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• W2076166111 abstract "The study of specific chromosomal loci through fluorescence in situ hybridization (FISH) is useful in differential diagnosis of melanocytic tumors. However, sensitivity rates vary, probably because of molecular heterogeneity. Acral lentiginous melanomas are characterized by copy number gains of small genomic regions, including CCND1, TERT, and AURKA. In a series of 58 acral melanocytic lesions, we explored the value of a four-color FISH probe, used in addition to determining MYC gene status, and assessed the potential diagnostic usefulness of newly developed probes targeting TERT and AURKA. Moreover, we tested CCND1, TERT, and AURKA protein expression by immunohistochemistry. The four-color FISH probe detected 85.3% of melanomas and 29.4% of TERT and AURKA copy number gains. Sensitivity was 97% (confidence interval 95%, 82.9% to 99.8%) for the combined results of all probes. No MYC copy number gains were detected. No nevi showed aberrations. Immunohistochemistry revealed a higher percentage of cells positive for CCND1, TERT, and AURKA protein in melanomas than in nevi (P ≤ 0.001). A significant correlation between gene copy number gain and protein expression was found for CCND1 (P = 0.015). Our results indicate that addition of specific FISH probes to the current probe could improve sensitivity for the diagnosis of acral melanomas. Further studies in larger numbers of cases are needed to validate these results. The study of specific chromosomal loci through fluorescence in situ hybridization (FISH) is useful in differential diagnosis of melanocytic tumors. However, sensitivity rates vary, probably because of molecular heterogeneity. Acral lentiginous melanomas are characterized by copy number gains of small genomic regions, including CCND1, TERT, and AURKA. In a series of 58 acral melanocytic lesions, we explored the value of a four-color FISH probe, used in addition to determining MYC gene status, and assessed the potential diagnostic usefulness of newly developed probes targeting TERT and AURKA. Moreover, we tested CCND1, TERT, and AURKA protein expression by immunohistochemistry. The four-color FISH probe detected 85.3% of melanomas and 29.4% of TERT and AURKA copy number gains. Sensitivity was 97% (confidence interval 95%, 82.9% to 99.8%) for the combined results of all probes. No MYC copy number gains were detected. No nevi showed aberrations. Immunohistochemistry revealed a higher percentage of cells positive for CCND1, TERT, and AURKA protein in melanomas than in nevi (P ≤ 0.001). A significant correlation between gene copy number gain and protein expression was found for CCND1 (P = 0.015). Our results indicate that addition of specific FISH probes to the current probe could improve sensitivity for the diagnosis of acral melanomas. Further studies in larger numbers of cases are needed to validate these results. Histopathological evaluation is the gold standard in differentiating benign from malignant melanocytic lesions. Nonetheless, its subjectivity and other limitations are widely accepted, and a number of cases cannot easily be classified as benign or malignant based only on histopathological evaluation.1Cerroni L. Barnhill R. Elder D. Gottlieb G. Heenan P. Kutzner H. LeBoit P.E. Mihm Jr., M. Rosai J. Kerl H. Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008.Am J Surg Pathol. 