Learning objectives 1. Understand that histiocytic neoplasms are heterogeneous with overlapping features and an unifying diagnosis requires:

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1 WHO has an update on the Histiocytoses?...Check your Blood: A brief update on the pathogenesis and histopathology of histiocytic neoplasms 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 Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their 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. Disclosure of Relevant Financial Relationships USCAP requires that all faculty in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their 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. Dr. Jennifer Picarsic declares he/she has no conflict(s) of interest to disclose. Learning objectives 1. Understand that histiocytic neoplasms are heterogeneous with overlapping features and an unifying diagnosis requires: Pathology: MIP Morphology, Immunophenotype, Pattern of involvement Clinical and Radiographic findings 2. Review updates to the classification scheme Pathogenesis: Inflammatory myeloid neoplasms? Mixed histiocytic lesions Molecular updates 1

2 WHO classification of tumours of haematopoietic and lymphoid tissues Swerdlow S, Campo E, Harris N et al. Lyon: IARC Press, 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): 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 Langerhans cell histiocytosis (LCH) **Taken out of the classification (mesenchymal origin): Follicular Dendritic Cell Sarcoma: FDC (CD21, CD23, CD35) Fibroblastic reticular cell tumor: Interstitial reticulum cell (CK, actins) MIP*: CD1a LCH LCH vs Dendritic cell/langerhans cell hyperplasia Pattern of involvement is important Updates to proposed classification 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

4 Pattern of Nodal LCH Sinus Disease CD1a CD207 LCH? Dendritic cell hyperplasia Not LCH LCH? CD1a S100 4

5 CLL with dendritic cell (DC) hyperplasia CD1a S100 CD207 CD207 Not LCH Bone marrow LCH CD1a Myeloid inflammatory neoplasia BM LCH?? CD163+, neg CD207 and CD1a 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) Clinically distinct LCH groups defined by: 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): *Berres ML, J Exp Med. 2014;211(4): BRAF Prognostic Marker? BRAF Mutation Correlates with High Risk LCH and Increased Resistance to First Line Therapy Heritier S. J Clin Oncol. 2016;34(25): Higher reactivation rate (5 year) 42.8% v. wt 28.1%; P =.006 Increased resistance to combined vinblastine and corticosteroid Rx 21.9% v. wt 3.3%; P =.001 Higher Rate of permanent consequence (including DI, ND LCH) 27.9% and wt 12.6%; P =.001 BRAF and beyond LCH BRAF V600E: Highly dependent of the method of testing: Highly sensitive PCR methods are recommended in order to detect small allelic fractions (~1% mutant) BRAF V600E can co occur with ARAF, MAP3K1 BRAF exon 12 in frame deletions* FAM73A BRAF gene fusion* *Chakraborty R,. Blood. 2016;128(21): Mutations and inframe deletions Allen CE, Parsons DW. Hematology Am Soc Hematol Educ Program. 2015;2015:

6 Diverse Kinase Alterations in LCH: Badalian Very, et al. Blood 2010 Kansal, et al. Genes Chrom Cancer 2013 Brown NA, et al. Blood 2014 Chakraborty, et al. Blood 2014 Nelson, et al. Genes Chrom Cancer 2015 Chakraborty et al. Blood 2016 Lee et al. JCI Insight 2017** ** ` Image courtesy of : Benjamin H. Durham, M.D., Genomic Pathology Research Fellow in Molecular Oncology Department of Pathology Memorial Sloan Kettering Cancer Center Future tools BRAF-V600E testing in circulating peripheral blood cells/bm (CLIA approved*) and/or cell free DNA *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; Clinical use of BRAF Mutations Profile in LCH Patients for Diagnosis and Monitoring of Treatment Response. Pediatric Blood & Cancer. 2016;63(S2):S31. Hyman DM, Diamond EL, Vibat CR, Hassaine L, Poole JC, Patel M, et al. Prospective blinded study of BRAFV600E mutation detection in cell free DNA of patients with systemic histiocytic disorders. Cancer discovery. 2015;5(1): L group Original skin biopsy of LCH, later shown to also be VE1+ VE1 Mixed ECD and LCH Emile JF, et al. Blood. 2016;Jun 2;127(22): and Hervier B et al. Blood Aug 14;124(7): Johnson et al. J Cutan Pathol Mar;43(3): nd skin lesions with XG phenotype and BRAF V600E+ prompted ECD workup VE1 Retroperitoneal biopsy F13a Johnson et al. J Cutan Pathol Mar;43(3): Johnson et al. J Cutan Pathol Mar;43(3):

