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Histiocytic Disorders Diagnosis and Treatment Resident Education Lecture Series.

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Presentation on theme: "Histiocytic Disorders Diagnosis and Treatment Resident Education Lecture Series."— Presentation transcript:

1 Histiocytic Disorders Diagnosis and Treatment Resident Education Lecture Series

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

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

4 Class I: Langerhans Cell Histiocytosis (LCH) Other names: 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 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) Thus, clinical manifestations depend on the site(s) of the lesions, the organs and systems involved, and their function(s) Restrictive vs. Extensive LCH Restrictive vs. Extensive LCH

6 Restricted LCH Skin lesions without any other site of involvement Skin lesions without any other site of involvement Monostotic lesion with or without diabetes insipidus, adjacent lymph node involvement, or rash 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 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 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 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

8 LCH-diagnosis S100 protein S100 protein CD1 antigen CD1 antigen Birbeck granule positive cells by Electron Microscopy 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) Skin (rash) Bone (single or multiple lesions) Bone (single or multiple lesions) Lung, liver and spleen (dysfunction) Lung, liver and spleen (dysfunction) Teeth and gums Teeth and gums Ear (chronic infections or discharge) Ear (chronic infections or discharge) Eye (vision problem or bulging) Eye (vision problem or bulging) CNS (Diabetes Insipidus) CNS (Diabetes Insipidus) Fever, weakness and failure to gain weight 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%. 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. Single or multiple lesions. Vertebral collapse can occur. Vertebral collapse can occur. Long bone involvement can induce fractures. 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 CBC MonthlyQ 6 moNone ALT, AST, ALP, bilirubin, total protein, albumin MonthlyQ 6moNone PT, aPTT, fibrinogen MonthlyQ 6 moNone Urine osmolality measurement after overnight water deprivation Q 6 mo None STUDY Involved Not Involved Single bone

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

20 StudyIndication Follow-up BMA, biopsy Anemia, leukopenia, or thrombocytopenia At 6 mo PFTsAbnormal 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 involvement6 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 6 mo

22 Small bowel series and biopsy 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 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 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 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. 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. Fever, weight loss, malaise, joint pain, and night sweats may be present. Cervical lymph nodes Cervical lymph nodes Other areas, including extranodal regions, can be affected. Other areas, including extranodal regions, can be affected. These disorders can manifest with only rash or bone involvement These disorders can manifest with only rash or bone involvement

27 Rosai-Dorfman disease Immunologic abnormalities in conjunction with the disease can be observed 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 Leukocytosis; mild normochromic, normocytic, or microcytic anemia; increased Immune globulins (Igs); abnormal rheumatoid factor; and positive lupus erythematosus

28 High power magnification (immersion oil 1000 X) reveals histiocytes, with abundant cytoplasm and vesicular nuclei, engulfing many lymphocytes, a process known as emperipolesis. Rosai-Dorfman Disease

29 Treatment The disease is benign and has a high rate of spontaneous remission, but persistent cases requiring therapy have been observed 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 True neoplasms Extremely rare Extremely rare Acute monocytic leukemia, malignant histiocytosis, true histiocytic lymphoma Acute monocytic leukemia, malignant histiocytosis, true histiocytic lymphoma Symptoms Symptoms  fever, wasting, LAD, hepatosplenomegaly, rash Treatment- Treatment-  Induction  prednisone, cyclophosphamide, doxorubicin  Maintenance  vincristine, cyclophosphamide, doxorubicin

31 Class II:HLH Underlying immune disorder Underlying immune disorder  Uncontrolled activation of the cellular immune system  Defective triggering of apoptosis Incidence 1.2/ 1,000,000 Incidence 1.2/ 1,000,000 M=F M=F Age: Familial: usually present < 1yr Secondary: may present at any age Age: Familial: usually present < 1yr Secondary: may present at any age

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

33 Familial HLH FHLH, FHL, FEL FHLH, FHL, FEL Hereditary transmitted disorder 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. 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. 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. Without perforin, cytoxic T cells & NK cells show reduced or no cytolytic effect on target cells.

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36 Infection-associated HLH VAHS VAHS Develops as the result of infection Develops as the result of infection Viral (most common), bacterial, fungal, parasites Viral (most common), bacterial, fungal, parasites Often in immunocompromised hosts (HIV, oncologic, Crohn’s disease) Often in immunocompromised hosts (HIV, oncologic, Crohn’s disease)

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

38 CNS disease CNS infiltration CNS infiltration  most devastating consequence(s) of HLH Seizures Seizures Alteration in consciousness-coma Alteration in consciousness-coma CNS deficits-cranial nerve palsies, ataxia CNS deficits-cranial nerve palsies, ataxia Irritability Irritability Neck stiffness Neck stiffness Bulging fontanel Bulging fontanel

39 Laboratory Abnormalities Cytopenias (Platelets, Hgb,WBC) Cytopenias (Platelets, Hgb,WBC) High Triglycerides High Triglycerides Prolonged PT, PTT, low Fibrinogen Prolonged PT, PTT, low Fibrinogen High AST, ALT High AST, ALT CSF- high protein, high WBC CSF- high protein, high WBC Low Natural Killer cell activity Low Natural Killer cell activity High Ferritin High Ferritin

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

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42 Diagnostic Criteria Clinical criteria: fever, splenomegaly. Clinical criteria: fever, splenomegaly. Laboratory Criteria 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 ( 3SD of normal for age) +/- low fibrinogen (<150) Pathology Criteria Pathology Criteria  hemophagocytosis - bone marrow, spleen or lymph nodes  No evidence of malignancy

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44 Additional Laboratory Criteria CSF-high WBC, high protein CSF-high WBC, high protein Liver-histiological- chronic persistent hepatitis Liver-histiological- chronic persistent hepatitis Low Natural Killer Cell activity Low Natural Killer Cell activity Familial etiology cannot be determined in first affected infant Familial etiology cannot be determined in first affected infant

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

46 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

47 Treatment Initial therapy (8 weeks)-induction 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 Treatment Protocol

49 Treatment Continuation Therapy 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 In FHLH BMT - only curative therapy  BMT performed ASAP:  acceptable donor  disease is non-active Non-familial disease Non-familial disease  BMT offered at relapse

51 HLH-94 Protocol Results 113 patients treated on protocol 113 patients treated on protocol  56% (63/113) alive at median 37.5 m.  3 year OS 55% +/- 9% BMT patients (n=65) 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 Neurological symptoms  severe and permanent CNS dysfunction  (32%) 35/109 pts 21/31 survivors had resolution of symptoms with therapy 21/31 survivors had resolution of symptoms with therapy

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

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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 Julie An Talano MD


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