myelodysplastic, myeloproliferative, and histiocytic disorders kenneth mcclain m.d. ph.d. texas...
TRANSCRIPT
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Myelodysplastic, Myeloproliferative, and Histiocytic Disorders
Kenneth McClain M.D. Ph.D.
Texas Children’s Cancer Center
Houston, TX
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Disclosure Information
• Own common stock of Johnson & Johnson Co.• No discussion of unlabeled uses
*=New material not in syllabus
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What is Myelodysplastic Syndrome (MDS)or… When Do Blasts in the Marrow Not =
Leukemia?
Pediatric version of WHO Criteria for MDS• Absence of AML cytogenetic findings• Two or more of the following:
Sustained cytopeniaDysplasia in 2 cell linesClonal cytognenetic abnormality (5q-, monosomy 7)5-19% Blasts (>20% Blasts = AML)
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MDS Can Become AML,But is not AML a priori
• May need several marrow exams to establish diagnosis of MDS vs. AML
• Incidence of MDS ~ 1.5 per million10-20% become AML
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Pediatric MDS Classification
Three major categories:
1. Adult-Type Myelodysplastic Syndromes
2. Down Syndrome with abnormal megakaryocyte proliferation
3. Myelodysplastic/Myeloproliferative Syndrome: JMML
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For Perspective-Adult MDS
• Predominant feature: Marrow Failure• Most frequent in adults 40-60 yrs. • Two major clinical groups
1. High incidence of progression to AML:Multilineage/Mutator Phenotype
2. Low Progression to AML:Unilineage
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Types of Adult MDS
• High Incidence of progression to AML:Refractory Cytopenia with multilineage dysplasia: (RCMD)Refractory Anemia with excess Blasts (RAEB)
• Low Incidence of progression to AML:Refractory AnemiaRefractory anemia with ringed sideroblastsdel 5q: Macrocytic anemia
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Pediatric MDS• Often with an underlying condition:
Aplastic anemia, Fanconi anemia, platelet storage pool defect, neurofibromatosis, secondary to malignancy treatment
Syndromes: Down, Kostmann’s, Shwachman-Diamond, Dyskeratosis congenita, Bloom’s, Noonan’s
Amegakaryocytic thrombocytopeniaFamilial monosomy 7, 5q-
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Differential Diagnoses of MDS:Need >1 Marrow Finding and Cytogenetic
Data
• Other anemias:megaloblasticcongenital dyserythropoieticsideroblastic anemia
• Leukemia/pre-leukemia:Megakaryocytic leuk.MyelofibrosisPNH
• Toxins: Arsenic, chemotherapy• Virus: HIV
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Myelodysplastic Syndrome (MDS)
• Refractory cytopenia (RC): <2% PB blasts,<5% marrow blasts
• Refractory anemia with excess blasts (RAEB):2-19% PB blasts, 5-19% marrow blasts
• *RAEB in transformation (RAEB-T) PB or marrow blasts 20-29%: Now = AML(Change from Handout)
• Marrow abnormalities: 2-3 lineages dysmorphic, erythroid most abnormal
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Molecular Genetics of MDS
• AML1/RUNX1 gene: point mutationsRegulates hematopoiesis & most frequent translocation in MDSAML
• Chromosome 7 & 20 abnormalities in Shwachman synd: “mutator phenotype”
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Treatment of MDS
• Refractory cytopenia: “expectant follow-up”• RAEB/RAEB-T:
Chemotherapy BMT
Event-free survival: 14-55% 65-80%
(If successful induction)
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Down Syndrome Proliferative Diseases
• Transient abnormal myelopoiesis (TAM)
• Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
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DOWN SYNDROMETransient Myeloproliferative Disorder or
Transient Abnormal Myelopoiesis
