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1/18/2019 Histiocytic and Dendritic Cell Lesions L. Jeffrey Medeiros, MD MD Anderson Cancer Center Outline 2016 classification of Histiocyte Society Langerhans cell histiocytosis / sarcoma Erdheim-Chester disease Juvenile xanthogranuloma Malignant histiocytosis Histiocytic sarcoma Interdigitating dendritic cell sarcoma Follicular dendritic cell sarcoma Rosai-Dorfman disease Hemophagocytic lymphohistiocytosis Writing Group of the Histiocyte Society 1 1/18/2019 Major Groups of Histiocytic Lesions Group Name L Langerhans-related C Cutaneous and mucocutaneous M Malignant histiocytosis R Rosai-Dorfman disease H Hemophagocytic lymphohistiocytosis Blood 127: 2672, 2016 L Group Langerhans cell histiocytosis Indeterminate cell tumor Erdheim-Chester disease S100 Normal Langerhans cells Langerhans Cell Histiocytosis “Old” Terminology Eosinophilic granuloma Single lesion of bone, LN, or skin Hand-Schuller-Christian disease Lytic lesions of skull, exopthalmos, and diabetes insipidus Sidney Farber Letterer-Siwe disease 1903-1973 Widespread visceral disease involving liver, spleen, bone marrow, and other sites Histiocytosis X Umbrella term proposed by Sidney Farber and then Lichtenstein in 1953 Louis Lichtenstein 1906-1977 2 1/18/2019 Langerhans Cell Histiocytosis Incidence and Disease Distribution Incidence Children: 5-9 x 106 Adults: 1 x 106 Sites of Disease Poor Prognosis Bones 80% Skin 30% Liver Pituitary gland 25% Spleen Liver 15% Bone marrow Spleen 15% Bone Marrow 15% High-risk organs Lymph nodes 10% CNS <5% Blood 127: 2672, 2016 N Engl J Med 379: 856, 2018 Langerhans Cell Histiocytosis Solitary lesion of bone Eosinophilic Granuloma CD1a Langerhans Cell Histiocytosis Lungs Associated with smoking BRAF V600E CD207 3 1/18/2019 Langerhans Cell Histiocytosis Lymph Nodes CD1a LNs can be localized or a part of disseminated disease This patient had generalized LNs and BRAF V600E mutation Langerhans Cell Histiocytosis Morphologic Features Frequency Feature 100% Langerhans cells (<5-75%) 92% Eosinophils 84% Multinucleated giant cells 75% Small lymphocytes 61% Necrosis 49% Neutrophils 29% Foamy histiocytes Mild atypia (reactive type) in ~50% of cases Mitotic rate: 0-23/10 high power fields Arch Pathol Lab Med 107: 59, 1983 Langerhans Cell Histiocytosis Immunophenotype and EM Immunophenotype S100+, CD1a+, CD207/langerin+ +/- BRAF V600E (mutation specific antibody) +/- CD4, CD11c, CD45/LCA, CD68, lysozyme+ Note: S100, CD1a, and CD207/langerin are not restricted to Langerhans cells Electron Microscopy Birbeck granules (aka Langerhans bodies) 4 1/18/2019 CD207 Am J Surg Pathol 41: 1390, 2017 Cyclin D1 Langerhans Cell Histiocytosis Birbeck Granules Also known as X bodies or Langerhans bodies Birbeck granules are characteristic (but not unique to) Langerhans cells Presence is a reflection of membrane activity; function debated Contain langerin = a type II transmembrane lectin receptor Francoise Basset, PhD J Invest Dermatol 37: 51, 1961 Michael S. C. Birbeck, PhD CR Acad Sci (Paris) 261:5719, 1965 1925-2005 Langerhans Cell Histiocytosis Mutations in BRAF/MAP2K1 Are Common Blood 116: 1919, 2010 BRAF V600E 18/40 (45%) MAP2K1 11/40 (27.5%) Blood 124: 1655, 2014 5 1/18/2019 Extracellular MAPK/ ERK PATHWAY RTK VEGFR PDGFR EGFR Cytoplasm RAS GTP-binding proteins: Proteins HRAS, KRAS and NRAS ARAF BRAF CRAF P Encoded by MAP2K1 gene MEK1/2 P ERK 1/2 Nucleus Transcription Regulation of proliferation, apoptosis, • MAPK: Mitogen-activated protein kinase p90Rsk factors metabolism and immune response • ERK: Extracellular signal-regulated kinase 85% of LCH cases have genetic abnormalities of the MAPK pathway They likely all do Blood 128: 2533, 2016 Langerhans Cell Histiocytosis Misguided Myeloid Dendritic Cell Model Model to explain the widely disparate presentations of LCH Distribution of disease depends on the cell in which mutation/ERK activation occurs Hematology Am Soc Hematol Educ Program 2015;2015:559-564 6 1/18/2019 Immunity 44: 439, 2016 “Histiocytosis X (HX) has the advantage of widespread use, although it has been applied to other types of histiocytosis. The generally recognized Langerhans cell derivation of HX makes Langerhans cell histiocytosis and attractive alternative.” Arch Pathol Lab Med 107: 59, 1983 Langerhans Cell Histiocytosis (LCH) Rarely Associated with Lymphomas Mantle cell lymphoma LCH No BRAF V600E or MAP2K1 mutations Lymphomas 5 Classical Hodgkin lymphoma 1 Mantle cell lymphoma 1 Angioimmunoblastic T-cell CD1a LCH was <10%; incidental Sergio Pina Oviedo, MD Mod Pathol 30: 734, 2017 7 1/18/2019 Langerhans Cell Histiocytosis Differential Diagnosis Dermatopathic lymphadenopathy Indeterminate dendritic cell tumor Langerhans cell sarcoma Dermatopathic Lymphadenopathy S100 Benign reaction pattern associated with skin disease