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Histiocytic Syndromes. Dendritic cell-related disorders Langerhans cells histiocytosis juvenile xanthogranuloma Macrophage-related disorders primary hemophagocytic syndromes (familial, sporadic) secondary hemophagocytic syndromes (viral, other) Malignant disorders monocytic leukemias

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histiocytic syndromes
Histiocytic Syndromes
  • Dendritic cell-related disorders
    • Langerhans cells histiocytosis
    • juvenile xanthogranuloma
  • Macrophage-related disorders
    • primary hemophagocytic syndromes (familial, sporadic)
    • secondary hemophagocytic syndromes (viral, other)
  • Malignant disorders
    • monocytic leukemias
    • malignant histiocytosis
langerhans cell histiocytosis epidemiology
Langerhans Cell Histiocytosis Epidemiology
  • Incidence:
    • 5 cases/million population/yr (childhood LCH)
    • incidence of adult LCH is unknown
  • more common in males than females (1.3 : 1)
  • average age at onset: 1.8 years
langerhans cell histiocytosis historical syndromes
Langerhans Cell Histiocytosis: Historical Syndromes
  • eosinophilic granuloma: isolated lytic lesion of bone or soft tissue mass
  • Hand-Schuller-Christian disease: skull lesions, exophthalmos, and DI (1893)
  • Letterer-Siwe disease: seborrheic rash, hepatosplenomegaly, lung involvement in infants (1924)
  • the spectrum of “Histiocytosis X” (1953)
langerhans cells
Langerhans cells
  • described by Paul Langerhans (medical student) in 1868
  • Langerhans cells (LC) reside in the epidermis (1-2% epidermal cells) & lung
  • LCs process antigens for presentation to T cells after migrating to lymph nodes
  • LCs contain Birbeck granules, and express CD1a and S-100
  • LCs associated with “Histiocytosis X” in 1973 (Nezelof et al)
generation of langerhans cells
Generation of Langerhans cells
  • LCs can be generated from stem cells:
  • obtain CD34+ stem cells
  • incubate w/ GM-CSF and TNF-alpha for 3 weeks
  • resulting cells have Birbeck granules and express CD1a
  • have functional characteristics of LC’s
langerhans cell histiocytosis pathology
Langerhans Cell Histiocytosis: Pathology
  • a clonal proliferation of Langerhans cells
  • LCs do not show dysplasia or atypia (features of malignant cells)
  • LCH lesions contain LCs, macrophages, T cells, eosinophils, and granulocytes
  • LCs associated with “Histiocytosis X” in 1973 (Nezelof et al)
langerhans cell histiocytosis clinical manifestations i
Langerhans Cell Histiocytosis: Clinical manifestations I
  • painful swelling of bones
    • unifocal bony lesion (31% at presentation)
    • isolated multifocal bone involvement (19%)
  • persistent otitis / mastoiditis
  • mandible involvement (“floating teeth”)
  • papular rash (37% at presentation)
  • hepatosplenomegaly
  • lymphadenopathy
langerhans cell histiocytosis clinical manifestations ii
Langerhans Cell Histiocytosis: Clinical manifestations II
  • pulmonary involvement (interstitial pattern -> “honeycombing”)
  • marrow involvement (cytopenias)
  • GI involvement (diarrhea, malabsorption)
  • endocrine involvement:
    • diabetes insipidus
    • growth failure
    • hypothyroidism
langerhans cell histiocytosis extent of disease at diagnosis
Langerhans Cell Histiocytosis: Extent of disease at diagnosis
  • single system / single site 33%
  • single system / multiple sites 15%
  • multisystem involvement 52%
langerhans cell histiocytosis diagnostic criteria histiocyte society 1987
Langerhans Cell Histiocytosis: Diagnostic criteria (Histiocyte Society, 1987)
  • Presumptive diagnosis
    • light morphology
  • Designated diagnosis
    • light morphology, plus
    • two or more positive stains for ATPase, S-100, a-D-mannosidase, peanut lectin
  • Definitive diagnosis
    • light morphology, plus
    • Birbeck granules and/or CD1a staining
langerhans cell histiocytosis natural history
Langerhans Cell Histiocytosis: Natural history
  • isolated skin involvement (“Hashimoto-Pritzker disease”): spontaneous resolution
  • eosinophilic granuloma: may resolve or progress; responds to biopsy, curettage
  • Hand-Schuller-Christian disease: usually fatal if untreated due to DI
  • Letterer-Siwe disease: usually fatal if untreated
langerhans cell histiocytosis therapeutic modalities
Langerhans Cell Histiocytosis: Therapeutic modalities
  • biopsy or curettage
  • radiation therapy (low dose)
  • topical steroids
  • intralesional steroid injections
  • oral or intravenous steroids
  • oral or intravenous chemotherapy
    • single agents (vinblastine, etoposide)
    • combination chemotherapy
lch i design
LCH-I: Design
  • first international clinical trial for LCH
  • compared vinblastine vs etoposide when given with steroids
  • enrolled 447 pts from 1991-1995
  • 143 randomized pts with multisystem disease
dal hx 83 and hx 90 studies design
DAL HX-83 and HX-90 studies: Design
  • two multi-center, non-randomized trials in Austria, Germany, Netherlands and Switzerland
  • risk-adapted assignment to treatment
  • intensive induction and continuation therapy (much like leukemia therapy)
  • total duration of therapy was 12 months
lch ii
  • compared vinblastine/prednisone +/- etoposide as induction therapy
  • continuation therapy: 6-MP, with pulses of induction therapy agents
  • total duration of therapy was 24 weeks
  • enrolled 697 pts from 1996-2000
  • stratified patients on basis of risk
lch ii risk stratification
LCH-II: Risk stratification
  • “Risk” patients: involvement of liver, spleen, lungs, bone marrow; age < 2 yrs
  • “Low-risk” patients: none of the above
dal hx lch i and lch ii conclusions
DAL HX, LCH-I and LCH-II: Conclusions
  • overall survival of multi-system patients was about 80% on all studies
  • patients with lack of response at week 12 have a high risk of poor outcome
  • 20% of patients do not respond to current therapy -> new treatments needed
  • prolonged therapy has potential benefit
lch iii overall goals
LCH-III: Overall Goals
  • to deliver risk-adapted therapy
  • to evaluate response in various risk groups
  • to assess morbidity in various risk groups
lch iii design
LCH-III: Design
  • adds methotrexate for “risk” patients
  • adds stratifications for multifocal bone only patients and CNS patients
  • patients with involvement of facial bones or middle cranial fossa have 3-fold risk for DI
lch in adults
LCH in Adults
  • most adults with LCH have pulmonary LCH
  • most are smokers
  • symptoms: cough, shortness of breath, chest pain, sputum production, pneumothoraces
  • CXR: diffuse bilateral infiltrates -> progress to cyst formation and “honeycombing”
  • Treatment: reports that 2-CdA is effective
lch children vs adults