2010; 34: 314-326Crossref PubMed Scopus (183) Google Scholar In recent years, investigations on melanocytic tumors have been focused on identifying gene alterations that can help to differentiate benign from malignant melanocytic tumors. Comparative genomic hybridization studies have demonstrated that benign and malignant melanocytic tumors differ dramatically in the presence of numerous chromosomal aberrations.2Bastian B.C. Olshen A.B. LeBoit P.E. Pinkel D. Classifying melanocytic tumors based on DNA copy number changes.Am J Pathol. 2003; 163: 1765-1770Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar Based on such results, a commercially available four-color fluorescence in situ hybridization (FISH) multiple probe targeting 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1), and centromere 6 (CEP6) was recently developed to assist in differentiating several problematic melanocytic lesions.3Gerami P. Jewell S.S. Morrison L.E. Blondin B. Schulz J. Ruffalo T. Matushek P. Legator M. Jacobson K. Dalton S.R. Charzan S. Kolaitis N.A. Guitart J. Lertsbarapa T. Boone S. LeBoit P.E. Bastian B.C. Fluorescence in situ hybridization (FISH) as an ancillary diagnostic tool in the diagnosis of melanoma [Erratum appeared in Am J Surg Pathol 2010, 34:688].Am J Surg Pathol. 2009; 33: 1146-1156Crossref PubMed Scopus (362) Google Scholar This FISH probe, which has been tested in a variety of clinicopathological settings, has proven useful in increasing sensitivity and specificity in the differential diagnosis between benign nevi and melanomas. However, results have differed, mainly depending on the melanocytic lesion subtype.4Dalton S.R. Gerami P. Kolaitis N.A. Charzan S. Werling R. LeBoit P.E. Bastian B.C. Use of fluorescence in situ hybridization (FISH) to distinguish intranodal nevus from metastatic melanoma.Am J Surg Pathol. 2010; 34: 231-237Crossref PubMed Scopus (77) Google Scholar, 5Díaz A. Valera A. Carrera C. Hakim S. Aguilera P. García A. Palou J. Puig S. Malvehy J. Alos L. Pigmented spindle cell nevus: clues for differentiating it from spindle cell malignant melanoma. A comprehensive survey including clinicopathologic, immunohistochemical, and FISH studies.Am J Surg Pathol. 2011; 35: 1733-1742Crossref PubMed Scopus (34) Google Scholar, 6Gerami P. Mafee M. Lurtsbarapa T. Guitart J. Haghighat Z. Newman M. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes.Arch Dermatol. 2010; 146: 273-278Crossref PubMed Scopus (99) Google Scholar, 7Kutzner H. Metzler G. Argenyi Z. Requena L. Palmedo G. Mentzel T. Rutten A. Hantschke M. Paredes B.E. Scharer L. Hesse B. El-Shabrawi-Caelen L. Fried I. Kerl H. Lorenzo C. Murali R. Wiesner T. Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests.Mod Pathol. 2012; 25: 838-845Crossref PubMed Scopus (33) Google Scholar, 8Newman M.D. Mirzabeigi M. Gerami P. Chromosomal copy number changes supporting the classification of lentiginous junctional melanoma of the elderly as a subtype of melanoma.Mod Pathol. 2009; 22: 1258-1262Crossref PubMed Scopus (43) Google Scholar Increasing evidence suggests that melanomas are heterogeneous at the molecular level and that specific tumor subtypes may harbor distinct genomic alterations.9Curtin J.A. Fridlyand J. Kageshita T. Patel H.N. Busam K.J. Kutzner H. Cho K.H. Aiba S. Bröcker E.B. LeBoit P.E. Pinkel D. Bastian B.C. Distinct sets of genetic alterations in melanoma.N Engl J Med. 2005; 353: 2135-2147Crossref PubMed Scopus (2126) Google Scholar In this sense, a broader probe set incorporating 8q24 (MYC) and 9p21 (CDKN2A) probes has been recently proposed to enhance the detection of melanomas, including the Spitzoid types.10Gerami P. Li G. Pouryazdanparast P. Blondin B. Beilfuss B. Slenk C. Du J. Guitart J. Jewell S. Pestova K. A highly specific and discriminatory FISH assay for distinguishing between benign and malignant melanocytic neoplasms.Am J Surg Pathol. 