Download Hemophagocytic Lymphohistiocytosis (HLH)

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
 Langerhans cell histiocytosis
Class II
 Non-Langerhans cell histiocytosis
 Hemophagocytic Lymphohistiocytosis
(HLH)
Class III
 Malignant Histiocytic Disorder
Class I:
Langerhans Cell Histiocytosis (LCH)

Other names:
 Histiocytosis-X
 Eosinophilic granuloma
 Hand-Schüller-Christian syndrome
 Letterer-Siwe disease
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



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


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
S100 protein
 CD1 antigen
 Birbeck granule positive cells by
Electron Microscopy

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 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
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

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 weeks20% survival.
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





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 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

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





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




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
HLH
Familial Hemophagocytic
Lymphohistiocytosis (FHLH)
 Primary HLH
 Infection Associated Hemophagocytic
Syndrome (IAHS)
 Secondary 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
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
VAHS
 Develops as the result of infection
 Viral (most common), bacterial, fungal,
parasites
 Often in immunocompromised hosts
(HIV, oncologic, Crohn’s disease)

Clinical Presentation
Fever
 Hepatosplenomegaly
 Neurological symptoms (seizures)
 Large lymph nodes
 Skin rash
 Jaundice
 Edema

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
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
Increased numbers of lymphocytes &
mature macrophages
 Prominent hemophagocytosis
 Spleen, lymph nodes, bone marrow,
CNS

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
CSF-high WBC, high protein
 Liver-histiological- chronic persistent
hepatitis
 Low Natural Killer Cell activity
 Familial etiology cannot be determined
in first affected infant

Treatment

Without treatment FHLH is rapidly fatal
Median survival- 2 months
Familial
Disease
HLH Pts
8 wks
chemo
If 2nd HLH
Treat cause of
immune reactivation
If persistent
consider 1st HLH
Continuation therapy,
BMT if donor
Persistent
non-familial
Resolved
non-familial
Continuation therapy,
BMT if donor
Stop
therapy
Reactivation
Continuation therapy,
BMT if donor
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
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
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
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
Credits

Julie An Talano MD