PHYSIOLOGY AND MANAGEMENT OF HISTIOCYTIC DISEASE. Brant Ward, MD, PhD Division of Rheumatology, Allergy, and Immunology

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1 PHYSIOLOGY AND MANAGEMENT OF HISTIOCYTIC DISEASE Brant Ward, MD, PhD Division of Rheumatology, Allergy, and Immunology

2 What do histiocytes do? Apoptotic body removal Phagocytosis Antigen presentation

3 Types of histiocytes Macrophages Dendritic cells Langerhans cells

4 Types of histiocytic disorders Primary/secondary HLH Acute monocyticleukemia Dendritic cell disorders Juvenile xanthogranuloma Rosai- Dorfman disease Macrophage disorders Histiocytic sarcoma Extramedulary monocytictumor DC- type histiocytoma Malignant disorders M- type histiocytoma Erdheim- Chester disease Langerhans cell histiocytosis

5 Blood Jun 2;127(22):

6 Epidemiology/Pathogenesis of LCH Children Adults Non- clonal Clonal

7 Organ system involvement Systems involved Single system disease Multi- system disease

8 Bone lesions Localized bone pain Exam shows raised, tender, soft spot Punched- out appearance on x- ray Most common involvement: Children Skull > femur, rib, humerus Rare in digits Adults Jaw > skull > vertebrae, pelvis, extremities > ribs Nearby areas may be involved: Hearing loss, scalp lesions, seizures, diabetes insipidus, cranial nerve palsies

9 Skin lesions Brownish or purplish papules Frequent in infants Benign if solitary, resolve within 1 yr Must carefully exclude multisystem disease and perform ongoing risk assessment about 50% have or develop multisystem disease Eczematous rash May present at any age Can by mistaken for seborrheic dermatitis on the scalp Ulcerative lesions behind ears, in the scalp, genitalia, or perenniummay be confused with bacterial or fungal infection

10 Lung disease More common in adults Smoking = risk factor Can present with: Spontaneous pneumothorax Non- productive cough Fever, weight loss Many adults are asymptomatic PFTs may show: Normal or reduce lung volumes Reduced diffusing capacity

11 Histopathologic features Morphology Special stains/techniques

12 Histopathologic features

13 Treatment of single system disease Close observation Skull lesion in frontal, occipital, or parietal bone Skull lesion in orbit, mastoid, temporal, or sphenoid bone Vertebra or femur with risk of collapse Lymph node Pulmonary lesions Skin only Vinblastine (6 mg/m 2 weekly) + prednisolone (40 mg/m 2 daily) Curettage Intralesional corticosteroids Surgical removal Smoking cessation Methotrexate (20 mg/m 2 weekly) +/- 6- mercaptopurine (50 mg/m 2 daily) Radiation therapy

14 Treatment of multisystem disease Induction chemotherapy: Prednisolone 40 mg/m 2 daily x4 weeks Taper over an additional 2 weeks Vinblastine 6 mg/m 2 IV weekly x6 weeks Supported by multiple large studies No apparent benefit with addition of other agents (etoposide, MTX) Response categorize as: No evidence of active disease (complete resolution) Continuous regression (sxs less prominent, no new lesions) Stable disease (persistence of sxs, no new lesions) Progressive disease (progressive sxs, new lesions)

15 Continuation of treatment Continuation chemotherapy for pts without active disease or with continuous regression but no risk organ disease: Prednisolone 40 mg/m 2 daily on days 1-5 Repeat every 3 weeks Vinblastine 6 mg/m 2 IV once on day 1 Repeat every 3 weeks Continuation therapy for pts with continuous regression with risk organ disease or stable disease (not risk organs ): Prednisolone 40 mg/m 2 TIW x6 weeks Proceed to above therapy if improvement For pts with stable disease with risk organ involvement and progressive disease, should proceed to second- line therapy

16 Post- treatment follow- up Assess for response at: 12, 18, 24 weeks of therapy, then Every 3 months for 2 years, then Every 6 months for 2 years, then Yearly Late affects of disease and/or treatment are possible:

17 Relapsed or refractory disease Patients with low- risk disease >12 months after induction: Vinblastine + prednisolone, plus oral MTX and 6- MP About 85% will achieve 2 nd remission Patients with low- risk disease <12 months after induction: Single- agent treatment with cladribine About 60% will achieve 2 nd remission Patients with high risk disease: Single agent clofarabine Pamidronate Vemurafenib (BRAF inhibitor) Combination high- dose cladribine + high- dose cytarabine Hematopoietic stem cell transplant

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19 Just kidding! All the data is for kids! For adults if you can find an open trial, enroll your patient! Single bone lesions may response to curettage with or without radiation and intralesional steroids For multiple bone lesions or multisystem disease, cytarabine 100 mg/m2 daily x5 days, repeat monthly for 12 months About 80% will achieve remission Better than cladribine (59% CR) or VB/pred (21% CR) For lung disease, smoking cessation is initial focus of therapy Corticosteroids and cytotoxic agent have limited value Lung transplantation may be considered (>50% 5- yr survival, 20% recurrence if extra- pulmonary disease was present)

20 Other disorders worth mentioning Rosai- Dorfman (aka, sinus histiocytosiswith massive lymphadenopathy): Massive LAD, typically cervical but also mediastinal, axillary, etc. Histology shows non- LC pattern (S100-, CD1a-, Langerin- ) May have increased plasma cells in lesions and elevated serum IgG Typically spontaneously regresses only treated if mass effect, etc. Juvenile xanthogranuloma/erdheim- Chester disease: Typically appears as reddish- brown plaque, papule, or nodule Usually found in skin, but can occur in other organs Histology shows infiltrate of mononuclear cells, giant cells, and spindle cells Lipidization increases with the age of the lesion Typically spontaneously regresses