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What's New in Dermatopathology Melanocytic Proliferations

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What's New in Dermatopathology Melanocytic Proliferations 3/27/2017 What’s New in Dermatopathology Melanocytic proliferations Aleodor (Doru) Andea, MD, MBA Associate Professor of Pathology and Dermatology Director of Dermatopathology Molecular Diagnostic Laboratory University of Michigan Ann Arbor, MI [email protected] @DoruAndea Disclosure of Relevant Disclosure of Relevant Financial Relationships Financial Relationships USCAP requires that all planners (Education Committee) in a position to USCAP requires that all faculty in a position to influence or control the content of CME disclose any relevant financial influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. the content of this educational activity and creates a conflict of interest. Dr. Aleodor Andea declares he has no conflict(s) of interest to disclose. • Why do we need more stuff? Overview 1. Case based presentation 2. Updates in molecular ancillary studies for the diagnosis of difficult melanocytic tumors (SNP Common nevus Melanoma microarrays) 3. Updates in diagnosis and prognosis of few melanocytic entities 1 3/27/2017 • A small proportion have ambiguous histology • 40-year old woman with a papule on the right shoulder • Clinical R/O BCC Common nevus Nevoid melanoma ? 8 • Melanocytic neoplasm with borderline features between nevus and melanoma • Suspicious for nevoid melanoma 2 3/27/2017 Molecular studies What else we can do? Molecular studies Molecular studies • Genomic instability in melanoma • Genomic instability in melanoma • Detection of numerical abnormalities in the tumor genome (CGH/SNP and FISH) Comparative Genomic Hybridization Molecular studies (CGH)/ Single Nucleotide Polymorphism (SNP) arrays • Detection of numerical abnormalities in the tumor genome • Screens the entire genome for gains and • Mass spectrometry losses in DNA material in one experiment • Gene expression profile • Identification of mutations (TERT gene promoter) • Variants: • Array based CGH –Gains and Losses • Array based SNP –Gains, Losses and Loss of Heterozygosity 3 3/27/2017 SNP arrays SNP arrays • Copy number changes SNP arrays SNP arrays • Copy number changes • Copy number changes 11p gain • Allele peak SNP arrays SNP arrays • Copy number changes • Copy number changes • Allele peak • Allele peak • Mutation data • BRAF • NRAS • PTEN • TP53 4 3/27/2017 Univ of Michigan Cohort Univ of Michigan Cohort Melanoma Melanoma Nevus Nevus Univ of Michigan Cohort Univ of Michigan Cohort Melanoma Melanoma Nevus Nevus Compound nevus Primary melanoma • No gains or losses • BRAF V600E • 19 CNA • 13 losses • 6 gains • BRAF V600E 5 3/27/2017 Metastatic melanoma • Chr 22 CN-LOH • 30 CNA • 25 gains • 2 losses • 3 CN-LOH • BRAF V600K • Chr 1p gain (NRAS) • Chr 9p21 homozygous loss (CDKN2A) • NRAS Q61R • Chr 13q loss (BRCA2) • Chr 9p 21 homozygous loss • Chr 22 CN-LOH • Chr 1p gain (NRAS) • Chr 13q loss (BRCA2) • NRAS Q61R 6 3/27/2017 This seems easy enough… Nevoid melanoma • No abnormalities – GOOD • Abnormalities – BAD • Not that simple 28 y/o F, Lt Temple Not all abnormalities are bad • Some can be used to classify nevi 39 BAP-1 negative nevus (BAP-oma) 3p loss (BAP-1 locus) BRAF V600E 7 3/27/2017 10 days old AA newborn BAP1 IHC Giant congenital nevus with several nodules 10 days old AA newborn CGH Proliferative nodule in a congenital nevus OncoScanTM Affymetrix Copy number • Result: Losses of whole chromosomes 3, 4, 5, 10, 11, 13, 14, 16, 17, 18, 21 1 year old More problems • How many abnormalities do we require for a melanoma diagnosis 8 3/27/2017 Histological # of cases with at least Average # CNV classification one significant copy number variation • >=3 abnormalities significant (but with exceptions) Nevi 0/6 (0%) 0 • Whole chromosomal abnormalities in proliferative nodules Atypical nevi 3/15 (20%) 1.6 (1-2) • Isolated homozygous deletion of 9p21 favors melanoma Ambiguous 15/25 (60%) 6.3 (1-25) • Others to come…. Melanoma 35/39 (90%) 21.7 (1-69) Sensitivity: 90% Specificity: 87% Alomari et al. Platform at USCAP meeting, Seattle WA, 2016 • >=3 abnormalities significant (but with exceptions) Ultimate question • Whole chromosomal abnormalities in proliferative nodules • Isolated homozygous deletion of 9p21 favors melanoma • Can CNV number and/or pattern predict adverse outcome in • Others to come…. borderline lesions? • Unfortunately not too many studies • Molecular pathologist job: Provide a comprehensive interpretation • Your job: Understand the report and communicate with your molecular pathologist Ambiguous cases with clinical follow Practical algorithm for use of