international hematology conference shiraz May 2017

New classification of Histiocytosis Abolghasemi H Professor of pediatrics hematologist oncologist Shahid beheshti university of medical sciences Baqiyatallah university of medical sciences

Histiocytoses DCs, monocytes, and macrophages are members of the mononuclear phagocyte system accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs (tissue-resident macrophages) Macrophages are large ovoid cells mainly involved in the clearance of apoptotic cells, debris, and pathogens. DCs are starry cells that present antigens on major histocompatibility complex molecules and activate naive T lymphocytes. Human DCs are classified into 2 main groups: plasmacytoid and myeloid (mDC). More than 100 different subtypes with wide range of clinical manifestations, presentations, and histologies.

history Dr. Lichtenstein proposed that the various clinical conditions with shared histopathology probably represent a common condition, which he proposed to be named ‘Histiocytosis X’, with the ‘X’ as an indication of incomplete understanding of the cell of origin (Lichtenstein, 1953). Histiocytosis X; integration of eosinophilic granuloma of bone, Letterer-Siwe disease, and Schüller-Christian disease as related manifestations of a single nosologic entity. Twenty years later, the Birbeck granule, a cytoplasmic structure associated with langerin (CD207), thought to have some function in antigen processing, was discovered by electron microscopy in the pathological mononuclear phagocytic cells of LCH lesions.

Historically, LCH has been presumed to arise from transformed or pathologically activated epidermal dendritic cells called Langerhans cells. new evidence supports a model in which LCH occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursors.

LCH is a neoplasm or a reactive disease? Pathologic LCs are clonal . Its demonstrated by : non random X chromosome inactivation both in whole LCH tissue and sorted CD1a cells Nearly 60% of LCH samples carry the oncogenic BRAF V600E variant

Routes to ERK activation in LCH Routes to ERK activation in LCH. Model of MAPK pathway activation resulting from serial phosphorylation from cellular receptors through RAS, RAF, MEK and, ultimately, ERK. Estimates of frequency of somatic mutations of BRAF and MAP2K1 are illustrated. (*) indicates genes with individual case reports of somatic mutations. ‘Unknown’ indicates ERK activation by mechanisms that have not yet been defined. While activated ERK has been identified in all lesions studied to date, there remains the possibility (dashed line) that Langerhans cell histiocytosis (LCH) may arise from alternative mechanisms in some cases.

Langerhans-Cell Histiocytosis Carl E. Allen, M.D., Ph.D., Miriam Merad, M.D., Ph.D., and Kenneth L. McClain, M.D., Ph.D August 30, 2018 N Engl J Med 2018; 379:856-868

Blood 2016 127:2672-2681 Jean-François Emile Examples of clinical involvement by histiocytoses. (A) Examples of cutaneous manifestations in (i) a child with multisystemic LCH, (ii) adult with intertrigo-like lesions, (ii) xanthelasma of ECD (ii), and (iii) skin manifestations of RDD. (B) Radiographic imaging and CT scans of (i) lytic skull bone lesions and (ii) pulmonary nodules and cysts in LCH, (iii) CT scan revealing typical “hairy kidney” lesions and (iv) micronodular ground-glass opacities and thickening of interlobular pulmonary septa in ECD. (C) 18F-labeled fluorodeoxyglucose (PET) imaging revealing (i) bilateral and symmetric signal in femurs, tibiae, and humeri in ECD, (ii) cutaneous multiple lesions in RDD, and (iii) signal over wrist, knees, and ankles of a patient with XD Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages Blood 2016 127:2672-2681 Jean-François Emile

Langerhans-Cell Histiocytosis Positron-emission tomographic (PET) images show a single bone lesion involving the humerus (Panel A, arrow); low-risk lesions involving the orbit, lymph nodes, bone (multifocal lesion), and thymus (Panel B); and high-risk lesions involving the liver, spleen, and bone marrow (Panel C). Other classic presentations include a lytic bone lesion (Panel D, arrow), cystic lung lesions (Panel E), and various skin lesions (Panels F through I). Examples of LCH lesions involving the skull and brain include multifocal skull lesions (Panel J, arrow), an orbital lesion (Panel K, arrow), a pituitary lesion (Panel L, arro), and LCH-associated neurodegeneration (Panel M, arrow). Langerhans-Cell Histiocytosis Carl E. Allen, M.D., Ph.D., Miriam Merad, M.D., Ph.D., and Kenneth L. McClain, M.D., Ph.D August 30, 2018 N Engl J Med 2018; 379:856-868

