Learning Objectives Financial Relationships 1
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3/24/2017 WHO has an update on the Disclosure of Relevant Histiocytoses?...Check your Blood: Financial Relationships A brief update on the pathogenesis USCAP requires that all planners (Education Committee) in a position to and histopathology of histiocytic influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their neoplasms 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. Jennifer Picarsic, MD Pediatric Pathologist Children’s Hospital of Pittsburgh of UPMC Assistant Professor, University of Pittsburgh School of Medicine Society for Hematopathology Companion Meeting USCAP 2017 Disclosure of Relevant Learning objectives Financial Relationships 1. Understand that histiocytic neoplasms are USCAP requires that all faculty in a position to heterogeneous with overlapping features and an influence or control the content of CME disclose any relevant financial unifying diagnosis requires: relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to Pathology: MIP the content of this educational activity and creates a conflict of interest. • Morphology, Immunophenotype, Pattern of involvement Dr. Jennifer Picarsic declares he/she has no conflict(s) of interest Clinical and Radiographic findings to disclose. 2. Review updates to the classification scheme… Pathogenesis: Inflammatory myeloid neoplasms? Mixed histiocytic lesions Molecular updates 1 3/24/2017 WHO classification of tumours of haematopoietic and lymphoid tissues Swerdlow S, Campo E, Harris N et al. Lyon: IARC Press, 2008 2008 Update: • Histiocytic sarcoma • Tumors derived from Langerhans cells • Interdigitating dendritic cell sarcoma • Follicular dendritic cell sarcoma • Other rare dendritic cell tumors: • Indeterminate dendritic cell tumor • Fibroblastic reticular cell tumor • Disseminated juvenile xanthogranuloma (ECD) • Not covered: Reticulohistiocytosis and Rosai Dorfman Disease –> WHO Classification of Tumours of Skin ** • Should be distinguished from other members of the juvenile xanthogranuloma family • Often associated with BRAF mutations * ** • Clonal relationship to lymphoid neoplasms recognized in some cases Emile JF, et al. Blood. 2016;Jun 2;127(22):2672‐81. Image courtesy of : Benjamin H. Durham, M.D., Genomic Pathology Research Fellow in Molecular Oncology Department of Pathology Memorial Sloan Kettering Cancer Center Langerhans cell histiocytosis (LCH) Erdheim‐Chester Disease (ECD) 2 3/24/2017 Langerhans cell histiocytosis (LCH) **Taken out of the classification • MIP*: CD1a ≠ LCH – LCH vs Dendritic cell/Langerhans cell hyperplasia (mesenchymal origin): – Pattern of involvement is important Follicular Dendritic Cell Sarcoma: FDC (CD21, CD23, CD35) • Updates to proposed classification Fibroblastic reticular cell tumor: Interstitial reticulum cell (CK, actins) – Myeloid inflammatory neoplasia – BRAF and beyond – “L” Group • LCH • Mixed LCH/ECD • ECD (Erdheim Chester Disease) • ICH (Indeterminate cell histiocytosis) *Morphology, Immunophenotype, Pattern of involvement CD1a CD1a S100 S100 CD1a CD1a VE1(+) BRAF VE1(‐) BRAF CD207 = Langerin CD207 3 3/24/2017 Pattern of Nodal LCH – Sinus Disease CD1a CD207 LCH? Dendritic cell hyperplasia‐ Not LCH LCH? CD1a S100 4 3/24/2017 CD1a S100 CLL with dendritic cell (DC) hyperplasia CD207 CD207 Not LCH Bone marrow LCH CD1a Myeloid inflammatory neoplasia • LCH distinct gene expression profile from skin LC • In vivo animal models and human studies – LCH is derived from immature myeloid dendritic cells of the bone marrow (BM) BM LCH?? CD163+, – Clinically distinct LCH groups defined by: neg CD207 and CD1a • BRAF‐V600E mutation within CD34+ BM progenitor cells and circulating CD11c+/CD14+ cells (MS‐LCH) versus only in tissue restricted CD207+ dendritic cells (SS‐LCH). • *Misguided myeloid differentiation model: “Mutations in the MAPK/ERK pathway at critical stages in myeloid differentiation appear to be an essential and universal driver of LCH pathology and clinical phenotypes” Allen CE, et al. J Immunol. 2010;184(8):4557‐67. *Berres ML, J Exp Med. 2014;211(4):669‐83. BRAF Prognostic Marker? BRAF and beyond …LCH BRAF Mutation Correlates with High‐Risk LCH and • BRAF‐V600E: Highly dependent of the method of Increased Resistance to First‐Line Therapy testing: Highly sensitive PCR methods are Heritier S. J Clin Oncol. 2016;34(25):3023‐30 recommended in order to detect small allelic fractions (~1% mutant) Higher reactivation rate (5‐year) – 42.8% v. wt 28.1%; P = .006 • BRAF‐V600E can co‐occur • Increased resistance to combined vinblastine and with ARAF, MAP3K1 corticosteroid Rx • BRAF exon 12 in‐frame – 21.9% v. wt 3.3%; P = .001 deletions* • Higher Rate of permanent consequence • FAM73A‐BRAF gene fusion* Mutations and in‐ (including DI, ND‐LCH) frame deletions – 27.9% and wt 12.6%; P = .001 *Chakraborty R,. Blood. 