Transcript Document

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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• single system / single site
33%
• single system / multiple sites
15%
• multisystem involvement
52%
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, aD-mannosidase, peanut lectin
• Definitive diagnosis
– light morphology, plus
– Birbeck granules and/or CD1a staining
Langerhans Cell Histiocytosis:
Natural history
• isolated skin involvement (“HashimotoPritzker 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
•
•
•
•
•
•
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
• 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
LCH- I
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
• “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
• 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
• to deliver risk-adapted therapy
• to evaluate response in various risk
groups
• to assess morbidity in various risk groups
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
• 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
• Children
• All lesions are
clonal
• Adults
• Some lesions are
not clonal
• LC cells less
mature: CD86-
• LC cells more
mature: CD86+
• IL-10 expressed in
macrophages
• No IL-10 in
macrophages
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
• 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
• 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?
• 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
• 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
• 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 Future
• New treatments for both newly diagnosed
and relapsed patients
– more effective
– fewer side effects
– “targeted” therapy (CD1a-linked radioisotope)