Are Diagnostic Criteria for Mastocytosis Developed for Adults Applicable to Children

Are diagnostic criteria for mastocytosis developed for adults applicable to children? Melody Carter, LAD Dean Metcalfe, LAD Linda Scott, LAD Jamie Robyn, LAD Alan Wayne, POB Clifford Takemoto, POB Mastocytosis Mastocytosis is a disease characterized by the presence of excessive numbers of mast cells in the skin and internal organs, such as the bone marrow, gastrointestinal tract, lymph nodes, liver and spleen • Demographics – Children and adults – M/F equal • Symptoms – Excess of mast cells – Mast cell derived mediators • Histamine, prostaglandins, leukotrienes, cytokines – Hematologic disorders WHO classification of mastocytosis-Adult • Cutaneous mastocytosis • Maculopapular CM • Diffuse CM • Mastocytoma • Systemic indolent mastocytosis (without AHD) • Smoldering systemic mastocytosis • Isolated bone marrow mastocytosis • Systemic mastocytosis with an AHNMD • MDS, MPD, AML, NHL • Systemic aggressive mastocytosis • with eosinophilia • Mast cell leukemia • Aleukemic MCL • Mast cell sarcoma • Extracutaneous mastocytoma WHO classification of mastocytosis-Adult 1 major + 1 minor or 3 minor Major: Characteristic multifocal dense infiltrates of mast cells in bone marrow biopsy (>15 in aggregate) Minor: -Morphology of mast cells: Spindle shaped (>25%) -Detection of a codon 816 c-kit mutation -Flow cytometric co-expression of CD117, CD2 and/or CD25 by the bone marrow mast cell population -Total serum tryptase >20 ng/ml Pediatric-Onset Mastocytosis • Mastocytosis is an unusual disease • Mastocytosis most commonly present before 6 months of age • ~50-60% of cases of mastocytosis are diagnosed in childhood • In children, the skin is the most common organ involved. • Children typically presents with one of three cutaneous disease patterns Aim • Define the characteristics of severe pediatric-onset mastocytosis whose diagnostic parameters may be discordant from classic adult-onset disease criteria. Study Design Children, birth-21 years Cutaneous mastocytosis and/or tryptase >20, organomegaly, abnormal hematologic findings CBC with diff, tryptase, PT/PTT LFTs, IgE, sed rate, Bone marrow bx & aspirate c-kit mutational analysis Determine the disease variant using WHO criteria Skin characteristics of UP Skin characteristics: DCM A B C D Skin characteristics of pediatriconset systemic mastocytosis Serum Tryptase Serum tryptase (ng/ml) 320 280 240 200 160 120 80 40 0 UP DCM SM UP DCM SM Sperr, Int Arch Allergy Immun, 2002:128 Pediatric-Onset Mastocytosis Brockow, J Am Acad Dermol, 2003:48 Bone Marrow Mast Cell Immunophenotype in Mastocytosis CD 117 051303.001 10 4 051303.008 0 0 10 4 Flow cytometry-DCM 081303.001 10 4 081303.008 2.65e-3 10 4 0 0.069 1.33e-3 6.67e-4 1.25 10 FL2-H: FL2-Height 3 FL2-H: Mouse IgG1 PE 10 FL2-H: FL2-Height 3 10 3 10 3 CD117 10 2 10 2 10 2 CD117 99.9 10 0 10 1 10 2 FL1-H: FL1-Height 10 3 0.12 10 4 FL2-H: CD117 PE 10 2 10 1 10 1 100 10 0 10 1 10 1 10 0 0.019 10 1 10 FL1-H: FL1-Height 2 10 3 10 4 10 0 10 1.89 0 98 10 1 10 4 0 10 0 11.1 10 0 10 1 10 2 FL1-H: CD45 FITC 10 3 87.7 10 4 051303.003 10 4 Control 0.063 8.4e-3 