{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:01:44Z","timestamp":1792119704772,"version":"4.4.0"},"reference-count":55,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,26]],"date-time":"2021-06-26T00:00:00Z","timestamp":1624665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The discrimination of malignant melanoma from benign nevi may be difficult in some cases. For this reason, immunohistological and molecular techniques are included in the differential diagnostic toolbox for these lesions. These methods are time consuming when applied subsequently and, in some cases, no definitive diagnosis can be made. We studied both lesions by imaging mass spectrometry (IMS) in a large cohort (n = 203) to determine a different proteomic profile between cutaneous melanomas and melanocytic nevi. Sample preparation and instrument setting were tested to obtain optimal results in term of data quality and reproducibility. A proteomic signature was found by linear discriminant analysis to discern malignant melanoma from benign nevus (n = 113) with an overall accuracy of &gt;98%. The prediction model was tested in an independent set (n = 90) reaching an overall accuracy of 93% in classifying melanoma from nevi. Statistical analysis of the IMS data revealed mass-to-charge ratio (m\/z) peaks which varied significantly (Area under the receiver operating characteristic curve &gt; 0.7) between the two tissue types. To our knowledge, this is the largest IMS study of cutaneous melanoma and nevi performed up to now. Our findings clearly show that discrimination of melanocytic nevi from melanoma is possible by IMS.<\/jats:p>","DOI":"10.3390\/cancers13133197","type":"journal-article","created":{"date-parts":[[2021,6,27]],"date-time":"2021-06-27T22:24:57Z","timestamp":1624832697000},"page":"3197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Imaging Mass Spectrometry-Based Proteomic Analysis to Differentiate Melanocytic Nevi and Malignant Melanoma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9054-4786","authenticated-orcid":false,"given":"Rita","family":"Casadonte","sequence":"first","affiliation":[{"name":"Proteopath GmbH, 54926 Trier, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7319-3646","authenticated-orcid":false,"given":"Mark","family":"Kriegsmann","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Kriegsmann","sequence":"additional","affiliation":[{"name":"Department of Hematology Oncology and Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Hauk","sequence":"additional","affiliation":[{"name":"Faculty of Medicine\/Dentistry, Danube Private University, 3500 Krems-Stein, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf R.","family":"Meli\u00df","sequence":"additional","affiliation":[{"name":"Institute f\u00fcr Dermatopathologie, 30519 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia S. L.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"MVZ f\u00fcr Histologie, Zytologie und Molekulare Diagnostik Trier, 54296 Trier, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Kriegsmann","sequence":"additional","affiliation":[{"name":"Proteopath GmbH, 54926 Trier, Germany"},{"name":"Faculty of Medicine\/Dentistry, Danube Private University, 3500 Krems-Stein, Austria"},{"name":"MVZ f\u00fcr Histologie, Zytologie und Molekulare Diagnostik Trier, 54296 Trier, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bevona, C., Goggins, W., Quinn, T., Fullerton, J., and Tsao, H. (2003). Cutaneous melanomas associated with nevi. Arch. Dermatol., 139.","DOI":"10.1001\/archderm.139.12.1620"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1001\/archderm.139.3.282","article-title":"The transformation rate of moles (melanocytic nevi) into cutaneous melanoma: A population-based estimate","volume":"139","author":"Tsao","year":"2003","journal-title":"Arch. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S0190-9622(89)70253-X","article-title":"Nevomelanocytic proliferations in association with cutaneous malignant melanoma: A multivariate analysis","volume":"21","author":"Gruber","year":"1989","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/S0046-8177(96)90157-4","article-title":"Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists","volume":"27","author":"Farmer","year":"1996","journal-title":"Hum. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"152550","DOI":"10.1016\/j.prp.2019.152550","article-title":"Utility of p16-Ki-67-HMB45 score in sorting benign from malignant Spitz tumors","volume":"215","author":"Garola","year":"2019","journal-title":"Pathol. Res. Pract."