2012; 36: 808-817Crossref PubMed Scopus (147) Google Scholar Acral lentiginous melanoma (ALM), one of the four major histopathological melanoma subtypes recognized in the current World Health Organization classification,11Tokura Y, Bastian BC, Duncan L: Acral-lentiginous melanoma. Pathology and Genetics of Skin Tumours. Edited by PE LeBoit, G Burg, D Weedon, A Sarasain. World Health Organization Classification of Tumours. Lyon, IARC Press, 2006, pp 73–75Google Scholar has distinctive clinicopathological and molecular characteristics. It frequently harbors multiple and distinctive chromosomal aberrations, mainly gene copy number gains of small genomic regions such as the CCND1, TERT, and AURKA genes.2Bastian B.C. Olshen A.B. LeBoit P.E. Pinkel D. Classifying melanocytic tumors based on DNA copy number changes.Am J Pathol. 2003; 163: 1765-1770Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar, 9Curtin J.A. Fridlyand J. Kageshita T. Patel H.N. Busam K.J. Kutzner H. Cho K.H. Aiba S. Bröcker E.B. LeBoit P.E. Pinkel D. Bastian B.C. Distinct sets of genetic alterations in melanoma.N Engl J Med. 2005; 353: 2135-2147Crossref PubMed Scopus (2126) Google Scholar, 12Bastian B.C. Kashani-Sabet M. Hamm H. Godfrey T. Moore 2nd, D.H. Bröcker E.B. LeBoit P.E. Pinkel D. Gene amplifications characterize acral melanoma and permit the detection of occult tumor cells in the surrounding skin.Cancer Res. 2000; 60: 1968-1973PubMed Google Scholar, 13Bastian B.C. LeBoit P.E. Hamm H. Bröcker E.B. Pinkel D. Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization.Cancer Res. 1998; 58: 2170-2175PubMed Google Scholar, 14North J.P. Kageshita T. Pinkel D. LeBoit P.E. Bastian B.C. Distribution and significance of occult intraepidermal tumor cells surrounding primary melanoma.J Invest Dermatol. 2008; 128: 2024-2030Crossref PubMed Scopus (71) Google Scholar, 15Puig-Butillé J.A. Badenas C. Ogbah Z. Carrera C. Aguilera P. Malvehy J. Puig S. Genetic alterations in RAS-regulated pathway in acral lentiginous melanoma.Exp Dermatol. 2013; 22: 148-150Crossref PubMed Scopus (42) Google Scholar Its low incidence in populations of European continental origin might render difficult any deeply clinicopathological and molecular characterization. To date, few cases of ALMs or acral nevi (AN) have been studied with the new multiprobe FISH set.6Gerami P. Mafee M. Lurtsbarapa T. Guitart J. Haghighat Z. Newman M. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes.Arch Dermatol. 2010; 146: 273-278Crossref PubMed Scopus (99) Google Scholar, 10Gerami P. Li G. Pouryazdanparast P. Blondin B. Beilfuss B. Slenk C. Du J. Guitart J. Jewell S. Pestova K. A highly specific and discriminatory FISH assay for distinguishing between benign and malignant melanocytic neoplasms.Am J Surg Pathol. 2012; 36: 808-817Crossref PubMed Scopus (147) Google Scholar, 16Gaiser T. Kutzner H. Palmedo G. Siegelin M.D. Wiesner T. Bruckner T. Hartschuh W. Enk A.H. Becker M.R. Classifying ambiguous melanocytic lesions with FISH and correlation with clinical long-term follow up.Mod Pathol. 2010; 23: 413-419Crossref PubMed Scopus (112) Google Scholar, 17Morey A.L. Murali R. McCarthy S.W. Mann G.J. Scolyer R.A. Diagnosis of cutaneous melanocytic tumours by four-colour fluorescence in situ hybridisation.Pathology. 2009; 41: 383-387Crossref PubMed Scopus (88) Google Scholar Furthermore, from the standpoint of daily practice, acral pigmented lesions may exhibit site-related atypical features that could hamper differentiation of benign from malignant tumors.18Hosler G.A. Moresi J.M. Barrett T.L. Nevi with site-related atypia: a review of melanocytic nevi with atypical histologic features based on anatomic site.J Cutan Pathol. 