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.
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