Fluorescence in situ hybridization as a tool for microstaging in malignant melanoma

Newman, Marissa; Lertsburapa, Terakeith; Mirzabeigi, Marjan; Mafee, Mariam; Guitart, Joan; Gerami, Pedram

doi:10.1038/modpathol.2009.72

Cited by 75 publications

(60 citation statements)

References 9 publications

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“…1 Although histological evaluation is a reliable means of accurately classifying melanocytic tumors as benign (nevi) or malignant (melanoma), this distinction can be difficult in a minority of cases. Based on the fact that melanomas are characterized by chromosomal aberrations, molecular genetic tests such as comparative genomic hybridization (CGH) [2][3][4] and fluorescence in situ hybridization [5][6][7][8] have been shown to be useful ancillary techniques, which assist accurate classification of melanocytic tumors. Multiple chromosomal gains and losses are identified with CGH in the majority (495%) of melanomas, whereas melanocytic nevi typically lack chromosomal aberrations.…”

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

et al. 2012

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“…It could be useful for microstaging of melanoma, allowing the distinction between melanoma arising on nevus vs nevoid melanoma. 21 It could also be useful if it really changes the treatment of patients, for example, with a thickness greater than 1 or 1.5 mm (according to the protocol), leading to interferon treatment or other adjuvant management such as sentinel node biopsy or adjuvant vaccine therapy. Other FISH applications have been reported to facilitate the differential diagnosis between (I) epithelioid blue nevus and cutaneous metastatic melanoma simulating blue nevus 22 or (ii) nevoid melanomas and mitotically active nevi, 23 (iii) conjunctival nevi from melanomas 24 or (iv) intranodal nevus from metastatic melanoma.…”

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confidence: 99%

Fluorescence in situ hybridization, a diagnostic aid in ambiguous melanocytic tumors: European study of 113 cases

et al. 2011

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Some melanocytic tumors are ambiguous, so the reproducible histopathological diagnosis of benign or malignant lesion is difficult. This study evaluated the contribution of fluorescence in situ hybridization (FISH) first in 43 non-equivocal melanomas and nevi, and then in 113 ambiguous melanocytic tumors selected by expert pathologists from six different European institutions. We included two groups of ambiguous tumors: patients without recurrence (5-year minimal follow-up) and with metastases. An independent triple-blind histopathological review was performed to classify tumors as 'favor benign' (AÀ) or 'favor malignant' (A þ ). A four-color probe set targeting 6p25, 6q23, 11q13 and CEP6 was used for FISH. In the 43 non-equivocal melanomas and nevi, sensitivity was 85% and specificity 90%. Ninety out of 95 ambiguous melanocytic tumors included were FISH interpretable (67 FISH negative and 23 FISH positive). Of the 90 patients, 69 presented no recurrence and 21/90 exhibited metastases. These ambiguous tumors were mostly spitzoid tumors (45/90). Histopathological reviewers classified these tumors as favor malignant (49/90) and favor benign (32/90), whereas nine cases had a discordant diagnosis. By comparison with outcome, the sensitivity and specificity of histopathological review were 95 and 52%, and the sensitivity and specificity of FISH were 43 and 80%. Compared with histopathological review, the sensitivity and specificity of FISH were 34.5 and 91%. Interestingly, by combining the histopathological diagnosis with FISH results, the diagnosis was optimized, especially by increasing specificity (76% instead of 52% for expert diagnosis alone) and by improving sensitivity compared with FISH alone (90 vs 43% for FISH result alone). The value of this FISH test is to add a reproducible demonstration of malignancy to the histopathological diagnosis, especially in doubtful/ambiguous melanocytic tumors. A positive FISH test reinforces the diagnosis of melanoma, allowing such tumors (particularly thick tumors) to be managed as melanomas.

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“…6 Numerous subsequent confirmatory 'proof of principle' studies validated the diagnostic utility of FISH in many different diagnostic settings, reporting a 75-100% sensitivity and 89-100% specificity of the assay in differentiating histologically unequivocal melanoma and nevi. 6,[9][10][11][12][13][14][15] However, most of the earliest proof of principle studies utilized histopathologically unambiguous nevi and melanomas to demonstrate the utility of FISH as an ancillary diagnostic test, yet FISH is predominantly deployed in the setting of morphologically ambiguous melanocytic tumors, where ancillary testing most usefully informs the diagnosis. 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.…”

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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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Fluorescence in situ hybridization as a tool for microstaging in malignant melanoma

Cited by 75 publications

References 9 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

Fluorescence in situ hybridization, a diagnostic aid in ambiguous melanocytic tumors: European study of 113 cases

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

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