2008; 35: 889-898Crossref PubMed Scopus (77) Google Scholar TERT, at 5p15.33, encodes for the catalytic subunit of telomerase reverse transcriptase, which stabilizes telomeric length. TERT up-regulation enhances cellular proliferation and plays a critical role in oncogenesis.19Shay J.W. Wright W.E. Telomerase therapeutics for cancer: challenges and new directions.Nat Rev Drug Discov. 2006; 5: 577-584Crossref PubMed Scopus (375) Google Scholar AURKA, at 20q13, encodes for aurora kinase A, a cell cycle–regulated kinase that is involved mainly in centrosome function and spindle assembly during chromosome segregation; its dysregulation leads to genetic instability and aneuploidy.20Fu J. Bian M. Jiang Q. Zhang C. Roles of Aurora kinases in mitosis and tumorigenesis.Mol Cancer Res. 2007; 5: 1-10Crossref PubMed Scopus (487) Google Scholar We studied a series of 58 acral melanocytic lesions, comprising both benign and malignant tumors, and we explored the usefulness of the currently available four-color FISH probe, together with MYC gene status, for differential diagnosis. We also evaluated the utility of additional FISH probes targeting TERT and AURKA genes for enhancing detection of ALM and tested CCND1, TERT, and AURKA protein expression by immunohistochemistry. A total of 58 formalin-fixed, paraffin-embedded samples of acral melanocytic tumors were collected from 2002 to 2008 from the archives of the Pathology Department at the Hospital Clínic of Barcelona, including 34 invasive ALMs and 24 ANs. Unequivocal diagnosis of ALM or AN was confirmed in a masked manner by two dermatopathologists (A.D. and L.A.). All patients were seen and their cases were monitored at the Melanoma Unit, Department of Dermatology, of the same hospital. Clinical data were retrieved from review of the clinical files. The study was approved by the Institutional Ethics Review Board, and written informed consent was obtained from each participant in accordance with the Declaration of Helsinki. Noncommercial probes targeting TERT and AURKA were elaborated using bacterial artificial chromosomes (BACs). BAC clones were obtained from the Children’s Hospital Oakland Research Institute (Oakland, CA) collection and were selected using the controlled-access genome browser of the Center for Genomic Regulation, Barcelona, Spain [http://davinci.crg.es/cgi-gbrowse/gbrowse/hg18, last accessed May 24, 2012 (login required)]. Next, DNA was labeled using a nick translation kit (Abbott Molecular, North Chicago, IL) with SpectrumGreen or SpectrumRed (Abbott Molecular). For AURKA, a centromeric probe was added (CEP20), labeled with SpectrumOrange (Abbott Molecular). For TERT, another BAC probe, located on 5q15 (MCTP1), was developed to be used as whole-chromosome copy number control. The gene locus, the BACs, and the labeling fluorochrome are listed in Table 1. Finally, all probes were hybridized to normal metaphase chromosomes, to verify their location, and to normal skin controls, to obtain the normal pattern of hybridization (two signals on average for each probe).Table 1Elaborated FISH Probes from BACs and Fluorochromes Used to Visualize the Specific GeneGeneLocusBACFluorochromeTERT5p15.33RP11-117B23SpectrumGreenMCTP1∗The gene MCTP1, located on 5q15, was used as chromosome 5 copy number control, instead of a centromeric probe.5q15RP11-73K22SpectrumRedAURKA20q13RP11-158O17SpectrumGreen∗ The gene MCTP1, located on 5q15, was used as chromosome 5 copy number control, instead of a centromeric probe. Open table in a new tab All cases were analyzed with the commercially available four-color probe set targeting the ras responsive element