7 Erdheim Chester Disease (ECD) 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) ECD = Clinical, Radiographic, and Pathologic *Morphology, Immunophenotype, Pattern of involvement Diamond EL, et al. Blood. 2014;124(4): PET 99 Tc CD68+ Xanthomatous his ocytes ECD CD68 PGM1 CD163 CD68 Fascin Factor 13a ECD with pericardial and pleural effusions ECD with brain involvement CD163 VE1 CD14 F13a Fascin 7

8 BRAF and beyond ECD BRAF V600E: Highly dependent of the method of testing: Highly sensitive PCR methods are recommended in order to detect small allelic fractions (~1% mutant) Diverse Kinase Alterations in ECD: BRAF V600E can co occur with ARAF, PIK3CA mutations New targetable kinase gene fusions* KIF5B ALK LMNA NTRK1 *Diamond EL, Durham BH, et al. Cancer Discovery. 2016;6(2): Allen CE, Parsons DW. Hematology Am Soc Hematol Educ Program. 2015;2015: ARAF MAP2K1 Mutations and inframe deletions Haroche, et al. Blood 2012 Diamond, et al. Blood 2013 Go, et al. Histopathology 2014 Emile, Diamond, et al. Blood 2014 O Malley, et al. Ann Diagn Pathol 2015 Kordes, et al. Leukemia 2015 Brown RA, et al. Blood 2015 Diamond, Durham, Haroche, et al. Cancer Discovery 2016 Durham, et al. Curr Opin Hematol Shanmugam, et al. Head Neck Pathol Lee, et al. JCI Insight 2017 Image courtesy of : Benjamin H. Durham, M.D., Genomic Pathology Research Fellow in Molecular Oncology Department of Pathology Memorial Sloan Kettering Cancer Center L group lesion: Both ECD and LCH Inflammatory myeloid neoplasms? BRAF V600E expressed in lesional cells along w/ BM progenitor cells and circulating monocytes/myeloid DC* Gene expression profiles may still support their divergent morphology/immunophenotype LCH from dendritic cells ECD from monocytes Diamond EL, Durham BH, et al. Cancer Discovery. 2016;6(2): *Emile J F, et al. Pediatric Blood & Cancer. 2016;63(S2):S60 *Collin M. Pediatric Blood & Cancer. 2016; 63(S2):S15 L group: Systemic JXG with mutations ECD: Extracutaneous or disseminated JXG with MAPK activating mutations or ALK translocations Emile JF, et al. Blood. 2016;Jun 2;127(22): Update on Xanthogranuloma family Growing molecular understanding: Chakraborty et al of 4 systemic or disseminated cutaneous JXG harbored 8 9 somatic mutations in various chromosomes, PI3KCD mutation and germline NF1 mutation Diamond and Durham et al of 12 (67%) systemic JXG harbored MAPK pathway mutations Growing molecular understanding: Systemic JXG 67% (n=12) with MAPK pathway alterations Wild Type 33% RNF11 BRAF 8% NRAS/ ARAF* 17% KRAS 17% MAP2K1 25% *Concurrent NRAS and ARAF mutation in same lesions Diamond EL, Durham BH, et al. Cancer Discovery. 2016;6(2):

