The mononuclear phagocytic system consists of dendritic cells and monocyte/macrophages, historically referred to as histiocytes. Rare and diverse conditions that affect both children and adults. Range from benign skin lesions to rapidly life-threatening systemic disorders. The best known histiocytoses, Langerhans cell histiocytosis (LCH), and hemophagocytic lymphohistiocytosis (HLH).

1. PAEDIATRIC HISTIOCYTOSIC
DISORDERS
Dr. Liza Bulsara
Pediatric Hematologist – Oncologist.

2. • The mononuclear phagocytic system consists of dendritic cells and monocyte/macrophages,
historically referred to as histiocytes.
• Rare and diverse conditions that affect both children and adults.
• Range from benign skin lesions to rapidly life-threatening systemic disorders.
• The best known histiocytoses, Langerhans cell histiocytosis (LCH), and hemophagocytic
lymphohistiocytosis (HLH).
• An estimated incidence : 1/50,000 to 1/150,000 . M:F=3:1
Alexandra Filipovich, Histiocytic Disorders: Recent Insights into Pathophysiology and Practical Guidelines, Biol Blood Marrow Transplant 16:S82-S89, 2010

3. No. Group of histiocytic
disorders
Histiocytosis
1 L group LCH
ICH:
– ECD
Mixed LCH/ECD
2 C group Cutaneous non-LCH:
– XG family: JXG, AXG, SRH, BCH, GEH, PNH
– Non-XG family: cutaneous RDD, NXG, other not otherwise specified
Cutaneous non-LCH with a major systemic component:
– XG family – XD
– Non-XG family – MRH
3 M group Primary MH
Secondary MH (following or associated with another hematologic neoplasia)
4 R group Familial RDD
Sporadic RDD:
– Classical (nodal)
– Extra-nodal
– RDD with neoplasia or immune disease
– Other, non-C, non-L, non-M, non-H histiocytoses
5 H group Primary HLH: Mendellan inherited conditions leading to HLH
Secondary HLH (non-Mendelian HLH)
HLH of unknown/uncertain origin
Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127:2672–81
The revised classification system of histiocytoses &
neoplasms of macrophage-dendritic cell lineages

4. LANGERHANS CELL HISTIOCYTOSIS (LCH)
• It is a disease characterized by clonal expansion of myeloid precursors that
differentiate into CD1a/CD207 in lesion.
• Incidence : 2.6 to 8.9 cases per million children <15 years per year.
• Median age at diagnosis of 3 years.

5. CLINICAL CLASSIFICATION OF LCH
Carlos Rodriguez-Galindo and Carl E. Allen, Langerhans cell histiocytosis, blood 16 APRIL 2020 | VOLUME 135, NUMBER 16

6. RISK ORGAN INVOLVEMENT IN LCH-IV
Carlos Rodriguez-Galindo and Carl E. Allen, Langerhans cell histiocytosis, Blood 16 APRIL 2020 | VOLUME 135, NUMBER 16
Hematopoietic involvement (with or without bone marrow involvement*), at least 2 of the following:
Anemia: hemoglobin <100 g/L (<10 g/dl), infants <90 g/L (<9.0 g/dL), not a result of other causes (eg, iron
deficiency)
Leukocytopenia: leukocytes <4000/Ml ;Thrombocytopenia: platelets <1,00,000/mL
Spleen involvement enlargement: >2 cm below costal margin in the midclavicular line†
Liver involvement,one or more of the following:
• Enlargement .>3 cm below costal margin in the midclavicular line†
• Dysfunction (ie, hypoproteinemia <55 g/L, hypoalbuminemia ,<25 g/L, not as a result of other causes)
• Histopathological findings of active disease

7. DIAGNOSIS APPROACH OF LCH

8. LCH LESION
HISTOLOGY
Carlos Rodriguez-Galindo and Carl E. Allen, Langerhans cell histiocytosis, Blood 16 APRIL 2020 | VOLUME 135, NUMBER 16
LCH imaging

9. TREATMENT GUIDELINE FOR NEWLY
DIAGNOSED CHILDHOOD LCH
Akira Morimoto, Recent advances in Langerhans cell histiocytosis, Pediatrics International (2014) 56, 451–461

10. NON-LANGERHANS CELL
HISTIOCYTIC DISORDERS

11. JUVENILE XANTHOGRANULOMA (JXG)
Allen et al. , Pediatric Lymphomas and Histiocytic Disorders of Childhood, Pediatr Clin North Am. 2015 February ; 62(1): 139–165. doi:10.1016/j.pcl.2014.09.010
• JXG is most common form of non-Langerhans cell
histiocytic disorder of childhood.
• 75% of cases, lesions appear during the first year of life, with
>15-20% of patients having lesions at birth.
• JXG is rare in adults, with a peak incidence: 20-30 years.
• solitary or multiple yellow-orange-brown firm papules
or nodules on face, neck, and upper torso.
• ocular involvement is the most common extracutaneous site
involved, followed by the lungs.

