Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

retinoblastoma, an occasional patient will present with an osteogenic or soft tissue sarcoma prior to detection of retinoblastoma. Because of its recognized association with germinal retinoblastoma, any person diagnosed with osteogenic or soft tissue sarcoma during the retinoblastoma-at-risk age period (birth to age 10 years) should probably be evaluated ophthalmologically to detect or rule out retinoblastoma.

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readily establish as short-term cultures and have consistent chromosomal alterations without the complexity and heterogeneity often experienced with most solid tumors. Such advantages have allowed an exponential growth in our knowledge of the relevant and specific changes associated with these primary eye tumors.

II.CYTOGENETIC STUDIES OF UVEAL MELANOMA

At the beginning of the last decade, five studies totaling 22 cases had reported observations on the chromosomal changes found in posterior uveal melanomas [4– 8]. Even at this early stage a consistent pattern of chromosomal involvement began to emerge, with changes of chromosomes 1, 3, 6, 8, and the Y chromosome repeatedly found [6–8]. The simplest alterations in uveal melanoma are losses or gains of entire chromosomes. In the majority of tumors from male patients the Y chromosome is lost; but for both sexes, the commonest change, found in approximately 50% of posterior uveal melanomas, is the loss of one copy of chromosome 3 (monosomy 3). In most instances tumors with monosomy 3 were also found to have changes of chromosome 8, which effectively produced gain of material from the long arm of chromosome 8 (8q). There is now strong evidence to indicate that these alterations are associated and define a subsection of uveal melanomas [8– 15]. Changes of chromosomes 1 and 6, although less frequent, seem equally important. For the most part they are present as structural alterations, which produce deletions of the short arm of chromosome 1 (1p), deletions of the long arm of chromosome 6 (6q), and gain of the short arm of chromosome 6 (6p). The aforementioned chromosomal alterations are not necessarily important to all uveal melanomas, and evidence suggests that melanomas of the anterior uvea, affecting the iris, may possess entirely different chromosomal alterations [16,17]. Iris melanomas are relatively benign in comparison to posterior uveal melanomas; it is possible that the distribution of chromosomal changes found in uveal melanoma contribute to these phenotypic differences.

Currently chromosomal studies in over 200 cases of posterior uveal melanomas have been detailed. Simple cytogenetic analysis of chromosomal changes has been increasingly supported by fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), spectral karyotyping (SKY), and microsatellite analysis (MSA) [15,18–21]. In combination, these studies have confirmed the nonrandom involvement of these chromosomes with primary uveal melanoma and have began to delineate other less common alterations that may also have a direct bearing on the pathogenesis of these melanomas.

A.Monosomy 3 and Isochromosome 8q

The high frequency with which monosomy 3 is found in posterior uveal melanomas would seemingly implicate this change in the malignant transformation of the uveal melanocyte. It is also of interest that, at least at the level of cytogenetics, an entire copy of chromosome 3 appears to be deleted, and there is a virtual absence of chromosome 3 rearrangements. There is also little heterogeneity for monosomy 3; when present, for the majority of cases, it is so within all abnormal cells of the tumor population analyzed. Occasionally monosomy 3 also appears to be the only visible

[13,22,24]. Loss of chromosome 3 arises prior to 8q amplification, and abnormalities of 8 are thought to be secondary chromosome changes associated with clonal evolution [6,18,19,22]. Indeed, in a total of eight metastatic lesions of uveal melanoma so far reported, all demonstrated abnormalities of chromosome 8 but not always monosomy 3 [4,25,26], suggesting that changes in chromosome 8 may be more important in the generation of a metastatic phenotype.

The association of certain chromosomal changes with clinical features established as prognostic parameters raised the possibility that chromosomal abnormalities themselves may correlate directly with the prognosis of uveal melanomas—a situation that is perhaps unparalleled in other adult solid tumors. In particular, monosomy 3 and 8q were found to be mainly correlated with ciliary body melanomas [8,10–12], and recent evidence suggests that these changes are also related to an epithelioid cell type [27]. Both of these factors are considered to be indicators of a poor prognosis [28]. The first chromosomal abnormality to be directly correlated to prognosis was also the most frequent—namely, monosomy 3. In this first report, by Prescher and coworkers, all patients with normal copies of chromosome 3 (n ¼ 24) survived 3 years after diagnosis, whereas only 57% of those patients with monosomy 3 (n ¼ 30) survived the same interval [15]. Loss of chromosome 3 was therefore suggested to correlate strongly with a poor prognosis of the patient. Following this initial report, the importance of monosomy 3 was again confirmed by a later study [18]. In addition, this later investigation also correlated extra copies of 8q with poor survival, suggesting a possible dosage effect, whereby increased amplification of 8q correlated with a reduced survival and a reduced disease-free interval [18]. White and associates again linked changes of both chromosomes 3 and 8 with poor prognosis, but they were predictive only when found together [29]. Besides cytogenetics, other techniques have also been employed to establish chromosomal abnormalities as prognostic indicators in uveal melanoma. CGH analysis contributed to the results of the first study associating chromosome alterations with prognosis [15]; of late, FISH in particular has been increasingly used. Initially, McNamara and associates used FISH to assess chromosome 3 copy number, but prognosis was not assessed [30]. More recently, Patel and associates applied FISH to determine the relative imbalance in copy numbers of chromosomes 3 and 8 and correlated these to patient survival [31]. An imbalance in chromosome 3 and 8 copy number was shown to significantly correlate with patient survival over a minimum follow-up of 9 years [31]. Only those patients with a genetic imbalance for chromosomes 3 and 8 died from metastatic disease, with the median survival being 37 months; while for the group with no abnormalities, median survival was 114 months [31]. In combination, the evidence from these studies suggests that monosomy 3 alone or when considered with amplification of 8q is a highly reliable indicator of prognosis.