binding protein 1 gene (RREB1) on 6p25, the v-myb avian myeloblastosis viral oncogene homolog gene (MYB) on 6q23, the cyclin D1 gene (CCND1) on 11q13, and the chromosome 6 centromeric region (Abbott Molecular, Des Plaines, IL). Additionally, cases were hybridized with the commercially available probes Vysis LSI Cyclin D1/CEP 11 (Abbott Molecular) and a Dako MYC/CEN-8 FISH probe mix (Agilent Technologies, Santa Clara, CA), which contain fluorescently labeled gene and centromere probes, and with noncommercial probes targeting TERT and AURKA. From each formalin-fixed, paraffin-embedded sample block, 4-μm-thick sections were mounted onto positively charged slides (SuperFrost Plus; Thermo Fisher Scientific, Waltham, MA), deparaffinized, and dehydrated. Next, pretreatment and pepsin digestion (3 minutes) was performed, followed by dehydration in 70%, 85%, and 96% ethanol for 2 minutes each. The slides were then incubated in a Dako hybridizer (S2450; Agilent Technologies) for denaturation at 90°C for 5 minutes and hybridization at 37°C for approximately 18 hours. Sections were placed in washing buffer at room temperature for 2 to 10 minutes to remove the coverslips, immersed in stringency buffer at 65°C for 10 minutes, and then were dehydrated, dried, and counterstained with DAPI. FISH evaluation was performed using an Eclipse 50i epifluorescence microscope (Nikon, Tokyo, Japan; Melville, NY) equipped with appropriate single band-pass filter sets (Abbott Molecular). First, each sample was examined at low-power magnification, to select areas with abnormal copy number. Next, ≥20 adjacent nuclei from three different areas were enumerated (for a total of ≥60 cells) under high-power magnification (×400). Overlapping nuclei and nuclei with less than two signals were not counted. Moreover, if <60 nuclei could be evaluated or if nuclei did not show signals for all probes, the case was excluded. For the four-color commercial probe set, a sample was considered as having a positive FISH result if any of the following criteria were met: i) gain in 6p25 (RREB1) relative to CEP6 in >55% of cells or ii) gain in 6p25 (RREB1) in >29% of cells, iii) gain in 11q13 (CCND1) in >38% of cells, or iv) loss in 6q23 (MYB) relative to CEP6 in >40% of cells, according to previously determined cutoffs. For the MYC/CEN-8 probe, a sample was considered positive if ≥50% of the enumerated melanoma cells harbored copy number gains of MYC.21Pouryazdanparast P. Cowen D.P. Beilfuss B.A. Haghighat Z. Guitart J. Rademaker A. Gerami P. Distinctive clinical and histologic features in cutaneous melanoma with copy number gains in 8q24.Am J Surg Pathol. 2012; 36: 253-264Crossref PubMed Scopus (27) Google Scholar For the LSI Cyclin D1/CEP 11 probe and the noncommercial probes, a tumor was considered positive (with copy number gains) if the ratio between gene copy number and centromere copy number was ≥1.5. A ratio of >2 was considered amplification.22Zhu C.Q. Cutz J.C. Liu N. Lau D. Shepherd F.A. Squire J.A. Tsao M.S. Amplification of telomerase (hTERT) gene is a poor prognostic marker in non-small-cell lung cancer.Br J Cancer. 