9/25/2017. Disclosure. I have nothing to disclose. Young S. Kim MD Dept. of Pathology
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1 Disclosure MAST CELLNEOPLASM I have nothing to disclose. Young S. Kim MD Dept. of Pathology 1
2 Objectives What is mast cell lineage? Changes in updated WHO 2016 mastocytosis Issues of Mastocytosis CD30 expression, CD2 and CD25 expression, KIT mutation, Mast cell leukemia, and Myelomastocytic leukemia. Case presentation Importance of inclusion of mast cell neoplasm in routine surgical case work up and the unexpected. 2
3 Classical scheme of hematopoiesis Add lineage diagram of hematopoietic cells Article of mast cell development from T cell progenitors by GATA 3
4 WHO 2001 WHO 2008 WHO classification of mast cell disease evolving and imperfect Mast cells in mastocytosis: not so myeloid and not so proliferative Peter Valent, Blood, 2010 Mast cells (SM) show myeloid and lymphoid antigens (CD43, CD117, CD68, CD2, CD25, CD308) In many SM, neoplastic mast cells do not show signs of significant proliferation Recommend Mastocytosis, a separate group of hematopoietic neoplasm as classified in 2001 WHO 4
5 2016 WHO classification Classification of mastocytosis Myeloproliferative neoplasms (MPN) Chronic myeloid leukemia (CML), BCR ABL1 + Chronic neutrophilic leukemia (CNL) Polycythemia vera (PV) Primary myelofibrosis (PMF) prefibrotic stage, overt fibrotic stage Essential thrombocythemia (ET) Chronic eosinophilic leukemia, not otherwise specified (NOS) MPN, unclassifiable Mastocytosis 2016 WHO Cutaneous mastocytosis (CM) Systemic mastocytosis Indolent systemic mastocytosis (ISM) Smoldering systemic mastocytosis (SSM) Systemic mastocytosis with an associated hematological neoplasm (SM AHN) Aggressive systemic mastocytosis (ASM) Mast cell leukemia (MCL) Mast cell sarcoma (MCS) 2008 WHO Cutaneous mastocytosis (CM) Indolent systemic mastocytosis (ISM) Systemic mastocytosis with associated hematological nonmast cell lineage disease (SH AHNMD) Aggressive systemic mastocytosis (ASM) Mast cell leukemia (MCL) Mast cell sarcoma (MCS) Extracutaneous mastocytoma Issues in mastocytosis Smoldering systemic mastocytosis (SSM) New entity in 2016 WHO It was a provisional subvariant of ISM. The prognosis is less favorable compared to ISM but favorable compared with ASM or MCL. CD2/CD25/CD30 expression KIT mutation D816V is one of miner criteria of SM, how about other KIT mutations? What is Mast cell leukemia? What is Myelomastocytic leukemia? Extracutaneous mastocytoma (ECM) Deleted b/c of rarity 5
6 CD2/CD25/CD30 expression Marker Nl BM ISM SSM ASM MCL CD / /+ CD / CD30 /+ +/ + + CD25 is more sensitive marker than CD2 CD30 is expressed in advanced SM KIT mutation KIT D816V detected >80% of SM and >90% in ISM inadults KIT D816V is considered a relatively weak driver that promotes MC differentiation and maturation rather than MC proliferation Recently, whole exon sequencing of KIT gene discovered many different KIT mutations in mastocytosis, especially in pediatric mastocytosis Pediatric mastocytosis: D816V (only ~42%) and many other KIT gene exons involved, especially exons 8 and 9 Molecular lesions in CM and SM Molecular Abnormality Reported in patients with Estimated frequency in patients with SM KIT D816V All SM variants and also in CM >80% (SM) 15 20% (CM) KIT D816Y CM, ISM, SM AHNMD <5% KIT D816F CM <5% KIT D816H MCL, ASM, SM AHNMD <5% KIT D820G ASM <5% KIT V560G ISM <5% KIT F522C ISM <5% KIT E839K CM <5% KIT V530I SM AHNMD <5% KIT K509I CM, SM (including familial Var) <5% Other KIT mutations CM and/or SM variants <5% Molecular lesions in CM and SM FIP1L1/PDGFRA SM CEL <5% AML1/ETO SM AML with t(8;21) <5% JAK2 V617F SM PMF <5% TET2 mutations SM AHNMD, ISM, ASM <5% SRSF2 mutations ASM, SM AHNMD <5% DNMT3A mutations ISM, SM AHNMD <5% ASXL1 mutations SM AHNMD <5% CBL mutations SM AHNMD <5% U2AF1 mutations SM AHNMD <5% EZH2 mutations SM AHNMD <5% RAS mutations ASM, SM AHNMD <5% 6
7 Alignment of gene mutations and phenotype. Kaplan-Meier estimates of overall survival of 38 SM patients with respect to the individual mutation status irrespective of disease subtype: 12 patients with KIT D816V alone (ISM, n = 7; SSM, n = 2; ASM, n = 3) vs 26 patients with KIT D816V + at least one a... Juliana Schwaab et al. Blood 2013;122: Juliana Schwaab et al. Blood 2013;122: by American Society of Hematology 2013 by American Society of Hematology Presence or absence of KIT and TET2 mutations in microdissected mast cells and CD15+ cells of 5 (A)SM patients with various subtypes of AHNMD Pediatric mastocytosis and c KIT mutations KIT D816V TET2 mutation Disease subtype BM mast cells (%) Mast cells CD15+ Mast cells CD15+ ASM CMML ASM CMML ASM MDS/MPNu ASM MDS/MPNu SM CMML
