5LCHLCH can be local and asymptomatic, as in isolated bone lesions, or it can involve multiple organs and systems with significant symptomatology and consequencesThus, clinical manifestations depend on the site(s) of the lesions, the organs and systems involved, and their function(s)Restrictive vs. Extensive LCH
6Restricted LCH Skin lesions without any other site of involvement Monostotic lesion with or without diabetes insipidus, adjacent lymph node involvement, or rashPolyostotic lesions involving several bones or more than 2 lesions in one bone, with or without diabetes insipidus, adjacent lymph node involvement, or rash
7Extensive LCHVisceral organ involvement +/- bone lesions, diabetes insipidus, adjacent lymph node involvement, and/or rashwithout signs of organ dysfunction of the lungs, liver, or hematopoietic systemwith signs of organ dysfunction of the lungs, liver, or hematopoietic system
8LCH-diagnosis S100 protein CD1 antigen Birbeck granule positive cells by Electron Microscopy
9Langerhans Histiocytosis in Lymph node Low magnification showing lymph node sinuses filled with pale staining Langerhans cells
10Cytospin of Langerhans cells dissociated from lymph node. Note abundant pale staining eosinophilic cytoplasm and kidney shaped nuclei
12LCH- sites of involvement Skin (rash)Bone (single or multiple lesions)Lung, liver and spleen (dysfunction)Teeth and gumsEar (chronic infections or discharge)Eye (vision problem or bulging)CNS (Diabetes Insipidus)Fever, weakness and failure to gain weight
13Bone involvementBone involvement is observed in 78% of cases and often includes the skull 49%, innominate bone 23%, femur 17%, orbit 11%, and ribs 8%.Single or multiple lesions.Vertebral collapse can occur.Long bone involvement can induce fractures.
18STUDY CBC ALT, AST, ALP, bilirubin, total protein, albumin MonthlyQ 6 moNoneALT, AST, ALP, bilirubin, total protein, albuminQ 6moPT, aPTT, fibrinogenUrine osmolality measurement after overnight water deprivationSTUDYNot InvolvedSingle boneInvolved
19X RAY Involved Not involved Single Bone CXRMonthlyEvery 6 moNoneSkeletal surveyOnce at 6 mo
20Anemia, leukopenia, or thrombocytopenia At 6 mo StudyIndicationFollow-upBMA, biopsyAnemia, leukopenia, or thrombocytopeniaAt 6 moPFTsAbnormal CXR, tachypnea6 moBAL/ lung biopsyAbnormal pretreatment chest radiograph findings to rule out infectionsNone
21Panoramic x-ray oral surgery consultation Oral involvement 6 mo Endocrine investigationGrowth failure, DI, hypothalamic syndromes, galactorrhea, precocious or delayed pubertyCT scan or MRI finding of hypothalamus/pituitary abnormalityNoneAudiogram, otolaryngology consultationAural discharge, impaired hearing
22Small bowel series and biopsy None Unexplained chronic diarrhea, failure to thrive, malabsorptionNoneLiver biopsyHigh liver enzyme levels and hypoproteinemia not caused by protein-losing enteropathy to rule out active LCH vs liver cirrhosisWhen all evidence of the disease has been resolved but liver dysfunction persistsCT scan of brain with IV contrast or MRI (preferable)Visual, neurologic, hormonal abnormalities6 mo
23LCH TREATMENT Localized disease-skin, bone, lymph nodes Good prognosis Minimal/no treatmentLocalized skin lesions, especially in infants, can regress spontaneouslyIf treatment is required, topical corticosteroids may be triedIntralesional steroids
24LCH Treatment-Extensive Multiple Organ diseaseBenefit from chemotherapy and/or steroids80% survival using prednisone, 6MP, VP16 or vinblastine (Velban™).If you do not respond to chemotherapy in the first 12 weeks- 20% survival.
25Sinus histiocytosis with massive lymphadenopathy: Rosai-Dorfman disease A persistent massive enlargement of the nodes with an inflammatory process characterizes this condition. The disease rarely is familial
26Rosai-Dorfman disease The male-to-female ratio is 4:3, with a higher prevalence in blacks than in whites.Fever, weight loss, malaise, joint pain, and night sweats may be present.Cervical lymph nodesOther areas, including extranodal regions, can be affected.These disorders can manifest with only rash or bone involvement
27Rosai-Dorfman disease Immunologic abnormalities in conjunction with the disease can be observedLeukocytosis; mild normochromic, normocytic, or microcytic anemia; increased Immune globulins (Igs); abnormal rheumatoid factor; and positive lupus erythematosus
28Rosai-Dorfman Disease High power magnification (immersion oil 1000 X)reveals histiocytes, with abundant cytoplasmand vesicular nuclei, engulfing many lymphocytes,a process known as emperipolesis.
29TreatmentThe disease is benign and has a high rate of spontaneous remission, but persistent cases requiring therapy have been observed
31Class II:HLH Underlying immune disorder Uncontrolled activation of the cellular immune systemDefective triggering of apoptosisIncidence 1.2/ 1,000,000M=FAge: Familial: usually present < 1yr Secondary: may present at any age
33Familial HLH FHLH, FHL, FEL Hereditary transmitted disorder Autosomal recessiveAffects immune regulationFamily history often negativeTriggered by infectionsPresence of perforin gene mutation leads to deficiency in triggering of apoptosisOnly 20-40% of familial HLH have perforin mutationH-Munc 13-4 (17q25) discovered 2003 assoc FHLH
34PerforinMembranolytic protein expressed in the cytoplasmic granules of cytotoxic T cells and NK cells.Responsible for the translocation of granzyme B from cytotoxic cells into target cells; granzyme B then migrates to target cell nucleus to participate in triggering apoptosis.Without perforin, cytoxic T cells & NK cells show reduced or no cytolytic effect on target cells.
44Additional Laboratory Criteria CSF-high WBC, high proteinLiver-histiological- chronic persistent hepatitisLow Natural Killer Cell activityFamilial etiology cannot be determined in first affected infant
45Treatment Without treatment FHLH is rapidly fatal Median survival- 2 months
46Continuation therapy, BMT if donor FamilialDisease8 wkschemoPersistentnon-familialHLH PtsContinuation therapy, BMT if donorIf 2nd HLHResolvednon-familialStop therapyTreat cause of immune reactivationReactivationIf persistent consider 1st HLHContinuation therapy, BMT if donor
47Treatment Initial therapy (8 weeks)-induction Decadron (8wks), CSA VP16 (2x/wk x 2 wks, 1x/wk x 6wks)ITM and steroids if CNS disease is present after 2 wks of therapy for 4 dosesIn non -familial cases treatment is stopped after 8 weeks if complete resolution of disease
49Treatment Continuation Therapy Week 9-52 VP16 every other week Decadron pulses every 2 wks for 3 daysCSA (level 300) QD
50Bone Marrow Transplant In FHLH BMT - only curative therapyBMT performed ASAP:acceptable donordisease is non-activeNon-familial diseaseBMT offered at relapse
51HLH-94 Protocol Results 113 patients treated on protocol 56% (63/113) alive at median 37.5 m.3 year OS 55% +/- 9%BMT patients (n=65)3 year OS 62%Only 15 /65 patients had matched related donors. The majority were unrelated.
52HLH-94 Results Neurological symptoms severe and permanent CNS dysfunction(32%) 35/109 pts21/31 survivors had resolution of symptoms with therapy
53More information Histiocytosis Association of America www. histio.org/association