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00403-018-1818-8","article-title":"Reevaluation of established and new criteria in differential diagnosis of Spitz nevus and melanoma","volume":"310","author":"Ritter","year":"2018","journal-title":"Arch. Dermatol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"153105","DOI":"10.1016\/j.prp.2020.153105","article-title":"The diagnostic utility of PRAME and p16 in distinguishing nodal nevi from nodal metastatic melanoma","volume":"216","author":"See","year":"2020","journal-title":"Pathol. Res. Pract."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1097\/PAS.0b013e31824b1efd","article-title":"A highly specific and discriminatory FISH assay for distinguishing between benign and malignant melanocytic neoplasms","volume":"36","author":"Gerami","year":"2012","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"151681","DOI":"10.1016\/j.anndiagpath.2020.151681","article-title":"Diagnostic application of cyclin D1 fluorescent in situ hybridization for histologically undetermined early lesions of acral melanoma in situ: A case series","volume":"50","author":"Cao","year":"2021","journal-title":"Ann. Diagn. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1097\/PAS.0b013e3181a92cbc","article-title":"Distinguishing epithelioid blue nevus from blue nevus-like cutaneous melanoma metastasis using fluorescence in situ hybridization","volume":"33","author":"Pouryazdanparast","year":"2009","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6001","DOI":"10.1158\/0008-5472.CAN-18-1079","article-title":"Clinical Proteomics of Breast Cancer Reveals a Novel Layer of Breast Cancer Classification","volume":"78","author":"Yanovich","year":"2018","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Guo, T., Li, L., Zhong, Q., Rupp, N.J., Charmpi, K., Wong, C.E., Wagner, U., Rueschoff, J.H., Jochum, W., and Fankhauser, C.D. (2018). Multi-region proteome analysis quantifies spatial heterogeneity of prostate tissue biomarkers. Life Sci. Alliance, 1.","DOI":"10.1101\/250167"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1080\/14789450.2016.1182431","article-title":"Advances in mass spectrometry-based cancer research and analysis: From cancer proteomics to clinical diagnostics","volume":"13","author":"Timms","year":"2016","journal-title":"Expert Rev. Proteom."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1002\/prca.201500140","article-title":"MALDI mass spectrometry imaging: A cutting-edge tool for fundamental and clinical histopathology","volume":"10","author":"Longuespee","year":"2016","journal-title":"Proteom. Clin. Appl."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1854","DOI":"10.1021\/pr901008d","article-title":"Classification of HER2 receptor status in breast cancer tissues by MALDI imaging mass spectrometry","volume":"9","author":"Rauser","year":"2010","journal-title":"J. Proteome Res."},{"key":"ref_17","first-page":"155","article-title":"Identifying prostate carcinoma by MALDI-Imaging","volume":"20","author":"Schwamborn","year":"2007","journal-title":"Int. J. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1074\/mcp.M115.057513","article-title":"Reliable Entity Subtyping in Non-small Cell Lung Cancer by Matrix-assisted Laser Desorption\/Ionization Imaging Mass Spectrometry on Formalin-fixed Paraffin-embedded Tissue Specimens","volume":"15","author":"Kriegsmann","year":"2016","journal-title":"Mol. Cell. Proteom."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6081","DOI":"10.7150\/jca.47698","article-title":"Mass Spectrometry Imaging Differentiates Chromophobe Renal Cell Carcinoma and Renal Oncocytoma with High Accuracy","volume":"11","author":"Kriegsmann","year":"2020","journal-title":"J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1800046","DOI":"10.1002\/prca.201800046","article-title":"Development of a Class Prediction Model to Discriminate Pancreatic Ductal Adenocarcinoma from Pancreatic Neuroendocrine Tumor by MALDI Mass Spectrometry Imaging","volume":"13","author":"Casadonte","year":"2019","journal-title":"Proteom. Clin. Appl."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/nmeth.3296","article-title":"Image fusion of mass spectrometry and microscopy: A multimodality paradigm for molecular tissue mapping","volume":"12","author":"Yang","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Welinder, C., Paw\u0142owski, K., Sugihara, Y., Yakovleva, M., J\u00f6nsson, G., Ingvar, C., Lundgren, L., Baldetorp, B., Olsson, H., and Rezeli, M. (2015). A protein deep sequencing evaluation of metastatic melanoma tissues. