international hematology conference shiraz May 2017 - PowerPoint Presentation

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international hematology conference shiraz May 2017

New classification of Histiocytosis

Abolghasemi H

Professor of pediatrics

hematologist oncologist

Shahid

beheshti university of medical sciencesBaqiyatallah university of medical sciences

HistiocytosesDCs, 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.

historyDr. 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. 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 HistiocytosisCarl E. Allen, M.D., Ph.D., Miriam Merad, M.D., Ph.D., and Kenneth L. McClain, M.D., Ph.DAugust 30, 2018N Engl J Med 2018; 379:856-868

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 lineagesBlood 2016 127:2672-2681Jean-François Emile

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.DAugust 30, 2018N Engl J Med 2018; 379:856-868

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 lineagesJean-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 SocietyBlood 2016 127:2672-2681

Histiocytoses

of the L group

DiseaseSubtypesLCH

LCH SS

LCH lung

+

LCH MS-RO+LCH MS-RO−Associated with another myeloproliferative/myelodysplastic disorderICH ECDECD classical type

ECD without bone involvement

Associated with another myeloproliferative/myelodysplastic disorder

Extracutaneous or disseminated JXG with MAPK-activating mutation or ALK translocations

Mixed ECD and LCH

Non-LCH of skin and mucosa (C group)

Non-LCH of skin and mucosa

Cutaneous non-LCH histiocytoses

 XG family

JXG

AXG

SRHBCHGEHPNH

 Non-XG family

Cutaneous RDD

NXG

Cutaneous histiocytoses not otherwise specified

Cutaneous non-LCH histiocytoses with a major systemic component

 XG family

XD

 Non-XG family

MRH

Malignant histiocytoses

(M group)Localization

SubtypePrimary MH

 Skin

 Lymph node

Histiocytic

 Digestive systemor CNSIDC Other or disseminatedorSecondary MH to

LC

 Follicular lymphoma

or

 Lymphocytic leukemia/lymphoma

indeterminate cell

 Hairy cell leukemia

or

 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 R group

Histiocytoses

of the H groupPrimary 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

Histiocytoses of the H group (HLH)