2006; 94: 1452-1459Crossref PubMed Scopus (84) Google Scholar In 19 ALMs, the in situ component was also evaluated. All cases were stained for CCND1 (1:100; clone SP4; Abcam, Cambridge, UK), TERT (1:100; clone Y182; Abcam), and AURKA (1:300; polyclonal; Abcam) using a Bond Max automated instrument (Leica Microsystems, Wetzlar, Germany) with a Bond Polymer Refine Red Detection system (Leica Microsystems). Appropriate positive and negative controls were used for each antibody. The percentage of positive cells was recorded semiquantitatively in each case for cytoplasmic (TERT and AURKA) or nuclear (CCND1, TERT, and AURKA) staining. All statistical analyses were performed using PASW Statistics version 18 (SPSS, Chicago, IL). Associations between variables were performed with use of the exact Fisher test. Quantitative data were compared between groups using either a Student’s t-test (for variables with a normal distribution) or a U-test (for variables without a normal distribution). Pearson correlations were performed on quantitative data. To determine the specificity and sensitivity of FISH, histopathology was considered the gold standard and the 95% confidence intervals (CIs) of sensitivity and specificity were calculated using the publicly available VassarStats Clinical Calculator 1 (http://www.vassarstats.net/clin1.html, last accessed October 23, 2013), which uses the Wilson score method. The results were considered statistically significant at P ≤ 0.05 (two-sided). The main clinicopathological characteristics of the patients with ALMs are listed in Table 2. The 34 patients were 17 men and 17 women (male-to-female ratio, 1:1); the median age was 67 years (range, 39 to 91 years). The tumor occurred on the feet in 30 of 34 patients (88%) and on the hands in 4 of 34 patients (12%). The median Breslow thickness was 3.8 mm (range, 0.4 to 12 mm). The Clark level was II in 2/34 lesions (6%), III in 4/34 lesions (12%), IV in 19/34 lesions (56%), and V in 9/34 lesions (26.5%). Ulceration was present in 18 of 34 cases (53%), and the median mitotic count was 4/mm2 (range, 0 to 18 mitoses).Table 2Main Clinicopathological Characteristics of Patients with ALMCase no.Age (years)SexSiteClark levelBreslow thickness (mm)161MSoleV12276FSoleIV5349FSoleV6489FHeelIV3.2567MRing fingerIII0.7668FSoleIV0.9782FSoleIV6858MSoleV4.5987FHeelV101051FSoleV4.61158MPalmV81254MSoleV121367MHeelV6.51491FHeelIV21571FPalmIV1.41683MSoleII0.91758MIndex fingerIV11874MGreat toeII0.41963MSoleIII12078FHeelIV32174FHeelIII12277MSoleIV42378FSoleIV32439MSoleIV22540MSoleV22661MGreat toeIII0.52775FHeelIV52860MSoleIV22973MSoleIV3.33090FSoleIV53166FSoleIV1.23245MHeelIV53358FHeelIV3.53483FSoleIV2.8M, male; F, female. Open table in a new tab M, male; F, female. The 24 patients with AN were 10 men and 14 women (male-to-female ratio, 1:1.4); the median age was 37 years (range, 16 to 64 years). Most of the lesions (22 of 24; 91%) occurred on the feet; histologically, the lesions were mostly compound (21 of 24; 87.5%). FISH data for the ALMs are summarized in Table 3. Overall, 29 of the 34 ALMs had a positive result when evaluated using the commercial FISH multiprobe set, resulting in a sensitivity of 85.3% (95% CI, 68.2%–94.4%). The RREB1 gain criterion was the most sensitive, observed in 25 of 34 cases (74%); 20 of 34 cases (59%) met the RREB1/CEP6 gain criterion, 14 of 34 (41%) met the MYB/CEP6 loss criterion (Figure 1), and 8 of 34 (24%) met the CCND1 gain criterion. CCND1 gains were confirmed in all cases with the commercial probe LSI Cyclin D1/CEP 11, which showed that all were gene amplifications [median CCND1/CEP11 ratio, 4.16 (range, 2.18 to 5.10)]. With the noncommercial probes, 10 of 34 tumors (29%) gave positive results. TERT copy number gains were present in 8 of 34 cases (24%), and in 6 of these 8 cases there were gene amplifications (average ratio of >2 (Figure 1). AURKA copy number gains were seen in 2 of 34 cases (6%). CCND1, TERT, and AURKA gains were mutually exclusive. No MYC copy number gains were detected in any case. With results of all probes combined, FISH had a positive result in 33 of 34 ALMs, for an overall sensitivity of 97% (95% CI, 82.9%–99.8%).Table 3FISH