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-Schller-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 weeks-
20% 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, Crohns 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


HLH Pts
If 2
nd
HLH
Treat cause of
immune reactivation
If persistent
consider 1st HLH
8 wks
chemo
Familial
Disease
Resolved
non-familial

Persistent
non-familial
Stop
therapy
Reactivation
Continuation therapy,
BMT if donor
Continuation therapy,
BMT if donor

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