Environ Health Perspect 106:385–91PubMedCrossRefGoogle Scholar
  24. Hod I, Herz A, Zimber A (1977) Pulmonary carcinoma (Jaagsiekte) of sheep. Ultrastructural study of early and advanced tumor lesions. Am J Pathol 86:545–58PubMedGoogle Scholar
  25. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53PubMedCrossRefGoogle Scholar
  26. Keohavong P, Demichele MA, Melacrinos AC, Landreneau RJ, Weyant RJ, Siegfried JM (1996) Detection of K-ras mutations in lung carcinomas: relationship to prognosis. Clin Cancer Res 2:411–8PubMedGoogle Scholar
  27. Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87: 159–70PubMedCrossRefGoogle Scholar
  28. Kishimoto Y, Murakami Y, Shiraishi M, Hayashi K, Sekiya T (1992) Aberrations of the p53 tumor suppressor gene in human non-small cell carcinomas of the lung. Cancer Res 52:4799–804PubMedGoogle Scholar
  29. Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–31PubMedCrossRefGoogle Scholar
  30. Liu YY, Chen YM, Huang MH, Perng RP (2000) Prognosis and recurrent patterns in bronchioloalveolar carcinoma. Chest 118:940–7PubMedCrossRefGoogle Scholar
  31. Marchetti A, Buttitta F, Pellegrini S, Chella A, Bertacca G, Filardo A, Tognoni V, Ferreli F, Signorini E, Angeletti CA, Bevilacqua G (1996) Bronchioloalveolar lung carcinomas: K-ras mutations are constant events in the mucinous subtype. J Pathol 179:254–9PubMedCrossRefGoogle Scholar
  32. Marchetti A, Pellegrini S, Bertacca G, Buttitta F, Gaeta P, Carnicelli V, Nardini V, Griseri P, Chella A, Angeletti CA, Bevilacqua G (1998) FHIT and p53 gene abnormalities in bronchioloalveolar carcinomas. Correlations with clinicopathological data and K-ras mutations. J Pathol 184:240–6PubMedCrossRefGoogle Scholar
  33. Marchevsky AM (1990) Malignant epithelial tumors of the lung. In: Marchevsky AM (ed. eds) Surgical pathology of lung neoplasms. Marcel Dekker, New York, pp 77–228Google Scholar
  34. Marcq M, Galy P (1973) Bronchioloalveolar carcinoma. Clinicopathologic relationships, natural history, and prognosis in 29 cases. Am Rev Respir Dis 107:621–9PubMedGoogle Scholar
  35. Mills NE, Fishman CL, Rom WN, Dubin N, Jacobson DR (1995) Increased prevalence of K-ras oncogene mutations in lung adenocarcinoma. Cancer Res 55:1444–7PubMedGoogle Scholar
  36. Morabia A, Wynder EL (1992) Relation of bronchioloalveolar carcinoma to tobacco. Bmj 304:541–3PubMedCrossRefGoogle Scholar
  37. Nobel TA, Perk K (1978) Bronchiolo-alveolar cell carcinoma. Animal model: pulmonary adenomatosis of sheep, pulmonary carcinoma of sheep, pulmonary carcinoma of sheep (Jaagsiekte). Am J Pathol 90:783–6PubMedGoogle Scholar
  38. Nuorva K, Soini Y, Kamel D, Pollanen R, Bloigu R, Vahakangas K, Paakko P (1995) p53 protein accumulation and the presence of human papillomavirus DNA in bronchiolo-alveolar carcinoma correlate with poor prognosis. Int J Cancer 64:424–9PubMedCrossRefGoogle Scholar
  39. Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, Mccue P, Druck T et al. (1996) The FHIT gene, spanning the chromosome 3p14.2 fragile site and rena l carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84:587–97PubMedCrossRefGoogle Scholar
  40. Okubo K, Mark EJ, Flieder D, Wain JC, Wright CD, Moncure AC, Grillo HC, Mathisen DJ (1999) Bronchoalveolar carcinoma: clinical, radiologic, and pathologic factors and survival. J Thorac Cardiovasc Surg 118:702–9PubMedCrossRefGoogle Scholar
  41. OMS (1981) Types histologiques des tumeurs du poumon. Genève, Organisation mondiale de la santéGoogle Scholar
  42. Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rosler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C (1998) Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit. Proc Natl Acad Sci USA 95:5484–9PubMedCrossRefGoogle Scholar
  43. Palmarini M, Maeda N,Murgia C, De-Fraja C,Hofacre A, Fan H (2001) A phosphatidylinositol- 3-kinase (PI3-K) docking site in the cytoplasmic tail of the jaagsiekte sheep retrovirus transmembrane protein is essential for envelopeinduced transformation of NIH 3T3 cells. J Virol 75:11002-11009PubMedCrossRefGoogle Scholar
  44. Palmarini M, Fan H (2001) Retrovirus-induced ovine pulmonary adenocarcinoma, an animal model for lung cancer. J Natl Cancer Inst 93:1603–14PubMedCrossRefGoogle Scholar