Some lesions are not clonal

LC cells more mature: CD86+

No IL-10 in macrophages


All lesions are clonal

LC cells less mature: CD86-

IL-10 expressed in macrophages

LCHChildren vs Adults
treatment options for recurrent refractory lch
Treatment Options for Recurrent/Refractory LCH
  • Other chemo (Ara-C, methotrexate, cytoxan)
  • cyclosporine
  • interferon
  • retinoic acid (France)
  • thalidomide (Texas Children’s Cancer Ctr)
  • allogeneic bone marrow transplantation
  • 2-chlorodeoxyadenosine (2-CdA) +/- Ara-C
2 cda for refractory lch
2-CdA for refractory LCH
  • Review: 27 pts with refractory LCH were treated with 2CdA (23) or 2-DCF (4)
  • Doses: 0.1 mg/kg/d - 13 mg/m2/day x 5-7 days for 1-6 courses
  • Results: 15 CR, 5 PR, 5 NR; no toxic deaths
  • Toxicities: myelosuppression, prolonged thrombocytopenia, peripheral neuropathies
lch s 98 salvage trial
LCH-S-98: Salvage trial
  • for pts with relapsed or refractory LCH
  • must have failed multi-agent therapy and have high-risk disease
  • 2-CdA 5 mg/m2/day x 5 days q 3 wks x 6 courses
  • next salvage trial will add low-dose Ara-C to this dose of 2-CdA
langerhans cell histiocytosis why does it happen
Langerhans Cell Histiocytosis: Why does it happen?
  • Epidemiologic study of possible risk factors published in 1997
  • conducted in conjunction with HAA
  • 22-page self-administered questionnaire
  • parents of 900 LCH patients in HAA
  • 63% response rate
  • 459 patients met all eligibility criteria
langerhans cell histiocytosis study of risk factors
Langerhans Cell Histiocytosis: Study of risk factors
  • Possible associations:
    • neonatal infections (cause or effect?)
    • exposure to solvents (acetone)
    • thyroid disease in family members
  • No association:
    • in utero exposure to cigarette smoke
    • maternal infections or medications
langerhans cell histiocytosis challenges for the future
Langerhans Cell Histiocytosis: Challenges for the Future
  • Better understanding of histiocyte biology
    • differences between normal LC’s, LCH
    • differences between localized, extensive LCH
    • differences between childhood, adult LCH
  • Better understanding of LCH epidemiology
    • genetic and environmental factors
langerhans cell histiocytosis challenges for the future1
Langerhans Cell Histiocytosis: Challenges for the Future
  • New treatments for both newly diagnosed and relapsed patients
    • more effective
    • fewer side effects
    • “targeted” therapy (CD1a-linked radioisotope)