simplified

1. Approach to Histiocytosis
Syndromes of Childhood
Dr. Irum Siddiquie
PGR-I Pediatrics BBH

3. It is a diverse group of disorders, that
are grouped together because they have
in common a prominent proliferation or
accumulation of cells of monocyte-
macrophage system of bone marrow
origin.

4. Pathophysiology
There are two broad lines of cell
differentiation that are included under the
title of "histiocytes“
• Dendritic cells
• Monocyte-macrophage series

7. DISEASE CELLULAR
CHARACTERIZATION
LCH Langerhanss cell histiocytosis Langerhanss-like cells (CD1a-
positive, CD207-positive) with
Birbeck granule
HLH
Familial hemophagocytic
lymphohitiocytosis
Infection associated
hemophagocytic syndrome
Associated with
immunocompromised state
Associated with
autoimmune/autoinflammatory
states
Morphologically normal
reactive macrophages with
prominent
erythrophagocytosis, and CD-8
positive T-cells
Others
Juvenile xanthogranuloma
Rosai-dorman disease
Malignant histiocytosis
Acute monocytic leukemia

8. CLASS SYNDROME CELL INVOLVED
I
Langerhans cell
histiocytosis
Langerhans cells
II
Reactive histiocytosis Macrophages
III
Malignant histiocytosis Acute monocytic
leukemia

10. Epidemiology
Incidence is rare, 4-10 per million population.
Sex
The overall male-to-female ratio is 1.5:1.
Age
LCH can occur in individuals of any age. The incidence
peaks in children aged 1-3 years.

11. LCH---Antigen presenting cell of skin---Hallmark
is the clonal proliferation of cells of monocyte
lineage---Immature cell of myeloid origin---
Characteristic electron microscopic findings---
BIRBECK granule.

12. Histiocytosis-X
The well known childhood histiocytosis,
previously known as Histiocytosis-X includes
clinical entities :
1. Eosinophyllic granuloma
2. Hand-schuller-christian disease
3. Letterer-siwe disease

13. Eosinophyllic Granuloma
• Unifocal LCH
• Eosinophyllic granuloma of bone
• Eosinophyllic granuloma of lung

14. Hand-Schüller-Christian disease
Multifocal LCH
Calvarial bone
defects (Osteophytic
bone lesions)
Exomphthalos Diabetes Insipidus

15. Letterer-siwe disease
• Multifocal multisystem
• Less than 2 y/o
• Aggressive systemic
disorder
• Fever,anemia,thromboc
ytopenia, pulmonary
infiltrates and skin
lesion, enlargment of
spleen, liver and
lymphnodes.
• Rapidly fatal

16. Clinical classification of LCH
Single System LCH (SS-LCH)
One organ/system involved (uni- or
multifocal):
• Bone: unifocal (single bone) or
multifocal (>1 bone)
• Skin
• Lymph node (not the draining lymph
node of another LCH lesion)
• Lungs
• Hypothalamic-pituitary / Central
nervous system
• Other (e.g. thyroid, thymus)
Multisystem LCH (MS-LCH)
Two or more organs/systems involved
With or without involvement of “Risk
Organs”

17. RISK Stratification
Risk organ – Positive patients
Involvement of liver, spleen,
hematopoietic system and lungs
Deciding criteria for intensity of
treatment approach as delineated
in histiocyte society protocols
Risk organ – Negative patients
No involvement of liver, spleen,
lungs and hematopoeitic
system.

18. Multisystem
disease
• Systemic multi-agent
chemotherapy required
Central
elements
• vinblastine
• Steroids
• Etoposide (recently
introduced)
Aims at
reduction of
• Mortality
• Reactivation
• Long term consequences.
Single system
disease
• Usually bone, lymph
node or skin.
High chance of
spontaneous
remission
• Minimal Treatment
Arrest of
progression
• Curettage
• Steroid injections
• Low dose local
radiotherapy

20. HLH---uncontrolled hemophagocytosis ---
uncontrolled activation ( up-regulation ) of
inflammatory cytokines.

21. Etiology
Primay (Genetic)
Familial HLH
Known genetic defect
• PFR1
• Stx 11
• Unknown gene defects
Immune deficiency syndromes
• Chediak-higashi syndrome
• Griscelli syndrome
• X linked lymphoproliferative
Secondary (Acquired)
• Infections
• Autoimmune
• Malignant diseases
• Immunesuppression/organ
transplantation.

22. Clinical presentation
• Common findings:
Prolonged fever
Hepatosplenomegaly
Neurological symptoms-seizures, cranial
nerve palsies etc..
• Less common findings:
Lymphadenopathy
Rash
Jaundice

23. Diagnostic criteria for HLH
• Fever
(Peak temp> 38.5 for 7 or more days)
• Splenomegaly
• Cytopenias
Hemoglobin 9g/dl or less
Platelets less than 100,000 /ul or
Absolute neutropenia <1000/ul

24. • Hypertriglyceridemia (>265mg/dl) and/or
hypofibrinogenemia (<150mg/dl)
• Hemophagocytosis in bone marrow, spleen or
lymph nodes without evidence of malignancy.
• Low or absent natural killer cell cytotoxicity
• Hyperferritinemia (>500ng/ml)
• Elevated soluble CD25
Diagnostic criteria for HLH

25. 1
• Molecular diagnosis
e.g. PRF mutation,
sap mutations etc.
2
• 5 out of 8
diagnostic criteria
3
•Hemophagocytic
lymphohistiocytosis
•Begin with appropriate
treatment.

