Langerhans Cell Histiocytosis

1. Langerhans Cell Histiocytosis Samuel Anim MD 4/9/2010 I have nothing to disclose

2. Case 3 year old Hispanic male persistent vomiting - 4 months Colonoscopy/biopsy � mild colitis /cryptitis� started on azulfidine for inflammation Headaches for 2 months CT scan showed a soft tissue mass in frontal area MRI revealed enhancing lesion in the posterior infundibulum Bone survey �lytic lesion in frontal bone Enuresis, polyuria and polydypsia 2 months prior PMHx: multiple ear and UR infection FHx: Type 2 DM in MGF and Thyroid problems Imm: UTD Meds: None Allergies: NKDA Devt : appropriate milestones till date

3. Examination Vital signs normal, Wt 62% and Ht 14% HEENT: Scar from resection PERRL, EOMI, fundoscopy normal, No LN, normal dentition RESP: CTAB CVS: S1 + S2, 2/6 systolic flow murmur. ABD: soft, NT/ND, + BS, No HS megaly EXT: Normal, cap refill 2 s Genitalia: Tanner stage 1, pre-pubertal male CNS: normal, CNII- 12 intact SKIN: no rash or pigmentation

4. Skeletal Survey

5. MRI - Brain

6. LABS HEME CBC, CMP, ferritin all normal ENDO TSH, Cortisol, Prl, Insulin like GF all normal Growth hormone and Cortisol stimulation tests normal U/A: SG 1.002 Water deprivation test not done Responded to DDAVP Pathology Bone marrow: No malignancy Biopsy: LCH with CD 1a and S- 100

7. Epidemiology Also known as Histiocytosis X, Eosinophilic granuloma, Diffuse reticuloendotheliosis 0.5 � 5/million new cases (1200) per year More common in children M>F W>B>A Clinical Course Spontaneous regression and resolution Reactivation Rapid progression with organ dysfunction Death

8. Pathogenesis Not fully understood Histiocytes: Langerhans, Macrophage/monocyte, Dendritic cells Derived from CD 34 + SC CD 14 � Langerhans cells CD 14 + Macro/Mono, Dendritic Immune dysfunction, T- cell and macrophage interaction IL 17 A Birbeck granules on Electron microscopy Eosinophilia 2 Theories Reactive Spontaneous remission or chronic course with good survival cytokines Malignancy Clonal proliferation of Langerhans cells Infiltration of organs Good response to chemotherapy

9. Clinical Features Spectrum of disease Depends on organs involved Single Vrs Multiple organs Age of the patient Letterer-Siwe up to 2 years of age Hand-Schuller-Christian 2-10 years Eosinophilic granuloma 5-15 years

10. Classification Single system � Low Risk Skin, Bone, lymph nodes or a combination of any of these Multisystem - High Risk One or more risk organs Liver, spleen, Lungs, +/- Bone marrow Worse prognosis Special site Multifocal bone disease Sphenoid, Orbits, Ethmoids, Temporal =/- any soft tissue involvement Vertebral lesions with intra spinal extension

11. Cutaneous Lesions Location Perineum, Retro auricular, Temporal , Trunk, Oral Nature Purpuric, Seborrheic , Erythematous papules, Nodular ulcerative Commonest presentation in Neonates and infants 86 % in multisystem and 90 % in single system 40 % may progress to develop multisystem disease. Benign and resolves by 1st Birth day Differentials Diaper rash/Fungal infection Seborrheic dermatitis Neonatal Neuroblastoma Congenital TORCH syndrome (blue muffin baby syndrome)

13. Bone Any bone may be affected Skull is commonest site, Calvaria, Base of skull/Sella turcica, temporal bone, Usually asymptomatic CNS extension Spine: cervical >thoracic>lumbar 60% multifocal spinal lesions Vertebral collapse likely Conservative Rx in the absence of spinal cord compression Long Bone fractures

14. Lymph Adenopathy Any lymph node group Cervical Lymph nodes most involved Mediastinal Lymph nodes May mimic lymphoma Respiratory symptoms My present with Lymph edema

16. Risk Organs Hepato spleenomegaly Hypesleenism with cytopenia +/- dysfunction Lungs Common in adults (smoking) Spontaneous pneumothorax commonest presentation SOB, tachypnea ? Worse outcome Improves with Chemotherapy Bone marrow Cytopenia , Myelodysplastic changes Associated with other organs

