Relevance Of Immunological Response To Orbital Tumors

Orbital tumors constitute a heterogeneous array of lesions that may originate from tissues of the orbit itself (primary tumors), extend from neighboring structures (secondary tumors), or come from distant sites (metastatic tumors),58 and, as such, they pose numerous challenges in terms of diagnosis, imaging and treatment. Moreover, given the heterogeneity of tumor types developing in the orbit, the causal role of genetic alterations, viruses, chemicals, gene methylation, histone acetylation, and so on, would not only be hard to define but would also require an entire book to be reported in detail. Few studies exist in the literature concerning molecular investigations on orbital tumors, with the exceptions of primary orbital rhabdomyosarcoma and retinoblastoma extended into orbital structures.

Even with these limitations, orbital tumors follow the general principles regarding cancer etiology cited in this chapter, and, as such, are of great interest for both pathology and molecular biology. Both retinoblastoma and rhabdomyosarcoma, the first as a secondary and the second as a primary orbital tumor, cover the entire spectrum of the evolution of knowledge reported so far in the field of cancer etiology and pathogenesis. Retinoblastoma has represented the prototype of cancer due to the loss or inactivation of a tumor suppressor gene, and for a long time has remained the most significant example of cancer determined by small structural modifications of a gene.59 Rhabdomyosarcoma of the orbit, to the contrary, while occurring at an average age quite close to that reported for retinoblastoma, has always shown a more complex pathogenesis. in particular, gross chromosomal alterations, such as the translocation t(2;13) (q35-q14) or t(1;13) (q36-q14), involving the PAX3 and PAX7 genes, have been detected in alveolar rhabdomyosar-coma,60 while a number of different genes (either oncogenes or tumor suppressor genes) have been reported to be involved in the genesis of the embryonal form of the disease.61 More recently, the investigation of the methylation profile of retinoblastoma has shown that RASSF1A and CASP8 (a tumor suppressor gene and a gene involved in the apoptotic process, respectively) are frequently methylated and "silenced" in retinoblastoma, thus showing that other genes may play a role in the genesis of retinoblastoma and that reducing its pathogenesis to the alteration of a single gene represents an oversimplification.62,63 Moreover, the recent observation that microsatellite instability often occurs in embryonal rhabdomyosarcoma of the orbit represents an important clue into the pathogen-esis of this disease, possibly implying a role for ge-nomic instability and the related events in the process of cancer development.64

The same reasoning can be applied to orbital malignant tumors arising later in life. A recent review65 has shown that malignant lymphoma is the most common malignant tumor of the orbit in the population over the age of 60 years, accounting for 24% of cases.65 Malignant lymphoma, particularly the diffuse large-cell lymphoma (DLCL) has been shown to depend from an aberrant hypermutation state whose nature and consequences appear to be very similar to those described elsewhere under the generic term of genomic instability, which can be in part, considered "physiologic" for lymphocytes belonging to the B-cell lineage.66 Finally, human papilloma virus has been reported in neoplas-tic and nonneoplastic conditions of the external eye,67 as well as its possible relationship with an increased expression of the p53 protein, with consequent prognostic implications, particularly in conjunctival squamous cell carcinoma (CSCC),68 thus demonstrating the potential of the application of molecular techniques in the study of orbital tumors.68

in summary, although the application of the principles and procedures of the molecular biology to cancer arising in the orbit is not very common, it can be of great potential value for both diagnostic and therapeutic purposes. Therefore, it is highly desirable for the ophthalmologist to become acquainted with the basic principles in the perspective of a modern and more effective approach to patients with tumors involving the orbit.


1. Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res 1970;13:1-23.

2. Wick M, et al. Antigenic cancer cells grow progressively in immune competent hosts without evidence of T-cell exhaustion or systemic anergy. J Exp Med 1997;186:229-238.

3. Joklik WK, Willett HP, Amos DB. Immunity to tumors and pregnancy. In: Zinsser Microbiology. 18th ed. Norwalk, CT: Appleton-Century-Crofts; 1984.


5. Li R, Sonik A, Stindl R, et al. Aneuploidy vs gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy. Proc Natl Acad Sci U S A 2000; 97:7, 3236-3241.



