Histiocytic Disorders Diagnosis and Treatment Resident Education Lecture Series

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

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

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

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

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

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

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

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

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

Electron micrograph showing characteristic Birbeck granules.

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

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.

Bone Involvement with LCH

Skull lytic lesions with LCH

Characteristic rash of LCH

Characteristic Scalp Rash with LCH

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

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

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

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

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

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

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.

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

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

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

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.

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

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

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

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

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

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.

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)

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

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

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

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

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

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

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

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

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

HLH- 2004 Treatment Protocol

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

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

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.

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

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

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

Credits Julie An Talano MD