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

3. Langerhans Cell Histiocytosis Epidemiology Incidence:Incidence: –5 cases/million population/yr (childhood LCH) –incidence of adult LCH is unknown more common in males than females (1.3 : 1)more common in males than females (1.3 : 1) average age at onset: 1.8 yearsaverage age at onset: 1.8 years

4. Langerhans Cell Histiocytosis: Historical Syndromes eosinophilic granuloma: isolated lytic lesion of bone or soft tissue masseosinophilic granuloma: isolated lytic lesion of bone or soft tissue mass Hand-Schuller-Christian disease: skull lesions, exophthalmos, and DI (1893)Hand-Schuller-Christian disease: skull lesions, exophthalmos, and DI (1893) Letterer-Siwe disease: seborrheic rash, hepatosplenomegaly, lung involvement in infants (1924)Letterer-Siwe disease: seborrheic rash, hepatosplenomegaly, lung involvement in infants (1924) the spectrum of “Histiocytosis X” (1953)the spectrum of “Histiocytosis X” (1953)

6. Langerhans cells described by Paul Langerhans (medical student) in 1868described by Paul Langerhans (medical student) in 1868 Langerhans cells (LC) reside in the epidermis (1-2% epidermal cells) & lungLangerhans cells (LC) reside in the epidermis (1-2% epidermal cells) & lung LCs process antigens for presentation to T cells after migrating to lymph nodesLCs process antigens for presentation to T cells after migrating to lymph nodes LCs contain Birbeck granules, and express CD1a and S-100LCs contain Birbeck granules, and express CD1a and S-100 LCs associated with “Histiocytosis X” in 1973 (Nezelof et al)LCs associated with “Histiocytosis X” in 1973 (Nezelof et al)

9. Generation of Langerhans cells LCs can be generated from stem cells:LCs can be generated from stem cells: obtain CD34+ stem cellsobtain CD34+ stem cells incubate w/ GM-CSF and TNF-alpha for 3 weeksincubate w/ GM-CSF and TNF-alpha for 3 weeks resulting cells have Birbeck granules and express CD1aresulting cells have Birbeck granules and express CD1a have functional characteristics of LC’shave functional characteristics of LC’s

11. Langerhans Cell Histiocytosis: Pathology a clonal proliferation of Langerhans cellsa clonal proliferation of Langerhans cells LCs do not show dysplasia or atypia (features of malignant cells)LCs do not show dysplasia or atypia (features of malignant cells) LCH lesions contain LCs, macrophages, T cells, eosinophils, and granulocytesLCH lesions contain LCs, macrophages, T cells, eosinophils, and granulocytes LCs associated with “Histiocytosis X” in 1973 (Nezelof et al)LCs associated with “Histiocytosis X” in 1973 (Nezelof et al)

12. Langerhans Cell Histiocytosis: Clinical manifestations I painful swelling of bonespainful swelling of bones –unifocal bony lesion (31% at presentation) –isolated multifocal bone involvement (19%) persistent otitis / mastoiditispersistent otitis / mastoiditis mandible involvement (“floating teeth”)mandible involvement (“floating teeth”) papular rash (37% at presentation)papular rash (37% at presentation) hepatosplenomegalyhepatosplenomegaly lymphadenopathylymphadenopathy

18. Langerhans Cell Histiocytosis: Clinical manifestations II pulmonary involvement (interstitial pattern -> “honeycombing”)pulmonary involvement (interstitial pattern -> “honeycombing”) marrow involvement (cytopenias)marrow involvement (cytopenias) GI involvement (diarrhea, malabsorption)GI involvement (diarrhea, malabsorption) endocrine involvement:endocrine involvement: –diabetes insipidus –growth failure –hypothyroidism

20. Langerhans Cell Histiocytosis: Extent of disease at diagnosis single system / single site33%single system / single site33% single system / multiple sites15% multisystem involvement52%

21. Langerhans Cell Histiocytosis: Diagnostic criteria (Histiocyte Society, 1987) Presumptive diagnosisPresumptive diagnosis –light morphology Designated diagnosisDesignated diagnosis –light morphology, plus –two or more positive stains for ATPase, S-100, a-D-mannosidase, peanut lectin Definitive diagnosisDefinitive diagnosis –light morphology, plus –Birbeck granules and/or CD1a staining

22. Langerhans Cell Histiocytosis: Natural history isolated skin involvement (“Hashimoto- Pritzker disease”): spontaneous resolutionisolated skin involvement (“Hashimoto- Pritzker disease”): spontaneous resolution eosinophilic granuloma: may resolve or progress; responds to biopsy, curettageeosinophilic granuloma: may resolve or progress; responds to biopsy, curettage Hand-Schuller-Christian disease: usually fatal if untreated due to DIHand-Schuller-Christian disease: usually fatal if untreated due to DI Letterer-Siwe disease: usually fatal if untreatedLetterer-Siwe disease: usually fatal if untreated

23. Langerhans Cell Histiocytosis: Therapeutic modalities biopsy or curettagebiopsy or curettage radiation therapy (low dose)radiation therapy (low dose) topical steroidstopical steroids intralesional steroid injectionsintralesional steroid injections oral or intravenous steroidsoral or intravenous steroids oral or intravenous chemotherapyoral or intravenous chemotherapy –single agents (vinblastine, etoposide) –combination chemotherapy

24. LCH-I: Design first international clinical trial for LCHfirst international clinical trial for LCH compared vinblastine vs etoposide when given with steroidscompared vinblastine vs etoposide when given with steroids enrolled 447 pts from 1991-1995enrolled 447 pts from 1991-1995 143 randomized pts with multisystem disease143 randomized pts with multisystem disease