9 Systemic ALK+ histiocytosis in infancy TPM3 ALK fusion Positive: ALK, CD163, CD68, lysozyme, and variable fascin, Factor 13a and S100 Negative: CD30, CD1a and CD207 Chan et al 2008; 3 female infants Hepatosplenomegaly with bland sinusoidal histiocytic infiltrates Differential diagnosis: Storage disease Clinical resolution An unique but self limited form of systemic histiocytosis of infancy? Renal S100 ALK Fascin L group ICH: Indeterminate cell histiocytosis L group: Indeterminate cell histiocytosis (ICH) Molecular Update: ETV3 NCOA2* Orphan L group lesion Langerhans like DC: CD1a+ /S100+; Lacks Birbeck granules (Langerin ) LCH can have sparse Birbeck granules /Langerin Adults, solitary or multiple skin lesions Emile JF, et al. Blood. 2016;Jun 2;127(22): Brown RA et al. Blood. 2015;126(20): ICH with ETV3 NCOA2 CD1a+, CD207 ve M group: Malignant neoplasms of the histiocytic phenotype Malignant cytomorphology: Pleomorphism, increased mitoses, ± atypical mitoses Updates to proposed classification Primary malignancies of the histiocytic phenotype Re grouping into M group: Histiocytic sarcoma (HS), Langerhans cell sarcoma (LCS), interdigitating cell sarcoma/tumor (IDCS), and indeterminate cell sarcoma Out: Follicular Dendritic Cell Sarcoma/Fibroblastic reticular cell tumor Molecular: BRAF and beyond BRAF V600E, HRAS, CLIP2 BRAF, BRAF V595L w/ HRAS, PTEN mutation Secondary malignancies of histiocytic phenotype Share common molecular signature of the primary malignancy 9

10 Histiocytic sarcoma Malignant cytomorphology Overlapping features: M group: LCS? HS? * CD1a+ * CD163 Ki 67 Langerhans cell sarcoma CD1a, CD163+ * CD1a+ CD163 Secondary histiocytic lesions following Prior hematopoietic malignancy Secondary histiocytic malignancy (HS) following: B and T cell acute lymphoblastic leukemia (ALL) Non Hodgkin lymphomas (Follicular, CLL, HCL) Secondary atypical histiocytic neoplasms, NOS following: B and T cell ALL Acute myeloid leukemia (JXG like lesion with shared inv16) Diffuse large B cell lymphoma (Lesion with mixed LCH/JXG/RDD phenotype with BRAF V600E) HS with shared t(8;14) as previous B ALL CD14 Ki 67 CD163 Castro et al. PDP. 2010; 13: Rosai Dorfman Disease (RDD) MIP Alone emperipolesis, S100+ RDD Morphology: Large cells, pale cytoplasm Variable emperipolesis, plasma cells, fibrosis IHC: S100, fascin, CD68, variable CD163 and CD14 Pattern of involvement (Lymph node: Sinus disease) Updates to proposed classification R group lesion Sporadic RDD Related conditions predisposing to RDD While no BRAF, other MAPK pathway mutations found R group: RDD updates Autoimmune, Genetic, Neoplasia Related : Increased IgG4 and RDD? Histiocytosis Lymphadenopathy plus syndrome (e.g. Faisalabad histiocytosis) with a homozygous or compound heterozygous mutation in the solute carrier family 29, SLC29A3 gene (OMIM #602782) Autoimmune lymphoproliferative syndrome (ALPS), type I with heterozygous germline mutation in TNFRSF6, the FAS gene (OMIM#601859) Concurrent lymphoma or LCH Molecular updates: NRAS, KRAS, and ARAF *Morphology, Immunophenotype, Pattern of involvement 10