• TMD/TAM: leukemoid reaction: usually megakaryocytic
• Progression to megakaryocytic leukemia:20%Blasts same in both by morphology, immuno-phenotype GATA-1 *exon 2 mutations in leukemia onlyUltimately clonal cytogenetic data differentiates
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Transient Abnormal Myelopoiesis in Down Syndrome
Median RangeAge at onset (days) 2 0-180Hepatosplenomegaly 69%Bruising/petech/bleeding 25%Resp. distress 21%WBC (per l) 47,000 5,000-384,000Absolute blast ct. 13,000 0-280,000Hgb (g/dl) 16.8 4-23.2Platelets (per l) 102,000 5,000-1,800,000
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TAM Marrow Characteristics
• Hypo- to hypercellular• Fibrosis common• Blasts 32% (range 6.8-80%)• *Immunophenotype: CD7,33,45,34+
Platelet markers CD41/42b/61: variably +Best is EM with immunogold labeling of CD61
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TAMClinical Outcomes
• Onset: median 16 mo. (range 1-30 mo.) No clinical differences between those with or without ANLL
• Duration: *Clear blasts median 2 mo., max 6 mo.• *Leukemia 20% (9-38 mo.) 90% M7, rare ALL• 17% died in first few mo. (not leukemia): sepsis,
congestive heart failure, hyperviscosity, “crib death”, DIC
• But….33% additional hematologic problems: 84% of these developed ANLL Others: CML, MDS, chronic thrombocytopenia
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Pediatric MDS Classification:Myelodysplastic/myeloproliferative
• Juvenile myelomonocytic leukemia1% of pediatric leukemia cases
• Chronic myelomonocytic leukemiaVery uncommon in children
• BCR/ABL-negative chronic myelogenous leukemia
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Juvenile Myelomonocytic Leukemia JMML
• Clinical criteria: hepatosplenomegaly, lymphadenopathy, pallor, fever, skin rash
• Minimal lab criteria (need all 3) No t9;22 or bcr/abl rearrangement
Peripheral blood monocytosis: >1X109/L
Bone marrow blasts <20% (differs from handout)
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JMMLAdditional Lab Criteria
Need at least 2 of these:-Hgb F increased for age-Myeloid precursors in periph. blood smear-WBC >109/L-Clonal abnormality not always present (monosomy 7, t(5;8), trisomy 8, monosomy 22)-GM-CSF hypersensitivity of monocyte progenitors in vitro-Autonomous growth of CD34+ cells
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Molecular Pathogenesis of JMML
• Frequent deletions of NF1Negative regulator of Ras signaling
• Missense mutations in PTPN11: all Noonan synd. Pts with JMML and 35% of other JMML
• Mutations of KRAS2 & NRAS
Bottom line: Ras activation central to JMML and other leukemias
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MDS vs AML vs JMML
DiagnosisMDS
Age
< 7 yr
Spleen/liver 20-25%
Nodes Rare
AML > 7 yr >50% ~25%
JMML 1.3 yr 75-80% 40%
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MDS vs AML vs JMML
Diagnosis
MDS
Extra-medul. Dx. No
WBC
~7,000/l
NormalCytogenet.23%
AML Rare+ M4/M5
>20,000/l Rare
JMML 77% >25,000/l 78%
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Transformation to Leukemia:JMML/MDS/TMS
TIME <2
TO
2-5
TRANSFORM (yr) 5-10
Total
JMML 5/60 3 8/6013%
MDS 33/101 6 2 41/10141%
TMS 4/6 1 5/6 83%
Total 42 10 2 54/167 32%
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Treatment of JMML
• Chemotherapy: 16% survival rate @ 3 yrs.Median time diagnosis to death is 15 mo.
• Stem cell transplant: 50% survival• *Current COG trial: pre-transplant chemotherapy
cis-Retinoic acid: inhib “spontanteous outgrowth CFU-GMfludarabine: potentiate metabolism of Ara-C to Ara-CTPAra-C: potent anti-myeloid malignancy therapyfarnesyl protein transferase inhb: anti-Ras
*= New data not in syllabus
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What is a myeloproliferative disorder?