17. Risk Organs Endocrine DI commonest symptom Does not resolve with treatment Growth Hormone Other anterior pituitary hormones GI Diarrhea, vomiting and malabsorption Episodic Poor prognosis : young age, organ dysfunction, TPN CNS Neurodegenerative symptoms Gait, Behavior, Cognitive problems

18. Endocrine DisordersDonadieu 2004

19. Neurodegenerative disease High with DI Systemic Treatment of LCH does not prevent Pituitary disease

20. Evaluation H and P Enuresis, polydypsia, Rash, FTT, Dental problems Radiology X-rays, CT Chest, MRI, PET scan Endocrine Random hormone levels, Hormone stimulation studies Heme CBC, Bone marrow Pulm PFT Ophthalmology/ENT /Surg Skin/Lymph node Biopsy

21. Management Multidisciplinary Team Cutaneous lesions PUVA Psoralene given systemically or Topical Repeated treatments required Ultraviolet B light Topical nitrogen mustard (20 %) Long term carcinogenicity Lymph node Resection or Steroids Bone Excision or curettage Chemotherapy, steroids, Bisphosphonate, Radiation

22. Multisystem LCHHelmut et al 2001 No difference between Initial response Probability of reactivation Mortality Developing permanent sequele Toxicity

23. LCH - II Vinblastin + Pred + 6 MP +/- Etoposide Treated for 24 weeks Slight improvement in risk organ group No effect on reactivation Etoposide of no benefit LCH - III Duration of treatment 6 Vrs 12 months Vinblastin /Pred +/- MTx Low risk: Pred and Vinblastin for 6 months Multisystem: 6-12 months depending on disease response after 6 weeks CNS/Multifocal bone (special site): 6-12 weeks of Vinblastin and pred and 6 months total duration of treament

24. Prognostic Factors Lack of rapid response to Chemo Multisystem disease (1.6 fold increase in risk for each organ involved ) Age less than 2 years Only bone involvement had a good prognosis

25. Reactivation  Minkov 2008

27. Progress Has completed 12 weeks of induction Chemotherapy with Vinblastin and Prednisone Now in consolidation with Vinblastin and Prednisone Q 3 Resolution of Skull lesion and thickening of infundibulum of pituitary On DDAVP for DI Growing and developing appropriately Will follow for late effects Leukemia, Recurrence of disease and other complications

28. Post treatment Images

29. Conclusion LCH rare in adults but fairly common in pediatrics High index of suspicion needed by Primary care Wide spectrum of presentation Benign to malignant Observation to chemotherapy Further studies needed to better understand pathology and immunology stratify patients New treatment for reactivation or recurrence

30. Thank you

31. References Gadner H, Grois N, Arico M, Broadbent V, Ceci A, Jakobson A, Komp D, Michaelis J, Nicholson S, P�tschger U, Pritchard J, Ladisch S, for the Histiocyte Society. A randomized trial of treatment for multisystem Langerhans� cell histiocytosis. The Journal of Pediatrics, May 200; 131(5):728-734 Minkov M, Steiner M, P�tschger U, Aric�, Braier J, Donadieu J, Grois N, Henter J, Janka G, McClain K, Weitzman S, Windebank K, Ladisch S, Gadner H, and International LCH Study Group. Reactivations in Multisystem Langerhans Cell Histiocytosis: Data of the International LCH Registry. The Journal of Pediatrics, November 2008; 153 (5):700-705.e2 � Donadieu J, Rolon M, Thomas C, Brugieres L, Plantaz D, Emile JF, Frappaz D, David M, Brauner R, Genereau T, Debray D, Cabrol S, Barthez MA, Hoang-Xuan K, Polak M, for the French LCH Study Group. Endocrine involvement in pediatric-onset langerhans' cell histiocytosis: a population-based study. The Journal of Pediatrics, March 2004, 144 (3):344-350 Gadner H, Heitger A, Grois N, Gatterer-Menz I, Ladisch S.�Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group.�Med Pediatr Oncol.�1994;23(2):72-80 Gadner H, Grois N, Potschger U, et al.�Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification.�Blood.�Mar 1�2008;111(5):2556-62