Original ArticlesImpact of Next-generation Sequencing on Interobserver Agreement and Diagnosis of Spitzoid NeoplasmsBenton, Sarah BA*; Zhao, Jeffrey BA*; Zhang, Bin MS*; Bahrami, Armita MD†; Barnhill, Raymond L. MD‡; Busam, Klaus MD§; Cerroni, Lorenzo MD∥; Cook, Martin G. MD, FRCPath¶; de la Fouchardière, Arnaud MD, PhD#; Elder, David E. MBChB, FRCPA**; Johansson, Iva MD††; Landman, Gilles MD, PhD‡‡; Lazar, Alexander MD, PhD§§; LeBoit, Philip MD∥∥; Lowe, Lori MD¶¶; Massi, Daniela MD, PhD##; Duncan, Lyn M. MD***; Messina, Jane MD†††; Mihic-Probst, Daniela MD‡‡‡; Mihm, Martin C. Jr MD§§§; Piepkorn, Michael W. MD, PhD∥∥∥,¶¶¶; Schmidt, Birgitta MD###; Scolyer, Richard A. MD****,††††,‡‡‡‡; Shea, Christopher R. MD§§§§; Tetzlaff, Michael T. MD, PhD∥∥; Tron, Victor A. MD, FRCPC∥∥∥∥,¶¶¶¶; Xu, Xiaowei MD, PhD**; Yeh, Iwei MD, PhD∥∥; Yun, Sook Jung MD, PhD####; Zembowicz, Artur MD, PhD*****; Gerami, Pedram MD* Author Information *Department of Dermatology, Feinberg School of Medicine, Northwestern University §§§§Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL †Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA ‡Departments of Pathology and Translational Research, Institut Curie, Paris Sciences and Lettres Research University, and Faculty of Medicine, University of Paris Descartes, Paris, France #Department of Biopathology, Centre Leon Bernard, Lyon, France §Department of Pathology, Dermatopathology Service, Memorial Sloan Kettering Cancer Center, New York City, NY ∥Department of Dermatology, Medical University of Graz, Graz, Austria ¶Department of Histopathology, Royal Surrey County Hospital, Guildford, UK **Department of Pathology and Laboratory Medicine, Division of Anatomic Pathology, Hospital of the University of Pennsylvania, Philadelphia, PA ††Department of Clinical Sciences, University of Gothenburg, Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden ‡‡Department of Pathology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil §§Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX ∥∥Departments of Dermatology and Pathology, University of California San Francisco, San Francisco, CA ¶¶Department of Dermatology and Pathology, University of Michigan Medical School, Ann Arbor, MI ##Department of Health Sciences, Section of Anatomic Pathology, University of Florence, Florence, Italy ***Dermatopathology Unit, Pathology Service, Massachusetts General Hospital, Harvard Medical School §§§Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School ###Division of Pathology, Boston Children’s Hospital and Harvard Medical School *****Dermatopathology Consultations LLC, Lahey Clinic and Tufts MedicalSchool, Boston, MA †††Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL ‡‡‡Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland ∥∥∥Division of Dermatology, Department of Medicine, University of Washington School of Medicine, Seattle ¶¶¶Dermatopathology Northwest, Bellevue, WA ****Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, and NSW Health Pathology ‡‡‡‡Faculty of Medicine and Health, The University of Sydney, Sydney ††††Melanoma Institute Australia, North Sydney, NSW, Australia ∥∥∥∥Lifelabs, Department of Laboratory Medicine, St Michael’s Hospital ¶¶¶¶Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada ####Department of Dermatology, Chonnam National University Medical School, Gwangju, Korea S.B. and J.Z. contributed equally to this article. Conflicts of Interest and Source of Funding: This study was supported by the IDP Foundation Inc. R.A.S. is supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant and Practitioner Fellowship. P.G. has received royalties from Elsevier for textbooks and has served as a consultant for Castle Biosciences and DermTech Inc. K.B. has received royalties from Elsevier for textbooks. R.A.S. has received fees for professional services from Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, and GlaxoSmithKline. C.R.S. has received fees for professional services from Myriad Genetics, Novartis, Orlucent, and SkinCure Oncology. M.T.T. has served as a consultant and advisor for Myriad Genetics, Merck Sharp & Dohme, Nanostring LLC, and Novartis. For the remaining authors none were declared. Correspondence: Pedram Gerami, MD, Northwestern University, Department of Dermatology, 676 N. St. Clair St., Suite 1765, Chicago, IL 60611 (e-mail: [email protected]). The American Journal of Surgical Pathology: December 2021 - Volume 45 - Issue 12 - p 1597-1605 doi: 10.1097/PAS.0000000000001753 Buy Metrics Abstract Atypical Spitzoid melanocytic tumors are diagnostically challenging. Many studies have suggested various genomic markers to improve classification and prognostication. We aimed to assess whether next-generation sequencing studies using the Tempus xO assay assessing mutations in 1711 cancer-related genes and performing whole transcriptome mRNA sequencing for structural alterations could improve diagnostic agreement and accuracy in assessing neoplasms with Spitzoid histologic features. Twenty expert pathologists were asked to review 70 consultation level cases with Spitzoid features, once with limited clinical information and again with additional genomic information. There was an improvement in overall agreement with additional genomic information. Most significantly, there was increase in agreement of the diagnosis of conventional melanoma from moderate (κ=0.470, SE=0.0105) to substantial (κ=0.645, SE=0.0143) as measured by an average Cohen κ. Clinical follow-up was available in all 70 cases which substantiated that the improved agreement was clinically significant. Among 3 patients with distant metastatic disease, there was a highly significant increase in diagnostic recognition of the cases as conventional melanoma with genomics (P<0.005). In one case, none of 20 pathologists recognized a tumor with BRAF and TERT promoter mutations associated with fatal outcome as a conventional melanoma when only limited clinical information was provided, whereas 60% of pathologists correctly diagnosed this case when genomic information was also available. There was also a significant improvement in agreement of which lesions should be classified in the Spitz category/WHO Pathway from an average Cohen κ of 0.360 (SE=0.00921) to 0.607 (SE=0.0232) with genomics. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.