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Histiocytic Disorders Diagnosis and Treatment. Resident Education Lecture Series. Histiocytosis. Group of Disorders- Clonal proliferation of cells of mononuclear phagocyte system (histiocytes) Histiocyte- central cell Form of a WBC. Classes of Histiocyte Disorders. Class I

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histiocytic disorders diagnosis and treatment

Histiocytic DisordersDiagnosis and Treatment

Resident Education Lecture Series

histiocytosis
Histiocytosis
  • Group of Disorders-
  • Clonal proliferation of cells of mononuclear phagocyte system (histiocytes)
    • Histiocyte- central cell
      • Form of a WBC
classes of histiocyte disorders
Classes of Histiocyte Disorders
  • Class I
    • Langerhans cell histiocytosis
  • Class II
    • Non-Langerhans cell histiocytosis
      • Hemophagocytic Lymphohistiocytosis (HLH)
  • Class III
    • Malignant Histiocytic Disorder
class i langerhans cell histiocytosis lch
Class I:Langerhans Cell Histiocytosis (LCH)
  • Other names:
    • Histiocytosis-X
    • Eosinophilic granuloma
    • Hand-Schüller-Christian syndrome
    • Letterer-Siwe disease
slide5
LCH
  • 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
restricted lch
Restricted 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
extensive lch
Extensive LCH
  • 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
lch diagnosis
LCH-diagnosis
  • S100 protein
  • CD1 antigen
  • Birbeck granule positive cells by Electron Microscopy
lch sites of involvement
LCH- sites of involvement
  • 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
Bone involvement
  • 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.
lch treatment
LCH TREATMENT
  • 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
lch treatment extensive
LCH Treatment-Extensive
  • 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.
sinus histiocytosis with massive lymphadenopathy rosai dorfman disease
Sinus 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
rosai dorfman disease
Rosai-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 nodes
  • Other areas, including extranodal regions, can be affected.
  • These disorders can manifest with only rash or bone involvement
rosai dorfman disease18
Rosai-Dorfman disease
  • 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
treatment
Treatment
  • The disease is benign and has a high rate of spontaneous remission, but persistent cases requiring therapy have been observed
class iii malignant histiocytic disorders
Class III:Malignant Histiocytic Disorders
  • 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
class ii hlh
Class II:HLH
  • 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
slide22
HLH
  • Familial Hemophagocytic Lymphohistiocytosis (FHLH)
    • Primary HLH
  • Infection Associated Hemophagocytic Syndrome (IAHS)
    • Secondary HLH
familial hlh
Familial 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
slide24

Perforin

  • 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.
infection associated hlh
Infection-associated HLH
  • VAHS
  • Develops as the result of infection
  • Viral (most common), bacterial, fungal, parasites
  • Often in immunocompromised hosts (HIV, oncologic, Crohn’s disease)
clinical presentation
Clinical Presentation
  • Fever
  • Hepatosplenomegaly
  • Neurological symptoms (seizures)
  • Large lymph nodes
  • Skin rash
  • Jaundice
  • Edema
cns disease
CNS disease
  • CNS infiltration
    • most devastating consequence(s) of HLH
  • Seizures
  • Alteration in consciousness-coma
  • CNS deficits-cranial nerve palsies, ataxia
  • Irritability
  • Neck stiffness
  • Bulging fontanel
laboratory abnormalities
Laboratory Abnormalities
  • 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
histopathological findings
Histopathological Findings
  • Increased numbers of lymphocytes & mature macrophages
  • Prominent hemophagocytosis
    • Spleen, lymph nodes, bone marrow, CNS
diagnostic criteria
Diagnostic Criteria
  • Clinical criteria: fever, splenomegaly.
  • Laboratory Criteria
    • Cytopenia (> 2 of 3 cell lines)
      • Hgb < 9 gm/dl, plts < 100, anc < 1000
    • High triglycerides (> 3SD of normal for age) +/- low fibrinogen (<150)
  • Pathology Criteria
    • hemophagocytosis - bone marrow, spleen or lymph nodes
    • No evidence of malignancy
additional laboratory criteria
Additional Laboratory Criteria
  • CSF-high WBC, high protein
  • Liver-histiological- chronic persistent hepatitis
  • Low Natural Killer Cell activity
  • Familial etiology cannot be determined in first affected infant
treatment33
Treatment
  • Without treatment FHLH is rapidly fatal

Median survival- 2 months

slide34

Continuation therapy, BMT if donor

Familial

Disease

8 wks

chemo

Persistent

non-familial

HLH Pts

Continuation therapy, BMT if donor

If 2nd HLH

Resolved

non-familial

Stop therapy

Treat cause of immune reactivation

Reactivation

If persistent consider 1st HLH

Continuation therapy, BMT if donor

treatment35
Treatment
  • 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

treatment36
Treatment
  • Continuation Therapy
    • Week 9-52
      • VP16 every other week
      • Decadron pulses every 2 wks for 3 days
      • CSA (level 300) QD
bone marrow transplant
Bone Marrow Transplant
  • In FHLH BMT - only curative therapy
    • BMT performed ASAP:
      • acceptable donor
      • disease is non-active
  • Non-familial disease
    • BMT offered at relapse
hlh 94 protocol results
HLH-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.
from abp certifying exam content outline
From ABP Certifying Exam Content Outline

Histiocytosis syndromes of childhood

  • Recognize the clinical manifestations of childhood histiocytosis syndromes
credits
Credits
  • Julie An Talano MD