PRACTICAL USE OF MOLECULAR MARKERS IN DIAGNOSTIC NEUROPATHOLOGY - PDF document

5/12/2014 PRACTICAL USE OF MOLECULAR MARKERS IN DIAGNOSTIC NEUROPATHOLOGY NOTHING TO DISCLOSE Tarik Tihan, MD, PhD UCSF Surgical Neuropathology ALGORITHM THE PREMISE  Is it normal or C abnormal? R • A PHENOTYPE CAN BE ASSOCIATED L A  Is it neoplastic or WITH MULTIPLE GENOTYPES AND I D N non-neoplastic? VICE VERSA I I O D  Is it benign or C • THE APPROACH TO THE USE OF DX L A malignant? A O T MOLECULAR MARKERS SHOULD BE L A G  Is it glial or non- BASED ON A MORPHOLOGICALLY I glial? D AND CLINICALLY SOUND ALGORITHM C A A  What kind of glial T L tumor? A 1

5/12/2014 OUTLINE • SMALL BIOPSY: GLIOSIS OR GLIOMA THIS LOOKS LIKE A GLIOMA BUT • IF IT IS A GLIOMA, DO I NEED COULD IT BE GLIOSIS ANYTHING OTHER THAN H&E? • POSTERIOR FOSSA TUMORS IN CHILDREN 2

5/12/2014 GLIAL MARKERS • GFAP • Olig-2 • VIM • S-100 • EMA • D2-40 • NSE IDH Gene Mutation TUMOR MARKERS Metabolic • MIB-1 • 1p19q, EGFR, Reprogramming: A PTEN, (FISH) Cancer Hallmark • P53 Even Warburg Did • MGMT, TERT Not Anticipate • IDH-1 (R132H) PROMOTER • ATRX (PCR) • WT-1 PS. Ward, CB. Thompson CANCER Cell vol 21 no (2012) 3

5/12/2014 IDH-1 IDH STORY • Useful for diagnosis YES • Useful for prognosis YES • Predictive for treatment decisions NO TERT MUTATIONS ALT by FISH ATRX by IHC COURTESY OF DR. MELIKE PEKMEZCI, UCSF 4

5/12/2014 FISH ‐ 1p/19q ATRX STORY • Useful for diagnosis YES • Useful for prognosis NO • Predictive for treatment decisions NO FISH- 19q FISH 1p 5

5/12/2014 MGMT promoter methylation in malignant gliomas: ready 1P19Q STORY for personalized medicine? Michael Weller, Roger Stupp, Guido Reifenberger, Alba A. Brandes, Martin J. • Useful for diagnosis YES van den Bent, Wolfgang Wick & Monika E. Hegi Nature Reviews Neurology 6, 39-51 (January 2010) • Useful for prognosis YES • Predictive for treatment decisions YES? What we now know about adult glioblastoma MGMT STORY • Useful for diagnosis NO • Useful for prognosis NO • Predictive for treatment decisions YES? 6

5/12/2014 5 distinct genetic/epigenetic/transcriptional subtypes of adult GBM COURTESY OF DRS. ANNETTE MOLIINARO & MARGARET WRENSCH, UCSF Brennan et al, Cell October 2013 A CHILD WITH A POSTERIOR FOSSA TUMOR  abnormal  neoplastic POSTERIOR FOSSA TUMORS IN  low grade or benign CHILDREN  glial  type? 7

5/12/2014 MIB-1 (Ki-67) GFAP OLIG-2 pERK P16 8

5/12/2014 PILOCYTIC AND PILOMYXOID ASTROCYTOMA Duplication Or mutation Mutation P16 TP53 etc. FISH analysis for KIAA1549-BRAF shows duplication IHC suggests downstream pERK activation SENESCENCE 33 34 A CHILD WITH A POSTERIOR FOSSA TUMOR  abnormal  neoplastic  malignant  non-glial!..well NOT SURE 9

5/12/2014 GFAP 10

5/12/2014 OLIG-2 SYNAPTOPHYSIN MIB-1 (Ki-67) MYCC FISH GREEN: CEP8 RED: MYC-C 11

5/12/2014 MEDULLOBLASTOMA GENETICS • GROUP A= Wnt Pathway APC, Wnt,  -catenin  -catenin mutations, classical histology TURCOT Syndrome , APC mutations • GROUP B= SHH Pathway PTCH, SHH, SMOH GAB-1 mutations (nodular/desmoplastic variant) GORLIN Syndrome, germline PTCH mutations • Isochromosome17q in 40% of classic type • MYC-C & MYC-N amplifications: poor prognosis (preferentially in the anaplastic/large cell variant) IBNC, March 15-19, 2013 REMEMBER • ONE GENOTYPE – ONE PHENOTYPE IS A MYTH, AND A GROSS UNDERESTIMATION OF BIOLOGY • STARTING POINT IS MORPHOLOGY (TODAY) • YOU CAN NO LONGER IGNORE MOLECULAR PATHOLOGY AND KEEP YOUR HEAD IN H&E THANK YOU!!!! 12