Results for ALM CasesCase no.Cells with gain or loss (%)Copy number ratioRREB1 gainRREB1 gain relative to CEP6CCND1 gainMYB loss relative to CEP6TERT/MCTP1AURKA/CEP201767020261.021.662938393100.960.933465316201.611.024101013700.981.075203016102.581.18666601031.030.967806053431.161.23860403431.020.969363380700.961.0910866610561.011.0011161010504.501.0712465613264.811.06139383100831.241.131480533501.020.951590566561.181.0616101610163.100.981770503200.961.1018161613201.000.9119707693660.941.0220808026161.031.00218076361.021.0322706020301.881.002310620501.001.3324666013160.910.982516100164.161.0026807690601.231.0227969096100.981.1828909013101.021.3329705016130.910.983016166100.982.243153733101.130.9832666620262.491.0533101013601.080.93349390100460.930.93Values that met the criteria for a positive FISH result are highlighted in bold. Open table in a new tab Values that met the criteria for a positive FISH result are highlighted in bold. We also evaluated the presence of gene copy number alterations in the in situ component of ALMs, which could be assessed confidently in 19 of the 34 cases. In all of these 19 cases, we found RREB1, TERT, and CCND1 gene copy number gains in the in situ portion, at levels similar to those in the invasive portion (Figure 2). In addition, in 5 of the 34 cases CCND1 and TERT gene copy number gains were also visualized in scattered cells on the basal layer of histologically normal-appearing skin beyond the in situ component. None of the 24 ANs showed any significant copy number changes in any of the targeted genes (Figure 3), resulting in an overall specificity of 100% (95% CI, 82.8%–100%). Comparison of clinicopathological characteristics of patients with melanomas harboring CCND1, TERT, and AURKA copy number gains revealed no differences among the three groups. In addition, no histological differences were found in tumor thickness, ulceration, mitotic rate, tumor cell type, amount of pigmentation, or presence of tumor-infiltrating lymphocytes among the three groups of melanomas. Immunohistochemical data are summarized in Table 4. In ALMs, a significantly higher percentage of cells were positive for nuclear CCND1, TERT, and AURKA, compared with ANs. Moreover, ANs exhibited a decreasing CCND1 immunopositivity in deep portions of the tumor, whereas ALMs exhibited a more homogeneous distribution of CCND1 immunopositivity. TERT and AURKA nuclear immunoreactivity did not exhibit any particular distribution pattern. All lesions (both ALM and AN) exhibited TERT and AURKA cytoplasmic positivity in nearly 100% of cells.Table 4Immunohistochemical Results of ALM and ANProteinNuclear positive cells [mean % (range)]PALMANCCND157.35 (30–95)19.58 (5–40)<0.001∗U-test.TERT4.24 (0–20)0.92 (0–10)<0.001†Student’s t-test.AURKA2.65 (0–15)0.50 (0–5)0.001∗U-test.∗ U-test.† Student’s t-test. Open table in a new tab A significantly higher percentage of cells were positive for CCND1 by immunohistochemistry in ALMs harboring CCND1 gains [median, 75% (range, 50% to 95%)], compared with ALMs without CCND1 gain [median, 45% (range, 30% to 80%)] (P = 0.002) (Figure 4). Moreover, in ALMs with CCND1 gains, a positive significant correlation was found between the percentage of nuclear positive cells and the average number of CCND1 signals (ρ = 0.90, P = 0.015). No correlation was found between TERT or AURKA gene copy number gains and the respective protein expression. ALMs are characterized by frequent gene copy number gains, and we have detected two genes related to oncogenesis that can show increased copy numbers in ALMs: TERT and AURKA. In the present study, we have confirmed that these genes do not show copy number gains in any benign AN, so both TERT and AURKA are promising genes for differentiating malignant from benign acral melanocytic tumors. Moreover, we have tested for the first time a commercially developed four-color FISH assay in a series of 58 acral melanocytic lesions, including both benign and malignant counterparts; only few acral melanocytic lesions have been included in previous studies.6Gerami P. Mafee M. Lurtsbarapa T. Guitart J. Haghighat Z. Newman M. