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Histiocytic Disorders Diagnosis and Treatment

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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


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

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