1. Histiocytic Disorders Diagnosis and Treatment
Resident Education Lecture Series

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

3. Classes of Histiocyte Disorders
Class I
Langerhans cell histiocytosis
Class II
Non-Langerhans cell histiocytosis
Hemophagocytic Lymphohistiocytosis (HLH)
Class III
Malignant Histiocytic Disorder

4. Class I: Langerhans Cell Histiocytosis (LCH)
Other names:
Histiocytosis-X
Eosinophilic granuloma
Hand-Schüller-Christian syndrome
Letterer-Siwe disease

5. 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

6. 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

7. 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
with signs of organ dysfunction of the lungs, liver, or hematopoietic system

8. LCH-diagnosis S100 protein CD1 antigen
Birbeck granule positive cells by Electron Microscopy

9. Langerhans Histiocytosis in Lymph node
Low magnification showing lymph node sinuses filled with pale staining Langerhans cells

10. Cytospin of Langerhans cells dissociated from lymph node.
Note abundant pale staining eosinophilic cytoplasm and kidney shaped nuclei

11. Electron micrograph showing
characteristic Birbeck granules.

12. 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

13. 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.

14. Bone Involvement with LCH

15. Skull lytic lesions with LCH

16. Characteristic rash of LCH

17. Characteristic Scalp Rash with LCH

18. STUDY CBC ALT, AST, ALP, bilirubin, total protein, albumin
Monthly
Q 6 mo
None
ALT, AST, ALP, bilirubin, total protein, albumin
Q 6mo
PT, aPTT, fibrinogen
Urine osmolality measurement after overnight water deprivation
STUDY
Not Involved
Single bone
Involved

19. X RAY Involved Not involved Single Bone
CXR
Monthly
Every 6 mo
None
Skeletal survey
Once at 6 mo

20. Anemia, leukopenia, or thrombocytopenia At 6 mo
Study
Indication
Follow-up
BMA, biopsy
Anemia, leukopenia, or thrombocytopenia
At 6 mo
PFTs
Abnormal CXR, tachypnea
6 mo
BAL/ lung biopsy
Abnormal pretreatment chest radiograph findings to rule out infections
None

21. Panoramic x-ray oral surgery consultation Oral involvement 6 mo
Endocrine investigation
Growth failure, DI, hypothalamic syndromes, galactorrhea, precocious or delayed puberty
CT scan or MRI finding of hypothalamus/pituitary abnormality
None
Audiogram, otolaryngology consultation
Aural discharge, impaired hearing

22. Small bowel series and biopsy None
Unexplained chronic diarrhea, failure to thrive, malabsorption
None
Liver biopsy
High liver enzyme levels and hypoproteinemia not caused by protein-losing enteropathy to rule out active LCH vs liver cirrhosis
When all evidence of the disease has been resolved but liver dysfunction persists
CT scan of brain with IV contrast or MRI (preferable)
Visual, neurologic, hormonal abnormalities
6 mo

23. 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

24. 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.

25. 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

26. 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

27. 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

28. 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.

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

30. 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

31. 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

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

33. 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

34. 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.

36. 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)

37. Clinical Presentation
Fever
Hepatosplenomegaly
Neurological symptoms (seizures)
Large lymph nodes
Skin rash
Jaundice
Edema

38. 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

39. 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

40. Histopathological Findings
Increased numbers of lymphocytes & mature macrophages
Prominent hemophagocytosis
Spleen, lymph nodes, bone marrow, CNS

42. 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

44. 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

45. Treatment Without treatment FHLH is rapidly fatal
Median survival- 2 months

46. 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

47. 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

48. HLH- 2004 Treatment Protocol

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

50. 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

51. 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.

52. HLH-94 Results Neurological symptoms
severe and permanent CNS dysfunction
(32%) 35/109 pts
21/31 survivors had resolution of symptoms with therapy

53. More information Histiocytosis Association of America
www. histio.org/association

55. From ABP Certifying Exam Content Outline
Histiocytosis syndromes of childhood
Recognize the clinical manifestations of childhood histiocytosis syndromes

56. Credits
Julie An Talano MD