Histiocytic Syndromes

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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
• malignant histiocytosis

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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

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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)

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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)

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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 LCs

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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)

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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

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Langerhans Cell Histiocytosis Clinical
manifestations II

• pulmonary involvement (interstitial pattern -gt
  honeycombing)
• marrow involvement (cytopenias)
• GI involvement (diarrhea, malabsorption)
• endocrine involvement
• diabetes insipidus
• growth failure
• hypothyroidism

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Langerhans Cell Histiocytosis Extent of disease
at diagnosis

• single system / single site 33
• single system / multiple sites 15
• multisystem involvement 52

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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

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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

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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

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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

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LCH- I
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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

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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

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LCH-II Risk stratification

• Risk patients involvement of liver, spleen,
  lungs, bone marrow age lt 2 yrs
• Low-risk patients none of the above

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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
  -gt new treatments needed
• prolonged therapy has potential benefit

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LCH-III Overall Goals

• to deliver risk-adapted therapy
• to evaluate response in various risk groups
• to assess morbidity in various risk groups

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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

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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 -gt progress to
  cyst formation and honeycombing
• Treatment reports that 2-CdA is effective

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LCHChildren vs Adults

• Adults
• Some lesions are not clonal
• LC cells more mature CD86
• No IL-10 in macrophages

• Children
• All lesions are clonal
• LC cells less mature CD86-
• IL-10 expressed in macrophages

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Treatment Options for Recurrent/Refractory LCH

• Other chemo (Ara-C, methotrexate, cytoxan)
• cyclosporine
• interferon
• retinoic acid (France)
• thalidomide (Texas Childrens Cancer Ctr)
• allogeneic bone marrow transplantation
• 2-chlorodeoxyadenosine (2-CdA) /- Ara-C

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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

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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

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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

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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

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Langerhans Cell Histiocytosis Challenges for the
Future

• Better understanding of histiocyte biology
• differences between normal LCs, LCH
• differences between localized, extensive LCH
• differences between childhood, adult LCH
• Better understanding of LCH epidemiology
• genetic and environmental factors

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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)