  45. Paloyan EB, Swinnen LJ, Montoya A, Lonchyna V, Sullivan HJ, Garrity E (2000) Lung transplantation for advanced bronchioloalveolar carcinoma confined to the lungs. Transplantation 69:2446–8PubMedCrossRefGoogle Scholar
  46. Pellegata NS, Sessa F, Renault B, Bonato M, Leone BE, Solcia E, Ranzani GN (1994) K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res 54:1556–60PubMedGoogle Scholar
  47. Regnard JF, Santelmo N, Romdhani N, Gharbi N, Bourcereau J, Dulmet E, Levasseur P (1998) Bronchioloalveolar lung carcinoma: results of surgical treatment and prognostic factors. Chest 114:45–50PubMedCrossRefGoogle Scholar
  48. Rusch VW, Reuter VE, Kris MG, Kurie J, Miller WH, Jr., Nanus DM, Albino AP, Dmitrovsky E (1992) Ras oncogene point mutation: an infrequent event in bronchioloalveolar cancer. J Thorac Cardiovasc Surg 104:1465–9PubMedGoogle Scholar
  49. Saleh HA, Haapaniemi J, Khatib G, Sakr W (1998) Bronchioloalveolar carcinoma: diagnostic pitfalls and immunocytochemical contribution. Diagn Cytopathol 18:301–6PubMedCrossRefGoogle Scholar
  50. Siegfried JM, Gillespie AT, Mera R, Casey TJ, Keohavong P, Testa JR, Hunt JD (1997) Prognostic value of specific KRAS mutations in lung adenocarcinomas. Cancer Epidemiol Biomarkers Prev 6:841–7PubMedGoogle Scholar
  51. Silini EM, Bosi F, Pellegata NS, Volpato G, Romano A, Nazari S, Tinelli C, Ranzani GN, Solcia E, Fiocca R (1994) K-ras gene mutations: an unfavorable prognostic marker in stage I lung adenocarcinoma. Virchows Arch 424:367–73PubMedCrossRefGoogle Scholar
  52. Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MA, Croce CM, Huebner K (1997) Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci USA 94:13771–6PubMedCrossRefGoogle Scholar
  53. Slebos RJ,Kibbelaar RE,Dalesio O,Kooistra A,Stam J,Meijer CJ,Wagenaar SS, Vanderschueren RG, van Zandwijk N, Mooi WJ et al. (1990) K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 323:561-5PubMedCrossRefGoogle Scholar
  54. Sorensen JB, Hirsch FR, Gazdar A, Olsen JE (1993) Interobserver variability in histopathologic subtyping and grading of pulmonary adenocarcinoma. Cancer 71:2971–6PubMedCrossRefGoogle Scholar
  55. Sozzi G, Tornielli S, Tagliabue E, Sard L, Pezzella F, Pastorino U, Minoletti F, Pilotti S, Ratcliffe C, Veronese ML, Goldstraw P, Huebner K, Croce CM, Pierotti MA (1997) Absence of Fhit protein in primary lung tumors and cell lines with FHIT gene abnormalities. Cancer Res 57:5207–12PubMedGoogle Scholar
  56. Thomas R, Kaplan L, Reich N, Lane DP, Levine AJ (1983) Characterization of human p53 antigens employing primate specific monoclonal antibodies. Virology 131:502–17PubMedCrossRefGoogle Scholar
  57. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E (1999) Histological typing of lung and pleural tumours, SpringerGoogle Scholar
  58. Travis WD, Travis LB, Devesa SS (1995) Lung cancer. Cancer 75:191–202PubMedCrossRefGoogle Scholar
  59. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–32PubMedCrossRefGoogle Scholar
  60. Vogelstein B, Lane D, Levine AJ (2000) Surfing the p53 network Nature 408:307–10PubMedCrossRefGoogle Scholar
  61. Wang X, Rao MS, Yeldandi AV (1995) Immunohistochemical analysis of p53 mutations in bronchioloalveolar carcinoma and conventional pulmonary adenocarcinoma. Mod Pathol 8:919–23PubMedGoogle Scholar
  62. Weintraub SJ (1996) Inactivation of tumor suppressor proteins in lung cancer. Am J Respir Cell Mol Biol 15:150–5PubMedCrossRefGoogle Scholar
  63. Yousem SA, Finkelstein SD, Swalsky PA, Bakker A, Ohori NP (2001) Absence of jaagsiekte sheep retrovirus DNA and RNA in bronchioloalveolar and conventional human pulmonary adenocarcinoma by PCR and RT-PCR analysis.Hum Pathol 32:1039–42PubMedCrossRefGoogle Scholar
  64. Zochbauer-Muller S, Fong KM, Maitra A, Lam S, Geradts J, Ashfaq R, Virmani AK, Milchgrub S, Gazdar AF, Minna JD (2001) 5′ CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer. Cancer Res 61:3581–5Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • J.-F. Mornex
    • 1
  • F. Thivolet
    • 1
  • M. De Las Heras
    • 2
  • C. Leroux
    • 1
  1. 1.Université Claude Bernard, UMR 754 UCB-INRA-ENVLLyonFrance
  2. 2.Departamento de Patologia AnimalUniversidad de ZaragozaZaragozaSpain

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