8 Mast cell leukemia Definition by WHO 2016: Satisfy the criteria of Systemic Mastocytosis The presence of at least 20% MCs on BM smears Leukemic infiltration of marrow If <10% of circulating leukocytes are MCs or no MCs in the blood aleukemic MCL, which is more frequent (>60%) Delineation between various forms of mast cell leukemia (MCL) Leukemic MCL Aleukemic MCL Acute MCL Chronic MCL Primary MCL Secondary MCL At least 10% circulating MCs <10% of blood leukocytes are MCs C Finding(s) present, mostly immature MCs C Findings usually absent, less aggressive course, mature MCs usually predominate Noantecedent SM or other myeloid neoplasm Transformation of SM (usually ASM) or MC sarcoma What is Myelomastocytic leukemia A term applied to advanced myeloid (non MC) neoplasms in which h MC differentiation is prominent, but SM criteria are not fulfilled, thereby distinguishing MML from MCL. MCs comprise >10% of all cells in blood and/or BM smears. Myelomastocytic leukemia (MML) is not recognized as a separate entity. Temporal Bone Mass 16 yo girl presenting with a 4.2 x 3.5 x 3.2 cm temporal bone mass growing into posterior fossa causing mass effect on cerebellum Reported IHC: Positive CD43, CD68 Negative CD1a, CD3, CD8, S 100, Initial Dx: Myeloid neoplasm with minimal mono histiocytic maturation 8
9 Experts diagnosis 1) Low grade appearing histiocytic proliferation with morphologic features of histiocytosis but with a highly abnormal immunophenotype of uncertain biologic potential 2) Non Langerhans cell histiocytosis with abundant eosinophils 9
10 At COH Additional IHC study: Positive CD33, Tryptase, CD25 Negative CD2, CD30, CD34, MPX, Molecular study for Positive for L799F, not D816V Negative for Birbeck granules by EM Pediatric Mast Cell Sarcoma of Temporal Bone With Novel L799F KIT mutation, Mimicking Histiocytic Neoplasm Y.Kimet al., Am J Surg Pathol 37, (3), 2013, Pt Courses Treated as LCH with chemotherapy, but disease progressed with multiple l spine metastasis Cytogenetic study: del 7q Additional IHC: CD117 positive Multiple chemoradiation treatments without improvement Seen at COH for evaluation of transplant CD1a Langerin CD117 CD33 10
11 Mast cell sarcoma Extremely rare Localized and destructive growth of highly atypical mast cells Often identified only after application of appropriate IHC stains, Tryptase and CD117 Occurs distant spread and can resemble MCL later What is a diagnosis? Pt history: see the end of discussion CBC: Mild pancytopenia, No cytosis, no blasts, no circulating mast cells. Increased mast cells (>20%), abnormal morphology in aspirate smears, no KIT mutation, no multifocal dense infiltrates of MCs, no increase in serum tryptase. CD2/CD25 not tested. What is a diagnosis? What is a diagnosis? 11
12 Targeted FISH Tryptase and t(8;21) Pt diagnosed with AML t(8;21). Bone marrow is Day 40 post hematopoietic stem cell transplantation. Increased mast cells disappeared on follow up biopsy without treatment. These mast cells showed t(8;21) by Targeted FISH P. Valent, et al. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts. Blood. 2017; 129: J. Schwaab, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood. 2013; 122: C. Bodemer, er al. Pediatric mastocytosis is a clonal disease assocaited D816V and other activating c KIT mutations. Journal of Investigative Dermatology , P. Valent, et al. Refined diagnostic criteria and classification of mast cell leukemia(mcl) and myelomastocytic leukemia (MML): a consensus proposal. Annals of Oncology 25: ,2014 O. Schmetzer, et al. Murine and human mast cell progenitors. European Journal of Pharmacology. 778(2016)2 10 S. Pullarkat, V. Pullarkat, A. Lagoo, R. Brynes, L. Weiss, K.Gaal, D. Weisenburger, and Y. Kim. Characterization of bone marrow mast cells in acute myeloid leukemia with t(8;21)(q22;q22);runx1 RUNX1T1. Leukemia Research, 37, 11, 2013, Y. Kim et al. Pediatric Mast Cell Sarcoma of Temporal Bone With Novel p L799F (2395 C>T) KIT Mutation, Mimicking Histiocytic Neoplasm. Am J Surg Pathol 2013;37:
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