26. Trigerring agent Antiviral Antibiotics
Etoposide
Kill over
stimulated
antigen
presenting cells.
Supportive Rx
Prophylactic
cotrimoxazole,
oral antimycotics
Gastoprotection
– ranitidine or
Ppi.
Replace
defective
immune system
Allogenic
hematopoeitic
stem cell
transplantation
Non
myeloablative or
reduced intensity
transplantation.

28. History
A complete history should include special reference to
the nature and duration of symptoms.
• Fever , loss of appetite
• Pain
• Swelling
• Skin rashes
• Otorrhea
• Irritability
• Weight loss , Poor weight gain
• Growth failure
• Polydipsia , Polyuria
• behavioral and neurological changes.

29. Clinical presentation
• Vitals
• Anthropometry
• Pubertal status (Tanner staging),
• Characterization of skin and scalp rashes
• Presence of jaundice, pallor,edema.
• Ear discharge, orbital abnormalities, gum and
palatal lesions,
• Lymphadenopathy.
• Dentition, soft tissue swelling, lesions on the
genital and anal mucosa,
• Hepatosplenomegaly, ascites.
• Neurological evaluation, cranial nerve abnormalities.
• tendon reflexes, visual deficits, and cerebellar
dysfunction.

30. Diagnostic Considerations
With the widely varied presentations of histiocytosis
disorders, the differential diagnosis can be broad.
When focal, establishing the diagnosis of Langerhanss cell
histiocytosis depends on a high level of suspicion.
Adequate workup to determine the extent of the disease
and possible complications is essential.
Biopsy and pathologic evaluation are needed to establish
the diagnosis.

31. Differential Diagnoses
• Acute Lymphoblastic Leukemia
• Chronic Anemia
• Craniopharyngioma
• Diabetes Insipidus
• Diaper Dermatitis
• Acute Otitis Media
• Hodgkin's disease
• Lymphadenopathy
• Lymphoproliferative Disorders
• Mastoiditis
• Osteomyelitis
• Acute Myelocytic Leukemia
• Atopic Dermatitis
• Non-Hodgkin Lymphoma

32. Recommended baseline evaluation
Full blood count Hemoglobin, white blood cell and
differential count, platelet count
Blood chemistry • Total protein, albumin, bilirubin,
ALT(SGPT), AST(SGOT), alkaline
• phosphatase
• BUN, creatinine, electrolytes
• Ferritin
Coagulation studies INR/PT, APTT/PTT, fibrinogen
Early morning urine sample Specific gravity and osmolality
Abdominal ultrasound Size and structure of liver and spleen
Chest radiograph
Skeletal radiograph survey

33. When indicated …
Indication Assessment / test
Bicytopenia, pancytopenia, or
persistent unexplained single
cytopenia
Bone marrow aspirate & trephine
biopsy to exclude other causes.
Liver dysfunction Liver biopsy only recommended if
there is
clinically significant liver
involvement and
the result will alter treatment
(i.e. to
differentiate between active LCH
and
sclerosing cholangitis)

34. Lung involvement (abnormal CXR or
symptoms/signs suggestive for
lung involvement)
Lung high resolution computed
tomography (HR-CT) or preferably
low dose multi-detector HR-CT if
available .
Lung function test (if age
appropriate)
Abnormal lung CT AND
findings not characteristic for
LCH or suspicion for atypical
infection
Bronchoalveolar lavage or lung biopsy
Suspected craniofacial bone
lesions including maxilla and
mandible
MRI of head
When indicated …

35. Suspected vertebral lesions MRI of spine (to exclude spinal cord
compression)
Visual or neurological
abnormalities
• MRI of head
• Neurology assessment
• Neuropsychometric assessment
Suspected endocrine
abnormality (i.e. short stature,
growth failure, polyuria,
polydipsia, hypothalamic
syndromes, precocious or
delayed puberty)
• Endocrine assessment (including
water deprivation test and
dynamic tests of the anterior
pituitary and thyroid)
• MRI of head
When indicated …

36. Aural discharge or suspected
hearing impairment/mastoid
involvement
Formal hearing assessment
• MRI of head
• HR-CT of temporal bone
Unexplained chronic diarrhea,
failure to thrive, or evidence of
malabsorption
Endoscopy and biopsy.
Immunohistochemistry CD1a
S-100 protein
HLA-DR
CD45 etc…
When indicated …

37. Follow up
YEAR 1 YEARS 2 – 5
Clinical examination Every 6 weeks Every 6 months
Height, weight,
pubertal status
Every 6 months Every 6 months
Lab-examinations in
patients
who have had
respective organ
involvement: Blood
count, ESR, liver and
renal function tests,
urine osmolality
Every 3 months Yearly
Radiographs of bone
lesions
Only if new lesions
or reactivation
suspected
Only if new lesions or
reactivation suspected

38. Adapt for individual patients on the basis of systems involved and clinical indications
Year 1 Year 2-5
Audiology in patients
with
history of ear/mastoid
involvement
At 1 year At 5 years
HR-CT, pulmonary
function
tests in patients with
pulmonary
involvement
Every 6 months Only if progression
suspected
Ultrasound in patients
with liver
involvement
Every 6 months Yearly
Neuropsychometric
assessment
in patients with CNS
involvement
At 1 year Every 2 years

39. • Extreme clinical heterogeneity, histiocytosis can
present to a variety of specialists (e.g. general
paediatricians, dentists, dermatologists and
orthopaedic surgeons).
• High index of suspicion is necessary to make a timely
diagnosis.
• Its a dilemma for treating physicians. An accurate
histological and immunochemical diagnosis is needed.
• Must be referred to a paediatric oncologist for
proper risk stratification, an appropriate treatment
plan and long-term follow-up.
• Systemic therapy is indicated to prevent irreversible
damage to normal tissue and long-term consequences.
Conclusion

40. Thank you!