11 Growing molecular understanding: Sporadic RDD 44% (n=9) with MAPK pathway mutations WT 56% NRAS 11% ARAF 11% KRAS 22% Diamond EL, Durham BH, et al. Cancer Discovery. 2016;6(2): *Unlike systemic JXG, No concurrent NRAS and ARAF mutation in same lesion H group Hemophagocytosis lymphohistiocytosis (HLH): His ocy c disorder; =Immunoregulatory disorder HLH may be associated with histiocytic lesions LCH and HLH in liver Updates to H group Primary New genetic entities: NLRC4 inflammasome Secondary Rheumatologic HLH: conditions = Best named as MAS HLH Mutations in 2 HLH with Partial cytolytic dysfunction Emile JF, et al. Blood. 2016;Jun 2;127(22): Conclusions 1. Pathology of histiocytic neoplasms can be heterogenous MIP* with clinical and radiographic findings *Morphology, Immunophenotype, Pattern of involvement 2. Updates to the classification scheme: LCH/ECD: Pathogenesis emerging as an inflammatory myeloid neoplasm Mixed histiocytic lesions still not defined but ever more recognized Malignant lesions of histiocytic phenotype Moving away from sarcoma designation while understanding phenotype heterogeneity and in secondary lesions: a shared clonality MAPK pathway mutations important in histiocytic lesions Targetable kinases playing increasing role in treatment Pathogenesis, Diagnosis, and Prognostic implications Collaborators: Dr. Ronald Jaffe Lori Schmitt Dr. Nathanael Bailey Dr. Carl Allen Dr. Ken McClain Dr. Rikhia Chakraborty Contact: picarsicj@upmc.edu Dr. Benjamin Durham Dr. Eli Diamond Dr. Omar Abdel Wahab Dr. Noah Brown 33 rd annual Histiocyte Society meeting Singapore October 2 4, 2017 Become a member of the Histiocyte Society! The North American Consortium for Histiocytosis (NACHO) is the first Multi Institutional consortium in North America with a solid scientific agenda and the research infrastructure necessary for the development and effective implementation of clinical and translational studies and biological research for histiocytic diseases. consortium.org/ The steps to join NACHO and open the LCH IV are outlined: consortium.org/openinglch iv.html. International Rare Histiocytic Disorders Registry (IRHDR) JXG family, ECD, Multifocal Reticulohistiocytosis, RDD and the Malignant lesions of histiocytic phenotype More information on HS website: websitepages/clinical trials/clinical studies/irhdr 11