25. LCH- I

26. DAL HX-83 and HX-90 studies: Design two multi-center, non-randomized trials in Austria, Germany, Netherlands and Switzerlandtwo multi-center, non-randomized trials in Austria, Germany, Netherlands and Switzerland risk-adapted assignment to treatmentrisk-adapted assignment to treatment intensive induction and continuation therapy (much like leukemia therapy)intensive induction and continuation therapy (much like leukemia therapy) total duration of therapy was 12 monthstotal duration of therapy was 12 months

27. LCH-II compared vinblastine/prednisone +/- etoposide as induction therapycompared vinblastine/prednisone +/- etoposide as induction therapy continuation therapy: 6-MP, with pulses of induction therapy agentscontinuation therapy: 6-MP, with pulses of induction therapy agents total duration of therapy was 24 weekstotal duration of therapy was 24 weeks enrolled 697 pts from 1996-2000enrolled 697 pts from 1996-2000 stratified patients on basis of riskstratified patients on basis of risk

28. LCH-II: Risk stratification “Risk” patients: involvement of liver, spleen, lungs, bone marrow; age < 2 yrs “Low-risk” patients: none of the above

29. DAL HX, LCH-I and LCH-II: Conclusions overall survival of multi-system patients was about 80% on all studiesoverall 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 outcomepatients 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 needed20% of patients do not respond to current therapy -> new treatments needed prolonged therapy has potential benefitprolonged therapy has potential benefit

30. LCH-III: Overall Goals to deliver risk-adapted therapyto deliver risk-adapted therapy to evaluate response in various risk groupsto evaluate response in various risk groups to assess morbidity in various risk groupsto assess morbidity in various risk groups

31. LCH-III: Design adds methotrexate for “risk” patientsadds methotrexate for “risk” patients adds stratifications for multifocal bone only patients and CNS patientsadds stratifications for multifocal bone only patients and CNS patients patients with involvement of facial bones or middle cranial fossa have 3-fold risk for DIpatients with involvement of facial bones or middle cranial fossa have 3-fold risk for DI

32. LCH in Adults most adults with LCH have pulmonary LCHmost adults with LCH have pulmonary LCH most are smokersmost are smokers symptoms: cough, shortness of breath, chest pain, sputum production, pneumothoracessymptoms: cough, shortness of breath, chest pain, sputum production, pneumothoraces CXR: diffuse bilateral infiltrates -> progress to cyst formation and “honeycombing”CXR: diffuse bilateral infiltrates -> progress to cyst formation and “honeycombing” Treatment: reports that 2-CdA is effectiveTreatment: reports that 2-CdA is effective

33. LCH Children vs Adults AdultsAdults Some lesions are not clonalSome lesions are not clonal LC cells more mature: CD86+LC cells more mature: CD86+ No IL-10 in macrophagesNo IL-10 in macrophages ChildrenChildren All lesions are clonalAll lesions are clonal LC cells less mature: CD86-LC cells less mature: CD86- IL-10 expressed in macrophagesIL-10 expressed in macrophages

34. Treatment Options for Recurrent/Refractory LCH Other chemo (Ara-C, methotrexate, cytoxan)Other chemo (Ara-C, methotrexate, cytoxan) cyclosporinecyclosporine interferoninterferon retinoic acid (France)retinoic acid (France) thalidomide (Texas Children’s Cancer Ctr)thalidomide (Texas Children’s Cancer Ctr) allogeneic bone marrow transplantationallogeneic bone marrow transplantation 2-chlorodeoxyadenosine (2-CdA) +/- Ara-C2-chlorodeoxyadenosine (2-CdA) +/- Ara-C

35. 2-CdA for refractory LCH Review: 27 pts with refractory LCH were treated with 2CdA (23) or 2-DCF (4)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 coursesDoses: 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 deathsResults: 15 CR, 5 PR, 5 NR; no toxic deaths Toxicities: myelosuppression, prolonged thrombocytopenia, peripheral neuropathiesToxicities: myelosuppression, prolonged thrombocytopenia, peripheral neuropathies

36. LCH-S-98: Salvage trial for pts with relapsed or refractory LCHfor pts with relapsed or refractory LCH must have failed multi-agent therapy and have high-risk diseasemust have failed multi-agent therapy and have high-risk disease 2-CdA 5 mg/m2/day x 5 days q 3 wks x 6 courses2-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-CdAnext salvage trial will add low-dose Ara-C to this dose of 2-CdA

37. Langerhans Cell Histiocytosis: Why does it happen? Epidemiologic study of possible risk factors published in 1997Epidemiologic study of possible risk factors published in 1997 conducted in conjunction with HAAconducted in conjunction with HAA 22-page self-administered questionnaire22-page self-administered questionnaire parents of 900 LCH patients in HAAparents of 900 LCH patients in HAA 63% response rate63% response rate 459 patients met all eligibility criteria459 patients met all eligibility criteria

38. Langerhans Cell Histiocytosis: Study of risk factors Possible associations:Possible associations: –neonatal infections (cause or effect?) –exposure to solvents (acetone) –thyroid disease in family members No association:No association: –in utero exposure to cigarette smoke –maternal infections or medications

39. Langerhans Cell Histiocytosis: Challenges for the Future Better understanding of histiocyte biologyBetter understanding of histiocyte biology –differences between normal LC’s, LCH –differences between localized, extensive LCH –differences between childhood, adult LCH Better understanding of LCH epidemiologyBetter understanding of LCH epidemiology –genetic and environmental factors

40. Langerhans Cell Histiocytosis: Challenges for the Future New treatments for both newly diagnosed and relapsed patientsNew treatments for both newly diagnosed and relapsed patients –more effective –fewer side effects –“targeted” therapy (CD1a-linked radioisotope)