Histiocytic Disorders Diagnosis and Treatment

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Histiocytic DisordersDiagnosis and Treatment

• Resident Education Lecture Series

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Histiocytosis

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

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Classes of Histiocyte Disorders

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

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Class ILangerhans Cell Histiocytosis (LCH)

• Other names
• Histiocytosis-X
• Eosinophilic granuloma
• Hand-Schüller-Christian syndrome
• Letterer-Siwe disease

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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

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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

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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

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LCH-diagnosis

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

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Langerhans Histiocytosis in Lymph node
Low magnification showing lymph node sinuses
filled with pale staining Langerhans cells
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Cytospin of Langerhans cells dissociated from
lymph node. Note abundant pale staining
eosinophilic cytoplasm and kidney shaped nuclei
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Electron micrograph showing characteristic
Birbeck granules.
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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

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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.

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Bone Involvement with LCH
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Skull lytic lesions with LCH
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Characteristic rash of LCH
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Characteristic Scalp Rash with LCH
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STUDY
Not Involved
Single bone
Involved
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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

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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.

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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

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Rosai-Dorfman disease

• The male-to-female ratio is 43, 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

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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

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Rosai-Dorfman Disease
High power magnification (immersion oil 1000 X)
reveals histiocytes, with abundant cytoplasm
and vesicular nuclei, engulfing many
lymphocytes, a process known as emperipolesis.
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Treatment

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

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Class IIIMalignant 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

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Class IIHLH

• Underlying immune disorder
• Uncontrolled activation of the cellular immune
  system
• Defective triggering of apoptosis
• Incidence 1.2/ 1,000,000
• MF
• Age Familial usually present lt 1yr
  Secondary may present at any age

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HLH

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

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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

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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.

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Infection-associated HLH

• VAHS
• Develops as the result of infection
• Viral (most common), bacterial, fungal, parasites
• Often in immunocompromised hosts (HIV, oncologic,
  Crohns disease)

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Clinical Presentation

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

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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

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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

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Histopathological Findings

• Increased numbers of lymphocytes mature
  macrophages
• Prominent hemophagocytosis
• Spleen, lymph nodes, bone marrow, CNS

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Diagnostic Criteria

• Clinical criteria fever, splenomegaly.
• Laboratory Criteria
• Cytopenia (gt 2 of 3 cell lines)
• Hgb lt 9 gm/dl, plts lt 100, anc lt 1000
• High triglycerides (gt 3SD of normal for age) /-
  low fibrinogen (lt150)
• Pathology Criteria
• hemophagocytosis - bone marrow, spleen or lymph
  nodes
• No evidence of malignancy

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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

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Treatment

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

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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
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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

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HLH- 2004 Treatment Protocol
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Treatment

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

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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

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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 (n65)
• 3 year OS 62
• Only 15 /65 patients had matched related donors.
  The majority were unrelated.

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HLH-94 Results

• Neurological symptoms
• severe and permanent CNS dysfunction
• (32) 35/109 pts
• 21/31 survivors had resolution of symptoms with
  therapy

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More information

• Histiocytosis Association of America
• www. histio.org/association

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From ABP Certifying Exam Content Outline

• Histiocytosis syndromes of childhood
• Recognize the clinical manifestations of
  childhood histiocytosis syndromes

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Credits

• Julie An Talano MD