8. Djeu JY, Jiang K, Wei S. A view to a kill: signals triggering cytotoxicity. Clin Cancer Res 2002;8:636-640.

9. Medzhitov R, Janeway CA Jr. Decoding the patterns of self and non-self by the innate immune system. Science 2002;296: 298-300.

10. Metzinger P. The danger model: a renewed sense of self. Science 2002;296:301-305.

11. Moretta L, Biassoni R, Bottino C, et al. Natural killer cells: a mystery no more. Scand J Immunol 2002;55:229-232.

12. Foss FM. Immunologic mechanisms of antitumor activity. Semin Oncol 2002;29(suppl 7):5-11.

13. Vicari AP, Caux C. Chemokines in cancer. Cytokines Growth Factors Rev 2002;13:143-154.

14. Homey B, Muller A, Zlotnik A. Chemokines: agents for the immunotherapy of cancer? Nat Rev Immunol 2002;2:175-184.

15. Finn OJ, Lotze MT. A decade in the life of tumor immunology. Clin Cancer Res 2001(suppl);7:759-760.

16. De Pinho RA. The age of cancer. Nature 2000;408:248-254.

17. American Cancer Society. Cancer Facts and Figures, 2000. Atlanta: American Cancer Society; 2000:1-7.

18. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956;6:298-300.

19. Ames BN, Shigenega MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A 1993;90:7915-7922.

20. Minnik DT, Kunkel DA. DNA synthesis errors, mutations and cancer. Cancer Surv 1996;28:3-20.

21. Kinzler KW, Vogelstein B. Familial cancer syndromes: the role of caretakers and gatekeepers. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 1. 8th ed. New York: McGraw-Hill Medical Publishing; 2001:675-676.

22. Karran P. Human mismatch repair: defects and predisposition to cancer. Encyclopedia of Life Sciences.

23. Anderson GR. Genomic instability in cancer. Curr Sci 2001;81: 501-507.

24. Loeb LA. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 1991;51:3075-3079.

25. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87:159-170.

26. Atkin NB. Microsatellite instability. Cytogenet Cell Genet 2001;92:177-181.

27. Granger MP, Wright WE, Shay JW. Telomerase in cancer and aging. Crit Rev Oncol/Hematol 2002;41:29-40.

28. Wright WE, Shay JW. Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nat Med 2000;6:849-851.

29. Mathon NF, Lloyd AC. Cell senescence and cancer. Nat Rev Cancer 2001;1:203-213.

30. Sheel C, Poremba C. Telomere lengthening in telomerase neg ative cells: the ends are coming together. Virchows Arch 2002; 440:573-582.

31. Shay JW, Wright WE. Telomeres and telomerase: implications for cancer and aging. Radiat Res 2001;155:188-193.

32. Artandi S, Chang S, Lee S-L, et al. Telomere dysfunction promotes non-reciprocal translocations in epithelial cancer in mice. Nature 2000;406:641-645.

33. Pathak S, Multani AS, Furlong CL, Sohn SH. Telomere dynamics, aneuploidy, stem cells, and cancer [review]. Int J Oncol 2002;20:637-641.

34. Butel JS. Viral oncogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis 2000;21: 405-426.

35. Rous P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J Exp Med 1911;13:397-411.

36. Lane TP, Crawford LV. T antigen is bound to a host protein in SV-40 transformed cells. Nature 1979;278:261-263.

37. Finlay CA, Hinds PW, Levine AJ. The p53 proto-oncogene can act as a suppressor of transformation. Cell 1989;57:1083-1093.

38. Whyte P, Buchowich KJ, Horowitz JM, et al. Association between an oncogene and an anti-oncogene. The adenovirus E1A protein binds to the retinoblastoma gene product. Nature 1988;334:124-129.

39. Butel JS, Ledniky JA. Cell and molecular biology of simian virus 40: implications for human infections and disease. J Natl Cancer Inst 1999;91:119-134.

40. Chang MH, Chen CJ, Lai MS, et al. for the Taiwan Childhood Hepatoma Study Group (1997). Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997;336:1855-1859.

41. Bischoff JH, Kim DH, Williams A, et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996;274:373-376.

42. Mullen JT, Tanabe KK. Viral oncolysis. Oncologist 2002;7: 106-119.

43. Upton AC. Historical perspectives in radiation carcinogenesis. In: Upton AC, Albert RE, Burns FJ, Shore RE, eds. Radiation Carcinogenesis. New York: Elsevier; 1986:1-10.