12 References* 1. Picarsic J, Jaffe R. Nosology and Pathology of Langerhans Cell Histiocytosis. Hematol Oncol Clin North Am. 2015;29(5): Histiocytosis syndromes in children. Writing Group of the Histiocyte Society. Lancet. 1987;1(8526): Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol. 1997; Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms. Blood May 19;127(20): Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, et al. Revised classification of histiocytoses and neoplasms of the macrophage dendritic cell lineages. Blood. 2016;Jun 2;127(22): Rollins BJ. Genomic Alterations in Langerhans Cell Histiocytosis. Hematol Oncol Clin North Am. 2015;29(5): Allen CE, Li L, Peters TL, Leung HC, Yu A, Man TK, et al. Cell specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol. 2010;184(8): Berres ML, Lim KP, Peters T, Price J, Takizawa H, Salmon H, et al. BRAF V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med. 2014;211(4): Heritier S, Emile JF, Barkaoui MA, Thomas C, Fraitag S, Boudjemaa S, et al. BRAF Mutation Correlates With High Risk Langerhans Cell Histiocytosis and Increased Resistance to First Line Therapy. J Clin Oncol. 2016;34(25): Chakraborty R, Burke TM, Hampton OA, Zinn DJ, Lim KP, Abhyankar H, Scull B, Kumar V, Kakkar N, Wheeler DA, Roy A, Poulikakos PI, Merad M, McClain KL, Parsons DW, Allen CE. Alternative genetic mechanisms of BRAF activation in Langerhans cell histiocytosis. Blood Nov 24;128(21): Allen CE, Parsons DW. Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders. Hematology Am Soc Hematol Educ Program. 2015;2015: Diamond EL, Durham BH, Haroche J, Yao Z, Ma J, Parikh SA, et al. Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms. Cancer Discovery. 2016;6(2): Haroche J, Cohen Aubart F, Charlotte F, Maksud P, Grenier PA, Cluzel P, et al. The histiocytosis Erdheim Chester disease is an inflammatory myeloid neoplasm. Expert review of clinical immunology. 2015;11(9): Durham BH, Diamond EL, Abdel Wahab O. Histiocytic neoplasms in the era of personalized genomic medicine. 2016;23(4): Diamond EL, Dagna L, Hyman DM, Cavalli G, Janku F, Estrada Veras J, et al. Consensus guidelines for the diagnosis and clinical management of Erdheim Chester disease. Blood. 2014;124(4): Collin M, Milne P, Bigley V, Neel A, Haniffa M, Durham B, et al. Abstracts from the 32ndAnnual Meeting of the Histiocyte SocietyDublin, IrelandOctober 17 19, 2016; The Hematopoietic Origin of Adult Histiocytosis. Pediatric Blood & Cancer. 2016; 63(S2):S Emile J F, et al. Abstracts from the 32nd Annual Meeting of the Histiocyte Society Dublin, Ireland October 17 19, 2016; BRAF Mutations in Bone Marrow and Blood of Patients with Erdheim Chester Disease. Pediatric Blood & Cancer. 2016;63(S2):S Go H, Jeon YK, Huh J, Choi SJ, Choi YD, Cha HJ, et al. Frequent detection of BRAF(V600E) mutations in histiocytic and dendritic cell neoplasms. Histopathology Aug;65(2): Zwerdling. Langerhans Cell Sarcoma: Case Report and Review of World Literature. Journal of pediatric hematology/oncology : official journal of the American Society of Pediatric Hematology/Oncology. 2014;36(6): Mourah S, Lorillon G, Meignin V, Vercellino L, de Margerie Mellon C, Pages C, et al. Dramatic transient improvement of metastatic BRAF(V600E) mutated Langerhans cell sarcoma under treatment with dabrafenib. Blood Dec 10;126(24): *See also the provided handout on USCAP website for additional Reference list 21.. Liu Q, Tomaszewicz K, Hutchinson L, Hornick JL, Woda B, Yu H. Somatic mutations in histiocytic sarcoma identified by next generation sequencing. Virchows Arch Jun Furmanczyk PS, Lisle AE, Caldwell RB, Kraemer KG, Mercer SE, George E, et al. Langerhans cell sarcoma in a patient with hairy cell leukemia: common clonal origin indicated by identical immunoglobulin gene rearrangements. J Cutan Pathol Jun;39(6): Muslimani A, Chisti MM, Blenc AM, Boxwala I, Micale MA, Jaiyesimi I. Langerhans/dendritic cell sarcoma arising from hairy cell leukemia: a rare phenomenon. Ann Hematol Sep;91(9): Kordes M, Roring M, Heining C, Braun S, Hutter B, Richter D, et al. Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling. Leukemia Apr;30(4): Castro EC et al. Pediatr Dev Pathol May June; 13(3): Gatalica Z, Bilalovic N, Palazzo JP, Bender RP, Swensen J, Millis SZ, Vranic S, Von Hoff D, Arceci RJ. Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD L1. Oncotarget Aug 14;6(23): Carrasco DR, Fenton T, Sukhdeo K, Protopopova M, Enos M, You MJ, Di Vizio D, Nogueira C, Stommel J, Pinkus GS, Fletcher C, Hornick JL, Cavenee WK, Furnari FB, Depinho RA. The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans. Cancer Cell Aug;10(2): O'Malley DP, Agrawal R, Grimm KE, Hummel J, Glazyrin A, Dim DC, et al. Evidence of BRAF V600E in indeterminate cell tumor and interdigitating dendritic cell sarcoma. Ann Diagn Pathol Jun;19(3): Brown RA, Kwong BY, McCalmont TH, Ragsdale B, Ma L, Cheung C, et al. ETV3 NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis. Blood. 2015;126(20): Chan JK, Lamant L, Algar E, Delsol G, Tsang WY, Lee KC, et al. ALK+ histiocytosis: a novel type of systemic histiocytic proliferative disorder of early infancy. Blood. 2008;112(7): Feldman AL. Clonal relationship between malignant lymphoma and histiocytic/dendritic cell tumors. Surgical Pathology The Clinics 6 (2013) Badalian Very, et al. Blood Sep 16;116(11): Kansal, et al. Genes Chromosomes Cancer Jan;52(1): Brown NA, et al. Blood Sep 4;124(10): Chakraborty, et al. Blood 2014 Nov 6;124(19): Nelson, et al. Genes Chrom Cancer 2015 Jun;54(6): Lee et al. JCI Insight 2017 Feb 9;2(3):e Gheorge G. ALK positive histiocytosis: oral presentation; workshop Accessory cell and Histiocytic neoplasms, European Association for Hematopathology meeting, Sep 7, Basel, Switzerland. *See also the provided handout on USCAP website for additional Reference list *See also the provided handout on USCAP website for additional Reference list Important Information Regarding CME/SAMs The Online CME/Evaluations/SAMs claim process will only be available on the USCAP website until September 30, No claims can be processed after that date! After September 30, 2017 you will NOT be able to obtain any CME or SAMs credits for attending this meeting. 12

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