• Elevated numbers of a particular cell line in peripheral blood
• Hyperplasia of that lineage in the marrow• No secondary causes: infection, drugs, toxins,
autoimmune, non-hematologic malignancy, trauma
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Types of Myeloproliferative Syndromes
• Erythroid: polycythemia vera• Granulocytic: CML• Monocytic: JMML• Megakaryocytic: Essential or familial
thrombocytosis, myeloproliferative disease of Down syndrome
• Gain of function mutation in Janus kinase 2 (9pLOH):polycythemia vera & familial thrombocytosis
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Myeloproliferative DisordersPolycythemia Vera
• <1% before age 25 • Symptoms:headache, weakness, pruritus,
dizziness, night sweats, weight loss• P.E.: hypertension, hepatosplenomegaly• Marrow: hypercellular• Erythropoietin normal or min. decreased• 10-25% have clonal abnormality
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Polycythemia Vera:Criteria for diagnosis
Need A1-3 or A1 &2 plus 2 of Category B
Category A:1. RBC vol. Males >36ml/kg, females>32ml/kg
2. Arterial oxygen saturation >92% (normal P-50)
3. Splenomegaly
Category B:
1. Thrombocytosis (>400,000/l)
2. Leucocytosis (12,000/ l)
3. Increased leukocyte alkaline phosphatase
4. Increased vit B12 (900 pg/ml) or unsat. B12 binding capacity (>2200 pg/ml)
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Polycythemia Vera
• Treatment: phlebotomy, keep hct <45%• Problems: vascular occlusion, bleeding,
thrombosis, myelofibrosis, leukemia
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Essential Thrombocytosis
After ruling out: nutritional, metabolic, infectious, traumatic, inflammatory, neoplastic, drug, and misc.
• Platelet count > 600,000/l• Hgb not > 13 gm/dl• Normal iron stores• No Ph. Chromosome• No fibrosis of marrow
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Essential Thrombocythemia
• Presents with: headache, thrombosis (0-32%), bleeding (12-37%) (G.I.,hemoptysis)
• Over ½ peds cases familial• Splenomegaly (30-60%)• Hepatomegaly (7-43%)• Abnl plt morphol: 75-85% (hyperlobulated,
dysplastic, early megs.,
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Essential Thrombocytosis:Therapy and late effects
• Safest therapy: anagrelide: anti-aggregating and decreased platelet synthesisOthers: hydroxyurea,
• Malignant transformation:0% Familial, 11% non-familial
• Thrombosis can occur @ plt cts of 600-800K
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Histiocytosis Syndromes
• Langerhans cell • Macrophage proliferations
Hemophagocytic lymphohistiocytosis Familial and “Secondary” to many etiologiesMacrophage activation syndromeRosai-Dorfman SyndromeJuvenile Xanthogranuloma
• Malignancies of macrophages or dendritic cells
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Where do all those histiocytes come from?
Stem Cell
Langerhans Cell LCH
FollicularDC
Myeloid DCHLH/RD
InterstitialDCJXG/ECD
Common Myeloid Progenitor
Common lymphoidProgenitor
Mono/preDC1
Monocyte
preDC2
Plasmcytoid DC
GM-CSF. IL-4TGF-, Flt-3L
TNF-, GM-CSF
TGF-
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Langerhans cell histiocysosis
• Incidence: 5-8/million children• Male/female: 1.3/1• Average age at presentation: 2.4 yrs• Multisystem and single system disease
Severity depends on organs involved• Epidemiologic associations: increased incidence
of thyroid/autoimmune disease in family
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Langerhans Cell Characteristics
• Dendritic cells derived from bone marrow stem cells
• Critical antigen-presenting cell• For correct diagnosis:
Intracellular Birbeck granules that stain with CD207 (Langerin) or Extracellular staining with CD1a
• Also found, but not specific: S100+
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Langerhans Cell Histiocytosis: Langerhans Cell Histiocytosis: Clinical manifestations IClinical manifestations I
• painful swelling of bonespainful swelling of bones– unifocal bone lesion (31% at presentation)unifocal bone lesion (31% at presentation)– isolated multifocal bone involvement (19%)isolated multifocal bone involvement (19%)
• persistent otitis / mastoiditispersistent otitis / mastoiditis• mandible involvement (“floating teeth”) mandible involvement (“floating teeth”) • Papular/scaly rash (37% at presentation)Papular/scaly rash (37% at presentation)• hepatosplenomegaly hepatosplenomegaly • lymphadenopathylymphadenopathy
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Langerhans Cell Histiocytosis: Langerhans Cell Histiocytosis: Clinical manifestations IIClinical manifestations II
• Pulmonary involvement : interstitial pattern -> Pulmonary involvement : interstitial pattern -> “honeycombing” (cysts) and nodules“honeycombing” (cysts) and nodules