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123661"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jdermsci.2020.03.008","article-title":"Proteomics: An emerging approach for the diagnosis and classification of cutaneous squamous cell carcinoma and its precursors","volume":"99","author":"Azimi","year":"2020","journal-title":"J. Dermatol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1002\/prca.200700022","article-title":"Diagnostic biomarkers differentiating metastatic melanoma patients from healthy controls identified by an integrated MALDI-TOF mass spectrometry\/bioinformatic approach","volume":"1","author":"Ratcliffe","year":"2007","journal-title":"Proteom. Clin. Appl."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5088","DOI":"10.1200\/JCO.2005.03.164","article-title":"Serum proteomic fingerprinting discriminates between clinical stages and predicts disease progression in melanoma patients","volume":"23","author":"Mian","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1016\/j.jprot.2011.04.013","article-title":"Protein signatures for survival and recurrence in metastatic melanoma","volume":"74","author":"Hardesty","year":"2011","journal-title":"J. Proteom."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e1800029","DOI":"10.1002\/prca.201800029","article-title":"Site-to-Site Reproducibility and Spatial Resolution in MALDI-MSI of Peptides from Formalin-Fixed Paraffin-Embedded Samples","volume":"13","author":"Ly","year":"2019","journal-title":"Proteom. Clin. Appl."},{"key":"ref_28","unstructured":"R Core Team (2019). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1097\/DAD.0b013e3182433f3a","article-title":"A proposal for improving multicolor FISH sensitivity in the diagnosis of malignant melanoma using new combined criteria","volume":"34","author":"Kerl","year":"2012","journal-title":"Am. J. Dermatopathol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ebbelaar, C.F., Jansen, A.M.L., Bloem, L.T., and Blokx, W.A.M. (2021). Genome-wide copy number variations as molecular diagnostic tool for cutaneous intermediate melanocytic lesions: A systematic review and individual patient data meta-analysis. Virchows Arch.","DOI":"10.1007\/s00428-021-03095-5"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/DAD.0000000000001551","article-title":"BAP-1 Expression Status by Immunohistochemistry in Cellular Blue Nevus and Blue Nevus-like Melanoma","volume":"42","author":"Chen","year":"2020","journal-title":"Am. J. Dermatopathol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Beleaua, M.A., Jung, I., Braicu, C., Milutin, D., and Gurzu, S. (2021). SOX11, SOX10 and MITF Gene Interaction: A Possible Diagnostic Tool in Malignant Melanoma. Life, 11.","DOI":"10.3390\/life11040281"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/his.13843","article-title":"Massively parallel sequencing analysis of benign melanocytic naevi","volume":"75","author":"Lozada","year":"2019","journal-title":"Histopathology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1097\/DAD.0b013e31823df1e2","article-title":"Imaging mass spectrometry--a new and promising method to differentiate Spitz nevi from Spitzoid malignant melanomas","volume":"34","author":"Lazova","year":"2012","journal-title":"Am. J. Dermatopathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1007\/s00216-019-02296-x","article-title":"Sample preparation of formalin-fixed paraffin-embedded tissue sections for MALDI-mass spectrometry imaging","volume":"412","author":"Hermann","year":"2020","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1039\/C7AN00565B","article-title":"Mass spectrometry imaging for clinical research\u2014Latest developments, applications, and current limitations","volume":"142","author":"Vaysse","year":"2017","journal-title":"Analyst"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/path.1797","article-title":"The origin of vimentin expression in invasive breast cancer: Epithelial-mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential?","volume":"206","author":"Korsching","year":"2005","journal-title":"J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1097\/00000478-198608000-00006","article-title":"Expression of vimentin in surgically resected adenocarcinomas and large cell carcinomas of lung","volume":"10","author":"Upton","year":"1986","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1007\/s00018-011-0735-1","article-title":"Vimentin in cancer and its potential as a molecular target for cancer