Resident Education Lecture Series

 Group of Disorders  Clonal proliferation of cells of mononuclear phagocyte system (histiocytes)  Histiocyte- central cell  Form of a WBC

 Class I  Langerhans cell histiocytosis  Class II  Non-Langerhans cell histiocytosis  Hemophagocytic Lymphohistiocytosis (HLH)  Class III  Malignant Histiocytic Disorder

 Other names:  Histiocytosis-X  Eosinophilic granuloma  Hand-Schüller-Christian syndrome  Letterer-Siwe disease

 LCH can be local and asymptomatic, as in isolated bone lesions, or it can involve multiple organs and systems with significant symptomatology and consequences  Thus, clinical manifestations depend on the site(s) of the lesions, the organs and systems involved, and their function(s)  Restrictive vs. Extensive LCH

 Skin lesions without any other site of involvement  Monostotic lesion with or without diabetes insipidus, adjacent lymph node involvement, or rash  Polyostotic lesions involving several bones or more than 2 lesions in one bone, with or without diabetes insipidus, adjacent lymph node involvement, or rash

  Visceral organ involvement +/- bone lesions, diabetes insipidus, adjacent lymph node involvement, and/or rash  without signs of organ dysfunction of the lungs, liver, or hematopoietic system Visceral organ involvement +/- bone lesions, diabetes insipidus, adjacent lymph node involvement, and/or rash  with signs of organ dysfunction of the lungs, liver, or hematopoietic system

 S100 protein  CD1 antigen  Birbeck granule positive cells by Electron Microscopy

 Skin (rash)  Bone (single or multiple lesions)  Lung, liver and spleen (dysfunction)  Teeth and gums  Ear (chronic infections or discharge)  Eye (vision problem or bulging)  CNS (Diabetes Insipidus)  Fever, weakness and failure to gain weight

 Bone 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.

Skull lytic lesions with LCH

Characteristic rash of LCH

Characteristic Scalp Rash with LCH

 Localized disease-skin, bone, lymph nodes  Good prognosis  Minimal/no treatment  Localized skin lesions, especially in infants, can regress spontaneously  If treatment is required, topical corticosteroids may be tried  Intralesional steroids

 Multiple Organ disease  Benefit from chemotherapy and/or steroids  80% survival using prednisone, 6MP, VP16 or vinblastine (Velban ™).
 If you do not respond to chemotherapy in the first 12 weeks 20% survival.

 A persistent massive enlargement of the nodes with an inflammatory process characterizes this condition. The disease rarely is familial

 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 nodes Other areas, including extranodal regions, can be affected.
These disorders can manifest with only rash or bone involvement

 Immunologic abnormalities in conjunction with the disease can be observed  Leukocytosis; mild normochromic, normocytic, or microcytic anemia; increased Immune globulins (Igs); abnormal rheumatoid factor; and positive lupus erythematosus

 The disease is benign and has a high rate of spontaneous remission, but persistent cases requiring therapy have been observed

     True neoplasms Extremely rare Acute monocytic leukemia, malignant histiocytosis, true histiocytic lymphoma Symptoms  fever, wasting, LAD, hepatosplenomegaly, rash Treatment  Induction   prednisone, cyclophosphamide, doxorubicin Maintenance  vincristine, cyclophosphamide, doxorubicin

 Underlying immune disorder  Uncontrolled activation of the cellular immune system  Defective triggering of apoptosis  Incidence 1.2/ 1,000,000  M=F  Age: Familial: usually present < 1yr Secondary: may present at any age

 Familial Hemophagocytic Lymphohistiocytosis (FHLH)  Primary HLH  Infection Associated Hemophagocytic Syndrome (IAHS)  Secondary HLH

  FHLH, FHL, FEL Hereditary transmitted disorder  Autosomal recessive  Affects immune regulation  Family history often negative  Triggered by infections  Presence of perforin gene mutation leads to deficiency in triggering of apoptosis  Only 20-40% of familial HLH have perforin mutation  H-Munc 13-4 (17q25) discovered 2003 assoc FHLH

   Membranolytic 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.

 VAHS  Develops as the result of infection  Viral (most common), bacterial, fungal, parasites  Often in immunocompromised hosts (HIV, oncologic, Crohn’s disease)

 Fever  Hepatosplenomegaly  Neurological symptoms (seizures)  Large lymph nodes  Skin rash  Jaundice  Edema

 CNS infiltration  most devastating consequence(s) of HLH  Seizures  Alteration in consciousness-coma  CNS deficits-cranial nerve palsies, ataxia  Irritability  Neck stiffness  Bulging fontanel

 Cytopenias (Platelets, Hgb,WBC)  High Triglycerides  Prolonged PT, PTT, low Fibrinogen  High AST, ALT  CSF- high protein, high WBC  Low Natural Killer cell activity  High Ferritin

 Increased numbers of lymphocytes & mature macrophages  Prominent hemophagocytosis  Spleen, lymph nodes, bone marrow, CNS

  Clinical criteria: fever, splenomegaly .
Laboratory Criteria  Cytopenia (> 2 of 3 cell lines)  Hgb < 9 gm/dl, plts < 100, anc < 1000  High triglycerides age) +/ (> 3SD of normal for low fibrinogen (<150)  Pathology Criteria  hemophagocytosis or lymph nodes - bone marrow, spleen  No evidence of malignancy

 CSF-high WBC, high protein  Liver-histiological- chronic persistent hepatitis  Low Natural Killer Cell activity  Familial etiology cannot be determined in first affected infant

 Without treatment FHLH is rapidly fatal Median survival- 2 months

HLH Pts If 2 nd HLH 8 wks chemo Treat cause of immune reactivation If persistent consider 1st HLH Familial Disease Continuation therapy, BMT if donor Persistent non-familial Continuation therapy, BMT if donor Resolved non-familial Stop therapy Reactivation Continuation therapy, BMT if donor

 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 doses In non -familial cases treatment is stopped after 8 weeks if complete resolution of disease

 Continuation Therapy  Week 9-52  VP16 every other week  Decadron pulses every 2 wks for 3 days  CSA (level 300) QD

 In FHLH BMT - only curative therapy  BMT performed ASAP:  acceptable donor  disease is non-active  Non-familial disease  BMT offered at relapse

 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.

From ABP Certifying Exam Content Outline
Histiocytosis syndromes of childhood
 Recognize the clinical manifestations of childhood histiocytosis syndromes

 Julie An Talano MD