• Marrow infiltration: cytopenias , sometimes Marrow infiltration: cytopenias , sometimes hemophagocytosis-macrophage activationhemophagocytosis-macrophage activation
• GI involvement (diarrhea, malabsorption)GI involvement (diarrhea, malabsorption)• Endocrine involvement:Endocrine involvement:
– diabetes insipidusdiabetes insipidus– growth failuregrowth failure– hypothyroidismhypothyroidism
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Originally thought to be a viral rash
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Pulmonary LCH in Children
• Presentation: wheezing, cough, pain,or nothing• Chest xray: interstitial infiltrates, sometimes
see nodules, cysts, or pneumothorax• Chest CT needed to define presence of nodules
and cysts. Probably reasonable to do on all infants
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CNS PROBLEMS IN LCH PTS. WITH BASE OF SKULL LESIONS
• Mastoid, orbital, temporal bone lesions:• If single agent or no treatment: 40%
incidence of diabetes insipidus• Velban/prednisone: still 20% D.I.• Chance of parenchymal brain disease:
May present 10 yrs after initial diagnosis
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Neurologic Syndromes in LCH
• Present with ataxia, dysarthria, dysmetria, behavior changes
• MRI: Masses or T2 hyper-intense signal in cerebellar white matter, pons, or basal ganglia may be long before symptoms appear
• Secondary to neurodegeneration/gliosis• Cause: Cytokines? Direct infiltration with
Langerhans cells or lymphocytes?
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Enhanced T2-weighted images in LCH patient with neurodegenerative syndrome
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LCH Therapy
• “Low Risk” (bone +/-skin,lymph nodes): velban/prednisone 6-12 mo.
• “High Risk” (liver, spleen, lung, bone marrow)velban/prednisone/6MP vs velban/prednisone/6MP/methotrexateBoth 12 mo.
• Etoposide (VP-16) no better than velban, now not considered “standard therapy”
• Radiotherapy or intra-lesion steroids only for spine, femur, or non-CNS Risk skull lesions
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LCH Therapy Results
• “Low Risk” pts: 100% cured18-25% reactivations
• “High Risk” pts: Depends on response @ 6wks
Good response: 6% fatalitiesIntermediate: 21% fatalities
Non-responder: 60% fatalities
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Hemophagocytic LymphohistiocytosisHLH
• Autosomal recessive and secondary formsBoth may be triggered by infections, malignancy, or immunizations
• Presentation: fever, irritability, rash, lymphadenopathy, hepatosplenomegaly
• Labs: pancytopenia, coagulopathy, elevated: LFTs, ferritin, triglyceride
• Histology of marrow, nodes, or liver: macrophages actively engulfing any blood cell
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HLH: Associated Conditions• Familial, especially in cultures with
consanguinity• Secondary to any infectious agent
Especially EBV, CMV, parvo• Malignancies: T and B cell leukemias, T-cell
lymphoma, germ cell tumor• Kawasaki synd., JRA, lupus• Other syndromes: X-linked lymphoprolif.,
Griscelli, Chediak-Higashi
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HLH Epidemiology
• Frequency: 1.2/million children or 1/50,000 live births. Compare PKU 1/31,000 or galactosemia 1/84,000
• Likely under-diagnosed. “Looks like” hepatitis, sepsis, multi-organ failure syndromes
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HLH: Clinical Signs
• Fever 91%• Hepatopmegaly 90%• Splenomegaly 84%• Neurologic symptoms 47%• Rash 43%• Lymphadenopathy 42%
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CNS Problems in HLH
• Cranial nerve signs• Confusion, seizures, increased intracranial
pressure• Brain stem symptoms, ataxia• Subdural effusions & bleeds, retinal hemorh.• CSF: mononuclear pleocytosis (lymphs &
monos), RBC• MRI: parameningeal infiltrations, masses or
necrosis- hypodense areas
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Diagnostic Criteria for HLH
• Familial disease/known genetic defect
• 5 of the following :
– Fever ≥ 7 days
– Splenomegaly
– Cytopenia ≥ 2 cell lines
– Hypertriglyceridemia and/or hypofibrinogenemia
– Ferritin ≥ 4000 μg/L
– sCD25 ≥ 2,400 U/mL
– Decreased or absent NK activity
– Hemophagocytosis (Absent 20% of time-treatment
may be indicated if other criteria fulfilled)
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FEVER OF UNKNOWN ORIGIN: EVALUATION MAY LEAD TO A SURPRISE
O R D E RIn fec tiou s ag e n ts te s ts
L A B F IN D IN G SC B C A b n l
L F T s /B ili upL D H In c rea sed
S T A R T H L H R xIF :
B M A +B M A - & clin ica l c rite ria s tro ng
H E M E C O N S U L TB o n e m arro w a sp .