44. Goodhead DT. Initial events in the cellular effects of ionising radiations: clustered damage in DNA. Int J Radiat Biol 1994;142:362-368.

45. Ward JF. Radiation mutagenesis: the initial DNA lesions responsible. Radiat Res 1995;79:7763-7767.

46. Jackson SP. Sensing and repairing DNA double-strand breaks. Carcinogenesis 2002;23:687-696.

47. Little JB. Radiation carcinogenesis. Carcinogenesis 2000;21: 397-404.

48. Anderson AG. Genomic instability in cancer. Curr Sci 2001;81: 501-507.

49. Wu L, Randers-Perhson G, Xu A, et al. Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells. Proc Natl Acad Sci U S A 1999;96:4959-4964.

50. Kawanishi S, Hiraka Y, Oikawa S. Mechanism of guanine-specific DNA damage by oxidative stress and its role in car-cinogenesis and aging. Mutat Res 2001;488:65-76.


52. Prise KM, Belyakov OV, Folkhard M, Michael BD. Studies of bystander effects in human fibroblasts using a charged particle microbeam. Int J Radiat Biol 1998;74:793-798.

53. International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals in Humans. No 29. Lyons, France: IARC, 1982:16.

54. Weisburger J, Williams G. Chemical carcinogens. In: Klaasen CD, Amdur MO, eds. Toxicology: The Basic Science of Poisons. 2nd ed. New York: Macmillan; 1980:84-138.

55. Ehremberg L, Brookes P, Druckrey H, et al. The relation of cancer induction and genetic damage. In: Ramel C, ed. Evaluation of Genetic Risks of Environmental Chemicals. Stock holm: University of Stockholm; 1973. AMBIO Special Report No 3, pp. 15-16.

56. Williams GM. Mechanisms of chemical carcinogenesis and application to human cancer risk assessment. Toxicology 2001; 166:3-10.

57. Klaunig JE, Xu SI, Isenberg JS, Bachowski S, et al. The role of oxidative stress in chemical carcinogenesis. Environ Health Perspect 1998;106(suppl 1):289-295.

58. Darsaut TE, Lanzino G, Lopes MB, Newman S. An introductory overview of orbital tumors. Neurosurg Focus 2001;10:1-9.

59. Newsham IF, Hadjistilianou T, Cavenee WK. Retinoblastoma. In: Vogelstein B, Kinzler KW, eds: The Genetic Basis of Human Cancer. 2nd ed. New York: McGraw-Hill; 2002:357-386.

60. Meltzer PS, Kallioniemi A, Trent JM. Chromosome alterations in human solid tumors. In: Vogelstein B, Kinzler KW, eds. The Genetic Basis of Human Cancer. 2nd ed. New York: McGraw-Hill; 2002:93-113.

61. Mastrangelo D, Sappia F, Bruni S, et al. Loss of heterozygosity on the long arm of chromosome 11 in orbital embryonal rhab-domyosarcoma (OERMS): a microsatellite study of seven cases. Orbit 1998;17:89-95.

62. Harada K, Toyooka S, Maitra A, et al. Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines. Oncogene 2002;21:4345-4349.

63. Harada K, Toyooka S, Shivapurkar N, et al. Deregulation of Caspase 8 and 10 expression in pediatric tumors and cell lines. Cancer Res. 2002;62:5897-5901.

64. Mastrangelo D, Hadjistilianou T, Mazzotta C, Loré C. Microsatellite instability in three cases of embryonal rhabdomyosarcoma of the orbit. Med Pediatr Oncol 2002;39:132-133.

65. Demirci H, Shields CL, Shields JA, et al. Orbital tumors in the older adult population. Ophthalmology 2002;109:243-248.

66. Pasqualucci L, Neumeister P, Goossens T, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphoma. Nature 2001;412:341-346.

67. Karcioglu ZA, Tawfik MI. Human papilloma virus in neoplastic and nonneoplastic conditions of the external eye. Br J Ophthalmol 1997;81:595-598.

68. Karcioglu ZA, Toth J. Relation between p53 overexpression and clinical behavior of ocular/orbital invasion of conjunctival squamous cell carcinoma. Ophthalmol Plast Reconstr Surg 2000;16:443-449.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment