## 4 Discussion
Previous authors have postulated a direct relationship between the duration of the time frame between radiotherapy and enucleation and the amount of histopathological alterations [24]. According to [PERSON] et al., in particular, areas of necrosis were more numerous and extensive several months after irradiation [24]. Necrosis in irradiated tumors is the result of a dual effect: (1) a direct cytotoxic effect of radiation on neoplastic cells, and (2) an indirect action through the damage of neoplastic vasculature with resultant ischemia. Immune response against degenerated and necrotic neoplastic cells, in the form of inflammatory infiltrates (often with a perivascular distribution), would also play a role in tumor regression [24; 27]. From a histological point of view, radiation-induced necrosis is characterized by dispersion of the melanin pigment with storage of pigment-laden macrophages [32]. In our study, at the histopathologic examination, we found necrosis in 5/9 irradiated tumors; in 4 of these patients necrosis was seen under MR imaging. Radiation-induced necrosis had a peculiar appearance under MR imaging. It showed low signal intensity on T2-weighted images because of melanin pigment dispersion. Moreover, when proton beam radiotherapy-induced necrosis and viable neoplastic tissue were present in the treated tumor, the border between these two areas was well-defined under MRI. This finding, particularly evident in T2-weighted sequences, had a strong overlap with histopathology, showing a stark transition between the two distinct portions of the tumor. Such an appearance is related to the physical properties of protons and, in particular, to the possibility of obtaining a highly collimated beam with minimal lateral scatter [22; 23]. Therefore, the appearance of radiation-induced necrosis is different from that of spontaneous necrosis, observable in nonirradiated melanomas, especially in those of considerable size. Our observation is in contrast with that of [PERSON] et al. who, in a previous article, assumed the impossibility of the pathologist being able to distinguish radiation-induced necrosis from spontaneous necrosis in uveal melanomas [22]. On the other hand, [PERSON] et al., taking into account different histologic findings, managed to distinguish irradiated from nonirradiated eyes in 85% of cases of their series [27]. [PERSON] et al. suggested that the time course of necrotic alterations after radiotherapy could be related to the baseline dimensions of the neoplasm; in particular, small lesions would exhibit necrotic alterations earlier than large tumors [29]. We agree with this hypothesis, not only as regards the necrosis, but also with regard to another degenerative alteration--namely, fibrosis. Indeed, in our series, the choroidal melanoma that showed fibrotic alterations was a relatively small lesion (basal diameters 4 \(\times\) 4 mm, prominence 6 mm), and the time course from radiotherapy to enucleation was rather short. In this patient, exhibiting complete tumor regression in the form of fibrotic remnants, the low signal intensity on T2-weighted images was related to fibroblasts, collagen deposition, and the abundant presence of melanophages. Our data are consistent with those of [PERSON] et al. who, in two uveal melanomas enucleated after proton beam radiotherapy, found areas of fibrosis characterized by storage of collagen inside the stroma [25]. In our opinion, however, factors other than tumor size should also be taken into account, such as tumor response to radiotherapy, which may be heterogeneous and related to other determinants, including histologic type, cell kinetics, and host immune response [33]. Inflammatory complications are rather common after proton beam radiotherapy, being reported in 28% of patients during the first 5 years of treatment. Tumor size is considered the main risk factor [34]. Inflammatory complications encompass a wide spectrum of clinical manifestations (uveitis, endophthalmitis, conjunctivitis, etc.).