1. international hematology conference shiraz May 2017

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

3. 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.

4. 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.

5. 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.

6. 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

7. 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.

8. 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:

9. 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 :
Jean-François Emile

10. 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:

11. 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 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

12. 1987 classification

13. 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.

14. 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 :

15. 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

16. 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

17. 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

18. 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

19. 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