title: Performance Testing of RREB1, MYB, and CCND1 Fluorescence In Situ Hybridization in Spindle-Cell and Desmoplastic Melanoma Argues for a Two-Step Test Algorithm.
abstract: BACKGROUND
  Diagnostic confirmation of spindle-cell melanoma (SM) or desmoplastic melanoma (DM) as a melanoma can be challenging. In conventional melanoma (CM), a recently established fluorescence in situ hybridization (FISH) assay for RREB1, MYB, CCND1 can be helpful. Here, we determined the presence of RREB1, MYB, and CCND1 abnormalities in an SM/DM/mixed cohort.
  
  
  METHODS
  We assembled 49 cases and performed 3 separate hybridizations for RREB1/MYB/CCND1. We assessed clinical utility in diagnostically challenging cases and performed a cost and turnaround time analysis.
  
  
  RESULTS
  With regard to the diagnosis of melanoma, the FISH assay is 76% sensitive (n = 31/41 true positives melanomas) and 88% specific (n = 1/8 false positive desmoplastic nevi). The prevalence of abnormalities in DM is lower (12/19 cases, 63%; P = .03) than in SM (15/18 cases, 83%; P = .27), mixed (4 of 4 cases), or the reported sensitivity in CM (345/411 cases, 84%). The implied genetic differences in DM result in a higher false negative rate in DM (37%). Despite these limitations, when restricted to diagnostically challenging cases (n = 23), the FISH assay and, in particular, RREB1 was able to confirm melanoma in 70% (n = 16/23). Individual probe sensitivities ( RREB1 > MYB > CCND1) and a cost and turnaround time analysis argues for a 2-step test algorithm that reduces the economic impact of FISH testing considerably (~55%; n = 69 vs 123 hybridizations).
  
  
  CONCLUSIONS
  We propose a step-by-step genetic testing algorithm to support the diagnosis of melanoma in the setting of SM/DM and show that FISH testing is useful in diagnostically challenging cases.
authors.affiliation: 1 University of Ulm, Ulm, Germany.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Weissinger
authors.affiliation: 1 University of Ulm, Ulm, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Frick
authors.affiliation: 1 University of Ulm, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.affiliation: 2 Columbia University Medical Center, New York, NY, USA.
authors.forename: Basil A
authors.initials: BA
authors.lastname: Horst
authors.affiliation: 1 University of Ulm, Ulm, Germany.|3 Massachusetts General Hospital/Harvard Medical, Boston, MA, USA.
authors.forename: Jochen K
authors.initials: JK
authors.lastname: Lennerz
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000032:analysis*; D019938:Cyclin D1 / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020570:Genes, myb / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008545:Melanoma / Q000175:diagnosis*; D008875:Middle Aged; D012680:Sensitivity and Specificity; D012878:Skin Neoplasms / Q000175:diagnosis*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics; D000096142:Cutaneous Malignant Melanoma
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D004268:DNA-Binding Proteins; C101743:RREB1 protein, human; D014157:Transcription Factors; D019938:Cyclin D1
keywords: BRAF; amelanotic; neurotropic