O T H E R L A B SP T /P T T up
F ib rin o ge n do w nF E R R IT IN : W A Y U P !!
C L IN IC A L F IN D IN G SF e ver
H yp o te n s ionR e sp ira to ry d is tre ss
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Immune Dysfunction in LCH
• Defective NK cell function (number variable) Decreased killing of target cellsDecreased perforin (usually)
• Defective Cytotoxic T cellsDecreased perforin (usually), may differ fromNK cell findings
• Effects of above: unregulated cytokine production, no apoptosis of lymphs and monos
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Peforin Defects in HLH
• Peforin: cytolytic effector protein, essential for regulation of NK and T cells
• Levels in NK and T cells depend on type of mutations in the gene. May be normal in patients with MUNC-13 or other mutations
• >50 mutations in the PRF1 gene known: cause absence of functional protein or truncated proteins. No gross deletions or insertions.
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Molecular Genetics of Familial HLH
LocusName
GeneSymbol
Chrmsm. Locus
Protein Name
FHL1 Unknown 9q21.3-q22 Unknown
FHL2 PRF1 10q22 Peforin 1
FHL3 UNC13D 17q25.1 Unc-13 homolog D
FHL4 STX11 6q24.1 Syntaxin-11
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Hypercytokinemia in HLH• Dysregulation of Th1 immunresponse
Markedly elevated levels of: Interferon ,TNF, IL-1, IL-6, IL-2 receptor (sCD-25)
• Cause fever, hyperlipidemia, endothelial activation, tissue infiltration by lymphs & histiocytes, hepatic triaditis, CNS vasculitis, demyelination, marrow hyperplasia or aplasia
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HLH-94 RESULTS
• 113 Patients, 1994-1998, < 15 yrs of age
• 25 familial, 88 sporadic
• Overall survival 55% +/-9%, 51% for familial casesBMT need for familial or genetically proven patients
• 23/113 alive with only immunochemotherapy
VP-16/dexamethasone/cyclosporine
• 78% of children respond well to immunochemother.
• 93 bone marrow transplants62% survival (52% for <3mo to 71% for 12-24 mo)
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One More---
Rosai Dorfman Syndrome ORSinus Histiocytosis with Massive
Lymphadenopathy
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Anatomic Sites of SHMLSite Frequency (%)Lymph nodes 87Skin and soft tissue 16Nasal cavity 16Eye 11Bone 11Central Nervous System 7Salivary gland 7Kidney 3*Respiratory tract 3*Liver 1*Breast, GI, Heart <1
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Immunohistochemistry
CD163
S100
• “Activated histiocyte”
– Pan macrophage
– Lysosomal
– Activation
• S100
• CD163
• Lacks CD1a
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Differential Diagnosis
• Reactive hyperplasia
• Hemato-lymphoid malignancy
• Metastasis
• Storage disorders
• Histiocytoses, particularly, LCH
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TreatmentThoughts from the Registry
• Randomized clinical trials unavailable
• Most patients do not require treatment?
• Treatment necessary in minority with organ
or life-threatening complications
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Chemotherapy
• Vinca alkaloids/alkylating agents/steroids
• Methotrexate + 6-mercaptopurine (2/2CR)
• Purine analog 2-chlorodeoxyadenosine used in
refractory LCH
– Short-term symptomatic relief in 2 children
with CNS disease without clinical response
Rodriguez-Galindo J Pediatr Hematol Oncol 2004