B.Chromosome 6

Chromosome 6 abnormalities are perhaps some of the earliest changes to be associated with posterior uveal melanoma, and appear to be among the most consistent cytogenetic alterations in these tumors. Although both arms of the chromosome are affected, producing deletions of 6q and gains of 6p (Fig. 2), these changes can occur independently and, unlike monosomy 3, they appear to arise as a

Figure 2 Representative karyotype from a primary posterior uveal melanoma. No obvious deletions of chromosome 3 are present, but an 8p deletion is present, and an additional large derivative chromosome 8. Also seen is involvement of band 11q23 and loss of 6q, resulting from an unbalanced translocation. Chromosomal painting confirmed that the large derivative chromosome 8 was almost entirely composed of additional chromosome 8 material. Small rearrangements of chromosome 3 appeared to be absent. 43,X-Y,-6,add(8)(p21), þ add(8)(p23),-9,add(11)(q23),der(14)t(6;14)(p21;p11),-21

result of more complex mechanistic structural alterations. Needless to say, they are often present in the form of an isochromosome of the short arm, i(6)(p10); therefore, assuming that change is not additional, they encompass both the deletion of the long arm and the gain of the short arm in a single alteration [7,12,24]. Using CGH, isochromosome formation, whether of chromosome 1, 6, or 8, has been suggested to be more often associated with the presence of monosomy 3 [26], and certainly cytogenetic studies confirm that chromosome 3 loss and i(6)(p10) do occur together [7,12,24]. Paradoxically, an alternative pathway has also been suggested, one in which loss of chromosome 3 and the gain of 6p are mutually exclusive [19]. This apparent contradiction may be explained through the work of Tschentscher and associates, who used MSA to investigate chromosomal changes [32]. The study was able in part to confirm the mutual exclusivity of monosomy 3 and 6p gain [32], finding that their occurrence together was much less frequent, occurring in only 1 of 13 tumors [32]. It would appear that 6p alterations are infrequent in tumors with monosomy 3, and it is possible that two distinct pathways exist [19].

Equally confusing is the potential association between chromosome 6 and prognosis, unlike those changes of chromosomes 3 and 8, which are indicators of poor outcome. One study has shown that rearrangements of chromosome 6 predict

better survival [29]. This effect appears to be maintained even in the presence of monosomy 3 and additional copies of 8q [29], but the relationship is complex, and it is unclear whether it is the overrepresentation of 6p or a loss of 6q that actually produces the association. The involvement of chromosome 6 changes in uveal melanoma seems at best to be contradictory. It is possible that by attempting to make comparisons between studies in which essentially different techniques are used—cytogenetics, FISH and MSA—a distortion of results may arise, providing contrary observations which, with continued study, may be resolved [32]. If two distinct pathways of genetic change do exist in uveal melanomas, one defined by monosomy 3 and i(8q) and indicting poor survival and the other by 6p gain, it would seem entirely plausible that 6p may under these circumstances give rise to an indication of favorable prognosis, thus leaving only those tumors in which visible changes of both chromosomes 3 and 6 occur together to be explained.

C.Chromosome 1

Changes in chromosome 1 are less frequent than those of 3, 6, and 8 but nevertheless are found in approximately 30% of all uveal melanomas [7,12,19,24,33]. Abnormalities mainly involve rearrangements or deletions of 1p, and the changes are comparable to those found in cutaneous melanomas, where distal alterations of 1p are one of the commonest changes, found in about 80% of cases [3,34]. Ciliary body melanomas tend to have more cytogenetic abnormalities of chromosome 1 than tumors arising from other parts of the uveal tract [7,12,24,33]. In cutaneous melanoma, rearrangements or deletions of 1p are thought to relate to tumor progression [7,35]. It is possible that a comparable situation exists in uveal melanoma, since deletions of 1p are less frequent than those of chromosomes 3 and 8 and may therefore be subsequent to these changes. In addition, a higher incidence of 1p rearrangements are reported in larger melanomas [24], and recent data have indicated that loss of chromosome 1p is present only in primary uveal melanoma that had metastasized and in metastases themselves [26]. It would seem likely that rearrangements of chromosome 1 are indicative of more advanced melanomas, suggesting that chromosome 1 is the location of a uveal melanoma metastatic suppressor gene or genes [26]. As changes in chromosome 1 have been directly correlated with aggressive uveal melanomas, it would be reasonable to anticipate that they may prove to be reliable indicators of poor prognosis, but confirmation is required by further study.

D.Other Chromosome Changes

As tumors progress, they appear to acquire more chromosomal abnormalities, and although uveal melanomas typically have relatively few chromosomal changes, they too show a correlation between additional chromosomal losses and gains and increasing tumor size, suggesting that such numerical alterations are random [24]. Some of these other changes, however, may be more specifically related, in particular those abnormalities producing structural rearrangements; evidence suggests that chromosomes 9, 10, 11, 21, and Y may be of more direct importance to uveal melanomas [7,11–14,24,33,36,37]. Most of these other alterations tend to occur in a limited number of cases, but the loss of the Y chromosome affects the majority of