therapy","volume":"68","author":"Satelli","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/1756-9966-29-109","article-title":"A novel function for vimentin: The potential biomarker for predicting melanoma hematogenous metastasis","volume":"29","author":"Li","year":"2010","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0959-437X(00)00154-4","article-title":"Cytoskeletal changes in cell transformation and tumorigenesis","volume":"11","author":"Pawlak","year":"2001","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7008","DOI":"10.1038\/s41598-019-43453-7","article-title":"Increased elasticity of melanoma cells after low-LET proton beam due to actin cytoskeleton rearrangements","volume":"9","author":"Sarna","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1097\/DAD.0000000000000147","article-title":"Comparison of the expression of vimentin and actin in spitz nevi and spitzoid malignant melanomas","volume":"37","author":"Alomari","year":"2015","journal-title":"Am. J. Dermatopathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.semcdb.2019.12.003","article-title":"Regulation of actin isoforms in cellular and developmental processes","volume":"102","author":"Kashina","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/164_2016_27","article-title":"From Cytoskeleton to Gene Expression: Actin in the Nucleus","volume":"235","author":"Viita","year":"2017","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Viita, T., Kyheroinen, S., Prajapati, B., Virtanen, J., Frilander, M.J., Varjosalo, M., and Vartiainen, M.K. (2019). Nuclear actin interactome analysis links actin to KAT14 histone acetyl transferase and mRNA splicing. J. Cell Sci., 132.","DOI":"10.1242\/jcs.226852"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/B978-0-12-380866-0.60002-2","article-title":"DNA methylation and cancer","volume":"70","author":"Kulis","year":"2010","journal-title":"Adv. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13072-015-0006-8","article-title":"Multi-faceted quantitative proteomics analysis of histone H2B isoforms and their modifications","volume":"8","author":"Molden","year":"2015","journal-title":"Epigenetics Chromatin"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s13148-020-00910-9","article-title":"Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis","volume":"12","author":"Azevedo","year":"2020","journal-title":"Clin. Epigenetics"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1097\/CMR.0000000000000648","article-title":"Utility of histone H3K27me3 and H4K20me as diagnostic indicators of melanoma","volume":"30","author":"Davis","year":"2020","journal-title":"Melanoma Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Hurkmans, D.P., Jensen, C., Koolen, S.L.W., Aerts, J., Karsdal, M.A., Mathijssen, R.H.J., and Willumsen, N. (2020). Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma. J. Immunother. Cancer, 8.","DOI":"10.1136\/jitc-2020-001193"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Osorio, A., Milne, R.L., Kuchenbaecker, K., Vaclov\u00e1, T., Pita, G., Alonso, R., Peterlongo, P., Blanco, I., de la Hoya, M., and Duran, M. (2014). DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004256"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1038\/nprot.2011.388","article-title":"Proteomic analysis of formalin-fixed paraffin-embedded tissue by MALDI imaging mass spectrometry","volume":"6","author":"Casadonte","year":"2011","journal-title":"Nat. Protoc."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1021\/acs.analchem.9b04473","article-title":"Using the Chemical Noise Background in MALDI Mass Spectrometry Imaging for Mass Alignment and Calibration","volume":"92","author":"Boskamp","year":"2020","journal-title":"Anal. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Boskamp, T., Casadonte, R., Hauberg-Lotte, L., Deininger, S., Kriegsmann, J., and Maass, P. (2021). Cross-normalization of MALDI mass spectrometry imaging data improves site-to-site reproducibility. Anal. Chem., submitted for publication.","DOI":"10.1021\/acs.analchem.1c01792"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/13\/3197\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:24:47Z","timestamp":1760163887000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/13\/3197"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,26]]},"references-count":55,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["cancers13133197"],"URL":"https:\/\/doi.org\/10.3390\/cancers13133197","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,26]]}}}