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes.Arch Dermatol. 2010; 146: 273-278Crossref PubMed Scopus (99) Google Scholar, 10Gerami P. Li G. Pouryazdanparast P. Blondin B. Beilfuss B. Slenk C. Du J. Guitart J. Jewell S. Pestova K. A highly specific and discriminatory FISH assay for distinguishing between benign and malignant melanocytic neoplasms.Am J Surg Pathol. 2012; 36: 808-817Crossref PubMed Scopus (147) Google Scholar, 16Gaiser T. Kutzner H. Palmedo G. Siegelin M.D. Wiesner T. Bruckner T. Hartschuh W. Enk A.H. Becker M.R. Classifying ambiguous melanocytic lesions with FISH and correlation with clinical long-term follow up.Mod Pathol. 2010; 23: 413-419Crossref PubMed Scopus (112) Google Scholar, 17Morey A.L. Murali R. McCarthy S.W. Mann G.J. Scolyer R.A. Diagnosis of cutaneous melanocytic tumours by four-colour fluorescence in situ hybridisation.Pathology. 2009; 41: 383-387Crossref PubMed Scopus (88) Google Scholar This FISH assay identified 29 of 34 ALMs; for ANs, all FISH findings were negative. These results correlate with a sensitivity of 85.3% (95% CI, 68.2%–94.4%) and a specificity of 100% (95% CI, 82.8%–100%), similar to rates in previous studies. However, sensitivity rates for this FISH probe have varied, ranging from 40% to 100%, depending mainly on the melanoma subtype.4Dalton S.R. Gerami P. Kolaitis N.A. Charzan S. Werling R. LeBoit P.E. Bastian B.C. Use of fluorescence in situ hybridization (FISH) to distinguish intranodal nevus from metastatic melanoma.Am J Surg Pathol. 2010; 34: 231-237Crossref PubMed Scopus (77) Google Scholar, 5Díaz A. Valera A. Carrera C. Hakim S. Aguilera P. García A. Palou J. Puig S. Malvehy J. Alos L. Pigmented spindle cell nevus: clues for differentiating it from spindle cell malignant melanoma. A comprehensive survey including clinicopathologic, immunohistochemical, and FISH studies.Am J Surg Pathol. 2011; 35: 1733-1742Crossref PubMed Scopus (34) Google Scholar, 6Gerami P. Mafee M. Lurtsbarapa T. Guitart J. Haghighat Z. Newman M. Sensitivity of fluorescence in situ hybridization for melanoma diagnosis using RREB1, MYB, Cep6, and 11q13 probes in melanoma subtypes.Arch Dermatol. 2010; 146: 273-278Crossref PubMed Scopus (99) Google Scholar, 7Kutzner H. Metzler G. Argenyi Z. Requena L. Palmedo G. Mentzel T. Rutten A. Hantschke M. Paredes B.E. Scharer L. Hesse B. El-Shabrawi-Caelen L. Fried I. Kerl H. Lorenzo C. Murali R. Wiesner T. Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests.Mod Pathol. 2012; 25: 838-845Crossref PubMed Scopus (33) Google Scholar, 8Newman M.D. Mirzabeigi M. Gerami P. Chromosomal copy number changes supporting the classification of lentiginous junctional melanoma of the elderly as a subtype of melanoma.Mod Pathol. 2009; 22: 1258-1262Crossref PubMed Scopus (43) Google Scholar When we added exploration for TERT and AURKA genes in our series, four of the five ALMs with negative results using the commercial four-color probe set showed amplifications. No nevi showed any alterations. Thus, including TERT and AURKA increased the sensitivity in differentiating ALM from AN to 97% (95% CI, 82.9%–99.8%) and maintained the" @default.
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