Use of fluorescence in situ hybridization to distinguish metastatic uveal from cutaneous melanoma.
ABSTRACT Metastatic lesions of malignant melanoma can on occasion be difficult to classify with regard to the primary site of origin. Given the lack of specificity of light microscopic features, ancillary studies are needed. In this study, the authors explored the possibility of distinguishing metastatic tumors derived from uveal primaries from those known to have originated from a cutaneous melanoma by fluorescence in situ hybridization (FISH) using probes for chromosome 3, 8q24, and 1p36. A total of 32 metastatic tumors were analyzed by FISH. Monosomy 3 was detected in 9 out of 16 (56.3%) cases of metastatic uveal melanoma but was not found in any of the 16 metastatic cutaneous melanomas (P < .001). With regard to 1p36, amplifications were found in 8 out of 16 (50%) cases of metastatic cutaneous melanoma but not in any case of uveal melanoma (P < .05). 1p36 was deleted in 3 cases of uveal and 1 case of cutaneous melanoma. Amplifications of 8q were found in 15 out of 16 (94%) cases of uveal melanoma metastases and in 12 out of 16 (75%) cases of cutaneous metastases. The findings suggest that FISH for monosomy 3 is a useful adjunct tool in the differential diagnosis of metastatic uveal versus cutaneous melanoma.
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ABSTRACT: Genetic abnormalities of chromosomal arm 8q have been reported by many studies in uveal melanoma. To better understand the role of 8q abnormalities in uveal melanoma development, copy number anomalies of the c-myc oncogene (located on 8q24.1) have been investigated. Forty-three uveal melanomas were analyzed by fluorescent in situ hybridization (FISH) with probes for c-myc and the chromosome 8 centromere. Results of the FISH analysis were compared with genetic changes previously detected by microsatellite analysis on chromosomes 3 and 6p. Thirty uveal melanomas (70%) had extra copies of c-myc, 2 tumors (5%) had loss of c-myc, and 11 tumors (25%) had no abnormalities in c-myc copy number. Of those with extra copies of c-myc, 13 tumors (43%) had amplification of the c-myc gene, 14 tumors (47%) had an intermediate relative increase in the c-myc copy number, and 3 tumors (10%) had a simple gain of chromosome 8. An association between larger tumor size and c-myc amplification was found (P < 0.01). Although extra copies of c-myc were seen in tumors with retention of chromosome 3, remarkably only tumors with monosomy 3 showed amplification of c-myc (P = 0.03). The specific amplification of the c-myc oncogene detected in at least 30% of primary uveal melanomas cannot be explained by the simple 8q abnormalities observed in cytogenetic studies. The striking association between c-myc amplification and monosomy 3 suggests a unique pathway of genetic progression in a subset of uveal melanomas.Investigative Ophthalmology & Visual Science 07/2001; 42(8):1679-84. · 3.44 Impact Factor
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ABSTRACT: Amplification and overexpression of the c-myc gene have been associated with neoplastic transformation in a plethora of malignant tumours. We applied interphase fluorescence in situ hybridization (FISH) with a locus-specific probe for the c-myc gene (8q24) in combination with a corresponding chromosome 8 alpha-satellite probe to evaluate genetic alterations in 8 primary melanomas and 33 advanced melanomas and compared it to 12 melanocytic nevi, 7 safety margins and 2 cases of normal skin. Additionally, in metaphase spreads of 7 melanoma cell lines a whole chromosome 8 paint probe was used. We investigated the functionality of the c-myc gene by detecting c-myc RNA expression with RT-PCR and c-myc protein by immunohistochemistry. 4/8 primary melanomas and 11/33 melanoma metastases showed additional c-myc signals relative to the centromere of chromosome 8 copy number. None of the nevi, safety margins or normal skin samples demonstrated this gain. In 2/7 melanoma cell lines (C32 and WM 266-4) isochromosome 8q formation with a relative gain of c-myc copies and a loss of 8p was observed. The highest c-myc gene expression compared to GAPDH was found in melanoma metastases (17.5%). Nevi (6.6%) and primary melanomas (5.0%) expressed the c-myc gene on a lower level. 72.7% of the patients with c-myc extra copies had visceral melanoma metastases (UICC IV), patients without c-myc gain in 35.0% only. The collective with additional c-myc copies also expressed the gene on a significantly higher level. These results indicate that a c-myc gain in relation to the centromere 8 copy number might be associated with advanced cutaneous melanoma.British Journal of Cancer 02/2001; 84(1):72-9. · 5.08 Impact Factor
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ABSTRACT: Melanomas of the ocular and adnexal structures comprise approximately 5% of all melanomas. The majority (85%) of ocular melanomas are uveal in origin; primary conjunctival and orbital melanomas are rare. The diagnosis of uveal melanoma is made by clinical examination including indirect ophthalmoscopy and by ancillary studies such as fluorescein angiography and ultrasonography. Metastases to the liver develop within 15 years after the initial diagnosis and treatment in approximately 50% of patients with posterior uveal melanoma; however, clinically evident metastatic disease at the time of initial presentation is uncommon, indicating that there is early subclinical metastasis in most cases.Ophthalmology Clinics of North America 04/2005; 18(1):75-84, viii.