12. HISTOPATHOLOGY
• well-demarcated lesion, dense invasion of numerous histiocytes
• mononuclear cells may show a spindled or elongated appearance.
• Foam cells, foreign body giant cells, and Touton giant cells - mature stage.
• The characteristic multinucleated giant cell (Touton cell) - 85% of
juvenile xanthogranulomas, appear garland-like.
• Lesions of juvenile xanthogranuloma classically stain markers: CD68 or
Ki-M1P and anti F XIIIa, vimentin, and anti-CD4
Pantalon A, Ștefănache T, Danciu M, Zurac S, Chiseliță D. Iris juvenile xanthogranuloma in an infant - spontaneous hyphema and secondary glaucoma. Rom J Ophthalmol. 2017 Jul-Sep;61(3):229-236.

13. HISTORY AND PHYSICAL
• Two forms:
A. multiple 2 to 5 millimeter dome-shaped papules, pink to
reddish brown hue turn yellow.
B. one or more large nodules (1 to 2 cms)
• Dermoscopy - noninvasive technique used -diagnosis of juvenile
xanthogranuloma.- setting sun appearance (red-yellow center and
discrete erythematous halo)
• Complete removal via surgical excision gives diagnostic confirmation
anssen D, Harms D. Juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the kiel pediatric tumor registry. Am J Surg Pathol. 2005; 29(1):21–8.

14. Haroche J, Abla O. Uncommon histiocytic disorders: Rosai-Dorfman, juvenile xanthogranuloma, and Erdheim-Chester disease. Hematology Am Soc Hematol Educ Program. 2015;2015:571-8
• Curative skin excisions /spontaneously involute and require no therapy.
• Management of non-cutaneous (internal) lesions - surgery, chemotherapy, radiotherapy, and immunosuppression.
• Patients with concurrent neurofibromatosis type 1 (NF-1) should receive frequent followup with a complete
blood count to monitor for juvenile chronic myelogenous leukemia (JMML).
• Eye exams are recommended for high-risk patients. Topical, intralesional, and subconjunctival corticosteroids
may be administered for ocular involvement.
Treatment / Management

15. ERDHEIM-CHESTER DISEASE (ECD)
• A rare non-Langerhans histiocytic multisystem disorder.
• manifest as multifocal sclerotic lesions of the long bones demonstrating sheets of foamy
histiocytes on biopsy, with or without histiocytic infiltration of extra-osseous tissues.
• ECD is most common in adult men; the male predominance is estimated to be 3:1.
• Rare pediatric cases (<15 years of age) have been reported.
Cavalli G, Guglielmi B,, The multifaceted clinical presentations and manifestations of Erdheim-Chester disease: comprehensive review of the literature and of 10 new cases. Ann Rheum Dis. 2013 Oct;72(10):1691-5.

16. CLINICAL
FEATURES
OF ECD
Gaurav Goya, The Mayo Clinic Histiocytosis Working Group Consensus Statement for the Diagnosis and Evaluation of Adult Patients With Histiocytic Neoplasms: Erdheim-Chester Disease, Langerhans
Cell Histiocytosis, and Rosai-Dorfman Disease, Mayo Clin Proc. n October 2019;94(10):2054-2071

17. HISTOPATHOLOGIC AND RADIOGRAPHIC FINDINGS OF ECD
Eli L. Diamond,Lorenzo Dagna, Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester diseaseBlood (2014) 124 (4): 483–492.

18. BASELINE CLINICAL EVALUATION RECOMMENDATIONS
it is strongly encouraged to confirm
negative BRAF V600E testing in ECD
using >1 genotyping modality
and/or genotyping from >1 anatomic
site (particularly when bone lesions
are found to be BRAF wild-type)

19. TREATMENT

20. ROSAI-DORFMAN DISEASE
• Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is an
intriguing and still poorly understood phenomenon of apparently nonmalignant proliferation of
histiocytes generally restricted to lymph nodes.
• extranodal lesions may also be observed, most often as subcutaneous nodules, sinus lesions, or bone
lesions.
• The classic clinical presentation, as noted by disease nomenclature, is massive painless bilateral
cervical lymphadenopathy.

21. CLINICAL
FEATURES
Gaurav Goya, The Mayo Clinic Histiocytosis Working Group Consensus Statement for the Diagnosis and
Evaluation of Adult Patients With Histiocytic Neoplasms: Erdheim-Chester Disease, Langerhans Cell
Histiocytosis, and Rosai-Dorfman Disease, Mayo Clin Proc. n October 2019;94(10):2054-2071

23. TREATMENT

24. CHARACTERISTIC OF NON LANGERHANS
HISTIOCYTOSIS

26. APPROACH TO CHILDHOOD HISTIOCYTIC
DISORDER

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

28. 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.

29. 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.

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

32. CONCLUSION
• 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.
• 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

33. THANK-YOU !