Classifying ambiguous melanocytic lesions with FISH and correlation with clinical long-term follow up

Gaiser, Timo; Kutzner, Heinz; Palmedo, Gabriele; Siegelin, Markus D.; Wiesner, Thomas; Brückner, Thomas; Hartschuh, Wolfgang; Enk, Alexander; Becker, Maria

doi:10.1038/modpathol.2009.177

Cited by 128 publications

(98 citation statements)

References 22 publications

(27 reference statements)

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“…diagnosis of melanoma, 5,6 but is of limited utility in the assessment of histologically ambiguous melanocytic skin tumors. 12 Although the aCGH profiles correlated well with the morphological features of MLN, the correlation with FISH was poorer. The higher sensitivity of aCGH is explained by the fact that the FISH test only evaluates four genomic loci for gains and losses, in contrast to aCGH, which surveys the entire genome (Figure 2c).…”

Section: Discussionmentioning

confidence: 89%

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Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests

et al. 2012

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Cutaneous melanomas are characterized by a range of histological appearances, and several morphological variants have been described. In this study, we report a variant of superficial spreading melanoma that is characterized by large, irregular junctional melanocytic nests. The junctional nests varied in shape and size, showed focal tendency to confluence, and were often surrounded by a cuff of epidermal keratinocytes. The melanocytes comprising the nests showed variable cytological atypia. In most of the cases, scant intraepidermal or junctional single melanocytes were seen, and other well-documented diagnostic criteria for melanoma were lacking, and as a result, histological recognition of these tumors as melanoma was difficult. Some cases were associated with an invasive dermal component or showed evidence of sun damage. To provide supporting evidence for malignancy, we analyzed these tumors for genomic aberrations. Using array comparative genomic hybridization (aCGH), we identified multiple genomic aberrations in all analyzed cases. A similar pattern of genomic aberrations was seen in a control group of bona fide superficial spreading melanomas, suggesting that these 'melanomas composed exclusively or predominantly of large nests' are indeed variants of superficial spreading melanoma. Fluorescence in-situ hybridization (FISH) was positive in 40% of the cases. However, using aCGH, the FISH-negative cases showed multiple genomic aberrations in regions that are not covered by FISH. The low sensitivity of the FISH test can be explained by the fact that FISH only evaluates four genomic loci for aberrations, whereas aCGH surveys the entire genome. In summary, we present histological and molecular genetic evidence for a morphological variant of superficial spreading melanoma. Awareness of the histological features will aid in their correct diagnosis as melanoma, and in difficult cases, judicious application of ancillary tests such as aCGH (rather than FISH) will assist accurate diagnosis. Modern Pathology (2012) 25, 838-845; doi:10.1038/modpathol.2012; published online 2 March 2012 Keywords: chromosomal aberrations; comparative genomic hybridization; fluorescence in-situ hybridization; melanocytic tumors; melanoma Cutaneous melanomas are characterized by a diverse range of histological appearances, and several morphological variants have been described. The most common subtypes in histological classification systems are superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. 1 Although histological evaluation is a reliable means of accurately classifying melanocytic tumors as benign

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Section: Discussionmentioning

confidence: 89%

“…5,12 The 5-mmthick sections were obtained from formalin-fixed paraffin-embedded tissue and mounted on SuperFrost Plus positively charged slides. The slides were baked overnight at 56 1C, deparaffinized in xylene, and dehydrated in ethanol.…”

Section: Fluorescence In Situ Hybridizationmentioning

confidence: 99%

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests

et al. 2012

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“…The sensitivity and specificity of the FISH method varies dramatically among existing reports with the lesion subtype, the probe set used, the number of observers, and the cutoff thresholds used. Various authors have reported a FISH sensitivity ranging from 43% to 94% and a specificity ranging from 60% to 98% 24, 25, 26, 27, 28. The original 4‐probe FISH assay targeting 6p25 (RREB1), 6q23 (MYB), Cep6 (centromere 6), and 11q13 (CCND1) was reported to discriminate between histologically unequivocal melanomas and benign nevi with a sensitivity of 86.7% and a specificity of 95.4% 24.…”

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confidence: 99%

An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi

Clarke

Flake

Busam

et al. 2016

Cancer

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BACKGROUNDRecently, a 23‐gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions.METHODSA set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis.RESULTSThe gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%.CONCLUSIONSThese results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617–628. © 2016 American Cancer Society.

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“…The diagnostic utility of FISH is controversial in the setting of such ambiguous melanocytic lesions, where the overall reported sensitivity lies between 43 and 100% and the specificity between 33 and 83% using clinical behavior or expert histopathologic review as the gold standard. 6,[16][17][18][19] Of note, within spitzoid tumors, FISH testing has a low sensitivity in detecting spitzoid melanoma around 70%. Thus, to improve on the diagnostic sensitivity and specificity and to overcome the limitations imposed by tetraploidy, probes for 9p21, a region homozygously deleted in a subset of spitzoid melanomas, and for 8q24, the gain of which is associated with poorer outcome, were integrated into the standard FISH panel to increase the diagnostic sensitivity and specificity of the assay and add prognostic relevance.…”

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Comparison between melanoma gene expression score and fluorescence in situ hybridization for the classification of melanocytic lesions

et al. 2016

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Melanoma accounts for most skin cancer-related deaths and has an increasing incidence. Accurate diagnosis and distinction from atypical nevi can be at times difficult using light microscopy alone. Fluorescence in situ hybridization (FISH) and melanoma gene expression score (myPath, Myriad Genetics) have emerged as ancillary tools to further aid in this differential diagnosis. Our aim in this study was to correlate FISH results, gene expression score, consensus histopathologic impression and clinical outcome on a series of 117 challenging melanocytic lesions collected from three separate institutions. The lesions were separated into two groups: 39 histopathologically unequivocal lesions (15 malignant, 24 benign) and 78 challenging lesions interpreted by expert consensus (27 favor malignant, 30 favor benign, and 21 ambiguous). Melanoma-FISH was performed using probes for 6p25, 11q13, 8q24, and 9p21/CEP9 and scored according to established criteria. Analysis by myPath gene expression score was performed and interpreted by the manufacturer as 'benign', 'indeterminate,' or 'malignant'. In the unequivocal group, melanoma-FISH and myPath score showed 97 and 83% agreement with the histopathologic diagnosis, respectively, with 93 and 62% sensitivity, 100 and 95% specificity, and 80% intertest agreement. In the challenging group, FISH and the myPath score showed 70 and 64% agreement with the histopathologic interpretation, respectively, with 70% inter-test agreement and similar sensitivities and specificities. The inter-test agreement was 73% overall, excluding indeterminate results. Discordant test results occurred in 27/117 cases from both unequivocal and challenging groups. Melanoma-FISH and gene expression score are valuable ancillary tools, though both have limitations and return discordant results in a subset of cases. Follow-up studies with more extensive clinical outcome data are warranted to establish the accuracy of these tests for the classification of melanocytic lesions.

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Classifying ambiguous melanocytic lesions with FISH and correlation with clinical long-term follow up

Cited by 128 publications

References 22 publications

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests

An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi

Comparison between melanoma gene expression score and fluorescence in situ hybridization for the classification of melanocytic lesions

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