CD1a Indeterminate Dendritic cell Tumor Thought to be derived from normal precursors of Langerhans cells (so-called indeterminate cells) Patients present with > nodules, papules or plaques on skin Dermis-based disease that can extend into subcutaneous fat Histologically looks like Langerhans cells histiocytosis But often no eosinophils Immunophenotype: CD1a+, S100+, CD207- Electron microscopy: No Birbeck granules Genetics: ETV3-NCOA2/t(1;8)(q23.1;8q13.3) reported in 3 cases Highly variable clinical course: Spontaneous regression or progression 8 1/18/2019 Indeterminate Dendritic Cell Tumor CD1a A negative langerin/CD207 is required to make this diagnosis CD207 Langerhans Cell Sarcoma Definition A high-grade neoplasm with overt malignant cytologic features and Langerhans cell phenotype History Rarely preceded by typical LCH (in my experience) Age and Sites of Disease Median 41 yrs (10-72yrs) Extranodal ~ 80% (most often skin); nodal ~ 20% Ancillary Support for Diagnosis Immunohistochemistry: S-100+, CD1a+, CD207/langerin+ Electron microscopy: Birbeck granules Genetics Rare cases with monoclonal IGH rearrangements Prognosis ~50% mortality as a result of progressive disease Langerhans Cell Sarcoma CD207 9 1/18/2019 Erdheim-Chester Disease Definition “A clonal, systemic proliferation of histiocytes, commonly having a foamy (xanthomatous) component and containing Touton giants cells.” 2017 WHO book p. 481 Described by W. Chester in single author paper in German in 1930. J. Erdheim was mentor Renamed Erdheim-Chester disease in 1972 Jacob Erdheim, MD William Chester, MD Erdheim-Chester Disease Clinicopathologic Features Age and Sex Ratio Median 53 years (range, 20-74) 3 men to 1 woman Symptoms Can be asymptomatic or aggressive; related to sites Dull and deep bone pain common (especially knees) Histologic features Bland histiocytes infiltrate tissues Foamy or eosinophilic cytoplasm; Touton giant cells Fibrosis is common; +/- lymphocytes, plasma cells, eos No mitoses, necrosis, granulomas, emperipolesis Looks/phenotypes like juvenile xanthogranuloma Imaging Bilateral, symmetric cortical osteosclerosis of long bones Surrounds aorta (“coated”) or kidney (“hairy kidney”) Genetics BRAF V600E mutations in ~50%, ~4% NRAS, ~10% PI3KA Blood Advances 1:357, 2017 Erdheim-Chester Disease Positive CD14 CD68 CD163 Fascin Factor XIII Negative CD1a CD207 S100+ ~20% CD68 CD1a 10 1/18/2019 Erdheim-Chester Disease Radiologic Images Case courtesy of Dr Andrew Lawson Radiopaedia.org, rID: 29803 Case courtesy of Dr Andrew Dixon, Radiopaedia.org, rID: 9351 C Group Many different lesions – most on skin Can subdivide into two broad groups Xanthogranuloma Non-xanthogranuloma Juvenile Xanthogranuloma Affects children >> adults Rare: < 1% of all pediatric tumors Single, few, or multiple lesions on skin: yellow papules 0.5-1 cm Often regress spontaneously Long bones are not involved Rarely patients have visceral involvement or disseminated disease Can cause symptoms or death due to local invasion Genetics Localized CGH: chromosomal abnormalities uncommon (~5%) Disseminated CGH: nonspecific chromosomal abnormalities described 1 case with MAPK1 mutation (Oncotarget 8: 46065, 2017) Mod Pathol 30:1234, 2017 11 1/18/2019 Juvenile Xanthogranuloma Immunophenotype CD14+ CD68+ CD163+ Factor XIIIa +/- S-100+ ~20% Fascin+ ~20% CD1a- CD207/langerin - MAPK Pathway Mutations in Histiocytic Lesions A Unifying Feature in Pathogenesis LCH = Langerhans cell histiocytosis JXG = Juvenile xanthogranuloma ECD = Erdheim-Chester disease Hematology Am Soc Hematol Educ Program 2015; 2015:559-564 M Group Histiocytic sarcoma Interdigitating dendritic cell sarcoma Langerhans cell sarcoma “…we recommend reusing the old-term malignant histiocytosis, and refer to the phenotype as a subtype.” Blood 127: 2672, 2016 12 1/18/2019 Histiocytic Sarcoma Definition and Clinicopathologic Features Definition A malignant proliferation of cells with morphologic and immunophenotypic features of mature tissue histiocytes Epidemiology Median age = 52 y; males = females Subset associated with B-cell lymphoma (transdifferentiation) Rare pts with mediastinal germ cell tumor and isochromosome 12p Presentation Often extranodal (GI tract, skin, soft tissues) Can be nodal or disseminated (“malignant histiocytosis”) Genetics Subset of cases with monoclonal IG rearrangements 40-50% of cases with BRAF V600E mutation Outcome Clinically aggressive; poor response to therapy 60-80% of patients die of disease 2017 WHO book p. 468-470 Histiocytic Sarcoma CD11c CD163 Histiocytic Sarcoma Immunophenotype Positive Vimentin S100 (weak or focal), Ki-67 10-20% ZBTZ46 (Mod Pathol 31:1479, 2018) Variably Positive Fascin Weakly and variably positive CD45/LCA, CD68, lysozyme Negative CD1a, CD207/langerin CD21, CD23, CD35,
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