2016;128(21):2533‐37. Allen CE, Parsons DW. Hematology Am Soc Hematol Educ Program. 2015;2015:559‐64. 5 3/24/2017 Diverse Future tools… ** BRAF-V600E testing in circulating peripheral blood Kinase ` Alterations cells/BM (CLIA approved*) and/or cell free DNA in LCH: • *Ferguson LS, Webb R, Sarabia S, Alvarez K, Allen C, McClain K, et al. A Highly Sensitive, Clinically‐Validated Assay to Quantitate BRAF p.V600E Mutations in Blood and Bone Marrow Samples of Langerhans Cell Histiocytosis Patients. Pediatric Blood & Cancer. 2016;63(S2):S34. • Donadieu J, Héritier S, Taly V, Sonia Garrigou, Terrones N, Normand C, et al. Abstracts from the 32nd Annual Meeting of the Histiocyte Society Dublin, Ireland October 17–19, 2016: Relevance of BRAFV600E Allele Detection in Circulating CFDNA as a Biomarker in Pediatric LCH. Pediatric Blood & Cancer. 2016;63(S2):S16‐7. • Santa‐Maria V, Celis V, C CdT, Mora J. Abstracts from the 32nd Annual Meeting of the Histiocyte Society Dublin, Ireland October 17–19, 2016; Badalian‐Very, et al. Blood 2010 Clinical use of BRAF Mutations Profile in LCH Patients for Diagnosis and Kansal, et al. Genes Chrom Cancer 2013 Monitoring of Treatment Response. Pediatric Blood & Cancer. Brown NA, et al. Blood 2014 2016;63(S2):S31. Chakraborty, et al. Blood 2014 • Hyman DM, Diamond EL, Vibat CR, Hassaine L, Poole JC, Patel M, et al. Nelson, et al. Genes Chrom Cancer 2015 Prospective blinded study of BRAFV600E mutation detection in cell‐free Image courtesy of : Benjamin H. Durham, M.D., DNA of patients with systemic histiocytic disorders. Cancer discovery. Chakraborty et al. Blood 2016 Genomic Pathology Research Fellow in Molecular Oncology 2015;5(1):64‐71. Lee et al. JCI Insight 2017** Department of Pathology Memorial Sloan Kettering Cancer Center “L” group Original skin biopsy of LCH, later shown to also be VE1+ VE1 Mixed ECD and LCH Johnson et al. J Cutan Pathol. 2015. Emile JF, et al. Blood. 2016;Jun 2;127(22):2672‐81 and Hervier B et al. Blood. 2014. Aug 14;124(7):1119‐26. Mar;43(3):270‐5. 2nd skin lesions with Retroperitoneal XG phenotype and biopsy BRAF‐V600E+ prompted ECD workup F13a VE1 Johnson et al. J Cutan Pathol. 2015. Johnson et al. J Cutan Pathol. Mar;43(3):270‐5. 2015. Mar;43(3):270‐5. 6 3/24/2017 Erdheim Chester Disease (ECD) ECD = Clinical, Radiographic, and Pathologic • MIP* ‐ Foamy CD68 histiocytes ≠ ECD – Clinicoradiographic correlation with xanthogranuloma phenotype is important – Molecular as an additional diagnostic aid • Updates to proposed classification – BRAF and beyond – Myeloid inflammatory neoplasia – “L” group lesion with XG immunophenotype • LCH • ECD (Erdheim Chester Disease) • Mixed LCH/ECD • ICH (indeterminate cell histiocytosis) PET 99Tc *Morphology, Immunophenotype, Pattern of involvement Diamond EL, et al. Blood. 2014;124(4):483‐92. CD68+ CD68 PGM1 CD163 Xanthomatous hisocytes ≠ ECD CD68 Fascin Factor 13a CD163 CD14 ECD with ECD with brain pericardial and pleural effusions involvement VE1 F13a Fascin 7 3/24/2017 BRAF and beyond …ECD Diverse • BRAF‐V600E: Highly dependent of the method of Kinase testing: Highly sensitive PCR methods are Alterations recommended in order to detect small allelic fractions in ECD: (~1% mutant) • BRAF‐V600E can co‐occur with ARAF, PIK3CA mutations • New targetable kinase gene fusions* ARAF – KIF5B‐ALK MAP2K1 Mutations and in‐ – LMNA‐NTRK1 frame deletions Image courtesy of : Haroche, et al. Blood 2012 Brown RA, et al. Blood 2015 Benjamin H. Durham, M.D., Diamond, et al. Blood 2013 Diamond, Durham, Haroche, et al. Cancer Discovery 2016 Genomic Pathology Research *Diamond EL, Durham BH, et al. Go, et al. Histopathology 2014 Durham, et al. Curr Opin Hematol. 2016 Cancer Discovery. 2016;6(2):154‐65. Emile, Diamond, et al. Blood 2014 Shanmugam, et al. Head Neck Pathol. 2016 Fellow in Molecular Oncology O’Malley, et al. Ann Diagn Pathol 2015 Lee, et al. JCI Insight 2017 Department of Pathology Kordes, et al. Leukemia 2015 Memorial Sloan Kettering Allen CE, Parsons DW. Hematology Am Soc Hematol Educ Program. 2015;2015:559‐64. Cancer Center L group lesion: Both ECD and LCH “L” group: Systemic JXG with mutations Inflammatory myeloid neoplasms? • BRAF‐V600E expressed in lesional cells along w/ BM progenitor cells and circulating monocytes/myeloid DC* ECD: • Gene expression profiles may still Extracutaneous or disseminated JXG support their divergent with MAPK activating mutations or ALK morphology/immunophenotype translocations – LCH from dendritic cells – ECD from monocytes Diamond EL, Durham BH, et al. Cancer