molecular up studies 10 33% Adverse events 9 8 N =14 3 7 6 0% Adverse events 5 4 3 6 5 2 1 0 Positive CNV Negative CNV No adverse events Adverse events Alomari et al. Platform at USCAP meeting, Seattle WA, 2016 9 3/27/2017 Histologic examination Histologic examination Melanocytic lesion Definitive diagnosis Melanocytic lesion Definitive diagnosis No further testing Ambiguous lesion No further testing Favor benign Borderline Favor malignant Histologic examination Histologic examination Ambiguous lesion Ambiguous lesion Favor benign Borderline Favor malignant Favor benign Borderline Favor malignant Molecular testing Mol - Mol - Mol + Mol - Mol + Mol + Histologic examination Histologic examination Ambiguous lesion Ambiguous lesion Favor benign Borderline Favor malignant Favor benign Borderline Favor malignant Mol - Mol - Mol + Mol - Mol + Mol + Mol - Mol - Mol + Mol - Mol + Mol + Nevus Melanoma Borderline favor Borderline favor nevus melanoma 10 3/27/2017 Histologic examination Histologic examination Melanocytic lesion Definitive diagnosis Ambiguous lesion Ambiguous lesion No further testing Favor benign Borderline Favor malignant Favor benign Borderline Favor malignant Mol - Mol - Mol + Mol - Mol + Mol + Mol - Mol - Mol + Mol - Mol + Mol + Borderline Borderline Nevus Borderline favor Borderline Borderline Borderline favor Melanoma nevus melanoma Risk assessment Histologic examination Melanocytic lesion Definitive diagnosis Cost and TAT Ambiguous lesion No further testing Favor benign Borderline Favor malignant Mol - Mol - Mol + Mol - Mol + Mol + Borderline favor Borderline favor Melanoma Nevus nevus Borderline Borderline melanoma • Excision with margins appropriate Excision with limited margins • Excision with margins appropriate for depth if possible for depth •+/-SLN •SLN Cost and TAT Microarray vs. FISH • Order Microarray if • Order FISH if Test Range TAT SNP/CGH array $1,800-$2,400 14-21 days FISH $800-$1,200 3-7 days 11 3/27/2017 Microarray vs. FISH Microarray vs. FISH • Order Microarray if • Order FISH if • Order Microarray if • Order FISH if • Can afford • Can afford • Have enough material • > 1mm2 • >30%tumor purity • 10 unst @ 10microns Microarray vs. FISH Microarray vs. FISH • Order Microarray if • Order FISH if • Order Microarray if • Order FISH if • Can afford • Can afford • Have enough material • Have enough material • > 1mm2 • > 1mm2 • >30%tumor purity • >30%tumor purity • 10 unst @ 10microns • 10 unst @ 10microns • Can wait 2-3 weeks • Can wait 2-3 weeks Advantage: higher sensitivity Microarray vs. FISH Microarray vs. FISH • Order Microarray if • Order FISH if • Order Microarray if • Order FISH if • Can afford • Microarray not covered • Can afford • Microarray not covered • Have enough material • Have enough material • Not enough material • > 1mm2 • > 1mm2 • Only few slides • >30%tumor purity • >30%tumor purity • Superficial lesions • 10 unst @ 10microns • 10 unst @ 10microns • Tumor infiltrated by benign cells/ • Can wait 2-3 weeks • Can wait 2-3 weeks inflammation Advantage: higher sensitivity Advantage: higher sensitivity 12 3/27/2017 Microarray vs. FISH Microarray vs. FISH • Order Microarray if • Order FISH if • Order Microarray if • Order FISH if • Can afford • Microarray not covered • Can afford • Microarray not covered • Have enough material • Not enough material • Have enough material • Not enough material • > 1mm2 • Only few slides • > 1mm2 • Only few slides • >30%tumor purity • Superficial lesions • >30%tumor purity • Superficial lesions • 10 unst @ 10microns • Tumor infiltrated by benign cells/ • 10 unst @ 10microns • Tumor infiltrated by benign cells/ • Can wait 2-3 weeks inflammation • Can wait 2-3 weeks inflammation • Need faster TAT • Need faster TAT Advantage: higher sensitivity Advantage: higher sensitivity Disadvantage: lower sensitivity, higher false positive (lower specificity) Key points • CNVs can assist in the diagnosis of melanocytic lesions • Should be used only in ambiguous lesion • Molecular data should not overturn histologic impression • >=3 abnormalities – significant for melanoma • Understand the molecular report 30 y/o male blue-colored plaque on the scalp with subcutaneous nodules Bx from the plaque 13 3/27/2017 Bx from the nodules Large plaque-type blue nevus with subcutaneous cellular nodules 6 years later 14 3/27/2017 Cellular blue nevus Melanoma ex cellular blue nevus Common blue nevus • Aka Malignant blue nevus Cellular blue nevus Atypical cellular blue nevus Common blue nevus 15 3/27/2017 Melanoma (MBN) arising in atypical cellular blue nevus • Predilection for scalp • Scalp lesions with GNA11 mutations (as opposed to GNAQ in other sites) • Loss of BAP1 associated
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