Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

with angiogenesis, one must assume that the endothelial cell markers used in the studies were specific for endothelium and were not expressed on tumor cells. It has been shown recently that endothelial cell markers are indeed expressed in uveal melanoma cells in tissue section and that the parameter called ‘‘microvascular density’’ measures both the number of blood vessels and genetically deregulated tumor cells [92a]. In fact, even students of angiogenesis [93] concede that, at the time of this writing, there are no markers, either ultrastructural or immunohistochemical, specific for endothelium. Perhaps, then, the attribute described as microvascular density includes not only counts of blood vessels but also highly aggressive, genetically deregulated tumor cells. In a tumor that lacks lymphatics [7], both new blood vessels and aggressive tumor cells might contribute to metastasis.

When observations originate from in vitro experiments, it is necessary to confirm the observations in human tissue samples. For example, although it has been validated repeatedly that the expression of keratins 8 and 18 by melanoma cells is associated with aggressive behavior in vitro [88,89,94,95]; studies of the labeling of melanoma cells in histological sections of eyes removed for uveal melanoma with this marker suggest an association with invasive behavior [96] but have failed to establish any association between keratin labeling and adverse outcome [97].

Likewise, animal models may mirror the behavior of human disease for some attributes and not others [98]. For example, there are elegant animal models of human uveal melanoma in which tumor cells disseminate to the liver [99], mimicking the behavior of most choroidal and ciliary body melanomas. Nevertheless, many animal models of uveal melanoma established by the xenotransplantation of human or animal melanoma cell lines to the eyes of immunosuppressed mice show evidence of extensive necrosis in the tumor (accompanied by robust angiogenesis) [62]. Extensive necrosis is not a feature typical of most human melanomas, and it becomes challenging to determine if the angiogenesis in these models is in response to necrosis or an intrinsic property of the tumor in the model. Thus, one of the most important reasons for maintaining large data sets of human uveal melanoma tissues is to test the validity of observations made in vitro and from animal models on robust human tissue sample repositories for which long-term outcome is known.

New markers identified from tissue studies of larger series of melanoma have now associated the expression of insulin growth factor receptor [100], integrins [101,102], ezrin [103], markers of cell cycling and apoptosis [41–43,104,104–109], HLA expression [110], and tissue macrophages [111] with adverse outcome. Cytogenetic studies, once restricted to analyses on fresh tissue samples, may now be applied to tissue sections by fluorescent in situ hybridization (FISH) techniques [112]. From these studies, one may then design experiments to delineate mechanisms associated with metastasis and thus develop new therapeutic strategies. Thus, the importance of the pathologist’s identification of new prognostic markers extends far beyond the goal of stratifying patients into risk categories and places the ophthalmic pathologist who studies tissue markers of prognosis on the front lines of cancer research.

ACKNOWLEDGMENTS

Supported by NIH grant E410457.

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Figure 1 Retinocytoma. Bland retinocytes with small nuclei and no mitotic activity have formed fleurettes.

studied clinically are identical to the retinocytomas of Margo and coworkers [6]. These benign tumors have a very similar appearance to retinoblastomas that have undergone regression after radiation therapy [8], and for this reason some investigators consider them to be spontaneously regressed retinoblastomas. Eagle et al. [9] described an interesting case in which a benign retinocytoma or retinoma, after remaining stable in this patient from age 4 until age 7, suddenly began to grow rapidly. Histology indicated that there were two distinct components to the tumor. The inner component was a typical endophytic retinoblastoma and the outer component was a typical retinocytoma. The delayed rapid growth of this tumor would be very unusual behavior if this were a spontaneously regressed tumor.

The pseudoretinoblastomas are nonneoplastic conditions that mimic retinoblastoma clinically. They include a variety of lesions, but the most common are Coats disease, which probably represents a vascular malformation of the retina; persistent hyperplastic primary vitreous, a congenital anomaly; and Toxocara endophthalmitis, a nematode infection. In series based on clinical experience, the frequency of pseudotumors (approximately 50%) is higher than in series based on pathological specimens, because when these entities are correctly diagnosed, they are usually managed without generating a pathological specimen [10].