Marie-Luise Berres,1,2,3,4 Miriam Merad,1,2,3 and Carl E. Allen5 Developmental stage of pathological DC precursor defines extent of disease. (A) Somatic mutation of BRAF or other inciting event in CD34+ haematopoietic stem cells or early DC progenitors induces proliferation, maturation and migration of pathological DCs in multiple tissues that results in high-risk multisystem LCH. (B) Somatic mutation of BRAF or other inciting event in a tissue-restricted DC precursor induces proliferation, maturation and tissue-limited migration of pathological DCs that results in low-risk multi-system LCH. (C) Somatic mutation of BRAF or other inciting event in mature DC results in proliferation and maturation of pathological DCs leading to low-risk single lesion LCH. (D) Regardless of cell of origin, the pathological DCs recruit ‘bystander’ immune cells in an inflammatory lesion characteristic of LCH. Cells in white areas indicate cells in circulation; cells in grey areas indicate cells that have migrated to tissue targets. LCH, Langerhans Cell Histiocytosis; DC, dendritic cell Br J Haematol. 2015 Apr; 169(1): 3–13. Progress in understanding the pathogenesis of Langerhans cell histiocytosis: back to Histiocytosis X? Marie-Luise Berres,1,2,3,4 Miriam Merad,1,2,3 and Carl E. Allen5

1987 classification

New classification for histiocytosis (1) Langerhans-related, (2) cutaneous and mucocutaneous (3) malignant histiocytoses (4) Rosai-Dorfman disease (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome.

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages Jean-François Emile, Oussama Abla, Sylvie Fraitag, Annacarin Horne, Julien Haroche, Jean Donadieu, Luis Requena-Caballero, Michael B. Jordan, Omar Abdel-Wahab, Carl E. Allen, Frédéric Charlotte, Eli L. Diamond, R. Maarten Egeler, Alain Fischer, Juana Gil Herrera, Jan-Inge Henter, Filip Janku, Miriam Merad, Jennifer Picarsic, Carlos Rodriguez-Galindo, Barret J. Rollins, Abdellatif Tazi, Robert Vassallo and Lawrence M. Weiss for the Histiocyte Society Blood 2016 127:2672-2681

Histiocytoses of the L group Disease Subtypes LCH LCH SS LCH lung+ LCH MS-RO+ LCH MS-RO− Associated with another myeloproliferative/myelodysplastic disorder ICH  ECD ECD classical type ECD without bone involvement Extracutaneous or disseminated JXG with MAPK-activating mutation or ALK translocations Mixed ECD and LCH

Non-LCH of skin and mucosa (C group) Cutaneous non-LCH histiocytoses  XG family JXG AXG SRH BCH GEH PNH  Non-XG family Cutaneous RDD NXG Cutaneous histiocytoses not otherwise specified Cutaneous non-LCH histiocytoses with a major systemic component XD MRH

Malignant histiocytoses (M group) Localization Subtype Primary MH  Skin  Lymph node Histiocytic  Digestive system or  CNS IDC  Other or disseminated Secondary MH to LC  Follicular lymphoma  Lymphocytic leukemia/lymphoma indeterminate cell  Hairy cell leukemia  ALL not specified  Histiocytosis (LCH, RDD, others)  Another hematologic neoplasia

Histiocytoses of the R group Familial RDD  Faisalabad (or H) syndrome (OMIM #602782)  FAS deficiency or ALPS-related RDD (OMIM #601859)  Familial RDD not otherwise specified Classical (nodal) RDD  Without IgG4 syndrome  IgG4 associated Extranodal RDD  Bone RDD  CNS RDD without IgG4 syndrome  CNS RDD, IgG4 associated  Single-organ RDD other than lymph node, skin, and CNS, without IgG4 syndrome  Single-organ RDD other than lymph node, skin, and CNS, IgG4 associated  Disseminated RDD Neoplasia-associated RDD  RDD postleukemia  RDD postlymphoma  RDD associated with MH  RDD associated with LCH or ECD Immune disease-associated RDD

Histiocytoses of the H group Histiocytoses of the H group (HLH) Histiocytoses of the H group Primary HLH: Mendelian inherited conditions leading to HLH  HLH associated with lymphocyte cytotoxic defects   FHL2 (PRF1)   FHL3 (UNC13D)   FHL4 (STX11)   FHL5 (STXBP2)   XLP1 (SH2D1A)   Griscelli Syndrome type 2 (RAB27A)   Chediak-Higashi Syndrome (LYST)  HLH associated with abnormalities of inflammasome activation   XLP2 (BIRC4)   NLRC4  HLH associated with defined Mendelian disorders affecting inflammation   Lysinuric protein intolerance (SLC7A7)   HMOX1   Other defined Mendelian disorders affecting inflammation