051303.004 10 4 CD45 0.062 10 FL1-H: FL1-Height 2 10 3 10 081303.003 10 4 Control 1.28 0.019 081303.004 10 4 CD45 1.29 0.018 2.4e-3 CD117 CD117 CD117 CD117 10 FL2-H: FL2-Height 3 10 FL2-H: FL2-Height 3 10 FL2-H: CD117 PE 3 10 3 FL2-H: CD117 PE 10 2 10 2 10 2 10 2 10 1 10 1 10 1 10 1 10 0 10 82.9 0 17 10 1 10 0 4 99.6 10 0 0.33 10 1 10 4 0 86.2 10 0 12.5 10 1 10 4 0 98.5 10 0 10 1 10 2 FL1-H: CD25 FITC 10 3 0.17 10 4 10 FL1-H: FL1-Height 2 10 3 10 10 FL1-H: FL1-Height 2 10 3 10 10 FL1-H: CD2 FITC 2 10 3 10 CD2 2004FC00218 10 4 CD2 081303.001 10 4 CD25 111803.008 2.65e-3 10 4 2004FC00218 0.069 10 4 CD25 6.67e-4 0.047 10 3 FL2-H: Mouse IgG1 PE 10 3 10 FL2-H: FL2-Height 3 CD117 10 CD117 99.9 10 0 10 1 10 2 FL1-H 10 3 0.027 10 4 2 FL3-H: CD117 PerCP-Cy5.5 1.33e-3 0 4.e-3 10 3 FL2-H 10 2 10 2 10 2 10 1 1 10 1 10 1 10 10 10 0 10 111803.003 10 4 0 10 0 5.23 10 0 10 1 10 2 FL1-H: CD45 FITC 10 3 94.7 10 4 99.9 0 0.12 10 1 10 0 4 7.32 10 0 92.7 10 1 Control 5.68e-3 3.7e-3 10 FL1-H: FL1-Height 2 10 3 10 111803.004 10 4 CD45 4.11e-3 10 FL1-H: FL1-Height 2 10 3 10 4 2004FC00218 10 2.65e-3 4 Control 0.033 0.031 2004FC00218 10 4 CD45 0.033 0.017 FL3-H: CD117 PerCP-Cy5.5 10 FL2-H: FL2-Height 3 CD117 CD117 CD117 CD117 10 FL2-H: FL2-Height 3 10 3 10 3 FL2-H: CD117 PE 10 2 10 2 10 2 10 2 10 1 10 1 76 10 0 10 1 10 1 10 0 24 10 1 10 FL1-H: FL1-Height 2 10 3 10 4 10 0 10 99.5 0 0.51 10 1 CD2 CD25 10 FL1-H: FL1-Height 2 10 3 10 4 10 0 95.2 10 0 10 1 10 2 FL2-H: CD2 PE 10 3 4.74 10 4 10 0 95.3 10 0 10 1 10 2 FL1-H: CD25 FITC 10 3 4.67 10 4 CD2 CD25 Bone marrow biopsies-DCM H&E Tryptase D B A Bone marrow biopsies-SM H&E Tryptase Results and Evaluation Patient Tryptase BM bx CD2/25 Spindle D816V+ Dx 1 2 3 4 5 6 7 8 9 10 11 69/27 5.56 5.85 8.29 20/9 16/7.7 92 126 74.3 167 23 neg neg neg pos NA NA NA pos neg neg neg neg neg neg neg NA NA NA neg neg neg neg neg neg neg neg NA NA NA neg neg neg neg neg neg neg neg NA NA NA neg neg neg neg UP UP UP UP UP UP UP DCM DCM DCM DCM Results and Evaluation Patient Tryptase BM bx CD2/25 >25% Spindle D816V+ Dx 12 13 14 15 16 17 18 45.4 86.5 32.9 53.7 348 238 153 pos pos neg neg pos pos neg pos NA pos pos pos pos pos neg neg neg neg pos pos neg pos NA pos pos pos pos pos SM SM SM SM SM SM SM Diagnosis-WHO Criteria Tryptase CD2/ BM >25% D816V+ Diagnosis >20 ng/ml CD25 aggreg spindle correct UP N=7 DCM N=4 SM N=7 5-92 Neg Neg Neg Neg 7/7 23-126 Neg Neg-3 Pos-1 Neg-3 Pos-4 Neg Neg 3/4 33-348 Pos Neg-5 Pos-2 Pos 7/7 Conclusion • 18 children with some characteristics of systemic disease were evaluated • Analysis of the data revealed the adult classification criteria was correct in 17/18 • 2001 consensus data is appropriate for the classification of children with mastocytosis Recommendations • Children should be evaluated for mastocytosis using the following parameters: 1. Skin exam: skin biopsy for definitive diagnosis 2. Complete physical exam 3. Serum tryptase, CBC and differential, platelets • Bone marrow considered for: 1. Serum tryptase >20 ng/ml and – Organomegaly or abnormal hematologic findings Acknowledgements • Dean Metcalfe • Cem Akin • Linda Scott • Alan Wayne • Pierre Noel • Irina Maric